CN110917387B

CN110917387B - Developable embolism microsphere and preparation method thereof

Info

Publication number: CN110917387B
Application number: CN201911230003.3A
Authority: CN
Inventors: 张超; 刘景龄; 杨越雄; 张阳; 黄丹
Original assignee: Sun Yat Sen University
Current assignee: Sun Yat Sen University
Priority date: 2019-12-04
Filing date: 2019-12-04
Publication date: 2021-02-12
Anticipated expiration: 2039-12-04
Also published as: CN110917387A

Abstract

The invention discloses a developable embolism microsphere and a preparation method thereof. The embolism microsphere is prepared by polyvinyl alcohol, beta-tricalcium phosphate, nano bismuth and glutaraldehyde through an inverse suspension polymerization technology, wherein the continuous phase is liquid paraffin and a surfactant, and the dispersed phase is polyvinyl alcohol, beta-tricalcium phosphate, nano bismuth and glutaraldehyde; the weight ratio of the polyvinyl alcohol to the beta-tricalcium phosphate to the nano bismuth to the glutaraldehyde is 10: 1-2: 0.1-0.8: 0.7-1.25. According to the embolism microsphere, the bismuth element is introduced into the embolism microsphere, so that the accuracy of real-time imaging of interventional embolism treatment is improved, misdiagnosis caused by phase separation is reduced, and a new design scheme is provided for the imageable embolism microsphere; meanwhile, bismuth ions can be discharged in vivo, and compared with iodine elements, the bismuth ions are safer; meanwhile, the embolism is simple in process, short in preparation time and easy to realize batch production; and the microspheres are added with TCP materials, so that the biocompatibility of the microspheres is improved.

Description

Developable embolism microsphere and preparation method thereof

Technical Field

The invention relates to the technical field of medical science of nuclear magnetic resonance contrast agents, in particular to a developable embolism microsphere and a preparation method thereof.

Background

Currently, in interventional embolization surgery, commercially available contrast agents in wide clinical use include iohexol, iodixanol, and the like. The contrast agent is mixed with embolism microsphere and injected into human body, and the microsphere has better imaging ability due to the existence of iodine element. However, when these commercial imaging agents are mixed with the embolic microspheres, two phases may separate, and the imaging result cannot accurately represent the actual position of the embolic microspheres, which brings certain misdiagnosis factors and adverse factors to diagnosis.

If the embolism microsphere has the self-developing function, the problem of two-phase separation of the developer and the embolism microsphere can be well solved. However, the current embolization microsphere with self-developing function has certain defects to be improved, and the preparation process of the current embolization microsphere is complex. For example, in CN106890606A, method for preparing porous beta-TCP microspheres with different particle sizes by oil-in-water solid emulsification, an oil phase is dispersed in a water phase, wherein the oil is used as an internal phase and the water is used as a dispersed phase; then sintering is carried out to obtain the beta-TCP microspheres, which takes long time and has complex operation process. For example, in the 'influence of chitosan crosslinking characteristics on the balling property of chitosan/beta-TCP microspheres' described in Qingfeng et al, primary crosslinking is performed by glutaraldehyde, secondary crosslinking is performed after a series of operations, washing is performed by chloroform, extraction is performed for 10h by ethanol, and drying is performed to obtain dried microspheres.

The existing process for preparing the beta-TCP microspheres has the defects of complicated process, sintering or secondary crosslinking in the preparation process, long time consumption, inconvenience for realizing batch production, need of being combined with a commercial developer and no self-development effect. Therefore, the microsphere with self-development is provided, the preparation method is simple and quick, and the microsphere has a great propulsion effect on the application of contrast agents.

Disclosure of Invention

The invention aims to provide a developable embolism microsphere. The embolism microsphere improves the accuracy of real-time imaging of interventional embolism treatment by introducing bismuth into the embolism microsphere, reduces misdiagnosis caused by phase separation, and provides a new design scheme for the imageable embolism microsphere. Meanwhile, bismuth ions can be discharged in vivo, and compared with iodine elements, the bismuth ions are safer; meanwhile, the embolism is simple in process, short in preparation time and easy to realize batch production; and the microspheres are added with TCP materials, so that the biocompatibility of the microspheres is improved.

It is another object of the present invention to provide a method for preparing the developable embolization microspheres.

The above object of the present invention is achieved by the following scheme:

a kind of embolism microballoons that can be developed, is prepared from polyvinyl alcohol, beta-tricalcium phosphate, nanometer bismuth and glutaraldehyde through the polymerization technique of the reverse phase suspension, wherein the continuous phase is liquid paraffin and surfactant active, the disperse phase is polyvinyl alcohol, beta-tricalcium phosphate, nanometer bismuth and glutaraldehyde;

the weight ratio of the polyvinyl alcohol to the beta-tricalcium phosphate to the nano bismuth to the glutaraldehyde is 10: 1-2: 0.1-0.8: 0.7-1.25.

