CN114533937A

CN114533937A - Biodegradable temperature-sensitive embolic gel and preparation method and application thereof

Info

Publication number: CN114533937A
Application number: CN202210134966.9A
Authority: CN
Inventors: 杨杨; 刘振涛; 臧庆武
Original assignee: Beijing Guanhe Medical Technology Co ltd
Current assignee: Beijing Guanhe Medical Technology Co ltd
Priority date: 2022-02-14
Filing date: 2022-02-14
Publication date: 2022-05-27
Anticipated expiration: 2042-02-14
Also published as: CN114533937B

Abstract

The application relates to the technical field of medical treatment and medical intervention embolism, and particularly discloses biodegradable temperature-sensitive embolism gel and a preparation method and application thereof, wherein the biodegradable temperature-sensitive embolism gel is prepared from a poloxamer aqueous solution and a premixed aqueous solution, and the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is (1-3) to (1-2); the solute of the premixed water solution is mainly prepared from the following raw materials by weight based on 100g of water: 16-26g of poloxamer, 0.1-5g of sodium alginate and 0.1-5g of synergistic auxiliary agent; the solute of the poloxamer aqueous solution is mainly prepared from the following raw materials by weight based on 100g of water: 6-25g of poloxamer. The temperature-sensitive embolic gel has good temperature sensitivity and drug slow release through the synergistic effect of the raw materials, has the advantages of simple preparation and convenient processing and control, improves the application range and safety of the temperature-sensitive embolic gel, and meets the market demand.

Description

Biodegradable temperature-sensitive embolic gel and preparation method and application thereof

Technical Field

The application relates to the technical field of medical and medical interventional embolization, in particular to biodegradable temperature-sensitive embolization gel and a preparation method and application thereof.

Background

Embolization, also known as embolization, is a controlled injection of an embolization material into the supply vessel of a diseased organ via an arterial or intravenous catheter, causing occlusion and interruption of the blood supply in order to control bleeding, treat tumors and vascular lesions and eliminate the function of the diseased organ. Embolization is an important technique in interventional therapy and also one of the three major techniques in interventional radiology. The research and clinical application of embolization in China has been almost thirty years old so far, some aspects have become mature slightly, but the embolization is still in the process of continuous development and perfection in general.

The chemotherapy embolism of hepatic artery is to insert catheter selectively or super selectively into the target artery supplying blood to tumor, inject proper amount of embolizing agent at proper speed to occlude the target artery and cause ischemic necrosis of tumor tissue. Embolization with anti-cancer drugs or drugs in combination with embolization agents may serve as a chemoembolization agent. The use of the embolic agent is necessary to use temperature sensitive embolic gel, the common synthetic polymer material of the temperature sensitive embolic gel is poloxamer generally, poloxamer is a triblock copolymer with two ends being polyoxyethylene and the middle being polyoxypropylene, and the poloxamer easily forms the temperature sensitive embolic gel with water. However, in practical application, the applicant finds that the temperature-sensitive embolic gel formed by poloxamer and water has poor deformability after being cured and needs to be improved.

Disclosure of Invention

In order to improve the temperature sensitivity of the temperature-sensitive embolic gel and the deformation capability after curing, the application provides a biodegradable temperature-sensitive embolic gel and a preparation method and application thereof.

In a first aspect, the present application provides a biodegradable temperature-sensitive embolic gel, which adopts the following technical scheme: a biodegradable temperature-sensitive embolic gel is prepared from a poloxamer aqueous solution and a premixed aqueous solution, wherein the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is (1-3) to (1-2);

the solute of the premixed water solution is mainly prepared from the following raw materials by weight based on 100g of water: 16-26g of poloxamer, 0.1-5g of sodium alginate and 0.1-5g of synergistic auxiliary agent;

the solute of the poloxamer aqueous solution is mainly prepared from the following raw materials by weight based on 100g of water: 6-25g of poloxamer.

