Gelatin sponge embolism particles as well as preparation process and application thereof

Abstract

The invention relates to the technical field of three types of implanted embolism medical instruments, in particular to gelatin sponge embolism particles as well as a preparation process and application thereof. The preparation process of the gelatin sponge embolism particles mainly comprises the following steps: preparing a gelatin solution and a formaldehyde solution; stirring and foaming the gelatin solution to obtain gelatin foam; adding a formaldehyde solution, and increasing the rotating speed to continue foaming; freezing and solidifying, unfreezing and crushing to obtain coarse sponge particles 1; extracting, centrifuging, cleaning and dehydrating the coarse sponge particles to obtain finely-cleaned sponge particles; and carrying out freeze drying, and sieving and grading the sponge particles to obtain the gelatin sponge embolism particles. The gelatin sponge embolism particles prepared by the invention are uniform in structure, low in residue, high in biological safety, strong in clinical operability and obvious in embolism effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of Class III implant embolization medical devices, and particularly relates to a gelatin sponge embolization particle, its preparation process and application. Background Art

[0002] After selectively or super-selectively inserting a catheter into the target artery supplying blood to a tumor, an appropriate amount of embolic agent is injected at an appropriate speed to occlude the target artery, causing ischemic necrosis of the tumor tissue. Using embolization particles, microspheres or a combination of drugs and particles, microspheres for embolization can play the role of chemoembolization, which is called TACE (transcatheter arterial chemoembolization). It is most commonly used for the treatment of liver cancer, and this method is also applicable to the treatment of hepatic hemangioma, renal cancer, pelvic tumors, etc., as well as embolization hemostasis for massive bleeding in nasopharyngeal carcinoma, lung cancer, digestive tract, pelvic tumors, etc.

[0003] Gelatin sponge embolization particles have a series of advantages such as being biodegradable in the human body, easy to use and operate, safe and easily available raw materials, simple preparation process, low production cost, controllable process parameters, and capable of large-scale continuous production. However, most of the existing technologies use foaming agents, formaldehyde cleaning agents, etc., thus having certain insecurity.

[0004] For example, Chinese Patent CN101161298A provides a process for preparing a gelatin sponge particle embolic agent using gelatin as a raw material, including the following steps: dissolving gelatin in water, adding a formaldehyde solution under water bath conditions and stirring evenly, freezing to obtain a white porous sponge-like product; thawing the white porous sponge-like product, washing and then removing water and formaldehyde to obtain a gelatin sponge; freezing the gelatin sponge and then crushing it to obtain gelatin sponge particles; thawing the gelatin sponge particles, dehydrating and then placing them in water for screening, drying after screening; screening the dried gelatin sponge particles and then sterilizing them to obtain a gelatin sponge particle embolic agent. The method of this invention has a low cost and easily makes the formaldehyde residue reach the clinical use standard. However, the result of the contrast absorption test of the embolic agent obtained by this invention is not ideal, and the clinical operability is poor.

[0005] For another example, Chinese Patent CN110876812A provides a gelatin sponge embolization agent, its preparation process and application, and a drug for treating vascular diseases or tumors. The preparation process of the gelatin sponge embolization agent includes the following steps: successively stirring and / or bubbling a gelatin aqueous solution, and drying to obtain a gelatin sponge, and then successively performing physical cross-linking and post-treatment on the gelatin sponge to obtain a gelatin sponge embolization agent; the physical cross-linking method includes: high-temperature cross-linking or γ-ray irradiation cross-linking, and the temperature of high-temperature cross-linking is 100-180°C. This method has a scientific process, does not introduce chemical cross-linking agents such as formaldehyde or glutaraldehyde, has good biocompatibility, is safe and non-toxic, and has the advantages of low cost and suitability for large-scale production. However, high-temperature cross-linking and γ-ray irradiation cross-linking in this invention are not easy to achieve, and there are also problems such as too fast degradation, short clinical use window period, and poor catheter passing operability.

