Mitomycin hydrogel vascular embolization agent capable of being delivered through catheter

Abstract

The invention discloses a hydrogel vascular embolization agent which is characterized in that mitomycin drug particles slightly soluble in water are assisted to suspend in hydrogel through a suspending aid dextran and smoothly pass through a catheter conveying system. The gel embolization agent can realize local rapid release of the mitomycin medicine and continuously maintain the concentration of the medicine in tumors.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, in particular to an implantable hydrogel medical device. Background Art

[0002] The present invention belongs to the field of biomedicine technology, and specifically relates to a method for slowing down the sedimentation of mitomycin particles in a hydrogel vascular embolic agent, thereby assisting the loading of slightly water-soluble anti-tumor drugs in the vascular embolic agent.

[0004] Treatment options vary depending on the extent of liver damage and the stage at which the tumor is detected. Partial liver resection or transplantation is the first-line treatment for patients with early-stage liver cancer. However, most patients with liver cancer do not have any symptoms before the middle and late stages, and are already in the middle and late stages when diagnosed, missing the best time for surgical resection. Therefore, surgical treatment is only suitable for 20% of cases. When the tumor is in the late stage, interventional comprehensive treatment based on transarterial chemoembolization (TACE) is the main treatment for liver cancer that cannot be surgically removed. It is recommended as the preferred standard treatment for middle and late stage liver cancer, with a 3-year survival rate of up to 50%. This is because the liver has two basic blood sources: the portal vein and the hepatic artery. The portal vein is mainly responsible for the blood supply of healthy liver parenchyma, while the hepatic artery is mainly responsible for the blood supply of the tumor. Transarterial embolization (TAE) is mainly to selectively or super-selectively insert a catheter into the target artery supplying the tumor, inject an appropriate amount of embolic agent, block the tumor blood vessels, and thus cause ischemic necrosis of the tumor tissue. Currently, the most commonly used embolic agents in clinical practice include super-liquidized iodized oil, gelatin sponge, and seaweed microspheres. With the development of embolic dosage forms, people have found that embolic agents are best to have both embolic effects and continuous chemotherapy. Therefore, anticancer drugs are loaded into embolic agents to play a chemoembolic role, namely transcatheter hepatic artery embolization chemotherapy (TACE). The most common chemoembolic agent in clinical practice is drug-loaded microspheres, which solve the problems of rapid diffusion of iodized oil and reduced systemic reactions, and increase the embolic effect. However, drug-loaded microspheres not only have a low drug loading rate, but can only load and release some chemotherapeutic drugs with good water solubility. For some chemotherapeutic drugs with poor water solubility or high drug concentration requirements, there are problems of being unable to load drugs and low drug release concentration.

[0005] Although most of the commonly used anti-tumor drugs in clinical practice have been tried for the treatment of liver cancer, there are not many effective drugs. Mitomycin is one of the most commonly used chemotherapy drugs for liver cancer patients, but its physical and chemical properties are that it is slightly soluble in water, so it is difficult to load mitomycin into drug-loaded microspheres.

[0006] Hydrogel is a soft material containing a large amount of water obtained by cross-linking hydrophilic polymers. It has excellent physical and chemical properties and biological characteristics, such as high water content, high elasticity, softness, and good biocompatibility. Polyethylene glycol (PEG) is a type of non-ionic polymer. Due to its good biocompatibility and safety, it is a type of synthetic polymer approved by the US Food and Drug Administration (FDA) for clinical use in humans. Polyethylene glycol hydrogel can load and release a variety of water-soluble chemotherapy drugs, but for some chemotherapy drugs with poor water solubility or high drug concentration requirements, there are problems of fast drug sedimentation and low drug release concentration. Adding a suspending agent to the polyethylene glycol hydrogel system is an effective method to slow down the sedimentation of the slightly soluble tumor chemotherapy drug mitomycin in the hydrogel vascular embolic agent and increase the drug release amount. Summary of the invention

[0007] The present invention provides a mitomycin hydrogel vascular embolic agent that can be delivered by catheter based on the research of existing medical hydrogels. The suspending agent dextran is used to reduce the sedimentation of mitomycin and increase the ability of drug sustained release.

[0008] The specific technical solutions of the present invention are as follows: A mitomycin hydrogel vascular embolic agent that can be delivered by a catheter comprises mitomycin drug particles, a hydrogel cross-linked by star-shaped multi-arm polyethylene glycol and polyamino compounds, and a suspending agent, dextran.

