An ultrasonic imaging hydrogel, its preparation method and application

Abstract

The present application belongs to the field of medical preparations, and particularly relates to an ultrasonic imaging hydrogel, a preparation method and application thereof. The present application adds imaging particles to the hydrogel system, so that the system has good ultrasonic imaging effect. Meanwhile, hydroxymethyl cellulose is specifically selected as a suspending agent, which not only significantly improves the stability of the imaging particles in the system, reduces the sedimentation of the imaging particles, but also is beneficial to maintaining the rapid gelation performance of the hydrogel, has great industrialization value and clinical use value, and can provide new materials for the fields of medicine and tissue engineering, and be applied to implantable medical devices, permanent embolization, artificial tissue scaffolds and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medical preparations, especially the field under the IPC classification number A61L24 / 00, and more particularly to an ultrasonic imaging hydrogel and a preparation method and application thereof. BACKGROUND

[0002] Hydrogel is a soft material containing a large amount of water obtained by cross-linking hydrophilic polymers. Due to its good biocompatibility and physicochemical properties, it is widely used in the field of biological medicine, especially in the aspects of local drug delivery, isolation and protection, permanent embolization, medical implantation, etc. However, conventional hydrogels cannot be imaged under ultrasound, so they cannot be positioned in real time during injection, which limits the use of hydrogels and cannot meet the use requirements of some special fields.

[0003] In order to make the hydrogel have imaging function, domestic and foreign researchers have focused on related research, but there are few effective methods at present. The main difficulty lies in that the hydrogel is made of hydrophilic polymers. For the imaging particles that are insoluble in water, there are common defects such as fast sedimentation speed, difficulty in gelation, and instability after gelation. In order to overcome this defect, the prior art usually adopts the means of connecting the imaging substance into the gel or microsphere system through chemical bonds, or directly making the imaging substance participate in cross-linking. For example, the self-imaging embolization microspheres disclosed in the prior art CN115487342A introduce iodobenzene compounds to provide imaging performance. The iodobenzene compounds are directly cross-linked with gelatin, so that the imaging substance is stably combined in the microspheres. However, the compounds with imaging function introduced by such means have poor stability and are prone to hydrolysis to release iodine ions, etc., which has certain safety hazards; and the preparation method is complex and requires a long reaction time, which is not suitable for industrial production. SUMMARY

[0004] In view of the defects of the prior art, the purpose of the present application is to provide an ultrasonic imaging hydrogel with good imaging effect, good gelation performance and stable gel performance.

[0005] On the other hand, the purpose of the present application is also to provide a preparation method of the above-mentioned ultrasonic imaging hydrogel.

[0006] On the other hand, the purpose of the present application is also to provide an application of the above-mentioned ultrasonic imaging hydrogel or the ultrasonic imaging hydrogel prepared by the above-mentioned preparation method.

[0007] In order to achieve the above-mentioned purposes, the present application adopts the following technical solutions:

[0008] An ultrasonic imaging hydrogel, the preparation raw materials of which comprise: a polyethylene glycol derivative, a polyamino polymer, an imaging particle, and a suspending agent.

[0009] Preferably, the developing particles are tantalum powder, calcium carbonate or microcrystalline cellulose.

[0010] Preferably, the tantalum powder is purchased from Shanghai Aladdin Biochem Technology Co., Ltd. with the item number T119283.

[0011] Preferably, the microcrystalline cellulose is purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd. with the item number BD120355.

[0012] Preferably, the suspending agent is CMC (hydroxymethyl cellulose).

[0013] Preferably, the CMC is purchased from Shanghai Aladdin Biochem Technology Co., Ltd. with the item number C104979.

[0014] Preferably, the mass ratio of the developing particles to the suspending agent is 4-6:1; further preferably, 5:1.