[0006] Therefore, it is urgent to study a gelatin sponge embolization particle with high safety, low residue, long degradation time, extended clinical operation window period (long suspension time), etc. Summary of the Invention

[0007] Based on the deficiencies of the prior art, the purpose of the present invention is to provide a preparation process and application of gelatin sponge embolization particles. This method has a scientific preparation process, controllable parameters, and can be mass-produced. Without introducing other foaming agents and formaldehyde cleaning agents, it can successfully prepare gelatin sponge embolization particles with irregular shapes and porous structures, high biological safety, strong clinical operability, and obvious embolization effects.

[0008] In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:

[0009] On the one hand, the present invention provides a preparation process of gelatin sponge embolization particles, including the following steps:

[0010] S1: Prepare a gelatin solution and a formaldehyde solution;

[0011] S2: Stir and foam the gelatin solution to obtain a gelatin foam;

[0012] S3: Add the formaldehyde solution to the gelatin foam obtained in step S2, increase the rotation speed and continue foaming, and then discharge the foaming liquid;

[0013] S4: Freeze and solidify the foaming liquid obtained in step S3, and then thaw and crush it to obtain crude sponge particles 1;

[0014] S5: Extract, centrifuge, wash, and dehydrate the crude sponge particles, and repeat this step to obtain finely washed sponge particles;

[0015] S6: Freeze-dry the finely washed sponge particles obtained in step S5 to obtain crude sponge particles 2;

[0016] S7: Sieving and classifying the crude sponge particles 2 obtained in step S6 to obtain refined gelatin sponge embolization particles;

[0017] S8: Packing, sterilizing, and externally packaging the refined gelatin sponge embolization particles obtained in step S7 to obtain the finished gelatin sponge embolization particles.

[0018] Preferably, in step S1, the method for preparing the gelatin solution is: dissolving gelatin in water, heating to 30 - 60°C, and stirring for 10 - 90 min;

[0019] More preferably, in step S1, the method for preparing the gelatin solution is: dissolving gelatin in water, heating to 45°C, and stirring for 90 min.

[0020] Preferably, in step S1, the type of gelatin is selected from one or more of porcine bone gelatin, bovine bone gelatin, porcine skin gelatin, bovine skin gelatin, and fish gelatin, and the mass concentration of the gelatin solution is 5.0 - 20.0%;

[0021] More preferably, in step S1, the gelatin is bovine bone gelatin, and the mass concentration of the gelatin solution is 10%.

[0022] Preferably, in step S1, the method for preparing the formaldehyde solution is: dissolving 10 - 300 mL of 37% formaldehyde solution in 100 - 2000 mL of water and stirring to make it uniformly mixed; the mass concentration of the formaldehyde solution is 5% - 10%.

[0023] More preferably, in step S1, the method for preparing the formaldehyde solution is: dissolving 200 mL of 37% formaldehyde solution in 1330 mL of water and stirring to make it uniformly mixed; the mass concentration of the formaldehyde solution is 5.5%.

[0024] Preferably, in step S2, the stirring speed of the gelatin solution is 100 - 800 r / min, preferably 500 - 700 r / min, and more preferably 700 r / min; the stirring and foaming time is 5 - 120 min, preferably 10 - 30 min, and more preferably 30 min.

[0025] Preferably, in step S3, after adding the formaldehyde solution, the increased rotation speed is 500 - 2500 r / min, preferably 800 - 1000 r / min, and more preferably 900 r / min; the stirring and foaming time is 1 - 10 min, preferably 5 - 10 min, and more preferably 10 min.

[0026] Preferably, in step S4, the freezing and solidifying temperature is -5 to -50°C, more preferably -20°C; the freezing and solidifying time is 24 - 120 h, more preferably 72 h.

[0027] Preferably, in step S4, the thawing temperature is 5 - 50°C, more preferably 25°C; the thawing time is 12 - 72 h, more preferably 12 h;

[0028] Preferably, in step S4, the crushing method is crushing by a crusher, the crushing time is 5 - 60 s, more preferably 5 - 30 s.

