CN115645635A

CN115645635A - Liquid-phase embolic agent, preparation method and application thereof

Info

Publication number: CN115645635A
Application number: CN202211302197.5A
Authority: CN
Inventors: 王杰; 马亚丹; 潘杰
Original assignee: Hangzhou Minshun Medical Technology Co ltd
Current assignee: Hangzhou Minshun Medical Technology Co ltd
Priority date: 2022-10-24
Filing date: 2022-10-24
Publication date: 2023-01-31

Abstract

The invention discloses a liquid-phase embolic agent, a preparation method and application thereof. The liquid-phase embolic agent is formed by raw materials comprising a material A, a material B and water; the material A is a water-soluble substance, and the material B is silicate.

Description

Liquid-phase embolic agent, preparation method and application thereof

Technical Field

The invention belongs to the technical field of medical high polymer materials, and particularly relates to a liquid-phase embolism material which is used for vascular embolism and has a developing and drug-loading function, and a preparation method thereof.

Background

The method for treating the primary liver cancer is complex, and for patients in middle and advanced stages, the Transcatheter Arterial Chemoembolization (TACE) technology is the first choice treatment method according to the treatment principle of clinical practice guidelines.

TACE is a method in which a catheter is introduced into a target artery for blood supply to a tumor, and an embolization agent is injected at an appropriate rate to occlude the target artery, thereby necrotizing the tumor tissue by ischemia. The current common embolic agents are divided into solid embolic agents and liquid embolic agents. The development of a novel interventional therapy scheme combining multifunctional embolic agents capable of carrying drugs and the like with TACE has important significance in clinical application. At present, alpha-cyanoacrylate medical adhesives, onyx, peptide promen and the like are used as liquid phase stoppers in the market, but most of the liquid phase stoppers are used as assistance, have single performance and have no medicine carrying capability; the embolism quality is poor, and the embolism can not be used for tumor embolism; the use of DMSO compatible microcatheters limits the referencing scenarios and drives up costs.

Therefore, there is a strong need in the art to provide a novel liquid phase embolic agent.

Disclosure of Invention

The invention aims to provide a novel aqueous phase liquid embolic agent.

In a first aspect of the present invention, there is provided a liquid-phase embolic agent formed from raw materials comprising material a, material B and water; the material A is a water-soluble substance, and the material B is silicate.

In another embodiment, the feedstock further comprises material C, which is a developable substance.

In another embodiment, the total amount of material a and material B is 2 to 10wt% based on the total weight of material a, material B and water.

In another embodiment, the weight ratio of material A to material B is from 1 to 3:1-3.

In another embodiment, the water-soluble substance is a polymer having a molecular weight of 1 to 100 ten thousand.

In another embodiment, the silicate is a nano-silicate, a layer or a disc.

In another embodiment, material C is used in an amount of 5 to 50 weight percent based on the total weight of material A, material B and water.

In another embodiment, the developable substance includes an iodine reagent, barium sulfate, tantalum powder.

In a second aspect of the present invention, there is provided a method for preparing the liquid-phase embolic agent provided by the present invention as described above, the method comprising the steps of: mixing material A, material B and water to form hydrogel.

In another embodiment, the mixing is at a speed of 200 to 400r/min.

In another embodiment, the mixing temperature is 40-60 ℃.

In another embodiment, the mixing time is 1 to 3 hours.

In another embodiment, the method further comprises the steps of: the hydrogel was mixed with material C.

In another embodiment, 5 to 50wt% of material C based on the total weight of the hydrogel is used.

In a third aspect of the invention there is provided the use of a liquid phase embolic agent as provided by the invention, as described above.

In another embodiment, the use comprises a product for the manufacture of a medicament for the treatment of cancer (liver cancer).

Accordingly, the present invention provides a novel liquid phase embolic agent.

Drawings

FIG. 1 is a liquid embolization product according to the invention.