Beta-tricalcium phosphate (TCP) is mainly composed of calcium and phosphorus elements, the components of which are similar to the inorganic components of bone matrix, and degradation products are alkaline. Has good biocompatibility and osteoinductivity, but the defects of large brittleness and poor toughness limit the application of the composite material.

Bismuth, a heavy metal element having a large X-ray attenuation coefficient. In the research of numerous biomedical materials, it provides a good choice for realizing Computed Tomography (CT) imaging. Meanwhile, the preparation method has the advantages of low production cost, capability of forming trivalent bismuth ions in a human body and successful elimination of the trivalent bismuth ions from the human body. In interventional embolization, the realization of real-time imaging of embolization microspheres is helpful for the application of interventional embolization, and is beneficial to clinical tracking observation and diagnosis. According to the invention, bismuth is introduced into the embolism microsphere, so that the accuracy of real-time imaging of interventional embolism treatment is improved, misdiagnosis caused by phase separation is reduced, and a new design scheme is provided for the imageable embolism microsphere. Meanwhile, bismuth ions can be discharged in vivo, and compared with iodine, the bismuth ion-doped bismuth-doped iodine is safer.

The embolism microsphere prepared by polyvinyl alcohol, beta-tricalcium phosphate, nano bismuth and glutaraldehyde not only well plays the role of bismuth, but also effectively overcomes the defects of large brittleness and poor toughness of the beta-tricalcium phosphate.

Preferably, the weight ratio of the polyvinyl alcohol to the liquid paraffin is 1: 1-1.5.

Preferably, the weight ratio of the liquid paraffin to the surfactant is 50: 20: 1.

Preferably, the surfactant is span-80, span-60, tween-80 or the like.

The invention also provides a preparation method of the developable embolism microsphere, which comprises the following steps:

s1, mixing polyvinyl alcohol and beta-tricalcium phosphate in water according to a formula, uniformly mixing, adding nano bismuth, and uniformly stirring;

s2, adding hydrochloric acid into the mixed solution in the step S1 for acidification;

s3, continuous phase configuration: uniformly mixing liquid paraffin and a surfactant according to the formula amount;

and S4, uniformly mixing the acidified mixed solution obtained in the step S2 with a glutaraldehyde solution for reaction, and then dropwise adding the mixed solution into a continuous phase to prepare the developable embolism microsphere.

Preferably, in the step S1, after the nano bismuth is added, the stirring speed is 200-700 r/min. .

Preferably, in step S2, the pH of the acidified mixed solution is 3.0 to 6.0.

Preferably, the specific process of step S3 is: and mixing the liquid paraffin and the surfactant, heating to 40-70 ℃, and stirring at the rotating speed of 200-700 r/min.

More preferably, in step S3, the liquid paraffin and the surfactant are heated at a temperature of 55 ℃.

Preferably, in step S4, the reaction time of the acidified mixed solution in S2 and the glutaraldehyde solution is 15S, and then the solution is quickly dropped into the continuous phase for forming and curing.

A developable embolizing microsphere prepared by the above preparation method is also within the scope of the invention.

Compared with the prior art, the invention has the following beneficial effects:

the embolism microsphere improves the accuracy of real-time imaging of interventional embolism treatment by introducing bismuth into the embolism microsphere, reduces misdiagnosis caused by phase separation, and provides a new design scheme for the imageable embolism microsphere. Meanwhile, bismuth ions can be discharged in vivo, and compared with iodine elements, the bismuth ions are safer;

meanwhile, the embolism is simple in process, short in preparation time and easy to realize batch production; and the microspheres are added with TCP materials, so that the biocompatibility of the microspheres is improved.

Drawings

FIG. 1 is a schematic flow chart of the preparation of developable embolizing microspheres of example 1.

FIG. 2 is a cold field Scanning Electron Microscope (SEM) image of the developable embolization microspheres prepared in example 1.

FIG. 3 is a scanning electron micrograph of a Karl Zeiss ZEISS EVO18 tungsten filament of the developable embolization microspheres prepared in example 1.

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.