[0029] Preferably, in step S5, the leaching is as follows: the crushed sponge particles and the leaching solution are mixed at a mass ratio of 1:3 - 10, and stirred and leached at 30 - 55°C for 50 - 60 min in a reaction kettle until formaldehyde fully enters the leaching solution, and the stirring speed is 100 - 150 r / min;

[0030] Preferably, the leaching solution is water and / or ethanol.

[0031] More preferably, the mass ratio of the sponge particles to the leaching solution is 1:3 - 8, further preferably 1:8;

[0032] More preferably, the leaching temperature is 43 - 45°C, the leaching time is 60 min, and the stirring speed is 100 r / min.

[0033] Preferably, in step S5, the centrifugation, washing, and dehydration are as follows: the mixture of the leached sponge particles and water is passed through a centrifuge to achieve the purpose of high-speed centrifugal dehydration to remove the leaching solution and the dissolved formaldehyde therein;

[0034] More preferably, the centrifuge speed is 1000 - 3000 r / min, and the centrifugation time is 1 - 5 min;

[0035] Further preferably, the centrifuge speed is 3000 r / min, and the centrifugation time is 5 min.

[0036] Preferably, in step S5, the number of times of repeating the steps of leaching, centrifugation, washing, and dehydration is 2 - 11 times (one complete cycle of leaching, centrifugation, washing, and dehydration is counted as one time); more preferably 3 - 10 times, further preferably 10 times.

[0037] Preferably, in step S6, the freeze-drying process is as follows: the finely washed sponge particles and water are mixed at a mass ratio of 1:1 - 10, pre-frozen at -50 to -10°C for 1 - 6 h, then evacuated and freeze-dried for 20 - 60 h, and then heated to 25 - 45°C and maintained for 5 - 30 h;

[0038] Further preferably, in the freeze-drying process, the mass ratio of the sponge particles after fine washing to water is 3:7, the pre-freezing temperature is -30°C, the pre-freezing time is 4 h, the freeze-drying time is 43.5 h, and then the temperature is raised to 39°C and maintained for 14 h.

[0039] Preferably, in step S7, the sieving and grading process is to sieve the freeze-dried crude sponge particles using a 100 μm - 2000 μm sieve to obtain the sieved sponge particles.

[0040] More preferably, in step S7, the sieving and grading process is to sieve the freeze-dried crude sponge particles using a 100 μm - 300 μm sieve.

[0041] Preferably, in step S8, the sterilization used is irradiation sterilization.

[0042] Compared with the prior art, the advantages of the present invention are as follows:

[0043] (1) Prepared with bovine bone gelatin, the raw materials are traceable. And the prepared sponge embolization particles, while meeting the specified index items of GBT16886 "Biological Evaluation of Medical Devices", have better uniformity in appearance, unified particle uniformity among different specifications, better absorbability of contrast agents, suspension in the contrast environment, and more excellent degradation time compared with the same type of products, and have better clinical operability and controllability.

[0044] (2) Using the high-speed stirring and foaming process, without introducing other foaming substances, the preparation process is simple and the product safety is high.

[0045] (3) Adopting the formaldehyde cleaning method of water and ethanol extraction and centrifugal dehydration, without introducing other organic substances and cleaning agents, the formaldehyde residue clearance rate is high, the formaldehyde residue rate is qualified and the control is stable.

[0046] (4) The sponge embolization particles have an irregular branched shape and a porous structure, with stronger adhesion to the blood vessel wall, can firmly fix the embolization site, cause the formation of thrombus, and thus improve the embolization effect. Description of the Drawings

[0047] Figure 1 It is a physical diagram of the gelatin sponge embolization particles prepared in Example 1 of the present invention;

[0048] Figure 2 It is a microscopic diagram of the gelatin sponge embolization particles (dry state) prepared in Example 1 of the present invention;

[0049] Figure 3 It is a microscopic diagram of the gelatin sponge embolization particles (in the contrast agent) prepared in Example 1 of the present invention;

[0050] Figure 4Micrograph of commercially available gelatin sponge particle embolic agent (dry state);

[0051] Figure 5 Micrograph of commercially available gelatin sponge particle embolic agent (in contrast agent). Detailed implementation manners

[0052] To better understand the present invention, the implementation schemes of the present invention will be described in detail in conjunction with the following embodiments. The following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope and the best implementation manner of the present invention. For those steps or conditions not specified in the embodiments, the operations or conditions of the conventional experimental steps described in the literature in this field can be carried out, and the reagents are all commercially available standard reagents.