FIG. 2 is a strain sweep test result, a temperature sweep test result and a viscosity characteristic curve of the liquid-phase embolic product provided in example 1; wherein,

a is a strain scanning test; b is temperature sweep (1 ℃/min); and c is a viscosity characteristic curve.

FIG. 3 shows the recoverable aspect of a liquid embolization product according to the invention; wherein,

a shows recoverability; b is a partial enlarged view of a.

FIG. 4 is a graphic representation of the visualization of the liquid embolization product provided in examples 2-9 of the present application (from left to right).

FIG. 5 is a graph showing the effect of injection force of liquid embolic product provided in example 11 of the present application.

FIG. 6 is a device for performing a bolus force test in an embodiment of the present application; wherein,

a is a testing device, b is a change curve obtained by setting a sample in the graph and testing a force value at a testing speed of 30 mm/min.

Fig. 7 shows the bolus force as a function of time.

Fig. 8 shows a simulation of hepatic artery embolization in example 14 of the present application.

Figure 9 shows the cisplatin release profile of example 15 of the present application.

Detailed Description

The inventor finds out in extensive and intensive research that the shear thinning material can be used for obtaining the liquid-phase embolic agent, the material has fluidity under the action of external force, but can be solidified in situ after the external force is removed, thereby having the function of blood vessel embolism, and also can be used for loading various medicines and developing and imaging. On the basis of this, the present invention has been completed.

The liquid-phase embolic agent provided by the invention can be hydrogel which is white or colorless, and the raw materials for forming the hydrogel comprise a material A, a material B and water.

The material a may be a water-soluble substance, and generally needs to have excellent solubility and biocompatibility, such as, but not limited to, gelatin, chitosan, sodium alginate, guar gum, polyvinyl alcohol, polyethylene glycol, and the like. The molecular weight of material A is generally between 1 and 100 ten thousand.

Gelatin molecular weight is generally related to congealing strength, and in one embodiment of the invention, gelatin with Bloom g values in the range of 100 to 400 is used, preferably gelatin with Bloom g values in the range of 180 to 300 is used.

In this context, the term "congealing strength" refers to the force required for an object of fixed shape and size to penetrate to a depth of 4 mm into a 6.7% strength gelatin solution, the force applied representing the congealing strength in Bloom g.

Said material B is negatively charged, the surface of which forms a net negative charge, balanced by cations (such as sodium ions), and the invention uses silicates, in particular nanosilicates, preferably layered or discotic nanosilicates.

In one embodiment of the invention, the phyllosilicates used are in the form of layers or disks having a thickness of approximately 1nm and a diameter of 25 to 30nm.

Water for use in the present invention is preferably water for injection.

The total amount of material A and material B used in the present invention is 2 to 10wt%, such as, but not limited to, 3 to 6wt%, 5 to 7wt%, 4 to 9wt%, etc., based on the total weight of material A, material B and water.

The weight ratio of the material A to the material B in the invention is 1-3:1-3.

The material A and the material B in the hydrogel provided by the invention are uniformly distributed on the surface or the edge of the nano particle of the material B under stirring through the interaction of anions and cations. Highly thixotropic hydrogels with different viscosity, coagulation properties, etc. can be obtained by varying the concentration of both. The hydrogel provided by the invention can flow under the action of a certain shearing force. Under the action of shearing force, each material B nano plate always tries to arrange itself longitudinally along the shearing direction naturally, and as the shearing rate or the shearing stress is increased, the viscosity is reduced due to the orientation of the nano plate molecules, so that the solid state is converted into the fluid state, and the product has fluidity.

The hydrogel is obtained by uniformly mixing the material A, the material B and water.

In one embodiment of the invention, material A is dissolved completely in water with stirring (preferably with heating at elevated temperature), then material B is added slowly and heated with stirring to form a transparent homogeneous hydrogel.

In another embodiment of the present invention, material a, material B and stirring are mixed to form a colorless hydrogel.

