X-ray visible embolization microspheres and a preparation method thereof
By preparing X-ray-visible embolization microspheres cross-linked with tantalum powder, calcium silicate, and gelatin, the problems of insufficient imaging and adverse reactions of existing embolization agents have been solved, achieving long-lasting imaging and suspension, and improving the safety and visualization of interventional therapy.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI RUINING BIOTECH CO LTD
- Filing Date
- 2023-10-11
- Publication Date
- 2026-06-16
AI Technical Summary
Existing embolization agents cannot achieve long-term imaging in interventional treatment. Adverse reactions caused by iodine-based contrast agents limit their application, and gadolinium ions may cause tissue deposition. Traditional embolization procedures require the mixing of contrast agents, which can lead to misdiagnosis and toxic side effects.
A microemulsion was prepared by using tantalum powder, calcium silicate, and gelatin as aqueous phase materials and an oil phase with an emulsifier. The microemulsion was then cross-linked with an aldehyde cross-linking agent to prepare X-ray visible embolization microspheres. The tantalum powder was then stably bound using a physical embedding method to achieve long-lasting imaging and suspension.
It provides longer-lasting imaging effects, reduces the risk of ectopic embolization, improves the efficacy and safety of embolization surgery, is suitable for patients with iodine allergy, and reduces adverse reactions.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of medical biopolymer materials technology, specifically to an X-ray visible embolization microsphere and its preparation method. Background Technology
[0002] Transcatheter arterial embolization (TAE) is widely used in the clinical treatment of hypervascular tumors, arteriovenous malformations (AVMs), aneurysms and hemorrhages, uterine fibroids, and especially advanced liver cancer. Guided and monitored by medical imaging equipment, an embolic agent is delivered to the target lesion site via a tiny catheter inserted into an artery, blocking blood flow and cutting off the tumor's supply of nutrients and oxygen, causing the tumor to shrink and die due to lack of nutrients. Compared with other treatment methods, TAE has advantages such as being minimally invasive, low-risk, and having a rapid recovery time.
[0003] During surgical procedures, real-time tracking of the location and distribution of embolic agents using imaging equipment is a fundamental requirement. Commercial embolic agents are generally not radiolucent themselves, requiring the use of iodine-based contrast agents for visualization during the embolization process. However, contrast agents can cause numerous adverse reactions in patients, such as edema, nausea, and vomiting, especially in patients with iodine allergies, limiting their application in embolization therapy. Secondly, contrast agents are prone to separating from the embolic agent, leading to blurred imaging and misdiagnosis; excessive free contrast agents can also cause toxic side effects. Furthermore, the rapid metabolism of contrast agents and short visualization time make postoperative follow-up examinations after transarterial embolization (TAE) difficult. Therefore, the development of X-ray-visible embolic agents offers new possibilities for improving the efficacy and safety of embolization surgery and postoperative tracking. Chinese patent application (publication number CN116440315A) discloses a multimodal radiopaque gelatin sponge microsphere and its preparation method. This method involves chemically cross-linking gelatin with radiopaque elements, introducing iodobenzene compounds that are radiopaque under X-ray and CT scans, and gadolinium ions that are radiopaque under MRI scans during the chemical cross-linking process. This enables visualization of the embolization microspheres during and after surgery. However, the iodobenzene compounds can cause many adverse reactions in patients, making it particularly unsuitable for those with iodine allergies, thus limiting its application. Furthermore, gadolinium ions may deposit in tissues or blood, leading to kidney problems, skin changes, neurological disorders, and muscle pain. Therefore, providing a safe, long-lasting radiopaque X-ray-visible embolization microsphere has significant clinical application value. Summary of the Invention
[0004] To address the aforementioned issues, this invention provides an X-ray-visible embolization microsphere. By optimizing the microsphere formulation, tantalum powder, calcium silicate, and gelatin are used as aqueous phase materials to form a microemulsion with an oil phase containing an emulsifier. This microemulsion is then cross-linked with an aldehyde cross-linking agent. Compared to existing imaging microspheres prepared via iodination reactions, this microsphere exhibits a longer-lasting imaging effect, providing new possibilities for improving the efficacy and safety of embolization surgery and postoperative tracking.