[0053] Among them, the bovine bone gelatin is a conventional commercially available pharmaceutical grade A bovine bone gelatin, and the gel strength of the gelatin is 200 (in 6.67% solution). The commercially available gelatin sponge particle embolic agent is purchased from Hangzhou Alikon Medical Technology Co., Ltd., and the model of the gelatin sponge particle embolic agent is "Gelfoam 150"; all the water mentioned is injection water; the porcine skin gelatin and bovine skin gelatin are purchased from chemical reagent distributors such as Merck-Sigma-Aldrich and Shanghai Aladdin Biochemical Technology Co., Ltd., and the gel strengths are 250 (in 6.67% solution) and 300 (in 6.67% solution) respectively.

[0054] The following specific embodiments are further descriptions of the present invention. The cases cited cannot list all the implementation manners of the present invention. Only some of the implementation manners are taken as examples for illustration. The specific embodiments are as follows.

[0055] Example 1 A preparation process of gelatin sponge embolization particles

[0056] Specifically, it includes the following steps:

[0057] S1: Add 8100 g of injection water to 900 g of bovine bone gelatin, stir and dissolve at 45 °C and 100 r / min for 90 min to obtain a 10.0 wt% gelatin solution; add 200 mL of 37 wt% formaldehyde solution to 1330 mL of injection water to obtain a 5.55 wt% formaldehyde solution;

[0058] S2: Transfer the gelatin solution prepared in S1 to a reaction kettle, and stir and foam at a rotation speed of 700 r / min for 30 min to obtain gelatin foam;

[0059] S3: Add 1200 g of the prepared formaldehyde solution to the gelatin foam obtained in S2, increase the rotation speed to 900 r / min, stir and foam for 10 min, and then discharge the foaming liquid;

[0060] S4: After freezing and solidifying the foaming liquid obtained in step S3 at -20°C in a low-temperature refrigerator for 72 h, thaw it at 25°C for 12 h, and then crush it with a crusher for 15 s to obtain crude sponge particles 1;

[0061] S5: Add water according to the mass ratio of crude sponge particles 1 to water of 1:8, control the extraction temperature at 43 - 45°C, stir and extract at a rotation speed of 100 r / min for 60 min, then unload the material, and centrifuge and dehydrate it at a rotation speed of 3000 r / min for 5 min. Repeat the extraction, centrifugation, washing, and dehydration 10 times to obtain finely washed sponge particles;

[0062] S6: Freeze-dry the finely washed sponge particles obtained in S5 to obtain crude sponge particles; Add injection water according to the mass ratio of sponge particles to injection water of 3:7, mix them evenly, and spread them out on a freeze-drying tray. Carry out freeze-drying treatment, with the freeze-drying parameters of pre-freezing at -30°C for 4 h, then evacuating and freeze-drying for 43.5 h, and then raising the temperature to 39°C and maintaining it for 14 h to obtain crude sponge particles 2;

[0063] S7: Screen the crude sponge particles obtained in S6 using a sieve with a pore size of 100 μm - 300 μm to obtain sieved sponge particles;

[0064] S8: After sieving the sponge particles, they are sub-packed into pre-filled syringes, inner-packed, irradiated and sterilized, and outer-packed to obtain the finished product of gelatin sponge embolization particles, as Figure 1 shown.

[0065] Example 2 A preparation process of gelatin sponge embolization particles

[0066] The difference from Example 1 is that the type of gelatin used in step S1 is pigskin gelatin.

[0067] Example 3 A preparation process of gelatin sponge embolization particles

[0068] The difference from Example 1 is that the type of gelatin used in step S1 is cowhide gelatin.