[0015] The present application realizes the self-developing function of hydrogel by adding developing particles to the hydrogel system. The developing particles selected by the present application not only have good ultrasonic developing performance, but also have stable properties and high biological safety. In particular, the tantalum powder shows excellent developing performance in the system of the present application. However, these developing particles have poor affinity in polyethylene glycol solution and start to settle in about two minutes, which cannot be stably prepared and used. In order to overcome the problem of sedimentation, the present inventors add a small amount of suspending agent to the system, which can stably suspend the tantalum powder in the solution for more than 20 minutes. On this basis, the present inventors accidentally found that when a specific CMC is selected as the suspending agent, the developing particles can be stably suspended for more than one hour, thereby facilitating subsequent preparation and use. Moreover, the specific CMC suspending agent selected by the present application can also promote the gelation of polyethylene glycol derivatives and polyamino polymers. When the developing particles are inserted into the crosslinking system, it will hinder the crosslinking reaction of amino and aldehyde groups, greatly prolonging the gelation time. However, the present inventors found that the addition of CMC can make the gelation time remain at a level comparable to that without adding developing particles, greatly improving the production and use efficiency.

[0016] Preferably, the polyethylene glycol derivative is aldehyde-terminated multi-arm polyethylene glycol with 2-8 arms.

[0017] Further preferably, the aldehyde-terminated multi-arm polyethylene glycol has 4-8 arms, which can be 4-arm, 6-arm or 8-arm.

[0018] Preferably, the aldehyde group is selected from one or both of aromatic aldehyde group and alkyl aldehyde group.

[0019] Preferably, the aldehyde group is connected to the multi-arm polyethylene glycol through an ether bond, an amide bond, an urethane bond, an imine bond or a urea bond.

[0020] Further preferably, the aldehyde-terminated multi-arm polyethylene glycol has a structural formula as shown in any one of formulas 1-3:

[0021]

[0022]

[0023] Preferably, the aldehyde-terminated multi-arm polyethylene glycol has a molecular weight of 10,000-20,000 Da.

[0024] Preferably, the aldehyde-terminated multi-arm polyethylene glycol has a structure of formula 1 and a molecular weight of 15,000 Da.

[0025] Preferably, the mass ratio of the aldehyde-terminated multi-arm polyethylene glycol to the developing particles is 3-5:1; further preferably, 4:1.

[0026] Preferably, the polyamino polymer comprises one or both of polylysine and polyethyleneimine.

[0027] Preferably, the polyamino polymer is a combination of polylysine and polyethyleneimine.

[0028] Preferably, the molar ratio of the aldehyde group of the aldehyde-terminated multi-arm polyethylene glycol, the amino group of the polylysine, and the amino group of the polyethyleneimine is 1:0.5-1:1-1.5; further preferably, 1:0.9:1.

[0029] Another aspect of the present application provides a preparation method of the above ultrasonic developing hydrogel, comprising the following steps:

[0030] S1: dissolving a polyethylene glycol derivative in a buffer solution, adding a suspending agent, mixing uniformly, and then adding developing particles to prepare a mixed solution;

[0031] S2: dissolving a polyamino polymer in a buffer solution to prepare a precursor solution;

[0032] S3: mixing and cross-linking the mixed solution and the precursor solution to obtain the ultrasonic developing hydrogel.

[0033] Preferably, the buffer solution is a phosphate buffer solution or a borax buffer solution with a pH of 4-10.

[0034] Preferably, the mass concentration of the tantalum powder in the mixed solution is 3-8%; further preferably, 5%.

[0035] Preferably, the mass concentration of the hydroxymethyl cellulose in the mixed solution is 0.6-1.6%; further preferably, 1%.

[0036] Further preferably, the preparation method of the ultrasound imaging hydrogel comprises the following steps in particular:

[0037] S1: dissolving the polyethylene glycol derivative in a phosphate buffer with pH=5.6, adding a suspending agent, mixing uniformly, and then adding the imaging particles to prepare a mixed solution;

[0038] S2: weighing the polylysine and polyethyleneimine according to the molar ratio of the aldehyde group of the aldehyde-terminated multi-arm polyethylene glycol, the amino group of the polylysine, and the amino group of the polyethyleneimine, dissolving in a borax buffer with pH=9.2 to prepare a precursor solution;

[0039] S3: mixing and cross-linking the mixed solution and the precursor solution at a volume ratio of 1:0.8-1.2 to obtain the ultrasound imaging hydrogel.