[0005] The present invention provides an X-ray visible embolization microsphere, comprising at least the following raw materials: an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials, an oil solution containing an emulsifier and a crosslinking agent solution containing an aldehyde crosslinking agent.
[0006] As a preferred technical solution, the mass ratio of tantalum powder, calcium silicate and colloidal raw material in the aqueous solution containing tantalum powder, calcium silicate and colloidal raw material is (0.1-0.5):(0.1-20):(0.1-50), preferably 0.3:5:10.
[0007] This invention leverages the biocompatibility, X-ray visibility, and safety of tantalum particles, introducing them into embolization microspheres to impart excellent X-ray visibility. However, due to the high density of tantalum powder, its introduction into the microspheres accelerates their settling velocity, which negatively impacts the ease of delivery. During their research, the inventors discovered that by controlling the amounts of tantalum powder and colloidal materials added to an aqueous solution containing tantalum powder, calcium silicate, and colloidal raw materials, and by controlling the sieve particle size of the X-ray visible embolization microspheres to 15-50 μm, a balance between the settling velocity and X-ray visibility of the microspheres was achieved. Furthermore, by co-introducing high-density X-ray visible tantalum powder and low-density calcium silicate into gelatin embolization microspheres, the inventors achieved microspheres with excellent X-ray visibility and suspension, uniform and controllable particle size, and high clinical usability.
[0008] As a preferred technical solution, the colloidal raw material is selected from at least one of plant gums, microbial gums, seaweed gums, and starch; preferably, the colloidal raw material is selected from one of konjac gum, gum arabic, gelatin, xanthan gum, gellan gum, carrageenan, and alginate, and more preferably gelatin, specifically type B gelatin with a gel strength of 250 bloom, derived from Sigma.
[0009] As a preferred technical solution, the solvent in the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials is PBS buffer solution, and the pH of the PBS buffer solution is 7.
[0010] As a preferred technical solution, the concentration of emulsifier in the oil phase solution containing emulsifier is 0.1-5% (v / v), preferably 0.5-2% (v / v).
[0011] As a preferred technical solution, the emulsifier is selected from one or more combinations of Span and Tween, preferably Span 80.
[0012] As a preferred technical solution, the solvent in the oil phase solution containing the emulsifier is an organic solvent that is immiscible with water, preferably one of soybean oil, sesame oil, liquid paraffin, and silicone oil, and more preferably liquid paraffin.
[0013] As a preferred technical solution, the volume ratio of the aqueous solution containing tantalum powder, calcium silicate and gelatin to the oil solution containing emulsifier is (2-20):(2-20), preferably 1:1.
[0014] As a preferred technical solution, the concentration of the aldehyde crosslinking agent in the crosslinking agent solution containing the aldehyde crosslinking agent is 20-30 wt%, preferably 25 wt%.
[0015] As a preferred technical solution, the solvent in the crosslinking agent solution containing the aldehyde crosslinking agent is water.
[0016] As a preferred technical solution, the aldehyde crosslinking agent is selected from at least one of formaldehyde, glutaraldehyde, dialdehyde starch, and dextranaldehyde, preferably glutaraldehyde.
[0017] Another aspect of the present invention provides a method for preparing X-ray-visible embolization microspheres, comprising at least the following steps:
[0018] (1) Prepare an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials;
[0019] (2) Prepare an oil phase solution containing an emulsifier;
[0020] (3) Add the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials to the oil phase solution containing emulsifier at 50-60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid;
[0021] (4) Repeatedly centrifuge and wash the mixture to obtain microspheres;
[0022] (5) The microspheres were transferred to a crosslinking agent solution containing aldehyde crosslinking agent and reacted at 2-8℃ for 2-3.5h. After washing with distilled water at 2-8℃ 3-5 times, X-ray visible embolization microspheres were obtained. After sieving, they were collected and stored in physiological saline.