[0009] The particle size of the mitomycin drug particles is 2±0.5 μm, and the content of the mitomycin drug particles loaded in the hydrogel is preferably 25-75 mg / mL.

[0010] The dextran is selected from one or more of dextran 20, dextran 40 and dextran 70. Dextran 20 is preferred.

[0011] Preferably, the mass volume percentage concentration of the dextran in the hydrogel is 2.5% to 7.5%, more preferably 5%.

[0012] The aldehyde group of the hydrogel of the present invention is connected to the star-shaped multi-arm polyethylene glycol by an ester bond, an ether bond, an amide bond, an urethane bond, an imine bond or a urea bond, and the polyamino compound is selected from one or more of polyethyleneimine and polylysine. (Chinese patent document CN109939065A).

[0013] The aldehyde-terminated star-shaped multi-arm polyethylene glycol is a multi-arm polyethylene glycol with an arm number of not less than 2 (preferably 2-8) and a molecular weight of not less than 2000 Da.

[0014] The aldehyde group is selected from one or more of aromatic aldehydes and alkyl aldehydes, and is preferably a benzaldehyde group.

[0015] The mitomycin hydrogel vascular embolic agent of the present invention is prepared by the following method: The aldehyde-terminated star-shaped multi-arm polyethylene glycol is dissolved in a pH 4-10 buffer to prepare a solution, and a suspending agent, dextran, is added to prepare a mixed solution A; a polyamino compound is dissolved in a pH 4-10 buffer to prepare a solution B; equal volumes of solutions A and B are mixed to obtain a hydrogel, and a slightly soluble water-based drug, mitomycin, is further added to obtain a drug-loaded hydrogel.

[0016] Alternatively, a slightly soluble water-based drug, mitomycin, is added to solution A, and solutions A and B are mixed to prepare a drug-loaded hydrogel.

[0017] The pH 4-10 buffer is preferably a pH 4-10 phosphate or borate buffer.

[0018] Preferably, the concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol solution in the hydrogel is 2-30% (w / v), more preferably 10-20%; the concentration of the polyamino compound is 0.5-20% (w / v), more preferably 1-5%.

[0019] The ratio of the amount of aldehyde groups in the aldehyde-terminated star-shaped multi-arm polyethylene glycol to the amount of amino substances in the polyamino compound is 0.01-5:1.

[0020] The suspending agent dextran of the present invention can be dissolved in the polyethylene glycol derivative solution and is used to slow down the precipitation of mitomycin in the polyethylene glycol derivative solution.

[0021] Advantages of the present invention: Based on the research of existing medical hydrogels, the present invention provides a method for effectively slowing down the sedimentation of mitomycin, a slightly soluble anti-tumor chemotherapy drug, in a hydrogel vascular embolic agent and increasing the drug release amount. Under the premise of not affecting the good injectability of the hydrogel, the suspending agent dextran achieves the ability to reduce the sedimentation of mitomycin and increase the sustained release of the drug. The results of the in vitro drug release of mitomycin confirm that dextran can quickly load mitomycin, and can achieve the ability to increase the sustained release of the drug and maintain the drug concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 .Drug release curve of mitomycin in hydrogel vascular embolic agent when the concentration is 25 mg / ml.

[0023] Figure 2 .Drug release curve of mitomycin in hydrogel vascular embolic agent when the concentration is 50 mg / ml. DETAILED DESCRIPTION

[0024] The specific steps of the present invention are described below by way of examples, but are not limited to the examples.

[0025] The terms used in the present invention, unless otherwise specified, generally have the meanings that are commonly understood by those of ordinary skill in the art.

[0026] The present invention is further described in detail below in conjunction with specific examples and with reference to data. It should be understood that these examples are only intended to illustrate the present invention, and are not intended to limit the scope of the present invention in any way.

[0027] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0028] Example 1 Effects of different suspending agents on drug-loaded hydrogels 1. Drug-loaded hydrogel without suspending agent: Step 1: Preparation of hydrogel precursor solution: 200 mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 15 kDa) was dissolved in 1 mL of phosphate buffer (pH 5.6) as solution A. A borax buffer (pH 9.2) solution of polylysine and polyethyleneimine (MW 1.8K) was prepared at a molar ratio of 1:0.9:1 between the aldehyde group of polyethylene glycol and the amino group of polyethyleneimine and the amino group of polylysine as solution B.