By adopting the technical scheme, the temperature-sensitive embolic gel has good gel temperature which is 30-38 ℃ and is close to the normal body temperature of a human body. And at 29 ℃, the gel has good fluidity, is convenient for storing temperature-sensitive embolic gel, can be effectively cured at 38 ℃, and has good deformation stress. After the medicine is delivered to a focus blood vessel through a catheter, the medicine is quickly solidified to complete the blood vessel embolism. Meanwhile, the temperature-sensitive embolic gel has low gelation time which is less than 80s, and has good elastic modulus which is 5940-6000Pa, so that the deformation stress of the temperature-sensitive embolic gel after phase change is improved.

The temperature-sensitive embolic gel also has good biodegradability. The three-dimensional network structure is formed by utilizing the synergistic effect of the raw materials, the drug loading and slow release effects can be realized, the good drug slow release effect is realized, and the application range of the temperature-sensitive embolic gel is enlarged. More importantly, the raw materials of the temperature-sensitive embolic gel are easy to obtain, the problem that the temperature-sensitive embolic gel has larger side effect due to more inevitable impurities introduced by adding more raw materials is reduced, and the safety of the temperature-sensitive embolic gel is improved.

The applicant finds that in the preparation of the temperature-sensitive embolic gel, the mixed aqueous solution of the sodium alginate and the synergistic additive and the poloxamer aqueous solution are mixed, the obtained temperature-sensitive embolic gel is in a liquid state, the temperature is gradually increased from 15 to 40 ℃, the temperature cannot be solidified, and the poloxamer cannot react with the sodium alginate and the synergistic additive to form the temperature-sensitive embolic gel. Furthermore, when the temperature-sensitive embolic gel carries medicine on the medicine solution, the medicine solution is mixed in the mixed aqueous solution/poloxamer aqueous solution, and then the materials are mixed, so that the medicine carrying of the temperature-sensitive embolic gel cannot be realized.

Applicants have found that by adding poloxamer to a pre-mixed aqueous solution to form a pre-mixed aqueous solution of poloxamer, sodium alginate and builder, and then mixing the aqueous poloxamer solution with the pre-mixed aqueous solution, solidification can occur at a temperature between 30 ℃ and 38 ℃. Furthermore, the temperature-sensitive embolic gel can also be subjected to drug slow release, and the water-soluble drug is uniformly dissolved by water or sodium chloride aqueous solution and then is uniformly mixed with the temperature-sensitive embolic gel, and the mixture is conveyed to a focus through a catheter to form an embolization and drug slow release effect, so that the application range of the temperature-sensitive embolic gel is expanded.

According to the temperature-sensitive embolic gel, sodium alginate is added, and the sodium alginate is natural polysaccharide, so that the temperature-sensitive embolic gel has stability, solubility, viscosity, hydrophilicity, biocompatibility, biodegradability and the like required by pharmaceutical preparation auxiliary materials. The temperature-sensitive embolism gel can reduce the gel temperature by adding the temperature-sensitive embolism gel into poloxamer, can also increase the active groups such as carboxyl, hydroxyl and the like in the temperature-sensitive embolism gel, enhances the interaction between sodium alginate and poloxamer, increases the crosslinking density of sodium alginate and poloxamer, and increases the gel strength of the sodium alginate and poloxamer. The synergistic additive is added, so that the conduit passing rate can be well increased, the crosslinking density of the temperature-sensitive embolic gel is enhanced, and the deformation stress of the temperature-sensitive embolic gel after curing is improved.

Optionally, the poloxamer in the poloxamer aqueous solution is the same as the poloxamer in the premixed aqueous solution.

By adopting the technical scheme, the preparation and control of the temperature-sensitive embolic gel are facilitated.

Optionally, the poloxamer is poloxamer 407.

By adopting the technical scheme, the poloxamer 407 is solid powder, is prepared by copolymerizing polyoxyethylene and polypropylene according to the weight ratio of 7:3, has the average molecular weight of 11500, is easy to obtain poloxamer 407 compared with poloxamer 188, poloxamer 237, poloxamer 338 and the like, and is easier for poloxamer 407 to form temperature-sensitive embolic gel, so that the temperature sensitivity of the temperature-sensitive embolic gel is improved.

Optionally, the solute of the poloxamer aqueous solution is mainly prepared from the following raw materials by weight: 17-25g of poloxamer.

