Ultrasonic developing degradable microsphere as well as preparation method and application thereof

Abstract

The invention relates to an ultrasonic developing degradable microsphere as well as a preparation method and application thereof, and belongs to the technical field of embolism microspheres. The preparation method comprises the following steps: mixing starch and nano inorganic particles in an aqueous solution to obtain a mixed solution; the nano inorganic particles comprise at least one of nano calcium carbonate or nano hydroxyapatite; mixing the mixed solution with a cross-linking agent to obtain a water phase solution; and adding the oil phase solution into the water phase solution, and reacting for a period of time at a certain temperature to obtain the ultrasonic developing degradable microspheres. The preparation method comprises the following steps: firstly, mixing starch and nano inorganic particles, then mixing with a cross-linking agent for cross-linking polymerization, and encapsulating the nano inorganic particles in degradable starch, so as to prepare the embolism microspheres with both ultrasonic development and degradability, so that the development mode can be expanded, and the development cost can be reduced. In addition, degradation of the microspheres can be monitored through ultrasonic imaging, and real-time dynamic monitoring in an operation and follow-up visit evaluation after the operation are achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of embolic microspheres, and particularly relates to an ultrasonically visible degradable microsphere and a preparation method and application thereof. BACKGROUND

[0002] Interventional embolization therapy (such as transcatheter arterial embolization, TAE) has become an important treatment method for tumors, hemorrhagic diseases and the like, but the core challenge is how to achieve precise embolization and postoperative monitoring. Although traditional embolic microspheres (such as polyvinyl alcohol and polyacrylic acid) can block blood flow, there are the following problems: (1) non-degradability: long-term retention in blood vessels may cause complications such as thrombosis and vascular obstruction, especially for patients who need multiple embolization or short-term embolization; (2) dependence on external contrast agent for imaging: the microspheres need to be mixed with a contrast agent for positioning during the operation, which is complicated and may cause mis-embolization due to leakage or uneven distribution of the contrast agent. In recent years, although microspheres using degradable materials (such as PLGA and sodium alginate) have appeared, their degradation rate and embolization effect are difficult to match, and they lack self-imaging function. Some studies attempt to achieve imaging by physically adsorbing a contrast agent (such as barium sulfate and iodine oil), but the contrast agent is prone to leakage and the effect is unstable. Although new products such as Vispearl microspheres achieve X-ray imaging by covalently binding iodine-containing molecules, their materials are still mainly non-degradable polyvinyl alcohol, which cannot solve the problem of long-term retention. Moreover, existing imaging techniques mostly rely on X-ray or CT imaging, which limits real-time dynamic monitoring during the operation and postoperative follow-up evaluation.

[0003] Therefore, it is necessary to develop an embolic microsphere with degradability, ultrasonic imaging and low-toxicity process to meet market demand. SUMMARY

[0004] To solve the above technical problems, the purpose of the embodiments of the present application includes providing an ultrasonically visible degradable microsphere and a preparation method and application thereof. The prepared microsphere has degradability and ultrasonic imaging performance. In a first aspect, the present application provides a preparation method of an ultrasonically visible degradable microsphere, comprising the following steps: S1: mixing starch and nano-inorganic particles in an aqueous solution to obtain a mixed solution; the nano-inorganic particles include at least one of nano-calcium carbonate or nano-hydroxyapatite; S2: mixing the mixed solution with a crosslinking agent to obtain an aqueous phase solution; S3: adding an oil phase solution to the aqueous phase solution, reacting at a certain temperature for a period of time, and obtaining an ultrasonically visible degradable microsphere. In the technical solution, the starch and the nano inorganic particles are mixed first, and then a cross-linking agent is mixed to perform cross-linking polymerization, so that the nano inorganic particles are encapsulated in the degradable polymer matrix (starch) to prepare the degradable embolization microspheres with ultrasonic imaging capability. Compared with MRI or CT, the imaging mode can be expanded, and the imaging cost is reduced. Moreover, the degradation of the microspheres can be monitored by ultrasonic imaging, so that real-time dynamic monitoring during the operation and postoperative follow-up evaluation can be realized.