[0029] Step 2: Preparation of drug-loaded hydrogel: Add mitomycin (2±0.5 μm) to 1 ml of solution A to form a suspension, and then mix the suspension with equal volumes of solution B to obtain a hydrogel loaded with mitomycin.

[0030] 2. Drug-loaded hydrogel containing suspending agents: Step 1: Preparation of hydrogel precursor solution: 200 mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 15 kDa) was dissolved in 1 mL of phosphate buffer (pH 5.6), and then a suspending agent was added as solution A. A solution of polylysine and polyethyleneimine (MW 1.8K) in a borax buffer (pH 9.2) was prepared at a molar ratio of 1:0.9:1 between the aldehyde group of polyethylene glycol and the amino group of polyethyleneimine and the amino group of polylysine, as solution B.

[0031] Step 2: Preparation of drug-loaded hydrogel: Add mitomycin to 1 ml of solution A to form a suspension, and then mix the suspension with equal volumes of solution B to obtain a hydrogel loaded with mitomycin.

[0032] The sedimentation time of mitomycin in drug-loaded hydrogels without suspending agents and drug-loaded hydrogels containing different suspending agents and whether they block the tube were investigated.

[0033] Steps: Aspirate solution A (1 ml) containing mitomycin and suspending agent into a 1 ml syringe, connect an interventional microcatheter (1.7F, inner diameter 0.43 mm) to the tail end of the syringe, push the syringe hard, and observe whether the drug suspension can flow out from the tail end of the catheter.

[0034] Table 1 Effect of different suspending agents on the sedimentation time and whether the tube is blocked by mitomycin When the concentration of mitomycin in the gel is 50 mg / ml, the sedimentation time under different suspending agents is shown in Table 1. Only the drug suspended with dextran can be smoothly injected through the catheter, and 5% dextran can significantly delay the sedimentation time of mitomycin.

[0035] Example 2 Effects of different drug concentrations on drug-loaded hydrogels Referring to Example 1, hydrogels with dextran (5%) suspension and without suspending agent were prepared at different drug concentrations, and the corresponding tube blocking conditions and sedimentation time were investigated. The results are shown in Table 2. The experimental results show that at lower mitomycin concentrations, both with and without suspending agent can pass through the catheter, but dextran can significantly slow down the drug sedimentation. When the drug concentration reaches 100 mg / ml, the drug suspension without suspending agent cannot pass through the catheter, and only the suspension with dextran can pass through the catheter. When the drug concentration is further increased to 200 mg / ml, the suspension with suspending agent cannot pass through the catheter.

[0036] Table 2 Effect of different drug concentrations on sedimentation time and whether the pipe is blocked Example 3 Effect of Dextran Concentration on Drug-Loaded Hydrogel Referring to Example 1, different concentrations of dextran were prepared with drug-loaded hydrogels, and the drug concentration was 50 mg / ml. The corresponding tube blockage and sedimentation time were investigated. The results are shown in Table 3. The experimental results show that when the dextran concentration is too low, the drug suspension cannot be promoted to pass through the catheter. Only when the concentration reaches 2.5%, the drug suspension can pass through the catheter smoothly. When the dextran concentration is too high (10%), it is difficult to inject due to the high viscosity.

[0037] Table 3 Effect of different dextran concentrations on sedimentation time and whether the pipe is blocked Example 4 Drug sustained release performance of drug-loaded hydrogel in simulated body fluid In this embodiment, 200 mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 15 kDa) was dissolved in 1 mL of phosphate buffer (pH 5.6) as liquid A, and a suspending agent and mitomycin were added to liquid A to form a uniform suspension. A borax buffer (pH 9.2) solution of polylysine and polyethyleneimine (MW 1.8K) was prepared with a molar ratio of 1:0.9:1 between the aldehyde group of polyethylene glycol and the amino group of polyethyleneimine and the amino group of polylysine as solution B. The suspension was mixed with liquid B and injected to obtain a hydrogel loaded with mitomycin (the concentration of the suspending agent in the hydrogel was 5%, and the concentration of mitomycin was 25 mg / ml), and the hydrogel without dextran was used as a control.