In the process of forming the hydrogel, the stirring speed is usually 200-400r/min.

In the process of forming the hydrogel, the heating temperature is 40-60 ℃.

In the process of forming the hydrogel, the mixing and forming time is generally 1 to 3 hours.

The liquid-phase embolic agent provided by the present invention can also be added with the material C in the hydrogel provided above, and the amount of the added material C is 5-50wt% based on the total weight of the hydrogel.

Material C used in the present invention is a developing substance, including iodine reagents including, but not limited to, iopromide, iohexol, diatrizoate sodium, iodized oil, iodixanol, etc., barium sulfate, tantalum powder, etc., preferably a powdery substance.

The material C used in the invention can increase the stability of the product to a certain extent, and the adjustment range of the viscosity and the coagulability of the product is wider. The inventors have found that the viscosity of the product changes after the developer is added, indicating that the added developer not only can play a developing role, but also can affect the physical and chemical properties of the product. Different developers cause the viscosity of the resulting product to vary, and the viscosity, coagulability, etc. of the product can be adjusted by selecting the particular materials to be added and the developers.

The liquid-phase embolic agent provided by the invention contains the material C, and in the aspect of development, the repeatability of the obtained liquid-phase embolic agent is high and the batch-to-batch stability is higher by quantitatively adding the developer. For example, NBCA (n-butyl-cyanoacrylate, alpha-butyl cyanoacrylate) embolization agent, the repeatability of embolization effect is a challenge, and the matching ratio of NBCA to iodized oil is mixed depending on the experience of doctors, so that the development effect is unstable and the repeatability is poor.

In one embodiment of the invention, tantalum powder is selected as material C in the liquid-phase embolic agent product, and the product has higher viscosity, which indicates that the acting force between the products is stronger and the product stability is better.

In the invention, the hydrogel can flow under vortex, and the material C is uniformly dispersed in the hydrogel through vortex oscillation; in one embodiment of the invention, the hydrogel is mixed with material C by vortexing to obtain a liquid phase embolization agent, i.e. a hydrogel with imaging properties.

The liquid-phase embolic agent provided by the invention controls the viscosity and the product application field by adjusting the solid content (such as material A, material B and material C) in the liquid-phase embolic agent to different proportions. The viscosity of the product can be reflected by the injection force (bolus injection force), the viscosity is high, the injection force is large, and the viscosity is low, and the injection force is small. The high viscosity liquid phase embolic agent can be applied to hepatic artery F portal vein fistula or hepatic artery F hepatic vein fistula; the low viscosity liquid phase embolism agent can be applied to the angiogenetic parenchymal organ malignant tumor.

It is also possible to encapsulate the material D in the above-mentioned hydrogel provided, or to add the material D to the above-mentioned hydrogel having a developing action. The material D is a drug, which may be 1. An alkylating agent, such as, but not limited to, cyclophosphamide; 2. antimetabolites such as, but not limited to, fluorouracil, carmofur, gemcitabine, tegafur, cytarabine, medroxypyridine, hydroxyurea, and the like; 3. anti-tumor antibiotics such as, but not limited to, epirubicin, pirarubicin, pingyangmycin, and the like; 4. antineoplastic animal and plant components such as, but not limited to, paclitaxel, I Li Tikang, etoposide, vincristine, and the like; 5. hormones such as, but not limited to, exemestane, tamoxifen, letrozole, megestrol, and the like; 6. other classes, such as, but not limited to, cisplatin, oxaliplatin, and the like.

In one embodiment of the invention, the hydrogel or hydrogel with a developing effect and material D are mixed thoroughly on a vortexer to load the drug.

In practice or during administration, the physician selects the amount of material D to be used for different patients and different sizes of tumors. In one embodiment of the present invention, more than 50mg/ml of material D, such as, but not limited to, 50-100mg/ml, may be encapsulated in the liquid phase embolic agent provided by the present invention described above.