[0023] As a preferred technical solution, the preparation of the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials specifically involves: adding tantalum powder, calcium silicate and colloidal raw materials to PBS buffer solution, and preparing the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials under water bath conditions of 65-72℃.
[0024] As a preferred technical solution, the preparation of the oil phase solution containing the emulsifier specifically involves: adding the emulsifier to an organic solvent that is immiscible with water, and preparing the oil phase solution containing the emulsifier under water bath conditions of 55-62°C.
[0025] As a preferred technical solution, the conditions for stirring and emulsifying are: water bath at 50-70℃, stirring speed at 100-200 r / min, and time at 20-40 min.
[0026] Preferably, the conditions for stirring and emulsifying are: water bath at 60°C, stirring speed at 150 r / min, and time at 30 min.
[0027] As a preferred technical solution, the conditions for cooling and continuing stirring are: ice bath at 2-8℃, stirring speed at 100-200 r / min, and time at 50-90 min.
[0028] Preferably, the conditions for cooling and continuing stirring are: ice bath at 4°C, stirring speed at 150 r / min, and time at 60 min.
[0029] As a preferred technical solution, the repeated centrifugation and washing in step (4) specifically involves: after centrifugation, washing the microspheres with water containing 1% (v / v) Span 80 at 2-8°C, and repeating the centrifugation and washing three times.
[0030] As a preferred technical solution, the amount of the crosslinking agent solution containing aldehyde crosslinking agent added is 25-50% based on the volume of the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials or the oil solution containing emulsifier.
[0031] As a preferred technical solution, the X-ray visible embolization microspheres are sieved to a particle size range of 15-150 μm, and are further sieved to X-ray visible embolization microspheres with a particle size range of 15-50 μm and X-ray visible embolization microspheres with a particle size range of 50-150 μm.
[0032] The X-ray visible embolization microspheres provided by this invention are prepared by mixing an aqueous solution containing tantalum powder, calcium silicate, and gelatin with an oil solution containing an emulsifier to form a microemulsion, and then cross-linking it with a cross-linking agent solution containing an aldehyde cross-linking agent. Through a physical embedding method, the tantalum powder is stably bound into the microspheres, making the embolization microspheres visible to X-rays. This changes the drawback of traditional interventional embolization surgery, which requires mixing the embolic agent and contrast agent for indirect localization of the embolic agent. It facilitates direct clinical observation of the embolic agent's location and determination of the embolization endpoint, thereby reducing the risk of ectopic embolization.
[0033] Beneficial effects
[0034] 1. This invention provides an X-ray visible embolization microsphere. By optimizing the embolization microsphere formulation, tantalum powder, calcium silicate and gelatin are used as aqueous phase materials to form a microemulsion with an oil phase containing an emulsifier, and then cross-linked with an aldehyde cross-linking agent. Compared with existing imaging microspheres prepared by iodination reaction, it has a longer imaging effect, providing new possibilities for improving the efficacy and safety of embolization surgery and postoperative tracking.
[0035] 2. This invention balances the settling velocity and X-ray visibility of X-ray visible embolization microspheres by controlling the amount of tantalum powder and colloidal raw materials added to an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials, and controlling the sieve particle size of X-ray visible embolization microspheres to 15-50μm.
[0036] 3. In this invention, high-density tantalum powder visible to X-rays and low-density calcium silicate are introduced together into gelatin embolization microspheres, so that the provided embolization microspheres have good X-ray visibility and suspension, uniform and controllable particle size, and high convenience for clinical use.
[0037] 4. The X-ray visible embolization microspheres provided by the present invention are prepared by mixing an aqueous solution containing tantalum powder, calcium silicate and gelatin with an oil solution containing an emulsifier to form a microemulsion, and then cross-linking treatment with a cross-linking agent solution containing an aldehyde cross-linking agent. The tantalum powder is stably bound in the microspheres by a physical embedding method, so that the embolization microspheres have X-ray visibility.