[0038] Accurately weigh the mitomycin drug-loaded hydrogel prepared above, place it in a glass bottle containing a PBS solution 200 times the mass of the drug-loaded hydrogel, take samples at preset time points, take out all the PBS in the glass bottle and weigh it each time, and add fresh PBS release medium 200 times the mass of the drug-loaded hydrogel. Use high performance liquid chromatography (C18 column (150x4.6mm, 5μm), methanol-water (35:65) as mobile phase, detection wavelength 365nm) to determine the concentration of mitomycin in the taken PBS sample, and measure the in vitro release of mitomycin in the hydrogel. When the concentration of mitomycin in the hydrogel vascular embolic agent is 25mg / ml, the drug release curve is as shown in the figure. Figure 1 As shown, the cumulative release of mitomycin in the hydrogel without the addition of suspending agent in PBS was 51% in 48 hours; after the addition of suspending agent dextran to the polyethylene glycol derivative, the cumulative release of mitomycin in the hydrogel formed by in situ cross-linking of the polyethylene glycol derivative, polyethylene imine and polylysine was 70% in 48 hours; after the addition of suspending agent CMC to the polyethylene glycol derivative, the cumulative release of mitomycin in the hydrogel formed by in situ cross-linking of the polyethylene glycol derivative, polyethylene imine and polylysine was 71% in 48 hours; after the addition of suspending agent Span80 to the polyethylene glycol derivative, the cumulative release of mitomycin in the hydrogel formed by in situ cross-linking of the polyethylene glycol derivative, polyethylene imine and polylysine was 55% in 48 hours, which were all higher than the release of the hydrogel without the addition of suspending agent.

[0039] Therefore, considering the three factors of whether it delays the sedimentation time of mitomycin in the hydrogel vascular embolic agent, whether it blocks the delivery system, and the amount of drug released, the group containing the suspending agent dextran and the group without the suspending agent were selected to observe the drug release curve when the mitomycin concentration in the hydrogel vascular embolic agent was 50 mg / ml. Figure 2As shown, the cumulative release of mitomycin in the hydrogel without the addition of suspending agent in PBS was 76% within 48 hours. After the suspending agent dextran was added to the polyethylene glycol derivative, the cumulative release of mitomycin in the hydrogel formed by in situ cross-linking of the polyethylene glycol derivative, polyethyleneimine and polylysine was 96% within 48 hours, and the drug release amount was significantly increased.

[0040] In summary, the preferred suspending agent is dextran, which can make the hydrogel vascular embolic agent loaded with a higher concentration of mitomycin injectable, reduce the sedimentation of mitomycin during delivery, and increase the drug release amount.

Claims

1. A catheter-deliverable mitomycin hydrogel vascular embolic agent, characterized in that The invention comprises mitomycin drug particles, a hydrogel cross-linked by star-shaped multi-arm polyethylene glycol and polyamino compounds, and a suspending agent, dextran.

2. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The particle size of the mitomycin drug particles is 2±0.5 μm, and the content of the mitomycin drug particles loaded in the hydrogel is 25-75 mg / mL.

3. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The dextran is selected from one or more of dextran 20, dextran 40 and dextran 70.

4. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The mass volume percentage concentration of the dextran in the hydrogel is 2.5% to 7.5%.

5. The mitomycin hydrogel vascular embolic agent according to any one of claims 1 to 4, characterized in that The aldehyde group of the hydrogel is connected to the star-shaped multi-arm polyethylene glycol by an ester bond, an ether bond, an amide bond, an urethane bond, an imine bond or a urea bond, and the polyamino compound is selected from one or more of polyethyleneimine and polylysine.

6. The mitomycin hydrogel vascular embolic agent according to claim 5, characterized in that The aldehyde-terminated star-shaped multi-arm polyethylene glycol is a multi-arm polyethylene glycol with an arm number of not less than 2 and a molecular weight of not less than 2000.

7. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The number of arms of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 2-8.

8. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The aldehyde group is selected from one or more of aromatic aldehydes and alkyl aldehydes.

9. The mitomycin hydrogel vascular embolic agent according to any one of claims 1 to 8, characterized in that The aldehyde-terminated star-shaped multi-arm polyethylene glycol is dissolved in a pH 4-10 buffer to prepare a solution, and a suspending agent, dextran, is added to prepare a mixed solution A; a polyamino compound is dissolved in a pH 4-10 buffer to prepare a solution B; equal volumes of solutions A and B are mixed to obtain a hydrogel, and mitomycin is further added to obtain a drug-loaded hydrogel; or mitomycin is added to solution A, and solutions A and B are mixed to obtain a drug-loaded hydrogel.

10. The mitomycin hydrogel vascular embolic agent according to claim 1, characterized in that The mass volume percentage concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol in the hydrogel is 2-30%, and the mass volume percentage concentration of the polyamino compound is 0.5-20%.

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