[0069] Comparative Example 1 A preparation process of gelatin sponge embolization particles

[0070] The difference from Example 1 is that the type of gelatin used in step S1 is pigskin gelatin and the concentration of formaldehyde solution is 2.5 wt%.

[0071] Example 4 A preparation process of gelatin sponge embolization particles

[0072] The difference from Example 1 is that the stirring speed of the gelatin solution in step S2 is 500 r / min.

[0073] Example 5 A preparation process of gelatin sponge embolization particles

[0074] Different from Example 1, the stirring speed of the gelatin solution in step S2 is 600 r / min.

[0075] Example 6 A preparation process of gelatin sponge embolization particles

[0076] Different from Example 1, the stirring time of the gelatin solution in step S2 is 10 min.

[0077] Example 7 A preparation process of gelatin sponge embolization particles

[0078] Different from Example 1, the stirring time of the gelatin solution in step S2 is 20 min.

[0079] Example 8 A preparation process of gelatin sponge embolization particles

[0080] Different from Example 1, the stirring and foaming time after adding the formaldehyde solution in step S3 is 5 min.

[0081] Comparative Example 2 A preparation process of gelatin sponge embolization particles

[0082] Different from Example 1, the stirring speed of the gelatin solution in step S2 is 900 r / min and the stirring time is 15 min.

[0083] Comparative Example 3 A preparation process of gelatin sponge embolization particles

[0084] Different from Example 1, the stirring speed of the gelatin solution in step S2 is 900 r / min and the stirring time is 30 min.

[0085] Comparative Example 4 A preparation process of gelatin sponge embolization particles

[0086] Different from Example 1, the stirring and foaming time after adding the formaldehyde solution in step S3 is 20 min.

[0087] Example 9 A preparation process of gelatin sponge embolization particles

[0088] Different from Example 1, the mass ratio of sponge particles to water in step S5 is 1:3.

[0089] Example 10 A preparation process of gelatin sponge embolization particles

[0090] Different from Example 1, the mass ratio of sponge particles to water in step S5 is 1:6.

[0091] Example 11 A preparation process of gelatin sponge embolization particles

[0092] Different from Example 1, the extraction time in step S5 is 30 min.

[0093] Comparative Example 5 A preparation process of gelatin sponge embolization particles

[0094] Different from Example 1, the extraction time in step S5 is 90 min.

[0095] Example 12 A preparation process of gelatin sponge embolization particles

[0096] Different from Example 1, the centrifugation time in step S5 is 1 min.

[0097] Example 13 A preparation process of gelatin sponge embolization particles

[0098] Different from Example 1, the centrifugation time in step S5 is 3 min.

[0099] Example 14 A preparation process of gelatin sponge embolization particles

[0100] Different from Example 1, the number of times of repeated extraction, centrifugation, washing and dehydration in step S5 is 3 times.

[0101] Example 15 A preparation process of gelatin sponge embolization particles

[0102] Different from Example 1, the number of times of repeated extraction, centrifugation, washing and dehydration in step S5 is 5 times.

[0103] Example 16 A preparation process of gelatin sponge embolization particles

[0104] Different from Example 1, the number of times of repeated extraction, centrifugation, washing and dehydration in step S5 is 8 times.

[0105] Comparative Example 6 A preparation process of gelatin sponge embolization particles

[0106] Different from Example 1, the number of times of repeated extraction, centrifugation, washing and dehydration in step S5 is 12 times.

[0107] Comparative Example 7 A preparation process of gelatin sponge embolization particles

[0108] Different from Example 1, the number of times of repeated extraction, centrifugation, washing and dehydration in step S5 is 15 times.

[0109] Comparative Example 8 A preparation process of gelatin sponge embolization particles

[0110] Different from Example 1, in step S5, vacuum pump filtration dehydration is used, and the total number of repeated extraction and vacuum pump filtration dehydration is 5 times.

[0111] Comparative Example 9 A preparation process of gelatin sponge embolization particles

[0112] Different from Example 1, in step S5, vacuum filtration is used for dehydration, and the repeated extraction and vacuum filtration dehydration are carried out 10 times in total.

