A raltitrexed medicated gel stabilized hepatic carcinoma embolism emulsion and a preparation method and application thereof

Abstract

The application discloses a stable liver cancer embolism emulsion of raltitrexed drug gel and a preparation method and application thereof, and belongs to the field of pharmaceutical preparations. The emulsion is composed of iodized oil embolism agent and raltitrexed drug gel; the raltitrexed drug gel is a nanofiber network hydrogel formed by self-assembly of raltitrexed molecules in an aqueous phase through ultrasonic treatment, and simultaneously serves as an active pharmaceutical ingredient and an emulsion stabilizer. The iodized oil and the raltitrexed drug gel are physically mixed and injected through a three-way valve to form a stable oil-in-water emulsion or a water-in-oil emulsion, and any additional chemical surfactant or cosolvent is not needed. The emulsion has excellent physical stability, and can effectively solve the problems of easy aggregation and sedimentation of a traditional iodized oil emulsion and increased systemic toxicity caused by drug burst release. The emulsion has good embolism effect and drug release behavior, can significantly inhibit tumor growth, and has a wide clinical transformation prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion, its preparation method, and its application. Background Technology

[0002] Liver cancer, a common malignant tumor, has a high incidence rate in Asia. While treatments for liver cancer include surgical resection, radiotherapy, and chemotherapy, these methods have limited effectiveness for patients with intermediate to advanced-stage liver cancer. Transcatheter arterial chemoembolization (TACE) is one of the main treatments for intermediate to advanced-stage liver cancer. Currently, iodized oil is commonly used in clinical practice for transhepatic artery interventional therapy of malignant liver tumors. This is mainly because the liver has two blood supply systems: the hepatic artery and the portal vein. Even if the hepatic artery is embolized, the portal vein blood supply system remains, ensuring that the blood supply to the non-tumor parts of the liver is not affected.

[0003] Traditional TACE treatment uses iodized oil as the embolic agent. This is typically prepared by mixing iodized oil with one or two chemotherapy drugs to form a temporary emulsion, which is then injected into the hepatic artery via a catheter. The iodized oil and the chemotherapy drugs it carries remain in the tumor's blood vessels or tissue, killing tumor cells. However, these iodized oil emulsions are mostly prepared by repeatedly pushing and pulling a three-way valve twenty to thirty times within half an hour before the procedure, which has the following drawbacks: First, their physical stability is poor, causing the chemotherapy drugs to be released into the systemic circulation quickly, resulting in poor efficacy and severe side effects; second, the local deposition effect is sometimes unsatisfactory, and the cytotoxic effect of the chemotherapy drugs on tumor tissue decreases over time; third, some chemotherapy drugs still enter the systemic circulation, increasing adverse reactions; and fourth, the concentration and retention time of the drugs within the lesion are relatively short, and the efficacy in inactivating the lesion needs to be improved.

[0004] To address the aforementioned issues, researchers have attempted to introduce hydrogels as drug carriers and combine them with iodized oil to prepare emulsions. Hydrogels are a class of polymeric materials with a three-dimensional network structure, high water content, and structural and mechanical properties similar to human soft tissue, exhibiting excellent biocompatibility. Furthermore, controlled and sustained drug release can be achieved through molecular design. Iodized oil emulsions prepared by combining hydrogels with iodized oil can improve emulsion stability, achieve sustained and controllable drug release, reduce blood drug concentration, and increase drug retention and duration in the liver. However, existing hydrogel-iodized oil emulsions all require the introduction of exogenous reagents such as surfactants, emulsifiers, and solubilizers to achieve emulsification of the aqueous and oil phases. These reagents may trigger in vivo toxic reactions, reduce the biosafety of the formulation, and increase the complexity of the formulation components, which is detrimental to clinical quality control. Therefore, how to provide a liver cancer embolization emulsion with high stability, good safety, and controllable drug release is an urgent problem to be solved. Summary of the Invention

[0005] One of the objectives of this invention is to provide a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion, which solves the problem of improving the physical stability of raltitrexed and iodized oil emulsion without introducing chemical surfactants, and effectively inhibiting the in vivo release of the drug.

[0006] The second objective of this invention is to provide a method for preparing a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion, which is used to prepare the aforementioned raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion.