Optionally, the solute of the premixed aqueous solution is mainly prepared from the following raw materials by weight: 21g of poloxamer, 1-2g of sodium alginate and 0.1-5g of synergistic auxiliary agent.

By adopting the technical scheme, the mass fraction of poloxamer in the poloxamer aqueous solution is further optimized, the solute in the premixed aqueous solution is further optimized, the crosslinking density of the temperature-sensitive embolic gel is improved, and the temperature sensitivity and the deformation stress after solidification of the temperature-sensitive embolic gel are also improved.

Optionally, the synergistic auxiliary agent is one or more of carboxymethyl chitosan, sodium carboxymethyl cellulose, polyethylene glycol and polyvinylpyrrolidone.

By adopting the technical scheme, the carboxymethyl chitosan, the sodium carboxymethyl cellulose, the polyethylene glycol and the polyvinylpyrrolidone have good compatibility, biodegradability and adhesion effects, and meanwhile, the lubrication degree of the surface of the temperature-sensitive embolic gel can be increased, and the passing rate of the temperature-sensitive embolic gel catheter is improved.

Further, the polyethylene glycol is polyethylene glycol 6000, and the polyvinylpyrrolidone is povidone K30.

In a second aspect, the present application provides a preparation method of the biodegradable temperature-sensitive embolic gel, which adopts the following technical scheme:

a preparation method of the biodegradable temperature-sensitive embolic gel comprises the following steps:

s1, adding sodium alginate and the synergistic auxiliary agent into water, stirring and dissolving, cooling to (-1) -8 ℃, adding poloxamer, stirring and dissolving to obtain a premixed aqueous solution;

s2, adding poloxamer into water at the temperature of (-1) -8 ℃, and stirring to dissolve to obtain a poloxamer aqueous solution;

s3, uniformly mixing the premixed water solution and the roxamel water solution at the temperature of (-1) -8 ℃, and sterilizing to obtain the temperature-sensitive embolic gel.

By adopting the technical scheme, the preparation method has the advantages of simple preparation, convenient preparation and control and stable mass production. And the water used based on the temperature-sensitive embolic gel is sterile injection water which hardly contains crystal nuclei, can be in a liquid state at the temperature of-1 ℃ through shaking, and realizes the preparation of the temperature-sensitive embolic gel.

Optionally, in step S1, after the synergist is added, heating is performed while stirring and dissolving;

in step S3, the premix aqueous solution and the poloxamer aqueous solution are mixed and then subjected to ultrasonic treatment.

By adopting the technical scheme, in the step S1, the heating treatment is adopted, so that the sodium alginate and the synergistic auxiliary agent are dissolved conveniently and mixed more uniformly. In step S3, ultrasonic treatment is used to improve the uniformity of the temperature-sensitive embolic gel, and also to effectively remove air bubbles in the temperature-sensitive embolic gel to improve the stability of the temperature-sensitive embolic gel.

Further, in step S1, the temperature of the heat treatment is 55-130 ℃, preferably 55-65 ℃, preferably 60 ℃; standing for 30-300min, preferably 30-40min, preferably 30min after dissolving poloxamer; in step S2, standing for 30-300min, preferably 30-40min, preferably 30min after dissolving poloxamer; in step S3, the ultrasonic treatment is carried out for 20-200min, preferably 2-30 min, preferably 20 min.

In a third aspect, the present application provides a biodegradable temperature-sensitive embolic gel dry powder, which adopts the following technical scheme:

a biodegradable temperature-sensitive embolization gel dry powder comprises the biodegradable temperature-sensitive embolization gel, and the temperature-sensitive embolization gel is prepared by freeze drying.

By adopting the technical scheme, the preparation and storage of the temperature-sensitive embolic gel dry powder are facilitated, and the storage, transportation and drug sustained-release application range of the temperature-sensitive embolic gel is widened.

In a fourth aspect, the present application provides a biodegradable imaging temperature-sensitive embolization gel dry powder, which adopts the following technical scheme:

a biodegradable development temperature-sensitive embolization gel dry powder comprises the biodegradable temperature-sensitive embolization gel and a developer.