[0113] Example 17 A preparation process of gelatin sponge embolization particles

[0114] Different from Example 1, in step S5, the extraction solution uses a mixed solution of ethanol and water.

[0115] Effect experiment

[0116] 1. The performance of the gelatin sponge obtained in Example 1 was tested. Specifically, it referred to GBT16886 "Biological Evaluation of Medical Devices", and the results are shown in Table 1 below:

[0117] Table 1: Performance of the gelatin sponge embolization particles obtained in Example 1

[0118] Evaluation index Intradermal reaction test No intradermal irritation Pyrogen test No pyrogenic reaction Acute systemic toxicity test No potential acute systemic toxicity Hemolysis test Less than 5% In vitro chromosome aberration test Negative Partial thromboplastin time (PTT) test No activation Platelet count No effect Skin sensitization test Did not cause skin sensitization reaction Bacterial reverse mutation test Negative Hematological test Complied with the regulations Bacterial endotoxin <20 EU

[0119] It can be seen from this that the gelatin sponge embolization particles obtained by the present invention have high safety and good compatibility.

[0120] 2. Contrast absorption test

[0121] The gelatin sponge embolization particles obtained in each of the above examples and comparative examples and the commercially available gelatin sponge particle embolization agent were respectively detected as follows:

[0122] Suspension test: The sponge particles were put into a contrast mixture of normal saline and contrast agent. The time from when the sponge particles were added to the mixture until the sponge particles showed a "suspended state" in the mixture was called the absorption time; the time from when the sponge particles were in the "suspended state" in the mixture until they completely floated up or sank was called the suspension time;

[0123] Degradation test: An appropriate amount of sponge particles were oscillated in a trypsin solution at 37°C until the sponge particles were completely degraded, and the required time was the degradation time. During clinical use, the embolization agent needs to reach a "suspended state" in the contrast mixture before embolization surgery can be performed. This is because the embolization agent in the "suspended state" has better dispersibility and uniformity in the contrast mixture, and is not easy to block the catheter and blood vessels during the contrast process, reducing the surgical risk. Obviously, the shorter the absorption time, the shorter the waiting time for the surgical operator and the patient, and the lower the surgical risk; the longer the suspension time, the longer the surgical safety time. The degradation time in the following table is the degradation time of the gelatin sponge particles in the trypsin solution. By vertical comparison, it can reflect the degradation time of the embolization agent in the human body to a certain extent. The longer the degradation time, the lower the probability of blood vessel recanalization and the less frequent the surgery. The obtained results are shown in Table 2 below:

[0124] Table 2: Contrast absorption test results

[0125]

[0126] Benefiting from capillary action, the more and smaller the internal micropores of the sponge particles are, the longer the absorption time of the sponge particles; the more uniform the texture of the sponge particles is, the more uniform the rate of absorbing the contrast mixture from all directions by the sponge particles is, and the longer the suspension time; the degradation time is closely related to the crosslinking degree of the sponge particles. The higher the crosslinking degree, the longer the degradation time. Only under high-speed and long-time stirring, air is introduced into the gelatin solution under mechanical agitation to form dense bubbles. The higher the rotation speed and the longer the time, the smaller and more uniform the volume of the bubbles. The increase in surface area leads to an increase in the reaction area, and the reaction crosslinking degree increases.

[0127] Obviously, a lower stirring speed of the gelatin solution and a shorter stirring and foaming time will result in larger bubble volumes, which in turn leads to a more non-uniform internal structure of the sponge particles; at the same time, part of the gelatin solution does not participate in foaming, resulting in a further increase in the non-uniformity of the sponge particle structure. Therefore, there are differences in the absorption time, suspension time, and degradation time between the sponge particles of Examples 4-8 and those of Example 1. In addition, over-crosslinking occurred in both Comparative Example 4 and Comparative Example 3. The former is because the reaction time was too long after adding formaldehyde, and the latter is because the mixing time of gelatin and formaldehyde solution was too early, resulting in an extended reaction time.