[0005] In the technical solution, the nano inorganic particles are used as the core component of ultrasonic imaging, are uniformly dispersed in the starch aqueous solution, and are encapsulated in the microspheres by the cross-linking agent to form a three-dimensional network structure, so that the nano inorganic particles are stably encapsulated in the microsphere structure to form an acoustic heterogeneous interface with a density gradient distribution. The microsphere structure can produce a heavy enhancement effect in the ultrasonic field, that is, the acoustic impedance difference between the particles and the polymer matrix induces a strong scattering effect, which significantly improves the ultrasonic echo intensity, so that the microspheres are characterized by high-brightness imaging in the ultrasonic image. At the same time, the starch microspheres maintain the basic spherical structure during the degradation process, and the nano inorganic particles are released and excreted by the body, so that the ultrasonic signal is down-regulated, and thus the ultrasonic signal can be used to simply monitor the in-vivo degradation of the embolization microspheres in a low-cost and non-invasive manner.

[0006] In addition, the preparation method does not use toxic reagents such as formaldehyde and dichloromethane, and the nano inorganic particles can be metabolized through the intestinal tract or the kidney, so that no exogenous contrast agent needs to be additionally introduced. In some embodiments, the nano inorganic particles account for 2% to 10% of the mass of the starch in the mixed solution. In the technical solution, the nano inorganic particles are used as the core component of ultrasonic imaging, and the addition amount is in a suitable range, which is beneficial to form a significant acoustic impedance difference, enhance the ultrasonic imaging signal, and uniformly disperse in the starch matrix, so as to further improve the accuracy and stability of the imaging. In addition, the nano inorganic particles are used as the filling phase in the starch matrix, and the addition amount is in a suitable range, which is beneficial to maintain the high mechanical strength of the microspheres and maintain the synergistic effect of the degradation and imaging. In some embodiments, the average particle size of the nano inorganic particles is 10 nm to 1000 nm. In the technical solution, the size of the nano inorganic particles is in a suitable range, which is beneficial to improve the ultrasonic imaging effect and uniformly disperse in the starch matrix to maintain the mechanical strength of the microspheres, and the degradation rate is controllable.

[0007] In some embodiments, the step S1 further includes: gelatinizing the starch in an alkaline aqueous solution. In the technical solution, the gelatinization treatment is performed before the starch is crosslinked, the crystalline structure of the starch is destroyed, more reaction sites are exposed, the crosslinking reaction efficiency is improved, the crosslinking uniformity is improved, and the stability, mechanical strength and controllable degradation of the microsphere structure are improved. In some embodiments, the crosslinking agent comprises at least one of sodium trimetaphosphate or sodium tripolyphosphate. Preferably, the crosslinking agent comprises sodium trimetaphosphate and sodium tripolyphosphate. Further preferably, the mass ratio of sodium trimetaphosphate to sodium tripolyphosphate is (2-20):1. In the technical solution, the mixture of sodium trimetaphosphate and sodium tripolyphosphate is used as the crosslinking agent to emulsify the crosslinked starch. The sodium trimetaphosphate and sodium tripolyphosphate have multiple phosphate groups. When the crosslinking reaction with the starch is performed, the phosphate groups react with the hydroxyl groups in the starch molecules to form phosphate ester bonds, thereby increasing the connection between the starch molecules and forming a three-dimensional network structure. In addition, the sodium ions in the sodium trimetaphosphate and sodium tripolyphosphate can form ionic bonding with the hydroxyl groups in the starch molecules, further enhancing the connection between the starch molecules.

[0008] In the technical solution, the sodium trimetaphosphate has a stronger crosslinking effect on the starch than the sodium tripolyphosphate. The higher the mass ratio of sodium trimetaphosphate, the higher the crosslinking degree and the longer the degradation time. Therefore, by controlling the mass ratio of sodium trimetaphosphate to sodium tripolyphosphate within a suitable range, the crosslinking degree of the microspheres can be controlled, and the degradation time can be controlled.

[0009] In some embodiments, the oil phase solution comprises an oil-soluble dispersant and an oil-soluble solvent; preferably, the oil-soluble dispersant comprises at least one of a Span series compound, a Tween series compound, an octylphenol polyoxyethylene ether, a dodecylphenol polyoxyethylene ether, cellulose acetate, or cellulose acetate butyrate; preferably, the oil-soluble solvent comprises at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate, or butyl acetate; preferably, the mass concentration of the oil-soluble dispersant in the oil phase solution is 0.1wt%-1wt%.