By adopting the technical scheme, the preparation and control of the developing temperature-sensitive embolic gel dry powder are facilitated, and the application range of the temperature-sensitive embolic gel is widened.

Further, the developer is a water-soluble developer, and the water-soluble developer is one of iohexol and iobitrol. And the developer is dissolved in the poloxamer aqueous solution. Iohexol and iobitridol have good developing effect under DSA, the developing effect of temperature-sensitive embolic gel in the operation process is solved, and the judgment and safety of doctors are improved.

In summary, the present application has the following beneficial effects:

1. the biodegradable temperature-sensitive embolic gel has good gel temperature which is 30-38 ℃ and is close to the normal body temperature of a human body through the synergistic effect of the raw materials. But also has good plasticity, developability, elastic deformation resistance, biodegradability and safety.

2. When the medicine is slowly released, the water-soluble medicine is uniformly dissolved by water or sodium chloride water solution and then is uniformly mixed with the temperature-sensitive embolic gel for use, so that the medicine is slowly released, and the application range of the temperature-sensitive embolic gel is widened.

3. The preparation method of the biodegradable temperature-sensitive embolic gel has the advantages of simple preparation, convenient control and convenient mass and stable production, and can be processed into liquid and dry powder according to the needs.

Drawings

FIG. 1 is a diagram showing the state of the temperature-sensitive embolic gel after the sample vial is laid flat in example 3.

FIG. 2 is a diagram showing the state of the temperature-sensitive embolic gel after inversion of the sample vial in example 3.

FIG. 3 is a graph showing the state of the temperature-sensitive embolic gel after the sample bottle in comparative example 1 is laid flat.

FIG. 4 is a diagram showing the state of the temperature-sensitive embolic gel after the inversion of the sample bottle in comparative example 1.

FIG. 5 is a diagram showing the state of the temperature-sensitive embolic gel in example 3 into water at 37 ℃.

FIG. 6 is a diagram showing the state of the temperature-sensitive embolic gel in comparative example 2 into water of 37 ℃.

FIG. 7 is a viscosity-temperature curve of the temperature sensitive embolic gel in example 3.

FIG. 8 is a viscosity-temperature curve of the temperature sensitive embolic gel of comparative example 1.

FIG. 9 is a viscosity-temperature curve of the temperature sensitive embolic gel of comparative example 2.

FIG. 10 is a plot of storage modulus/loss modulus versus time for the temperature sensitive embolic gel of example 3.

Detailed Description

The present application will be described in further detail with reference to examples.

Raw materials

The water is sterile injection water; the poloxamer in the poloxamer aqueous solution is the same as the poloxamer in the premixed aqueous solution, and is poloxamer 407 selected from basf germany; the sodium alginate, carboxymethyl chitosan and sodium carboxymethyl cellulose are all selected from Shanghai Mecline; the polyethylene glycol is polyethylene glycol 6000 selected from Shanghai Michellin; the polyvinylpyrrolidone is povidone K30 selected from Mecanol of Shanghai; iohexol is selected from the group consisting of Haishen of Taizhou, Zhejiang.

Examples

Table 1 shows the contents of the respective raw materials of the premixed aqueous solution and the poloxamer aqueous solution

Example 1

A biodegradable temperature-sensitive embolic gel is prepared from a poloxamer aqueous solution and a premixed aqueous solution, wherein the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 2:1, and the raw material ratio of the poloxamer aqueous solution to the premixed aqueous solution is shown in Table 1.

A preparation method of biodegradable temperature-sensitive embolic gel comprises the following steps:

s1, adding sodium alginate and a synergistic agent into water, heating to 60 ℃, stirring for 30min at the rotating speed of 600r/min, then cooling to 4 ℃, adding poloxamer, continuing stirring for 1h, and standing for 30min to obtain a premixed aqueous solution.

And S2, adding poloxamer into water at the temperature of 4 ℃ and the rotating speed of 600r/min, stirring for 1h, and standing for 30min to obtain the poloxamer aqueous solution.

And S3, adding the poloxamer aqueous solution into the premixed aqueous solution at the temperature of 4 ℃ and the rotating speed of 600r/min, stirring for 10min, carrying out ultrasonic treatment for 20min, standing for 10min, and sterilizing to obtain the temperature-sensitive embolic gel.