[0128] 3. Free formaldehyde residue test

[0129] The performance of the dried gelatin sponge particle embolization agents obtained in each of the above examples and comparative examples was detected respectively: The test was carried out according to the method for determining free formaldehyde in General Rule 3207 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition). The results are shown in Table 3. The free formaldehyde residue of the currently commercially available gelatin sponge particle embolization agent measured by this method is 45 - 49 μg / 100 mg.

[0130] Table 3: Test results of free formaldehyde residue

[0131]

[0132] The free formaldehyde in the gelatin sponge particles can be continuously reduced by extraction - water washing. During extraction, the free formaldehyde attached to the particles diffuses from the inside of the sponge particles with high concentration to the water with low concentration under the action of osmotic pressure and reaches an equilibrium value within a certain time; centrifugal dehydration can remove as much water containing formaldehyde as possible. At the same time, under the action of high centrifugal force, part of the formaldehyde inside the sponge pores will be thrown out at the same time. Therefore, theoretically, the content of free formaldehyde in the sponge particles will gradually decrease with the increase of the amount of water used and the number of water washing times. On the other hand, when the gelatin sponge particles are placed in water for a long time, they will swell and gelatinize, resulting in structural changes. At this time, not only the morphology of the porous sponge particles is destroyed, but also because the sponge particles become gelatinized, the adsorption force between the particles increases, resulting in an increase in the adsorption force of formaldehyde, making it more difficult to remove formaldehyde. The lower the water content of the sponge particles, the less likely they are to undergo structural changes, the more firmly the morphology is maintained, and the easier it is to remove formaldehyde.

[0133] Therefore, in Examples 9, 10 and 14 - 16, due to less water consumption and fewer cleaning times, the content of free formaldehyde is relatively high; in Example 11, due to the short extraction time, formaldehyde is not completely extracted, resulting in a relatively high content of free formaldehyde; in Examples 12 and 13, due to the short centrifugal dehydration time, the water containing formaldehyde is not completely removed, and the dehydration rate of the sponge particles is low, resulting in a relatively high content of free formaldehyde; in Comparative Example 5, Examples 15 and 16, it is because the sponge particles undergo structural changes due to too long extraction time in water. For Comparative Examples 8 and 9, the difference between them and Example 1 is that the dehydration method of the sponge particles is filtration dehydration, and this dehydration method has a low dehydration rate, so the content of free formaldehyde in Comparative Example 8 is relatively high. Also, due to the low dehydration rate, the water content of the sponge particles is high, and the degree of structural change of the sponge particles is high, resulting in gelatinization, leading to the results of Comparative Example 9; in Example 17, a mixed solution of ethanol and water is used in the processes of extraction, centrifugation, cleaning and dehydration of the sponge particles, which can accelerate dehydration and improve the cleaning efficiency.

[0134] 4. Microscopic observation

[0135] Place the gelatin sponge embolization particles prepared in Example 1 above on a dry and clean glass slide, observe under a stereomicroscope at a magnification of 50 - 200 times, take pictures, and the particle image in the dry state as shown can be obtained. Figure 2 The image of the commercially available gelatin sponge particle embolic agent in the dry state can be obtained by using the same method, as shown in Figure 4 Add the gelatin sponge embolization particles prepared in Example 1 above to the contrast agent solution and mix for 10 min (the contrast agent is iodixanol / iopamidol, and the ratio of the contrast agent to normal saline is 1:1), so that the particles fully absorb the contrast agent and are evenly dispersed in the contrast agent. Aspirate the mixed solution of the sponge particles and the contrast agent, drop it on a dry and clean glass slide, observe under a stereomicroscope at a magnification of 50 - 200 times, take pictures, and the image as shown can be obtained.Figure 3 The particle images in the contrast agent shown; the images in the commercially available gelatin sponge particle embolization agent contrast agent can be obtained by the same method, such as Figure 5 shown.

[0136] It can be seen from Figures 2 - 5 that the internal bubbles generated by the uneven foaming and curing process can be clearly seen in the image of the commercially available gelatin sponge particle embolization agent in the contrast agent, and the surface roughness of the particles is relatively low; compared with the commercially available gelatin sponge particle embolization agent, the pores of this product are uniform in appearance, the internal structure is uniform, and the branched structure is clear, with good stability and embolization effect.