[0010] In the technical solution, the oil phase is configured to improve the stability of the emulsion, control the size of the microspheres within a suitable range, and maintain the morphology of the microspheres. In some embodiments, the mass of the water phase solution is 10%-35% of the mass of the oil phase solution. In the technical solution, the water phase is used as the dispersed phase and is dispersed in the oil phase in the form of droplets to form an emulsion. By controlling the mass ratio of the water phase solution to the oil phase solution within a suitable range, the stability of the emulsion can be improved, the morphology, particle size, and particle size distribution of the microspheres can be controlled, and the embolization effect, development uniformity, and degradation consistency of the microspheres can be further improved.

[0011] In some embodiments, in step S3, the reaction temperature is 20-50°C, and the reaction time is 18-48h.

[0012] In the above technical solution, controlling the cross-linking polymerization reaction temperature and time in a suitable range is conducive to controlling the cross-linking reaction rate, improving the cross-linking uniformity, and stabilizing the structure of the microspheres. In a second aspect, the embodiments of the present application provide an ultrasonic imaging degradable microsphere prepared by the above preparation method.

[0013] In the above technical solution, the ultrasonic imaging degradable microsphere provided by the present application has both ultrasonic imaging performance and degradability, can realize safe metabolism in vivo through the degradability of starch, can realize precise monitoring through the ultrasonic scattering of nano inorganic particles, and can monitor the degradation of the microsphere through ultrasonic imaging, thereby realizing real-time dynamic monitoring during operation and postoperative follow-up evaluation. In a third aspect, the embodiments of the present application also provide a use of the ultrasonic imaging degradable microsphere as an embolic agent for interventional embolization therapy.

[0014] In the above technical solution, the ultrasonic imaging degradable microsphere has both ultrasonic imaging performance and degradability, and is used as an embolic agent for interventional embolization therapy, which is conducive to expanding the imaging mode, reducing the imaging cost, improving the safety and reliability of interventional embolization therapy, and realizing real-time dynamic monitoring during operation and postoperative follow-up evaluation. BRIEF DESCRIPTION OF DRAWINGS

[0015] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can also be obtained without creative labor.

[0016] Figure 1 The process flow chart of the preparation method of the ultrasonic imaging degradable microsphere provided by the embodiments of the present application.

[0017] Figure 2 The imaging graph of the ultrasonic imaging degradable microsphere in Example 1 under an optical microscope.

[0018] Figure 3 The imaging graph of the ultrasonic imaging degradable microsphere in Example 2 under an optical microscope.

[0019] Figure 4 The imaging graph of the ultrasonic imaging degradable microsphere in Example 3 under an optical microscope.

[0020] Figure 5An imaging graph of the ultrasound-visualized degradable microspheres in Example 4 under an optical microscope.

[0021] Figure 6 An imaging graph of the ultrasound-visualized degradable microspheres in Comparative Example 1 under an optical microscope.

[0022] Figure 7 An imaging graph of the ultrasound-visualized degradable microspheres in Example 3 after degradation under an optical microscope. DETAILED DESCRIPTION

[0023] Hereinafter, specific embodiments of the ultrasound-visualized degradable microspheres, the preparation method and the application thereof disclosed in the present application are described in detail with appropriate reference to the accompanying drawings, but there are cases where unnecessary detailed descriptions are omitted. For example, there are cases where detailed descriptions of matters well known, repeated descriptions of substantially identical structures are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate understanding by those skilled in the art. In addition, the accompanying drawings and the following description are provided to enable those skilled in the art to fully understand the present application, and are not intended to limit the subject matter recited in the claims.

[0024] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit, a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of a particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, i.e., any lower limit can be combined with any upper limit to form a range. If not specifically stated, all embodiments and optional embodiments of the present application can be combined to form new technical solutions. If not specifically stated, all technical features and optional technical features of the present application can be combined to form new technical solutions. If not specifically stated, all steps of the present application can be performed in sequence or randomly, preferably in sequence.