Example 1

A developable embolism microsphere is prepared by polyvinyl alcohol (PVA), beta-tricalcium phosphate (TCP), nano bismuth and glutaraldehyde through an inverse suspension polymerization technology, the preparation flow chart is shown in figure 1, and the specific preparation process is as follows:

s1, dissolving 2g of polyvinyl alcohol in 18g of pure water to obtain 20mL of 10% polyvinyl alcohol solution, and adding 0.25g of beta-tricalcium phosphate into the solution, namely, according to the PVA: TCP-8: 1 proportion, mixing and dispersing, stirring for 1h, adding 20mg of Bi nanoparticles, and stirring at 400 r/min;

s2, adding 200 mu L of concentrated hydrochloric acid into the polyvinyl alcohol solution containing the TCP/Bi in the step S1 for acidification;

s3, adding span-800.6 g into a beaker containing 30mL of liquid paraffin, placing the beaker in an oil bath at 55 ℃, rotating speed of 400r/min, and magnetically stirring.

S4, adding 80 mu L of 50% glutaraldehyde (the density of the glutaraldehyde is about 1.06g/mL, and the converted mass of 80 mu L is about 0.0848g) into 10mL of the mixed solution (containing 1g of PVA) in the step S2, mixing the two solutions for 15S under magnetic stirring, and quickly dropwise adding the two solutions into liquid paraffin to prepare the developable embolization microsphere.

The characterization of the developable embolization microspheres prepared above, the results obtained are shown in fig. 2 and 3, wherein fig. 2 is a cold field scanning topography of the microspheres; fig. 3 shows the elemental analysis result of the EVO electron microscope, and it can be seen from fig. 2 and fig. 3 that the composite microsphere based on polyvinyl alcohol has good balling properties, and the microsphere is loaded with β -tricalcium phosphate.

The microspheres are nitrified and subjected to ICP (plasma atomic emission spectrometer) detection on bismuth, and the Bi element is detected as a test result, wherein the content of the Bi element is 3.78mg/mL, which indicates that the metal bismuth nanoparticles are successfully encapsulated into the microspheres.

Example 2

A developable embolization microsphere was prepared as in example 1, except that: the mass ratio of PVA to TCP in step S1 was 10:2, and the other steps were the same as in example 1.

Example 3

A developable embolization microsphere was prepared as in example 1, except that: the PVA/TCP mass ratio in step S1 was 6:1, span-800.5 g in step S3 was put in an oil bath at 60 ℃ and the other steps were the same as in example 1.

Example 4

A developable embolization microsphere was prepared as in example 1, except that: in step S1, the Bi nanoparticles are 100mg, the temperature of the oil bath is set at 60 ℃ in step S3, the rotating speed is 600r/min, and the magnetic stirring is carried out, wherein the other steps are the same as those of the embodiment 1.

Example 5

A developable embolization microsphere was prepared as in example 1, except that: the amount of Bi nanoparticles in step S1 was 80mg, the temperature of the oil bath in step S3 was set at 50 ℃, the rotational speed was 500r/min, and magnetic stirring was carried out with the amount of glutaraldehyde being 100. mu.L (the equivalent mass of 100. mu.L glutaraldehyde was about 0.106g), and the other steps were the same as in example 1.

The results of the cold field scanning electron microscopy and Karl Zeiss ZEISS EVO18 tungsten filament scanning electron microscopy of the developable embolization microspheres prepared in examples 2 to 5 above were the same as in example 1.

It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. The developable embolism microsphere is characterized by being prepared from polyvinyl alcohol, beta-tricalcium phosphate, nano bismuth and glutaraldehyde, wherein the continuous phase is liquid paraffin and a surfactant, and the dispersed phase is polyvinyl alcohol, beta-tricalcium phosphate, nano bismuth and glutaraldehyde;

wherein the polyvinyl alcohol, the beta-tricalcium phosphate, the nano bismuth and the glutaraldehyde are used in a proportion of 10: 1-2: 0.1-0.8: 0.7-1.25 by weight;

the preparation method of the developable embolism microsphere comprises the following steps:

s3, continuous phase configuration: mixing liquid paraffin and a surfactant, heating to 40-70 ℃, and stirring at the rotating speed of 200-700 r/min;

and S4, uniformly mixing the acidified mixed solution obtained in the step S2 with a glutaraldehyde solution, reacting for 5-60S, then quickly dropwise adding the mixed solution into the continuous phase, forming and curing, and preparing the developable embolism microsphere.

2. The developable embolization microsphere of claim 1, wherein the weight ratio of the polyvinyl alcohol to the liquid paraffin is 1:1 to 1.5.

3. The developable embolization microsphere of claim 1, wherein the weight ratio of the liquid paraffin to the surfactant is 20-50: 1.

4. The developable embolic microsphere of claim 1, wherein the surfactant is span-80, span-60, tween-60, or tween-80.

5. The developable embolization microsphere of claim 1, wherein in step S1, after the nano bismuth is added, the stirring speed is 200-700 r/min.

6. The developable embolization microsphere of claim 1, wherein in step S2, the pH of the acidified mixed solution is 3.0-6.0.