[0038] 5. The X-ray-proof, highly suspendable embolization microspheres provided by this invention are easy to inject and change the drawback of traditional interventional embolization surgery, which requires mixing embolic agents and contrast agents to indirectly locate the embolic agent. This makes it easier to directly observe the location of the embolic agent and determine the embolization endpoint in clinical practice, thereby reducing the risk of ectopic embolization. Attached Figure Description
[0039] Figure 1 The images shown are light micrographs of the X-ray visible embolization microspheres obtained in Examples 1-4 of the present invention, where 1-4 correspond to Examples 1-4 respectively.
[0040] Figure 2 The figures show a comparison of the suspension performance of X-ray visible embolization microspheres provided in Examples 2-4 and Comparative Examples 2-4. In the figures, a, b, c, and d correspond to 0, 3, 7, and 10 min, respectively. From left to right, figures a, b, c, and d correspond to Example 4, Comparative Example 3, Example 3, Comparative Example 2, Example 2, Comparative Example 1, and Comparative Example 4, respectively.
[0041] Figure 3The figures show a comparison of the suspension performance of X-ray visible embolization microspheres provided in Examples 1 and 3. In the figures, a, b, c, and d correspond to 0, 1, 3, and 5 min, respectively. In figures a, b, c, and d, the left side represents Example 1, and the right side represents Example 3.
[0042] Figure 4 The figure shows a comparison of the dispersibility of uncoated tantalum powder and coated tantalum powder. In the figure, a, b, and c correspond to Example 2, Comparative Example 2, and uncoated tantalum powder, respectively. Detailed Implementation
[0043] Example 1
[0044] In one aspect, Embodiment 1 of the present invention provides an X-ray visible embolization microsphere, which is prepared from the following raw materials: an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials, an oil solution containing an emulsifier and a crosslinking agent solution containing an aldehyde crosslinking agent.
[0045] The mass ratio of tantalum powder, calcium silicate, and colloidal raw materials in the aqueous solution containing tantalum powder, calcium silicate, and colloidal raw materials is 0.3:5:10.
[0046] The colloidal raw material is gelatin, specifically type B gelatin with a gel strength of 250 bloom, sourced from Sigma. The tantalum powder is micron-sized with a particle size of 1-10 μm, sourced from Guangzhou Yinna Technology Co., Ltd.
[0047] The solvent in the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials is PBS buffer solution, and the pH of the PBS buffer solution is 7.
[0048] The concentration of the emulsifier in the oil phase solution containing the emulsifier is 0.5% (v / v).
[0049] The emulsifier is Span 80.
[0050] The solvent in the oil phase solution containing the emulsifier is liquid paraffin.
[0051] The volume ratio of the aqueous solution containing tantalum powder, calcium silicate, and gelatin to the oil solution containing emulsifier is 1:1.
[0052] The concentration of the aldehyde crosslinking agent in the crosslinking agent solution containing the aldehyde crosslinking agent is 25 wt%.
[0053] The solvent in the crosslinking agent solution containing aldehyde crosslinking agent is water.
[0054] The aldehyde crosslinking agent is glutaraldehyde.
[0055] Another aspect of Embodiment 1 of the present invention provides a method for preparing X-ray-visible embolization microspheres, comprising the following steps:
[0056] (1) Prepare 20 mL of an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials;
[0057] (2) Prepare 20 mL of an oil phase solution containing emulsifier;
[0058] (3) Add the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials to the oil solution containing emulsifier at 60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid;
[0059] (4) Repeatedly centrifuge and wash the mixture to obtain microspheres;
[0060] (5) The microspheres were transferred to 8 mL of a crosslinking agent solution containing aldehyde crosslinking agent, reacted at 4 °C for 3 h, and then washed 4 times with distilled water at 4 °C to obtain X-ray visible embolization microspheres. After sieving, they were collected and stored in physiological saline.