Example 2

A biodegradable temperature sensitive embolic gel, which differs from example 1 in that the weight ratio of the poloxamer's aqueous solution, the pre-mixed aqueous solution is 2: 1.

Example 3

A biodegradable temperature sensitive embolic gel, which differs from example 1 in that the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 3: 2.

Examples 4 to 6

A biodegradable temperature-sensitive embolic gel is different from that of example 3 in that the proportions of the raw materials of the poloxamer aqueous solution and the premixed aqueous solution are different, and the proportions of the raw materials of the poloxamer aqueous solution and the premixed aqueous solution are shown in Table 1.

Example 7

A biodegradable temperature-sensitive embolic gel, which is different from that of embodiment 3 in that the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 3:2, and the raw material ratios of the poloxamer aqueous solution and the premixed aqueous solution are different, and are shown in table 1.

Example 8

A biodegradable temperature-sensitive embolic gel, which is different from that of embodiment 3 in that the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 2:1, and the raw material ratios of the poloxamer aqueous solution and the premixed aqueous solution are different, and are shown in table 1.

Example 9

A biodegradable temperature-sensitive embolic gel, which is different from that of embodiment 3 in that the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 1:1, and the raw material ratios of the poloxamer aqueous solution and the premixed aqueous solution are different, and are shown in table 1.

Example 10

Example 11

A biodegradable temperature-sensitive embolic gel, which is different from that of embodiment 3 in that the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is 3:1, the raw material ratios of the poloxamer aqueous solution and the premixed aqueous solution are different, and the raw material ratios of the poloxamer aqueous solution and the premixed aqueous solution are shown in table 1.

Application example

Application example 1

A biodegradable temperature-sensitive embolization gel dry powder is prepared by the following method:

and (3) freeze-drying the biodegradable temperature-sensitive embolic gel obtained in the embodiment 1 to obtain the temperature-sensitive embolic gel dry powder.

Application example 2

A biodegradable development temperature sensitive embolization gel dry powder, which is different from that in example 3, is characterized by further comprising a developer, wherein the developer is iohexol, and the addition amount of the developer is 10 g.

A biodegradable development temperature sensitive type embolism gel dry powder is prepared by the following method:

And S2, adding poloxamer and a developer into water at the temperature of 4 ℃ and the rotating speed of 600r/min, stirring for 1h, and standing for 30min to obtain the poloxamer aqueous solution.

And S3, adding the poloxamer aqueous solution into the premixed aqueous solution at the temperature of 4 ℃ and the rotating speed of 600r/min, stirring for 10min, carrying out ultrasonic treatment for 20min, standing for 10min, and carrying out freeze drying and sterilization to obtain the development temperature-sensitive embolic gel dry powder.

Comparative example

Comparative example 1

A biodegradable temperature-sensitive embolic gel, which is different from example 3 in that poloxamer is not added to the raw materials of the premixed aqueous solution.

Comparative example 2

A biodegradable temperature-sensitive embolic gel, which is different from that of example 3 in that sodium carboxymethylcellulose and sodium alginate are not added to the raw materials of the premixed aqueous solution.

Comparative example 3

A biodegradable temperature-sensitive embolic gel, which is different from example 3 in that sodium carboxymethylcellulose is not added to the raw material of the premixed aqueous solution.

Comparative example 4

A biodegradable temperature-sensitive embolic gel, which is different from example 3 in that sodium alginate is not added to the raw material of the premixed aqueous solution.

Security detection

The temperature-sensitive embolic gels prepared in the embodiments 1 to 11 are taken as samples, hemolysis tests, cytotoxicity tests and the like are carried out on the samples according to GB/T16886 medical instrument biology evaluation, the hemolysis tests of the samples are less than or equal to 5%, the cytotoxicity tests are less than or equal to grade I, the mouse lymphoma tests are all negative, the chromosome aberration tests are all negative, the subacute toxicity tests are all absent, the safety is good, and the market safety requirement is met.