The hydrogel with the developing property provided by the invention can interact with the drug through different mechanisms, so that the drug is loaded and the release is completed in vivo. There are two main categories: 1. physically wrapping or dissolving, uniformly mixing the drug molecules with the hydrogel, and dispersing or dissolving the drug particles in the hydrogel; 2. the resulting hydrogel may be associated with different classes of drugs (non-charged, non-polar, aromatic or alkyl) by chemical bond interactions, such as the formation of van der waals bonds. Drugs having cation exchange capacity (e.g., drugs containing amine, NH ring, and heterocyclic nitrogen groups), cation/water complex bonds (e.g., drugs containing carboxylate, amine, carbonyl, and alcohol groups), and hydrogels capable of forming van der waals bonds may be loaded at the interlaminar sites. The drug molecules have different sizes and charges, and can be loaded between particles and between layers and also can be adsorbed on the surface or the edge of the nano silicate.

The curing time of the various liquid-phase embolic agents provided by the invention can be within 10 seconds, and the injection force is within 50N.

The various liquid-phase embolic agents provided by the invention can realize multi-specification liquid-phase embolic products with different viscosities and different purposes by regulating and controlling solid content proportion parameters.

The various liquid-phase embolic agents provided by the invention are shear thinning materials, under the action of 1-50N external force, the loss modulus is greater than the storage modulus (figure 2), and the product has certain fluidity and can be injected into a pathological change part through an injector; the raw material composition and the formula can form a three-dimensional network interpenetrating hydrogel structure, and the hydrogel structure is free from tube blockage, easy to inject and good in operability.

The various liquid-phase embolic agents provided by the invention are shear thinning materials, can be gelatinized after the injection force is removed, can promote the gelation in the presence of electrolytes, can rapidly gel in vivo and cure in situ, has reasonable gel strength, is resistant to blood flow scouring, has low dissipation rate, and can effectively avoid false embolism and revascularization. Has high recovery performance, can recover 97 percent of relieved strain under the action of high strain, can support multiple injections, and enhances the operation controllability in clinic. The injection time is controllable, and can be adjusted according to requirements. The embolism condition can be observed by the doctor in the process of operation in a pause injection mode, the high restorability of the product enables the doctor to continue injection after the pause injection for a period of time without the problems of pipe blockage solidification or great change of injection force and the like, and the use by the doctor is facilitated. (FIG. 3).

The various liquid-phase embolization agents provided by the present invention may have a wide range of applications, such as, but not limited to, products for treating cancer and/or for preparing products for treating vascular embolization and/or for preparing embolization, and the like, such as, but not limited to, TACE, HAIC (Hepatic Arterial Infusion Chemotherapy), and embolization of angiogenetic parenchymal organ malignant tumors. Such cancers include, but are not limited to, liver cancer.

As used herein, the term "treatment" includes prophylactic (i.e., prophylactic), curative or palliative treatment that results in a desired pharmaceutical and/or physiological effect. Preferably, the effect is a medical treatment that partially or completely cures or prevents the growth of cancer cells. Further, the term "treating" as used herein refers to administering or applying a compound of the present disclosure to a subject (or patient) with the intent of partially or completely reducing, delaying the onset of, inhibiting the progression of, lessening the severity of, and/or reducing the incidence of one or more symptoms of a particular disease, disorder, and/or medical condition, particularly to a subject having a medical condition, a symptom of the medical condition, a disease or disorder resulting from the medical condition, or a prior condition that would progress toward the medical condition. Individuals who have not yet developed overt signs of a particular disease, abnormality, and/or medical condition, and/or individuals who only develop early signs of that particular disease, abnormality, and/or medical condition, may be treated in an effort to reduce the risk of developing pathology associated with that particular disease, abnormality, and/or medical condition. Herein, the condition, disease, abnormality and/or medical condition may be an in situ cancer or a metastatic cancer. A reduction in one or more signs or clinical indicators indicates that the treatment is "effective".