[0007] A third objective of this invention is to provide a raltitrexate drug gel-stabilized hepatocellular carcinoma embolization emulsion for the preparation of a transcatheter arterial chemoembolization agent for the treatment of hepatocellular carcinoma.

[0008] The objective of this invention can be achieved through the following technical solutions: In a first aspect, a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion is composed of an iodized oil embolization agent and a raltitrexed drug gel; wherein the raltitrexed drug gel serves as an active pharmaceutical ingredient and an emulsion stabilizer, and is uniformly dispersed in the iodized oil to form a stable emulsion system.

[0009] Raltitrexed is an antimetabolite-like folic acid analog that specifically inhibits thymidylate synthase, thereby exerting its antitumor effect. However, raltitrexed exhibits poor dispersibility in iodized oil, resulting in insufficient physical stability of the prepared iodized oil emulsion, and its burst release can easily trigger systemic side effects. Raltitrexed molecules can self-assemble into a hydrogel under ultrasound, enabling it to serve as a drug carrier for local delivery of chemotherapeutic drugs; it also boasts high water content and good adjustability. Currently, there are no reports on iodized oil emulsions using raltitrexed hydrogels as both therapeutic agents and stabilizers. Since it does not require the introduction of additional surfactants, it holds great potential for application in liver cancer embolization systems.

[0010] Furthermore, the raltitrexed drug gel is a gel with a three-dimensional network structure formed by the ultrasonic-induced self-assembly of raltitrexed molecules in an aqueous phase. Raltitrexed serves both as a chemotherapeutic drug exerting antitumor effects and as a gel matrix material stabilizing emulsions. This design, which eliminates the need for additional surfactants, significantly improves the biocompatibility of the formulation.

[0011] Furthermore, the aqueous phase can be any pharmaceutically acceptable aqueous medium, such as sterile water, ultrapure water, physiological saline, or phosphate-buffered saline (PBS), to suit different clinical configuration needs.

[0012] Furthermore, to achieve optimal therapeutic effect and embolization fluidity, the concentration of raltitrexed in the emulsion is 5 mg / mL to 10 mg / mL; the volume ratio of the iodized oil to the raltitrexed drug gel is 4:1 to 1:4.

[0013] Furthermore, the emulsion is either water-in-oil or oil-in-water, and its type is achieved by adjusting the volume ratio of iodized oil to raltitrexed drug gel.

[0014] By adjusting the volume ratio of the oil phase to the water phase, the type of emulsion (water-in-oil or oil-in-water) can be easily controlled to meet the needs of tumor vascular embolization for different types of tumors.

[0015] Furthermore, as an extension of the present invention, in order to achieve synergistic treatment of liver cancer or address the complex tumor microenvironment, the aqueous phase of the raltitrexed drug gel may also be loaded with at least one other antitumor drug. These drugs include, but are not limited to: small molecule chemotherapeutic drugs (such as doxorubicin, cisplatin, and fluorouracil), nucleic acid protein drugs, metal preparations, antibody drugs (such as bevacizumab), immunomodulators, or targeted drugs. These drugs can be encapsulated in the three-dimensional network of the gel and delivered to the tumor site along with the emulsion, achieving combined spatiotemporal controlled release of multiple drugs.

[0016] Secondly, a method for preparing a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion is disclosed. This method is simple to operate and suitable for immediate preparation before clinical surgery, and includes the following steps: (1) Preparation of raltitrexed drug gel: Accurately weigh raltitrexed powder, disperse it evenly in a selected volume of aqueous phase, and then place it in an ultrasonic processor for ultrasonic treatment. The ultrasonic power is controlled within a certain range to promote the self-assembly of raltitrexed molecules to form a uniform and stable hydrogel.

[0017] (2) Emulsification: The raltitrexed drug gel prepared in step (1) and the iodized oil commonly used in clinical practice are drawn into two different syringes respectively. The two syringes are connected by a sterile three-way valve. Then, the pistons of the syringes are pushed alternately to mix the two phases thoroughly under turbulent action. The injection is repeated at least 30 times until a uniform emulsion without layering is formed, which is the raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion.

[0018] Furthermore, the ultrasonic treatment in step (1) has a power of 80-120 W and an ultrasonic time of 5-15 min.