[0025] Figure 1 A process flow chart of the preparation method of the ultrasound-visualized degradable microspheres provided in the embodiments of the present application. Please refer to Figure 1 The preparation method of the ultrasound-visualized degradable microspheres provided in the present application comprises the following steps: S1: mixing starch and nano-inorganic particles in an aqueous solution to obtain a mixed solution; the nano-inorganic particles include at least one of nano-calcium carbonate or nano-hydroxyapatite.

[0026] In some embodiments, the nano-inorganic particles account for 2% to 20% of the mass of the starch. As an example, the nano-inorganic particles account for 2%, 4%, 6%, 8%, 10%, 20% or any intermediate value between any two of the above values of the mass of the starch.

[0027] In some embodiments, the average particle size of the nano-inorganic particles is 10 nm to 1000 nm. For example, the average particle size of the nano-inorganic particles is 10 nm, 50 nm, 100 nm, 200 nm, 500 nm, 800 nm, 1000 nm, or any value between any two of the above values.

[0028] In some embodiments, before step S1, the method further comprises step S0: gelatinizing the starch in an alkaline aqueous solution. Specifically, the starch is heated and stirred in the alkaline aqueous solution until gelatinization and transparency are achieved. The alkaline aqueous solution can be a sodium hydroxide aqueous solution, the mass concentration of which can be 1 wt%, the heating temperature can be 80°C, and the stirring time can be 1 h.

[0029] It can be understood that the starch can be amylopectin, or comprise amylose and amylopectin.

[0030] In some embodiments, step S1 comprises: stirring and mixing the starch and sodium hydroxide (NaOH) in an aqueous solution, and heating to gelatinization and transparency to obtain a starch solution; under stirring, adding nano-inorganic particles to the starch solution, and stirring and mixing uniformly to obtain a mixed solution.

[0031] S2: mixing the mixed solution with a crosslinking agent to obtain an aqueous phase solution.

[0032] In some embodiments, the crosslinking agent comprises at least one of sodium trimetaphosphate or sodium tripolyphosphate.

[0033] Preferably, the crosslinking agent comprises sodium trimetaphosphate and sodium tripolyphosphate.

[0034] Further preferably, the mass ratio of sodium trimetaphosphate to sodium tripolyphosphate is (2-20):1. For example, the mass ratio of sodium trimetaphosphate to sodium tripolyphosphate is 2:1, 2.5:1, 5:1, 10:1, 15:1, 20:1, or any value between any two of the above values.

[0035] It can be understood that the sodium trimetaphosphate and the sodium tripolyphosphate can be directly added to the mixed solution for stirring and mixing, or the sodium trimetaphosphate and the sodium tripolyphosphate can be configured into an aqueous solution before stirring and mixing with the mixed solution.

[0036] S3: adding an oil phase solution to the aqueous phase solution, and reacting at a certain temperature for a period of time to obtain ultrasonic imaging degradable microspheres. In some embodiments, the oil phase solution comprises an oil-soluble dispersant and an oil-soluble solvent.

[0037] Preferably, the oil-soluble dispersant includes at least one of Span series compounds, Tween series compounds, octylphenol polyoxyethylene ether, dodecylphenol polyoxyethylene ether, cellulose acetate, or cellulose acetate butyrate. As an example, the oil-soluble dispersant can be Span 60, Span 80, Tween 80, OP-4, or the like.

[0038] Preferably, the oil-soluble solvent includes at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate, or butyl acetate.

[0039] Preferably, the mass concentration of the oil-soluble dispersant in the oil phase solution is 0.1wt%-1wt%. As an example, the mass concentration of the oil-soluble dispersant is 0.1wt%, 0.2wt%, 0.5wt%, 0.6wt%, 0.8wt%, 1wt%, or any intermediate value between any two of the above values.

[0040] In some embodiments, the water phase solution accounts for 10%-35% of the mass of the oil phase solution. As an example, the water phase solution accounts for 10%, 20%, 25%, 30%, 32%, 35%, or any intermediate value between any two of the above values of the mass of the oil phase solution.