[0040] Preferably, the volume ratio of the mixed solution and the precursor solution for mixing and cross-linking is 1:1.

[0041] Another aspect of the present application provides an application of the above-mentioned ultrasound imaging hydrogel or the ultrasound imaging hydrogel prepared by the above-mentioned preparation method as a material of implantable medical devices.

[0042] Compared with the prior art, the present application has the following beneficial effects:

[0043] 1. The present application realizes the ultrasound imaging of the hydrogel by adding imaging particles to the hydrogel, and exhibits excellent imaging performance;

[0044] 2. The present application significantly reduces the sedimentation of the imaging particles by adding the suspending agent CMC, improves the stability of the ultrasound imaging hydrogel, expands the application range, and improves the use safety;

[0045] 3. The suspending agent selected by the present application overcomes the influence of the imaging particles on the gelation performance, can make the hydrogel system of the present application maintain a shorter gelation time, and has higher industrialization and practical value. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 Ultrasound imaging photos of the blank group hydrogel (a) and the ultrasound imaging hydrogel of Example 1 under the rat skin (b and c);

[0047] Figure 2 Ultrasound imaging photos of the ultrasound imaging hydrogels of Examples 2 (a and b) and 3 (c and d) under the rat skin DETAILED DESCRIPTION

[0048] The concentrations of the solutions in the examples refer to mass concentrations, and the reagents are purchased from the preferred sources in the detailed description.

[0049] Example 1

[0050] The present example provides an ultrasound imaging hydrogel, the raw materials for the preparation of which include an aldehyde-terminated 8-arm polyethylene glycol (molecular weight 15000 Da, purchased from Beijing Keyeike Technology Co., Ltd.) shown in formula 1, polylysine, polyethyleneimine, suspending agent CMC, and imaging particles microcrystalline cellulose.

[0051] The preparation method is as follows:

[0052] S1: 200 mg of aldehyde-terminated 8-arm polyethylene glycol (molecular weight 15000 Da, purchased from Beijing Keyeike Technology Co., Ltd.) shown in formula 1 is dissolved in 1 mL of phosphate buffer with pH = 5.6, 10 mg of suspending agent CMC is added, and after uniform mixing, 50 mg of imaging particles microcrystalline cellulose is added to prepare a mixed solution;

[0053] S2: Polylysine (purchased from Shanghai Maikelin Biochemical Co., Ltd.) and polyethyleneimine (purchased from Shanghai Maikelin Biochemical Co., Ltd.) are weighed in a molar ratio of 1:0.9:1 of the aldehyde group of the aldehyde-terminated multi-arm polyethylene glycol, the amino group of the polylysine, and the amino group of the polyethyleneimine, and dissolved in 1 mL of borax buffer with pH = 9.2 to prepare a precursor solution;

[0054] S3: The mixed solution and the precursor solution are mixed and cross-linked to obtain an ultrasound imaging hydrogel.

[0055] Example 2

[0056] The present example provides an ultrasound imaging hydrogel, the raw materials and preparation method of which are the same as those of Example 1, except that the imaging particles are replaced by calcium carbonate.

[0057] Example 3

[0058] The present example provides an ultrasound imaging hydrogel, the raw materials and preparation method of which are the same as those of Example 1, except that the imaging particles are replaced by tantalum powder.

[0059] Comparative Example 1

[0060] The present comparative example provides an ultrasound imaging hydrogel, the raw materials and preparation method of which are the same as those of Example 1, except that the suspending agent is replaced by dextran (purchased from Shanghai Maikelin Biochemical Technology Co., Ltd., product number D806715) with a dosage of 50 mg.

[0061] Comparative Example 2

[0062] The present comparative example provides an ultrasound imaging hydrogel, the raw materials and preparation method of which are the same as those of Example 2, except that the suspending agent is replaced by dextran with a dosage of 50 mg.