The term "administered" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug (produg), derivative (derivative), or analog (analog) of the active compound, which results in an equivalent amount of the active compound in the individual to whom it is administered.

The terms "subject" or "patient" are used interchangeably herein to refer to an animal (including a human) that is amenable to treatment with the compounds and/or methods. "individual" or "patient" herein encompasses both the male and female sex unless specifically stated otherwise. Thus, a "subject" or "patient" includes any mammal, including, but not limited to, humans, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cows, etc., which would benefit from treatment with the compounds. Preferably, the animal suitable for treatment with the compounds and/or methods of the invention is a human. In general, the terms "patient" and "individual" are used interchangeably herein.

Although numerical ranges and parameters setting forth the broad scope of the invention are approximate, the values set forth in the specific examples are presented as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the individual testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean, as considered by those skilled in the art. Except in the experimental examples, or where otherwise expressly indicated, it is to be understood that all ranges, amounts, values and percentages herein used (e.g., to describe amounts of materials, length of time, temperature, operating conditions, quantitative ratios, and the like) are to be modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning the number of significant digits recited and the number resulting from applying ordinary carry notation.

Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as is commonly understood and used by one of ordinary skill in the art. Furthermore, as used herein, the singular tense of a noun, unless otherwise conflicting with context, encompasses the plural form of that noun; the use of plural nouns also covers the singular form of such nouns.

To make the features and effects of the invention comprehensible to those skilled in the art, general description and definitions shall be provided below with respect to terms and words mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The theory or mechanism described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.

The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All features disclosed in this specification may be combined in any combination, provided that there is no conflict between such features and the combination, and all possible combinations are to be considered within the scope of the present specification. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The main advantages of the invention are:

1. the various liquid-phase embolic agents or products thereof provided by the invention have excellent macroscopic mechanical properties, can quickly load various medicaments, including medicaments which are difficult to dissolve in water, have large medicament amount (50-100 mg), are convenient to mix, and have the advantages of slow release, high medicament release rate, high medicament utilization rate and low side effect.

2. The various liquid-phase embolic agents or products thereof provided by the invention can enhance X-ray images in the treatment process, thereby being more beneficial to monitoring the embolization process and the embolization effect after operation; through suitable developer, make it develop under the perspective, the developer can not be dispersed by the blood flow, sustainable development, the development is respond well, can monitor the embolism condition for a long time, effectively avoids the mistake to tie.

3. The various liquid-phase embolic agents or products thereof provided by the invention can be specifically applied to blood vessels for super-selective embolization, and meanwhile, the chemotherapeutic drugs are slowly released, so that higher blood concentration can be maintained for a longer time, the treatment effect is further improved, and the liquid-phase embolic agents or the products thereof have important significance in the fields of promotion of interventional embolization, clinical application and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The units in weight volume percent in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100 ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

The Bloom g values of the gelatins used in the examples below were 250

The nanosilicates used in the following examples were 1nm thick and 25-30nm in diameter, commercially available from BYK Pic chemistry

The pure water used in the following examples is water for injection

Example 1

(1) 4.5g of gelatin, 1.5g of nano silicate and 94g of pure water are added into a beaker, stirred at the temperature of 40 ℃ for 1 hour at 200rpm to form colorless hydrogel.

(2) And (3) taking 2g of the hydrogel obtained in the step (1), adding 300mg of iohexol into a 10ml centrifuge tube, and mixing for 20min on a vortex instrument. And preparing the developable liquid-phase plug.

And (3) performing viscosity characteristic scanning, temperature scanning and strain scanning (1 Hz, strain is 0-1000%) on a rheometer at the sample temperature obtained in the step (2), so that the product belongs to a shear-thinning material, the sample is stable in the range of 15-45 ℃, and the viscosity does not change, and the result is shown in a figure 2. Thixotropy testing showed that the 5 minute low strain (1%) and 5 minute high strain (100%) sample recoverability at repeated oscillation cycles of 1Hz is shown in figure 3. The apparatus used was an AresG2 rheometer from TA, usa. Fig. 3a is enlarged between 280s-320 s. It can be seen that the removal of the external force after 300s of the product already achieved curing (G' > G ") after 305s, the gelation time being within 10 s.