[0137] In summary, through the comparison of each example and comparative example, the gelatin sponge embolization particles prepared by the present invention have significant advantages in terms of biosafety performance and operability. Without introducing a foaming agent, sponge-like particles with irregular shapes and porous structures and strong clinical operability can be successfully prepared; the methods of extraction and centrifugal dehydration are innovatively used, and without introducing other organic solvents and adsorbents, the content of free formaldehyde in the product is greatly reduced, enhancing the safety of the product. At the same time, the preparation process is relatively simple, the participation of controllable equipment is high, the productivity is high, and it can be mass-produced in batches.

[0138] Obviously, the above examples are only for clear illustration and not for limitation of the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. A process for preparing gelatin sponge embolization particles, characterized in that: The following steps are involved: S1: prepare gelatin solution and formaldehyde solution; S2: stirring the gelatin solution to obtain gelatin foam; S3: adding formaldehyde solution to the gelatin foam obtained in step S2, and continuing to stir and foam to obtain a foaming liquid; S4: freezing and solidifying the foaming liquid obtained in step S3, and then thawing and crushing it to obtain crude sponge particles 1; S5: extracting, centrifuging, washing and dehydrating the crude sponge particles 1, and repeating the steps of extracting, centrifuging, washing and dehydrating to obtain finely washed sponge particles; S6: freeze-drying the finely washed sponge particles obtained in step S5 to obtain crude sponge particles 2; S7: Screening the crude sponge particles 2 obtained in step S6 to obtain the gelatin sponge embolization particles.

2. The preparation process according to claim 1, characterized in that: The gelatin in step S1 is selected from one or more of pig bone gelatin, cattle bone gelatin, pig skin gelatin, cattle skin gelatin or fish gelatin; the mass concentration of the gelatin solution is 5.0-20.0%; the mass concentration of the formaldehyde solution is 4.0%-10.0%.

3. The preparation process according to claim 2, characterized in that: In step S2, the gelatin solution is stirred at a speed of 100-800 r / min, and the stirring and foaming time is 5-120 min.

4. The preparation process according to claim 1, characterized in that: The stirring speed in step S3 is 500-2500 r / min; the stirring time is 1-10 min.

5. The preparation process according to claim 1, characterized in that: The freezing and solidification temperature in step S4 is -5 to -50°C; the freezing and solidification time is 24-120h; the thawing temperature is 5-50°C; and the thawing time is 12-72h.

6. The preparation process according to claim 1, characterized in that: The extraction in step S5 is as follows: the crude sponge particles 1 and the extract are mixed in a mass ratio of 1:3-10, and stirred and extracted at 30-55° C. for 30-60 min; the stirring speed is 100-150 r / min; the centrifugal speed is 1000-3000 r / min, and the centrifugal time is 1-5 min; the extraction, centrifugation, washing, and dehydration steps are repeated 2-11 times.

7. The preparation process according to claim 6, characterized in that: The extract in step S5 is water and / or ethanol.

8. The preparation process according to claim 6, characterized in that: The mass ratio of the crude sponge particles 1 to the leaching solution is 1:8, the leaching temperature is 43-45°C, the leaching time is 60 minutes, and the stirring speed is 100 r / min; the centrifugal speed is 3000 r / min, and the centrifugal time is 5 minutes; the leaching, centrifugation, washing, and dehydration steps are repeated 10 times.

9. The preparation process according to claim 1, characterized in that: The freeze-drying process in step S6 is: mix the fine washing sponge particles and water in a mass ratio of 1:1-10, pre-freeze at -50 to -10°C for 1-6h, then vacuum freeze-dry for 20-60h, and then heat to 25-45°C and keep for 5-30h.

10. Gelatin sponge embolic particles prepared by the preparation process according to any one of claims 1 to 9.

11. Use of the gelatin sponge embolic particles prepared by the preparation process according to any one of claims 1 to 9 in preparing drugs for treating vascular diseases or tumors.

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