[0063] Comparative Example 3

[0064] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Example 3, except that the suspending agent is replaced by dextran, and the amount is 50 mg.

[0065] Comparative Example 4

[0066] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 1, except that the amount of dextran is 100 mg.

[0067] Comparative Example 5

[0068] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 2, except that the amount of dextran is 100 mg.

[0069] Comparative Example 6

[0070] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 3, except that the amount of dextran is 100 mg.

[0071] Comparative Example 7

[0072] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 1, except that the amount of dextran is 150 mg.

[0073] Comparative Example 8

[0074] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 2, except that the amount of dextran is 150 mg.

[0075] Comparative Example 9

[0076] This comparative example provides an ultrasound imaging hydrogel, which has the same raw materials and preparation method as Comparative Example 3, except that the amount of dextran is 150 mg.

[0077] Performance test

[0078] 1. Sedimentation time test:

[0079] Prepare blank samples 1-3, respectively, according to the methods of Examples 1-3, except that no suspending agent is added.

[0080] After the mixed solution of the blank sample, the example and the comparative example is shaken by the shaker for 1 min, it is placed on the table to start timing, and the time of appearing precipitation or stratification is observed, which is counted as the sedimentation time and recorded in Table 1.

[0081] Table 1

[0082]

[0083]

[0084] 2. Gelation time test:

[0085] Prepare a blank group in the same way as in Example 1, except that no developing particles and suspending aids are added.

[0086] Prepare the mixed solution and the precursor solution according to the methods of the blank group, Examples 1-3, and Comparative Examples 1-9, respectively. Take 0.6 mL of the mixed solution and the precursor solution, respectively, and place them in 2.5 mL vials. After standing in a 37±0.5°C water bath for 5 minutes, take 200 μL of the mixed solution in a 2.5 mL vial using a pipette, and then take 200 μL of the precursor solution in the vial using another pipette. Add the precursor solution to the vial containing the mixed solution, shake the wrist at a frequency of 3 times / s, and shake the vial for 3 s. Then, repeatedly tilt the vial at a frequency of 1 time / s and observe until the liquid does not flow. Start timing from the time when the precursor solution is added, and end timing when the liquid does not flow. The length of time is the gelation time. Repeat each group three times, calculate the average value, and record the results in Table 2.

[0087] Table 2

[0088]

[0089]

[0090] 3. Developing effect test:

[0091] Implant the blank group hydrogel and the ultrasonic developing hydrogels of Examples 1-3 in the above gelation time test into rats subcutaneously, and take ultrasonic developing photos, as shown in Figs. 1-3, respectively. Figure 1 and 2 ​

Claims

1. An ultrasonically visualizing hydrogel, characterized in that, The preparation raw materials include: polyethylene glycol derivative, polyamino polymer, developing particles, suspending agent; The developing particles are tantalum powder, calcium carbonate or microcrystalline cellulose; The suspending agent is hydroxymethyl cellulose; The mass ratio of the developing particles to the suspending agent is 4-6:1; The polyethylene glycol derivative is aldehyde group terminated multi-arm polyethylene glycol with arm number of 2-8; The polyamino polymer includes one or both of polylysine and polyethylene imine.

2. The ultrasonic contrast hydrogel of claim 1, wherein, The mass ratio of the aldehyde group terminated multi-arm polyethylene glycol to the developing particles is 3-5:

1.

3. A method of preparing the ultrasonographic hydrogel according to any one of claims 1-2, characterized in that, The method includes the following steps: S1: dissolving the polyethylene glycol derivative in a buffer solution, adding the suspending agent, mixing uniformly, then adding the developing particles, and preparing a mixed solution; S2: dissolving the polyamino polymer in a buffer solution, and preparing a precursor solution; S3: mixing and cross-linking the mixed solution and the precursor solution to obtain the ultrasonic developing hydrogel.

4. The method of claim 3, wherein the ultrasound imaging hydrogel is prepared by the steps of: The buffer solution is phosphate buffer solution or borax buffer solution with pH of 4-10.

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