Example 2

(1) Adding 3g of gelatin, 3g of nano silicate and 94g of pure water into a beaker, stirring at the temperature of 40 ℃ for 1h at 200rpm to form colorless hydrogel.

(2) And (3) taking 2g of the hydrogel obtained in the step (1), adding 160mg of tantalum powder into a 10ml centrifuge tube, and mixing for 20min on a vortex instrument. And preparing the developable liquid-phase plug.

(3) The sample obtained in (2) is developed under DSA digital subtraction condition, and the development effect is clear (as shown in FIG. 4).

Taking 1g of the colorless hydrogel in the step (1) and the sample in the step (2), respectively, adding the samples into 10ml of PBS buffer solution, and leaching for 24h at 37 ℃; filtering the supernatant with 0.45um filter, and respectively scanning the ultraviolet and visible light with a wavelength of 200-500nm to obtain two kinds of leaching solutions. The results are shown in the following table:

using PBS buffer as blank control, and the absorbance under the above-mentioned wave band scanning is 0

The tantalum powder is less added with extract and is more stable.

Examples 3 to 9

TABLE 1

(1) The hydrogels were obtained according to the formulation in table 1.

(2) 2g of the hydrogel obtained in (1) was put into a 10ml centrifuge tube, added with the developer as shown in Table 1 above, and mixed on a vortex machine for 20min.

(3) 2ml of the sample obtained in the step (2) is subjected to a development experiment under DSA digital subtraction conditions, and the development effect is clear.

The product does not have the developing characteristic without adding the developer, the position of the product is difficult to observe clinically, and the conditions such as product drift and the like cannot be identified. Examples 2-9 we can achieve product tracking by adding a developer.

Example 10

The colorless hydrogel obtained in the step (1) of example 2 was taken, and tested by a rheometer to recover when the strain was 1%

The number viscosity is 79.1081Pa.s;

2g of the colorless hydrogel obtained in the step (1) of example 2 was put in a 10ml centrifuge tube, 300mg of iohexol was added thereto, and the mixture was mixed on a vortex apparatus for 20min to obtain a developable liquid phase plug. Complex viscosity of 472.487Pa.s when strain is 1% by rheometer test;

2g of the colorless hydrogel obtained in the step (1) of example 2 was put in a 10ml centrifuge tube, 200mg of tantalum powder was added thereto, and the mixture was mixed on a vortex apparatus for 20min to obtain a developable liquid-phase plug. The complex viscosity at 1% strain was 101.541pa.s as measured by rheometer.

EXAMPLE 11

(1) 1.5g of gelatin, 1.5g of nano silicate and 97g of pure water are added into a beaker, stirred at 200rpm and 40 ℃ for 1 hour to form colorless hydrogel.

(3) The obtained product is liquid and cannot be used as a shear thinning material.

EXAMPLE 12

(1) 4.5g of gelatin, 4.5g of nano silicate and 91g of pure water are added into a beaker, stirred at 200rpm and 40 ℃ for 1 hour to form colorless hydrogel.

(3) The sample is injected through a 5Fr micro catheter, the catheter is blocked after 4s, and the injector and the catheter fall off and cannot be pushed continuously. The variation of the injection force is shown in fig. 5.

Example 13

(1) The hydrogel was prepared according to the formulation of example 2.

(2) Subpackaging into 1ml, 2ml and 5ml syringes respectively.

(3) The sample push force was tested on a tensile machine. The product belongs to easy-to-inject liquid phase embolism (injection force < 50N) through testing. The test apparatus is shown in FIG. 6a, in which the sample is set and the force value curve is measured at a test speed of 30mm/min (FIG. 6 b). The results are summarized in Table 2.