[0019] Furthermore, the number of times the injection mixture is applied in step (2) is 30-50 times.

[0020] Thirdly, the application of a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion in the preparation of a transcatheter arterial chemoembolization agent for the treatment of hepatocellular carcinoma; The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion is injected via catheter into the hepatic artery or renal artery to embolize the tumor-supplying blood vessels and slowly release chemotherapy drugs.

[0021] The beneficial effects of this invention are: (1) The liver cancer embolization emulsion with raltitrexed drug gel stabilized by the present invention has excellent physical stability. The emulsion prepared by utilizing the interfacial stabilization effect of the self-assembled hydrogel of raltitrexed has uniform particle size and can remain stable in vitro for a long time without layering or aggregation, which is far superior to the traditional iodized oil emulsion prepared on the spot, thus ensuring the accuracy and consistency of the dosage.

[0022] (2) The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion prepared in this invention significantly reduces systemic toxicity, and the high stability of the emulsion effectively inhibits the burst release phenomenon of the drug. In vitro release experiments show that the emulsion has near-zero-order slow release kinetics, and the drug release cycle is significantly prolonged. This helps to reduce the amount of drug entering the systemic circulation while maintaining high local efficacy in the tumor, thereby reducing the systemic toxic side effects of chemotherapy drugs.

[0023] (3) The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion prepared by this invention contains only two components: iodized oil and raltitrexed. The raltitrexed gel itself is the drug, eliminating the need for any additional chemically synthesized surfactants or solubilizers, thus completely avoiding the potential toxicity risks caused by excipients and exhibiting extremely high biosafety. Furthermore, the resulting stable emulsion can penetrate deep into peripheral blood vessels to achieve complete embolization. In addition, the preparation of this emulsion requires only two steps: ultrasound and three-way valve injection, eliminating the need for complex equipment and conforming to the operational habits of TACE surgery, facilitating its widespread use in hospitals at all levels. Simultaneously, this system can also serve as a platform technology, conveniently loading various other anti-tumor drugs to achieve combined therapy. Attached Figure Description

[0024] The invention will now be further described with reference to the accompanying drawings.

[0025] Figure 1 This is a schematic diagram illustrating the preparation process of the raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion of the present invention; Figure 2 Images showing the appearance of raltitrexed drug gel iodized oil emulsions (stained) at different volume ratios; Figure 3 Appearance images for stability testing of raltitrexed drug gel iodized oil emulsions with different volume ratios; Figure 4 The in vitro cumulative release curves of the raltitrexed drug gel iodized oil emulsion with different proportions of the present invention and the control example in different pH buffers; Figure 5 This is an evaluation diagram of the effect of the raltitrexed drug gel iodized oil emulsion embolizing rabbit renal artery for 4 weeks; Figure 6 This is a comparison of the therapeutic effects of different formulations injected into the in situ tumor in a rat N1S1 in situ hepatocellular carcinoma model according to the present invention. Figure 7 The curves show the changes in tumor volume in each group of the rat N1S1 orthotopic liver cancer model. Detailed Implementation

[0026] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0027] Example 1 In this embodiment, raltitrexed drug gels of different concentrations were prepared to investigate the gel-forming ability of raltitrexed at different concentrations.

[0028] (1) Weigh out 5 mg, 8 mg and 10 mg of raltitrexate powder respectively and place them in different 5 mL glass vials.

[0029] (2) Add 1 mL of ultrapure water to each bottle to make the final concentrations of raltitrexed 5 mg / mL, 8 mg / mL and 10 mg / mL respectively.

[0030] (3) Place the vial in an ultrasonic cleaner and ultrasonically treat it for 10 minutes at 150W power.

[0031] (4) After the ultrasound is finished, remove the vial and let it cool to room temperature.

[0032] Results: Samples at concentrations of 5 mg / mL, 8 mg / mL, and 10 mg / mL formed homogeneous, transparent, and stable hydrogels after sonication. Unless otherwise specified, the raltitrexed gel concentration in subsequent examples was 8 mg / mL.

[0033] Example 2 This embodiment describes the preparation of raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsions with different oil-to-water volume ratios according to the method of the present invention. The preparation process is as follows: Figure 1 As shown. Five ratios were set up, namely gel: iodized oil = 4:1, 2:1, 1:1, 1:2, and 1:4.