[0061] The preparation of the aqueous solution containing tantalum powder, calcium silicate, and colloidal raw materials specifically involves adding tantalum powder, calcium silicate, and colloidal raw materials to a PBS buffer solution and preparing 20 mL of an aqueous solution containing 5 g / mL tantalum powder, 0.3 g / mL calcium silicate, and 10 g / mL colloidal raw materials in a water bath at 70°C.
[0062] The preparation of the oil phase solution containing the emulsifier specifically involves adding the emulsifier to the solvent and preparing 20 mL of the oil phase solution containing the emulsifier under a water bath at 60°C.
[0063] The conditions for stirring and emulsifying are: water bath at 60°C, stirring speed at 150 r / min, and time at 30 min.
[0064] The conditions for cooling and continuing stirring are: ice bath at 4°C, stirring speed at 150 r / min, and time at 60 min.
[0065] The specific steps of centrifugation and washing in step (4) are as follows: after centrifugation, the microspheres are washed with water at 4°C containing 1% (v / v) Span 80, and the centrifugation and washing are repeated 3 times.
[0066] The particle size range of the X-ray visible embolization microspheres after sieving is 15-50 μm.
[0067] Example 2
[0068] Embodiment 2 of the present invention provides an X-ray visible embolization microsphere, which is prepared from the following raw materials: an aqueous solution containing tantalum powder and colloidal raw materials, an oil phase solution containing an emulsifier, and a crosslinking agent solution containing an aldehyde crosslinking agent.
[0069] The mass ratio of tantalum powder to colloidal raw material in the aqueous solution containing tantalum powder and colloidal raw material is 10:10.
[0070] The colloidal raw material is gelatin, specifically type B gelatin with a gel strength of 250 bloom, sourced from Sigma. The tantalum powder is micron-sized with a particle size of 1-10 μm, sourced from Guangzhou Yinna Technology Co., Ltd.
[0071] The solvent in the aqueous solution containing tantalum powder and colloidal raw materials is PBS buffer solution, and the pH of the PBS buffer solution is 7.
[0072] The concentration of the emulsifier in the oil phase solution containing the emulsifier is 0.5% (v / v).
[0073] The emulsifier is Span 80.
[0074] The solvent in the oil phase solution containing the emulsifier is liquid paraffin.
[0075] The volume ratio of the aqueous solution containing tantalum powder and gelatin to the oil solution containing emulsifier is 1:1.
[0076] The concentration of the aldehyde crosslinking agent in the crosslinking agent solution containing the aldehyde crosslinking agent is 25 wt%.
[0077] The solvent in the crosslinking agent solution containing aldehyde crosslinking agent is water.
[0078] The aldehyde crosslinking agent is glutaraldehyde.
[0079] Another aspect of Embodiment 2 of the present invention provides a method for preparing X-ray-visible embolization microspheres, comprising the following steps:
[0080] (1) Prepare 20 mL of an aqueous solution containing tantalum powder and colloidal raw materials;
[0081] (2) Prepare 20 mL of an oil phase solution containing emulsifier;
[0082] (3) Add the aqueous solution containing tantalum powder and colloidal raw materials to the oil solution containing emulsifier at 60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid;
[0083] (4) Repeatedly centrifuge and wash the mixture to obtain microspheres;
[0084] (5) The microspheres were transferred to 8 mL of a crosslinking agent solution containing aldehyde crosslinking agent, reacted at 4 °C for 3 h, and then washed 4 times with distilled water at 4 °C to obtain X-ray visible embolization microspheres. After sieving, they were collected and stored in physiological saline.
[0085] The preparation of the aqueous solution containing tantalum powder and colloidal raw material specifically involves adding tantalum powder and colloidal raw material to PBS buffer solution and preparing 20 mL of aqueous solution containing 10 g / mL tantalum powder and 10 g / mL colloidal raw material under a water bath at 70°C.
[0086] The preparation of the oil phase solution containing the emulsifier specifically involves adding the emulsifier to the solvent and preparing 20 mL of the oil phase solution containing the emulsifier under a water bath at 60°C.