Performance detection

(1) The temperature-sensitive embolic gel obtained in example 3 was placed in 2 sample bottles, each sample bottle was added in an amount of 5g, and the 2 sample bottles were left to stand at 37 ℃ for 1min, then one of the sample bottles was turned over by 90 degrees, i.e., laid flat, and the remaining one was turned over by 180 degrees, i.e., inverted, and then left to stand for 5min, and the state of the temperature-sensitive embolic gel in the 2 sample bottles was observed.

As can be seen from fig. 1 and fig. 2, the temperature-sensitive embolic gel of the present application is turned over by 90 degrees and 180 degrees, the temperature-sensitive embolic gel is adhered to the bottom of the sample bottle and is in a solid state, and the temperature-sensitive embolic gel has good temperature sensitivity and adhesion.

(2) The temperature-sensitive embolic gel obtained in the comparative example 1 is taken and placed in 2 sample bottles, the addition amount of each sample bottle is 5g, the 2 sample bottles are placed at 37 ℃ for standing treatment for 1min, then one sample bottle is turned over for 90 degrees, namely, the sample bottle is horizontally placed, the other sample bottle is turned over for 180 degrees, namely, the sample bottle is inverted, then the sample bottle is placed for standing treatment for 5min, and the state of the temperature-sensitive embolic gel in the 2 sample bottles is observed.

As can be seen from fig. 3, the temperature-sensitive embolic gel of comparative example 1 is turned over by 90 degrees, and the temperature-sensitive embolic gel flows to the circumferential surface of the sample vial; as can be seen from fig. 4, the temperature-sensitive embolic gel of comparative example 1 is turned over by 180 degrees, the temperature-sensitive embolic gel flows to the top of the vial of the sample vial and assumes a liquid state, and the temperature-sensitive embolic gel of comparative example 1 cannot be cured.

(3) Placing the temperature-sensitive embolic gel obtained in the comparative example 1 into 6 sample bottles, wherein the addition amount of each sample bottle is 5g, placing the 6 sample bottles at 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ and 40 ℃ in sequence, standing for 1min, turning the 6 sample bottles 180 ℃ respectively, namely inverting, standing for 5min, observing that the temperature-sensitive embolic gel in the 6 sample bottles flows to the bottle tops of the sample bottles and is in a liquid state, and gradually raising the temperature of the temperature-sensitive embolic gel in the comparative example 1 at 15-40 ℃ so that the temperature-sensitive embolic gel cannot be cured.

(4) The temperature-sensitive embolic gels obtained in example 3 and comparative example 2 were used as samples, and the state of the samples in water was observed by introducing the samples into water at a temperature of 37 ℃ through a catheter having a specification of 2.7Fr and a flow rate of 3 g/min.

As can be seen from FIG. 3, the temperature-sensitive embolic gel of the present application is instantly in a solid state after entering water of 37 ℃, and stably sinks to the water bottom, and the temperature-sensitive embolic gel has good stability. As can be seen from FIG. 4, the temperature-sensitive embolic gel of comparative example 2 was rapidly dispersed and dissolved after entering water of 37 deg.C, and the temperature-sensitive embolic gel of comparative example 2 was poor in stability.

(5) The temperature-sensitive embolic gels obtained in examples 1 to 11 and comparative examples 1 to 4 were used as samples, and the following performance tests were carried out on the samples, and the test results are shown in Table 2.

The viscosity change detection adopts the following method: and (3) gradually heating the in-situ gel sample by using a DHR-2 rheometer, wherein the heating rate is 5 ℃/min, measuring the viscosity of the sample at different temperatures, and drawing a viscosity-temperature curve. When the viscosity is gradually increased, then rapidly increased and gradually decreased along with the increase of the temperature, the phase change of the sample is generated. And reading the temperature corresponding to the sample when the sample is solidified as a phase change starting temperature, reading the temperature corresponding to the sample when the sample is completely solidified as a phase change finishing temperature, and calculating the gel time.

Gel time/(s) ═ 5 × 60 (end temperature of phase transition-start temperature of phase transition).