[0034] (1) Preparation of raltitrexed gel: Raltitrexed hydrogel with a concentration of 8 mg / mL (aqueous phase is ultrapure water) was prepared according to the method in Example 1, and a total of 5 mL was prepared.

[0035] (2) Emulsification: Prepare five 5mL sterile syringes, labeled A, B, C, D, and E respectively. Draw the gel and iodized oil into the syringes according to the following ratio: A: Take 2 mL of gel + 0.5 mL of iodized oil (volume ratio 4:1). B: Take 2 mL of gel + 1 mL of iodized oil (volume ratio 2:1). C: Take 1.5 mL of gel + 1.5 mL of iodized oil (volume ratio 1:1). D: Take 1 mL of gel + 2 mL of iodized oil (volume ratio 1:2). E: Take 0.5 mL of gel + 2 mL of iodized oil (volume ratio 1:4). (3) Connect each syringe to a three-way valve and another empty 5mL syringe. Through the three-way valve, inject the gel and iodized oil rapidly and forcefully back and forth between the two syringes. Repeat the injection 40 times to obtain a homogeneous raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion.

[0036] Result: As Figure 2 As shown, all five sample ratios formed emulsions after emulsification (dye was added for clarity). Emulsions (without dye) with gel:iodized oil ratios of 2:1, 1:1, and 1:2 were left to stand at room temperature to observe their stability. Figure 3 As shown, none of the emulsions prepared in this invention exhibited significant stratification, demulsification, or precipitation after standing for two weeks, demonstrating exceptional physical stability. This indicates that the iodized oil emulsion stabilized by raltitrexed gel possesses excellent anti-agglomeration capabilities.

[0037] Example 3 The in vitro release monitoring of the raltitrexate drug gel-stabilized hepatocellular carcinoma embolization emulsion in this invention includes the following steps: Experimental Groups: Control group 1 (traditional mixture): 8 mg raltitrexed powder was directly mixed with 1 mL iodized oil and ultrasonically dispersed to prepare raltitrexed-iodized oil mixture.

[0038] Control group 2 (gel group): 8 mg / mL raltitrexed gel prepared in Example 1.

[0039] Experimental group (emulsion of the present invention): Three emulsions with a gel-to-iodized oil volume ratio of 1:2, 1:1, and 2:1 were prepared according to the method of Example 2.

[0040] Experimental methods: (1) Take each group of samples (each equivalent to 8 mg of raltitrexed) and place them in pretreated dialysis bags (MWCO: 500 Da) and seal them.

[0041] (2) Immerse the dialysis bag in a centrifuge tube containing 30 mL of release medium (pH 7.4 phosphate buffer and pH 5.4 phosphate buffer, respectively simulating the normal physiological environment and the tumor acidic microenvironment, each containing 0.5% Tween-80 to maintain the leak conditions).

[0042] (3) Place the centrifuge tube in a constant temperature shaker at 37°C and shake horizontally at 100 rpm.

[0043] (4) At the preset time points (0.083, 0.167, 0.333, 0.5, 1, 1.5, 2, 6, 12, 24, 36, 72, 144, 216, 360, 480, 720 hours), remove all the release medium and immediately add an equal volume of fresh preheated release medium.

[0044] (5) After filtering the extracted sample solution through a 0.22 μm filter membrane, the content of raltitrexed was determined by high performance liquid chromatography (HPLC) at 324 nm. The cumulative release percentage was calculated. Each experiment was repeated 3 times, and the average value was taken. The release curve was plotted as follows. Figure 4 As shown.

[0045] Results analysis: The average cumulative release rate (%) for each group at each time point is shown in Tables 1 and 2. The data show that the emulsion of the present invention exhibits significant sustained-release characteristics under both pH 7.4 and pH 5.4 conditions, with no burst release phenomenon, and the release rate decreases with increasing oil phase ratio, demonstrating its superiority as a TACE formulation.

[0046] Figure 4 The raltitrexed-iodized oil mixture forms an unstable suspension rather than an emulsion. The raltitrexed powder cannot be uniformly dispersed in the iodized oil. When it is injected into water, the drug immediately diffuses out in large quantities, demonstrating its extreme instability under simulated physiological conditions.