[0087] The conditions for stirring and emulsifying are: water bath at 60°C, stirring speed at 150 r / min, and time at 30 min.
[0088] The conditions for cooling and continuing stirring are: ice bath at 4°C, stirring speed at 150 r / min, and time at 60 min.
[0089] The specific steps of centrifugation and washing in step (4) are as follows: after centrifugation, the microspheres are washed with water at 4°C containing 1% (v / v) Span 80, and the centrifugation and washing are repeated 3 times.
[0090] The particle size range of the X-ray visible embolization microspheres after sieving is 15-50 μm.
[0091] Example 3
[0092] In one aspect, Embodiment 3 of the present invention provides an X-ray visible embolization microsphere, which is prepared from the following raw materials: an aqueous solution containing tantalum powder and colloidal raw materials, an oil solution containing an emulsifier, and a crosslinking agent solution containing an aldehyde crosslinking agent.
[0093] The mass ratio of tantalum powder to colloidal raw material in the aqueous solution containing tantalum powder and colloidal raw material is 5:10.
[0094] The colloidal raw material is gelatin, specifically type B gelatin with a gel strength of 250 bloom, sourced from Sigma. The tantalum powder is micron-sized with a particle size of 1-10 μm, sourced from Guangzhou Yinna Technology Co., Ltd.
[0095] The solvent in the aqueous solution containing tantalum powder and colloidal raw materials is PBS buffer solution, and the pH of the PBS buffer solution is 7.
[0096] The concentration of the emulsifier in the oil phase solution containing the emulsifier is 0.5% (v / v).
[0097] The emulsifier is Span 80.
[0098] The solvent in the oil phase solution containing the emulsifier is liquid paraffin.
[0099] The volume ratio of the aqueous solution containing tantalum powder and gelatin to the oil solution containing emulsifier is 1:1.
[0100] The concentration of the aldehyde crosslinking agent in the crosslinking agent solution containing the aldehyde crosslinking agent is 25 wt%.
[0101] The solvent in the crosslinking agent solution containing aldehyde crosslinking agent is water.
[0102] The aldehyde crosslinking agent is glutaraldehyde.
[0103] Embodiment 3 of the present invention provides a method for preparing X-ray-visible embolization microspheres, comprising the following steps:
[0104] (1) Prepare 20 mL of an aqueous solution containing tantalum powder and colloidal raw materials;
[0105] (2) Prepare 20 mL of an oil phase solution containing emulsifier;
[0106] (3) Add the aqueous solution containing tantalum powder and colloidal raw materials to the oil solution containing emulsifier at 60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid;
[0107] (4) Repeatedly centrifuge and wash the mixture to obtain microspheres;
[0108] (5) The microspheres were transferred to 8 mL of a crosslinking agent solution containing aldehyde crosslinking agent, reacted at 4 °C for 3 h, and then washed 4 times with distilled water at 4 °C to obtain X-ray visible embolization microspheres. After sieving, they were collected and stored in physiological saline.
[0109] The preparation of the aqueous solution containing tantalum powder and colloidal raw material specifically involves adding tantalum powder and colloidal raw material to PBS buffer solution and preparing 20 mL of aqueous solution containing 5 g / mL tantalum powder and 10 g / mL colloidal raw material in a water bath at 70°C.
[0110] The preparation of the oil phase solution containing the emulsifier specifically involves adding the emulsifier to the solvent and preparing 20 mL of the oil phase solution containing the emulsifier under a water bath at 60°C.
[0111] The conditions for stirring and emulsifying are: water bath at 60°C, stirring speed at 150 r / min, and time at 30 min.
[0112] The conditions for cooling and continuing stirring are: ice bath at 4°C, stirring speed at 150 r / min, and time at 60 min.
[0113] The specific steps of centrifugation and washing in step (4) are as follows: after centrifugation, the microspheres are washed with water at 4°C containing 1% (v / v) Span 80, and the centrifugation and washing are repeated 3 times.