The elastic change is carried out by the following method: the storage/loss modulus-time curves were plotted at 37 ℃ using a DHR-2 rheometer with sample pressure for 300 s. The storage modulus is the elastic modulus, and when the storage modulus is larger than the loss modulus, the sample is in a solid state.

TABLE 2 test results

As shown in FIG. 7, the temperature-sensitive embolic gel of example 3 tends to have a gradual, rapid and gradual increase in viscosity with an increase in temperature. Referring to fig. 8, the temperature sensitive embolic gel of comparative example 1 is gradually increased in viscosity with the increase of temperature, and is not cured by the gradual increase of temperature of 15-40 ℃. Referring to fig. 9, the temperature-sensitive embolic gel of comparative example 2 shows a tendency of gradual increase, and gradual decrease in viscosity with increase in temperature. Referring to FIG. 10, the temperature sensitive embolic gel of example 3 has a storage modulus greater than a loss modulus and is in a solid state.

As can be seen from Table 2 and FIGS. 1-10, the temperature-sensitive embolic gel of the present application undergoes a phase change between 30-38 deg.C, which is close to the normal body temperature of human body. Furthermore, it also has a low gel time, which is 70-80 s. Meanwhile, the material also has higher elastic modulus which is 5940-6000Pa, and the deformation stress of the solidified temperature sensitive embolism gel is improved.

Comparing example 3 with comparative example 1, it can be seen that the addition of poloxamer to the premixed aqueous solution facilitates the gelling of the temperature sensitive embolic gel. Comparing with the comparative examples 2-4, it can be seen that the carboxymethylcellulose sodium and the sodium alginate are added into the premixed aqueous solution, and the synergistic effect among the carboxymethylcellulose sodium, the sodium alginate and the poloxamer is utilized to ensure that the temperature-sensitive embolic gel has good temperature sensitivity and deformation stress after solidification.

The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.

Claims

1. A biodegradable temperature-sensitive embolic gel, comprising: the poloxamer aqueous solution is prepared from a poloxamer aqueous solution and a premixed aqueous solution, wherein the weight ratio of the poloxamer aqueous solution to the premixed aqueous solution is (1-3) to (1-2);

the solute of the premixed water solution is mainly prepared from the following raw materials by weight based on 100g of water: 16-26g of poloxamer, 0.1-5g of sodium alginate and 0.1-5g of synergistic additive;

2. A biodegradable temperature-sensitive embolic gel according to claim 1, wherein: the poloxamer in the poloxamer aqueous solution is the same as the poloxamer in the premixed aqueous solution.

3. A biodegradable temperature-sensitive embolic gel according to claim 2, wherein: the poloxamer is poloxamer 407.

4. A biodegradable temperature-sensitive embolic gel according to claim 1, wherein: the solute of the poloxamer water solution is mainly prepared from the following raw materials in parts by weight: 17-25g of poloxamer.

5. A biodegradable temperature-sensitive embolic gel according to claim 4, wherein: the solute of the premixed water solution is mainly prepared from the following raw materials in parts by weight: 21g of poloxamer, 1-2g of sodium alginate and 0.1-5g of synergistic auxiliary agent.

6. A biodegradable temperature-sensitive embolic gel according to claim 1, wherein: the synergistic auxiliary agent is one or more of carboxymethyl chitosan, sodium carboxymethyl cellulose, polyethylene glycol and polyvinylpyrrolidone.

7. A method of preparing a biodegradable temperature sensitive embolic gel according to any of claims 1-6, wherein: the method comprises the following steps:

8. The method of claim 7, wherein the temperature sensitive embolic gel is biodegradable and characterized by comprising the following steps: in step S1, after the synergistic additive is added, heating treatment is adopted while stirring and dissolving;

in step S3, the premixed aqueous solution and the aqueous solution of loxam are mixed and then subjected to ultrasonic treatment.

9. A biodegradable temperature-sensitive embolic gel dry powder, characterized in that: comprising a biodegradable temperature sensitive embolic gel according to any of claims 1-6, the temperature sensitive embolic gel being prepared by freeze-drying.

10. A biodegradable development temperature sensitive type embolism gel dry powder is characterized in that: the biodegradable temperature-sensitive embolic gel of any of claims 1-6, further comprising a contrast agent.