[0041] In some embodiments, in step S3, the reaction temperature is 20℃-50℃, and the reaction time is 18h-48h. As an example, the reaction temperature is 20℃, 30℃, 40℃, 50℃, or any intermediate value between any two of the above values; and the reaction time is 18h, 24h, 36h, 48h, or any intermediate value between any two of the above values.

[0042] In some embodiments, after step S3, the method further includes: terminating the reaction, filtering, washing, and sieving to obtain ultrasonic imaging degradable microspheres of different particle sizes.

[0043] Further, the method can further include: adding a certain amount of ethanol or ethyl acetate to the cross-linking polymerization reaction system, and then washing the filtered product with ethanol or ethyl acetate three times to remove oil-soluble impurities, and then adding water to sieve.

[0044] In addition, the present application also provides an ultrasonic imaging degradable microsphere prepared by the above preparation method.

[0045] The ultrasonic imaging degradable microsphere includes a three-dimensional network structure formed by cross-linking polymerization of starch and a cross-linking agent, and nano-inorganic particles encapsulated and dispersed in the three-dimensional network structure, and has both ultrasonic imaging performance and degradability.

[0046] In addition, the present application also provides a use of the above ultrasonic imaging degradable microsphere as an embolic agent for interventional embolization therapy.

[0047] Embodiment In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. If specific conditions are not indicated in the embodiments, the conditions are implemented according to conventional conditions or the conditions recommended by the manufacturers. If the manufacturers of the reagents or instruments are not indicated, the reagents or instruments are conventional products that can be purchased in the market.

[0048] Embodiment 1 The present embodiment provides an ultrasonic imaging degradable microsphere, and a preparation method thereof includes the following steps: (1) 10 g of starch and 1 g of NaOH were added to 100 mL of distilled water, stirred and heated to paste transparency, and then cooled and reserved for use, to obtain a starch solution.

[0049] (2) 0.05 g of nano calcium carbonate powder (average particle size of 100 nm) was added to 25 mL of the starch solution under stirring, and stirred until fully mixed, to obtain a mixed solution.

[0050] (3) 7 mL of a crosslinking agent aqueous solution containing 1.4 g of sodium trimetaphosphate (STMP) and 0.14 g of sodium tripolyphosphate (STPP) was added to the mixed solution, and stirred until fully mixed, to obtain an aqueous phase solution.

[0051] (4) 100 mL of a mixed solution of cyclohexane and n-decane was prepared according to a volume ratio of 1:1, 0.5 g of octylphenol polyoxyethylene ether (OP-4) was added and mixed, to obtain an oil phase solution.

[0052] (5) The oil phase solution was added to the aqueous phase solution, and after fully mixed, stirred and reacted at room temperature (25°C) for 24 h, and then stirred overnight at room temperature, a certain amount of ethyl acetate was added, filtered, washed with ethyl acetate for 3 times to remove oil-soluble impurities, and then washed with purified water and sieved, to obtain ultrasonic imaging degradable microspheres with different particle sizes.

[0053] Embodiment 2 The present embodiment provides an ultrasonic imaging degradable microsphere, and the difference between the preparation method thereof and that of Embodiment 1 is that: In step (2), 0.10 g of nano calcium carbonate powder was added to 25 mL of the starch solution.

[0054] Embodiment 3 The present embodiment provides an ultrasonic imaging degradable microsphere, and the difference between the preparation method thereof and that of Embodiment 1 is that: In step (2), 0.25 g of nano calcium carbonate powder was added to 25 mL of the starch solution.

[0055] Embodiment 4 The present embodiment provides an ultrasonic imaging degradable microsphere, and the difference between the preparation method thereof and that of Embodiment 1 is that: In step (2), 0.5 g of nano calcium carbonate powder was added to 25 mL of the starch solution.

[0056] Example 5 This example provides an ultrasound imaging degradable microsphere, and the difference between its preparation method and that of Example 3 is that: In step (2), 0.25 g of nano hydroxyapatite powder (average particle size of 50 nm) was added to 25 mL of the starch solution.

[0057] Example 6 This example provides an ultrasound imaging degradable microsphere, and the difference between its preparation method and that of Example 1 is that: In step (2), the average particle size of the nano calcium carbonate powder was 200 nm.