[0114] The particle size range of the X-ray visible embolization microspheres after sieving is 15-50 μm.
[0115] Example 4
[0116] Example 4 of the present invention provides an X-ray visible embolization microsphere, which is prepared from the following raw materials: an aqueous solution containing colloidal raw materials, an oil solution containing an emulsifier, and a crosslinking agent solution containing an aldehyde crosslinking agent.
[0117] The colloidal raw material is gelatin, specifically type B gelatin with a gel strength of 250 bloom, sourced from Sigma. The tantalum powder is micron-sized with a particle size of 1-10 μm, sourced from Guangzhou Yinna Technology Co., Ltd.
[0118] The solvent in the aqueous solution containing the colloidal raw material is a PBS buffer solution, and the pH of the PBS buffer solution is 7.
[0119] The concentration of the emulsifier in the oil phase solution containing the emulsifier is 0.5% (v / v).
[0120] The emulsifier is Span 80.
[0121] The solvent in the oil phase solution containing the emulsifier is liquid paraffin.
[0122] The volume ratio of the aqueous solution containing gelatin to the oil solution containing emulsifier is 1:1.
[0123] The concentration of the aldehyde crosslinking agent in the crosslinking agent solution containing the aldehyde crosslinking agent is 25 wt%.
[0124] The solvent in the crosslinking agent solution containing aldehyde crosslinking agent is water.
[0125] The aldehyde crosslinking agent is glutaraldehyde.
[0126] Embodiment 4 of the present invention provides a method for preparing X-ray-visible embolization microspheres, comprising the following steps:
[0127] (1) Prepare 20 mL of an aqueous solution containing colloidal raw materials;
[0128] (2) Prepare 20 mL of an oil phase solution containing emulsifier;
[0129] (3) Add the aqueous solution containing colloidal raw materials to the oil solution containing emulsifier at 60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid;
[0130] (4) Repeatedly centrifuge and wash the mixture to obtain microspheres;
[0131] (5) The microspheres were transferred to 8 mL of a crosslinking agent solution containing aldehyde crosslinking agent, reacted at 4 °C for 3 h, and then washed 4 times with distilled water at 4 °C to obtain X-ray visible embolization microspheres. After sieving, they were collected and stored in physiological saline.
[0132] The preparation of the aqueous solution containing the colloidal raw material is specifically as follows: the colloidal raw material is added to the PBS buffer solution, and 20 mL of aqueous solution containing 10 g / mL of colloidal raw material is prepared under a water bath at 70°C.
[0133] The preparation of the oil phase solution containing the emulsifier specifically involves adding the emulsifier to the solvent and preparing 20 mL of the oil phase solution containing the emulsifier under a water bath at 60°C.
[0134] The conditions for stirring and emulsifying are: water bath at 60°C, stirring speed at 150 r / min, and time at 30 min.
[0135] The conditions for cooling and continuing stirring are: ice bath at 4°C, stirring speed at 150 r / min, and time at 60 min.
[0136] The specific steps of centrifugation and washing in step (4) are as follows: after centrifugation, the microspheres are washed with water at 4°C containing 1% (v / v) Span 80, and the centrifugation and washing are repeated 3 times.
[0137] The particle size range of the X-ray visible embolization microspheres after sieving is 15-50 μm.
[0138] Comparative Example 1
[0139] Comparative Example 1 of the present invention provides an X-ray visible embolization microsphere and its preparation method. The specific implementation method is the same as that of Example 2, except that the particle size range of the X-ray visible embolization microsphere after sieving is 50-150 μm.
[0140] Comparative Example 2
[0141] Comparative Example 2 of the present invention provides an X-ray visible embolization microsphere and its preparation method. The specific implementation method is the same as that of Example 3, except that the particle size range of the X-ray visible embolization microsphere after sieving is 50-150 μm.
[0142] Comparative Example 3
[0143] Comparative Example 3 of the present invention provides an X-ray visible embolization microsphere and its preparation method. The specific implementation method is the same as that of Example 4, except that the particle size range of the X-ray visible embolization microsphere after sieving is 50-150 μm.