[0047] Table 1. Cumulative release rate of raltitrexed in each group under pH 7.4 conditions (%, mean ± SD, n=3)

[0048] Table 2. Cumulative release rate of raltitrexed in each group under pH 5.4 conditions (%, mean ± SD, n=3)

[0049] Example 4 The application of the raltitrexate drug gel-stabilized hepatocellular carcinoma embolization emulsion of this invention in interventional embolization therapy includes the following steps: Experimental methods: (1) The rabbits were randomly divided into a sham surgery group (injected with saline) and an experimental group (n=3).

[0050] (2) After anesthetizing the animals in the experimental group, the femoral artery was punctured, a catheter sheath was inserted, and the microcatheter was superselectively inserted into the left renal artery under DSA guidance.

[0051] (3) 1 mL of the emulsion of the present invention (gel: iodized oil = 1:1) prepared according to Example 2 was slowly injected through the catheter. The endpoint of embolization was the stagnation of the contrast agent or the occurrence of reflux.

[0052] (4) Immediately after embolization, DSA angiography was performed to confirm the obstruction of renal artery blood flow. At the same time, a plain CT scan was performed to observe the deposition of iodized oil in the kidney.

[0053] (5) Four weeks after the operation, a contrast-enhanced CT scan was performed again to assess the blood supply of the embolized kidney. The animal was then euthanized, and both kidneys were dissected for gross observation and histopathological examination.

[0054] Results analysis: like Figure 5 As shown, Figure 5 The image shows a rabbit kidney dissected 4 weeks after embolization. The untreated kidney in the rabbit was intact, while the embolized kidney showed obvious necrosis. This indicates that the raltitrexed drug gel iodized oil emulsion has excellent embolizing properties and can completely embolize both the large and peripheral blood vessels of the kidney. Figure 5 Figures b and 5c show that 4 weeks after the embolization procedure, a contrast-enhanced CT scan was performed. Through three-dimensional reconstruction, it was found that the boundary of the embolized kidney was unclear and the contrast signal was significantly reduced, indicating that the embolized kidney did not experience embolization recanalization within 4 weeks after the embolization procedure.

[0055] Example 5 This experiment used a rat N1S1 orthotopic liver cancer model to evaluate the antitumor efficacy of the emulsion of this invention.

[0056] Experimental methods: (1) Model establishment: The suspension containing N1S1 rat liver cancer cells was inoculated into the parenchyma of the left lobe of the rat liver to establish an orthotopic liver cancer model.

[0057] (2) Grouping and treatment: When the tumors grew to about 5-8 mm, the rats were randomly divided into 5 groups of 4 rats each: Blank control group: normal saline was injected via the hepatic artery.

[0058] Iodized oil treatment group: Iodized oil was injected via the hepatic artery.

[0059] Gel group: 8 mg / mL raltitrexed gel was injected via the hepatic artery.

[0060] Traditional mixed solution group: Raltitrexed-iodized oil physical mixture was injected via the hepatic artery.

[0061] The emulsion group of the present invention: the emulsion of the present invention prepared in a 1:1 ratio according to Example 2 by hepatic artery injection.

[0062] (3) The corresponding drugs were slowly injected into each group of animals via hepatic artery cannulation. The animals were then fed according to routine care after the operation.

[0063] (4) Evaluation of efficacy: Tumor volume was measured by animal in vivo imaging system and ultrasound before treatment and on days 3, 7 and 14 after treatment, and the tumor growth inhibition rate was calculated. The average tumor volume (mm3) at each time point is shown in Table 3.

[0064] Results analysis: As shown in Table 3, Figure 6 and Figure 7 As shown: In the blank control group and the iodized oil treatment group, the tumors progressed rapidly and increased in size quickly, and the effect of iodized oil embolization alone was limited.

[0065] Traditional mixed solution group: Due to the burst release of drugs and the lack of sustained embolization, it has a certain inhibitory effect in the early stage of treatment, but the inhibitory effect is limited as the tumor continues to grow in the later stage.

[0066] Gel group: Since raltitrexed gel alone does not have a vascular embolization effect and is easily washed away by blood flow, its anti-tumor effect is weaker than that of the emulsion of the present invention.