[0058] Example 7 This example provides an ultrasound imaging degradable microsphere, and the difference between its preparation method and that of Example 1 is that: Step (3) includes: adding 7 mL of a crosslinking agent aqueous solution containing 1.1 g of sodium trimetaphosphate (STMP) and 0.44 g of sodium tripolyphosphate (STPP) to the mixed solution, and stirring until fully mixed to obtain an aqueous solution.

[0059] Comparative Example 1 This comparative example provides an ultrasound imaging degradable microsphere, and the difference between its preparation method and that of Example 1 is that: step (2) is not included; step (3) includes: under stirring, 7 mL of a crosslinking agent aqueous solution containing 1.4 g of sodium trimetaphosphate (STMP) and 0.14 g of sodium tripolyphosphate (STPP) is added to 25 mL of the starch solution, and stirring until fully mixed to obtain an aqueous solution.

[0060] Comparative Example 2 This comparative example provides an ultrasound imaging degradable microsphere, and the difference between its preparation method and that of Example 1 is that: (2) Under stirring, 7 mL of a crosslinking agent aqueous solution containing 1.4 g of sodium trimetaphosphate (STMP) and 0.14 g of sodium tripolyphosphate (STPP) was added to 25 mL of the starch solution, and stirring until fully mixed to obtain a mixed solution; (3) 0.05 g of nano calcium carbonate powder (average particle size of 100 nm) was added to the mixed solution, and stirring until fully mixed to obtain an aqueous solution.

[0061] Some of the preparation conditions of the ultrasound imaging degradable microspheres in the examples and comparative examples are shown in Table 1.

[0062] Table 1 Some of the preparation conditions of the examples and comparative examples

[0063] Test case In Examples 1-7 and Comparative Examples 1-2, 100 mL of sieved 100 μm-300 μm and 300 μm-600 μm ultrasonic biodegradable microspheres were taken, 100 mL of physiological saline was added, and after standing for the microspheres to settle and separate into layers, the supernatant was removed, and 100 mL of physiological saline was added again. The operation was repeated more than 3 times to obtain replacement microspheres with physiological saline as the storage medium.

[0064] Experimental Example 1 Displacement microspheres of 300μm to 600μm were taken and their morphology was observed using an optical microscope. Figure 2 This is an image of the ultrasonically biodegradable microspheres from Example 1 under an optical microscope. Figure 3 This is an image of the ultrasonically biodegradable microspheres from Example 2 under an optical microscope. Figure 4 This is an image of the ultrasonically biodegradable microspheres from Example 3 under an optical microscope. Figure 5 This is an image of the ultrasonically biodegradable microspheres from Example 4 under an optical microscope. Figure 6 This is an image of the ultrasonically biodegradable microspheres in Comparative Example 1 under an optical microscope.

[0065] from Figures 2-6 As can be seen from the results, the ultrasonic biodegradable microspheres prepared in Examples 1-4 of this application have a regular spherical morphology and the internal encapsulated nano-inorganic particles are distributed relatively evenly, while no nano-inorganic particles were observed in the microspheres of Comparative Example 1.

[0066] Experimental Example 2 Using the ultrasound grayscale signal of a simulated blood vessel wall as a benchmark, the evaluation was conducted by comparing the ratio (Ax / A0) of the grayscale integral value of the contrast region of the 300μm~600μm replacement microspheres in Examples 1~7 and Comparative Examples 1~2 to the baseline luminance integral value (A0) of the simulated blood vessel wall. This ratio is positively correlated with the acoustic reflection efficiency of the microspheres; a larger ratio indicates a better ultrasound contrast enhancement effect of the microspheres. The results are shown in Table 2.

[0067] Table 2. Results of ultrasonic imaging performance tests of the replaced microspheres in the examples and comparative examples.

[0068] As shown in Table 2, in Examples 1 to 4, the Ax / A0 value gradually increased with the increase of the amount of nano-inorganic particles added, and was greater than 1.2, indicating a good ultrasonic display effect. However, in Comparative Example 1, no nano-inorganic particles were added, and its Ax / A0 value was only 0.79. The microspheres prepared in Comparative Example 2 also had an unsatisfactory effect, with an Ax / A0 value of only 0.98.