[0144] Comparative Example 4
[0145] Comparative Example 4 of the present invention provides an X-ray visible embolization microsphere and its preparation method. The specific implementation method is the same as that of Example 4, except that the tantalum powder is nanoscale with a particle size of 10-100nm and is sourced from Guangzhou Yinna Technology Co., Ltd.
[0146] Performance testing methods
[0147] 1. Optical Microscopy Test: The X-ray visible embolization microspheres obtained in Examples 1-4 of this invention were tested using an optical microscope. The test results are shown in [reference needed]. Figure 1 .
[0148] 2. Suspension performance test: X-ray visible embolization microspheres of the same weight provided by Examples 2-4 and Comparative Examples 2-4 were placed in vials containing the same volume of PBS buffer solution for suspension experiment. The dispersion of microspheres was observed at time intervals of 0, 3, 7, and 10 min. The results showed that as time went on, the sedimentation rate of the microspheres in Comparative Example 2-4 was faster than that in Example 2-4. The X-ray visible embolization microspheres provided by Example 3 had relatively superior X-ray visibility and suspension performance.
[0149] 3. Suspension performance test: X-ray visible embolization microspheres of the same weight provided in Examples 1 and 3 were placed in vials containing the same volume of PBS buffer solution for suspension experiment. The dispersion of the microspheres was observed at time intervals of 0, 1, 3 and 5 min. The results showed that the X-ray visible embolization microspheres provided in Example 1 had better dispersion performance than those provided in Example 3.
[0150] 4. Uncoated tantalum powder was directly dispersed in PBS buffer solution, and the dispersibility of the tantalum powder was observed. The results were compared with those of the X-ray visible embolization microspheres provided in Example 2 and Comparative Example 2 in PBS buffer solution. (See attached table for results.) Figure 4 This indicates that the X-ray visible embolization microspheres provided in Example 2 and Comparative Example 2 have better dispersibility than tantalum powder.
Claims
1. An X-ray visible embolization microsphere, characterized in that, The material comprises at least the following raw materials: an aqueous solution containing tantalum powder, calcium silicate, and colloidal raw materials; an oil solution containing an emulsifier; and a crosslinking agent solution containing an aldehyde crosslinking agent. The mass ratio of tantalum powder, calcium silicate, and colloidal raw materials in the aqueous solution is (0.1-0.5):(0.1-20):(0.1-50). The concentration of the emulsifier in the oil solution is 0.1-5%. The volume ratio of the aqueous solution containing tantalum powder, calcium silicate, and gelatin to the oil solution containing the emulsifier is (2-20):(2-20). The concentration of the aldehyde crosslinking agent in the crosslinking agent solution is 20-30 wt%. The colloidal raw material is gelatin. The emulsifier is Span 80. The aldehyde crosslinking agent is glutaraldehyde. The particle size range of the X-ray visible embolization microspheres after sieving is 15-50 μm.
2. The X-ray-visualized embolization microsphere according to claim 1, characterized in that, The solvent in the oil phase solution containing the emulsifier is an organic solvent that is immiscible with water.
3. A method for preparing X-ray-visible embolization microspheres according to any one of claims 1-2, characterized in that, At least the following steps are included: (1) Prepare an aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials; (2) Prepare an oil phase solution containing an emulsifier; (3) Add the aqueous solution containing tantalum powder, calcium silicate and colloidal raw materials to the oil phase solution containing emulsifier at 50-60℃, stir to emulsify, cool down and continue stirring to obtain a mixed liquid; (4) Repeatedly centrifuge and wash the mixture to obtain microspheres; (5) Transfer the microspheres to a crosslinking agent solution containing aldehyde crosslinking agent, react at 2-8℃ for 2-3.5h, wash with distilled water at 2-8℃ 3-5 times to obtain X-ray visible embolization microspheres, sieve and collect them in physiological saline for storage.