TABLE 2

The product can be suitable for syringes of 1ml, 2ml, 5ml and the like commonly used in hospitals. The product has high practicability.

Example 14

(1) The liquid-phase embolism materials are obtained according to the mixture ratio of the examples 2, 3 and 6.

(2) The mixture was separately filled into 1ml glass syringes.

(3) The sample push force was tested on a tensile machine. The different viscosity products during the 2.7Fr injection are shown in figure 7. The liquid-phase embolism material with different viscosity can be obtained by adjusting the content types of the gelatin, the nano silicate and the developer, and the method is suitable for different fields.

The difference between the material C (developer) added in example 3 and the material C added in example 6 results in different product viscosity, and the boosting force is obviously different.

Example 15

(1) The hydrogel was prepared according to the formulation of example 3.

(2) The hepatic artery takes PBS buffer solution as simulation solution, the flow rate is set to be 0.2L/min, and the hydraulic pressure is 70-150mmHg;

(3) 1ml was injected into the hepatic right artery model through a 2.4Fr microcatheter (injection rate 1 ml/min). The vessel was successfully embolized and no recanalization occurred after 24h of operation. It is clear that liquid-phase embolization materials can be successfully embolized.

Example 16

(1) The hydrogel was prepared according to the formulation of example 2.

(2) 1ml of the liquid phase plug obtained in (1) was added with 50mg of cisplatin and mixed well on a vortex apparatus for 20min.

This was injected into a body fluid simulant containing 200 ml. And detecting the cis-platinum content in the solution for 1h, 2h, 3h, 4h, 5h, 6h and 21 h. More than 90% of cisplatin was found to be released at around 24 hours (9). Considering that hepatic artery perfusion chemotherapy (HAIC) is one of the commonly used means for interventional therapy of liver cancer at present, for patients with tumors over 7cm in diameter and circulation in the medial branches of the liver, TACE alone is difficult to achieve complete embolization and may cause severe postembolization syndrome. HAIC is most widely used in Asian, especially in Japan, where HAIC is mainly based on cisplatin. Obviously, the liquid-phase embolism material capable of carrying cisplatin and other chemotherapeutic drugs can be a potential alternative method for HAIC.

The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.

Claims

1. A liquid-phase embolic agent, wherein the liquid-phase embolic agent is formed from raw materials comprising a material a, a material B and water; the material A is a water-soluble substance, and the material B is silicate.

2. A liquid-phase embolic agent as in claim 1, wherein said raw material further comprises a material C, said material C being a developable substance.

3. A liquid phase embolic agent according to claim 1, wherein the total amount of material a and material B is 2-10wt% based on the total weight of material a, material B and water; and/or

The weight ratio of the material A to the material B is 1-3:1-3.

4. A liquid phase embolic agent as in claim 1, wherein said water soluble substance is a polymer having a molecular weight of 1 to 100 ten thousand; and/or the silicate is a nano-silicate, a layer or a disc.

5. A liquid phase embolic agent according to claim 2, wherein material C is present in an amount of 5-50wt%, based on the total weight of material a, material B and water; and/or the developable substance comprises an iodine reagent, barium sulfate, tantalum powder.

6. A method of preparing a liquid-phase embolic agent according to claim 1, comprising the steps of: mixing material A, material B and water to form hydrogel.

7. The method of claim 6, wherein the mixing is at a speed of 200 to 400 r/min; and/or the mixing temperature is 40-60 ℃; and/or the mixing time is 1-3 hours.

8. The method of claim 6, further comprising the step of: mixing the hydrogel with material C; and/or using 5 to 50wt% of material C, based on the total weight of the hydrogel.

9. Use of a liquid phase embolic agent as claimed in any of claims 1 to 5.

10. The use according to claim 9, comprising a product for the treatment of cancer (liver cancer).