[0069] Test Example 3 Take 2 mL of 100 μm~300 μm displacement microspheres, add to 18 mL of physiological saline solution containing α-amylase, configure enzyme concentration to be 5000 U / L, incubate on a shaking table at 37°C, visually observe the reaction bottle at intervals, after the microspheres are not visible, take 0.5 mL of the mixed liquid and dilute to 1 mL, take a micrograph, and take a micrograph without finding microspheres as the complete degradation time of the microspheres. The results are shown in Table 3.

[0070] At the same time, the displacement microspheres in Example 3 were subjected to real-time ultrasonic performance monitoring under the same degradation environment as described above, and the ultrasonic performance results are shown in Table 4.

[0071] Table 3 Degradation time of displacement microspheres in examples and comparative examples

[0072] Table 4 Ultrasonic performance test results of displacement microspheres in Example 3 during degradation

[0073] It can be seen from Table 1 and Table 3 that the microspheres prepared in Examples 1~7 and Comparative Examples 1~2 can all be completely degraded within 24 h, and when the addition amount of nano-inorganic particles is within a certain range, the degradation time does not change significantly, but when the addition amount exceeds a certain range, the degradation time will decrease significantly, which may be due to the nano-inorganic particles filled in the polymer matrix reducing the stability of the microsphere structure.

[0074] Figure 7 The above-described examples are part of the embodiments of the present application, rather than all the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but only represents selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application. Figure 7 It can be seen that during the degradation process, the starch microspheres maintain the basic spherical structure, while the nano-inorganic particles are released and excreted by the body, resulting in a decrease in the ultrasonic signal, so that the ultrasonic signal can be used to monitor the in vivo degradation of embolization microspheres in a low-cost and non-invasive manner.

[0075] The above-described examples are part of the embodiments of the present application, rather than all the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but only represents selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

Claims

1. A method for preparing ultrasonically visualizable degradable microspheres, characterized by, The method comprises the following steps: S1: mixing starch and nano inorganic particles in an aqueous solution to obtain a mixed solution; the nano inorganic particles comprise at least one of nano calcium carbonate or nano hydroxyapatite; S2: mixing the mixed solution with a crosslinking agent to obtain an aqueous phase solution; S3: adding an oil phase solution to the aqueous phase solution, reacting at a certain temperature for a period of time, and obtaining ultrasound imaging degradable microspheres.

2. The production method according to claim 1, characterized by, In the mixed solution, the nano inorganic particles account for 2% to 10% of the mass of the starch.

3. The production method according to claim 1, characterized by, The average particle size of the nano inorganic particles is 10 nm to 1000 nm.

4. The method of claim 1, wherein, Before step S1, the starch is gelatinized in an alkaline aqueous solution.

5. The preparation method according to claim 1, characterized in that, The crosslinking agent comprises at least one of sodium trimetaphosphate or sodium tripolyphosphate; Preferably, the crosslinking agent comprises sodium trimetaphosphate and sodium tripolyphosphate; Preferably, the mass ratio of sodium trimetaphosphate to sodium tripolyphosphate is (2-20):

1.

6. The method of claim 1, wherein, The oil phase solution comprises an oil-soluble dispersant and an oil-soluble solvent; Preferably, the oil-soluble dispersant comprises at least one of a Span series compound, a Tween series compound, an octylphenol polyoxyethylene ether, a dodecylphenol polyoxyethylene ether, cellulose acetate, or cellulose acetate butyrate; Preferably, the oil-soluble solvent comprises at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate, or butyl acetate; Preferably, the mass concentration of the oil-soluble dispersant in the oil phase solution is 0.1wt% to 1wt%.

7. The preparation method according to claim 1, characterized in that, The aqueous phase solution accounts for 10% to 35% of the mass of the oil phase solution.

8. The method of claim 1, wherein, In step S3, the reaction temperature is 20°C to 50°C, and the reaction time is 18h to 48h.

9. Ultrasound-visualizable degradable microspheres, characterized in that, The ultrasound imaging degradable microspheres are prepared by the preparation method of any one of claims 1 to 8.

10. The ultrasound imaging degradable microspheres of claim 9 for use as embolic agents in interventional embolization therapy.

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