[0067] The emulsion group of this invention exhibited the most significant tumor growth inhibition effect. Throughout the observation period, the tumor volume hardly increased or even shrank. On day 14, the average tumor volume was only about 89.78 mm. 3 The tumor tissue necrosis was significantly smaller than that of the other groups. Pathological examination showed that the emulsion group of this invention had the largest area of ​​tumor tissue necrosis, the highest number of apoptotic cells, and the lowest proliferation index.

[0068] Table 3. Tumor volume changes (mm) in different groups of rat N1S1 orthotopic liver cancer model 3 (mean ± SD, n=4)

[0069] Example 6: Preparation of Expandable Emulsions Loaded with Other Antitumor Drugs This embodiment demonstrates the feasibility of further loading other drugs into the system of the present invention.

[0070] (1) Weigh 8 mg of raltitrexate and 4 mg of doxorubicin hydrochloride and add them together to 1 mL of physiological saline.

[0071] (2) Following the method in Example 1, the mixture was sonicated at 150W for 10 minutes. The results showed that the addition of doxorubicin did not affect the self-assembly of raltitrexed, and a uniform, red composite drug gel with the characteristic color of doxorubicin was formed.

[0072] (3) Following the method of Example 2, this composite drug gel was emulsified with iodized oil at a 1:1 volume ratio to obtain a dual-drug embolization emulsion loaded with raltitrexate and doxorubicin. This emulsion also exhibited good stability. This example demonstrates that the system of the present invention can serve as a universal delivery platform for various hydrophilic antitumor drugs.

[0073] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion, characterized in that, The liver cancer embolization emulsion is composed of iodized oil embolization agent and raltitrexed drug gel; the raltitrexed drug gel, as an active pharmaceutical ingredient and emulsion stabilizer, is uniformly dispersed in iodized oil to form a stable emulsion system.

2. The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 1, characterized in that, The raltitrexed drug gel is a gel with a three-dimensional network structure formed by the ultrasonic-induced self-assembly of raltitrexed molecules in an aqueous phase.

3. The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 2, characterized in that, The aqueous phase is selected from one or more of sterile water, ultrapure water, physiological saline, or phosphate buffer solution.

4. The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 1, characterized in that, The concentration of raltitrexed in the liver cancer embolization emulsion is 5 mg / mL-10 mg / mL; the volume ratio of iodized oil to raltitrexed drug gel is 4:1 to 1:

4.

5. The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 1, characterized in that, The emulsion is either water-in-oil or oil-in-water, and its type is determined by adjusting the volume ratio of iodized oil to raltitrexed drug gel.

6. The raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 1, characterized in that, The raltitrexed drug gel is also loaded with at least one other antitumor drug; The other antitumor drugs include small molecule chemotherapy drugs, nucleic acid protein drugs, metal preparations, antibody drugs, immunomodulators, or targeted drugs; the small molecule chemotherapy drugs include doxorubicin, cisplatin, or fluorouracil.

7. A method for preparing a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion as described in any one of claims 1-6, characterized in that, Includes the following steps: (1) Preparation of raltitrexed drug gel: raltitrexed powder was dispersed in an aqueous phase and subjected to ultrasonic treatment to allow it to self-assemble into a hydrogel; (2) Emulsification: The raltitrexed drug gel obtained in step (1) and the iodized oil are placed in two syringes respectively, connected by a three-way valve, and injected alternately to mix at least 30 times until a homogeneous emulsion is formed, which is the raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion.

8. The method for preparing a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 7, characterized in that, The ultrasonic treatment in step (1) has a power of 80-120 W and an ultrasonic time of 5-15 min.

9. The method for preparing a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion according to claim 7, characterized in that, The number of times the injection mixture is mixed in step (2) is 30-50 times.

10. The use of a raltitrexed drug gel-stabilized hepatocellular carcinoma embolization emulsion as described in any one of claims 1-6 in the preparation of a transcatheter arterial chemoembolization agent for the treatment of hepatocellular carcinoma; The liver cancer embolization emulsion is injected into the hepatic artery or renal artery via a catheter to embolize the blood vessels supplying the tumor and slowly release chemotherapy drugs.

Images