Embolism hydrogel capable of achieving radiography and drug loading and moderate in degradation and preparation method of embolism hydrogel

Abstract

The invention belongs to the field of medical embolism agents, and particularly relates to embolism hydrogel which can be used for radiography and drug loading and is moderate in degradation and a preparation method of the embolism hydrogel. The embolism hydrogel provided by the invention comprises two powders and two solutions, and the powders and the solutions are matched and combined with corresponding tools during use. The powder I is a multi-arm polyethylene glycol derivative with a double-bond group, the powder II is an iodine-containing contrast agent, the solution I comprises a reducing agent and an acidity regulator, and the solution II is an initiator. According to the prepared embolism agent, the problem of secondary embolism caused by the fact that the degradation time is short and the embolism effect of the embolism agent is not enough is solved, and targeted step-by-step embolism is achieved; and the double requirements of radiography and drug loading can be met at the same time.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to an embolic hydrogel capable of imaging, carrying drugs and moderate degradation, and a preparation method thereof. Background Art

[0002] Interventional embolization refers to the technology of embolizing blood vessels through interventional techniques. With the help of a catheter, through a small incision in the carotid artery or femoral artery, some embolic agents are injected into the area where embolization is required to form intravascular embolism. Interventional embolization is mostly used to stop bleeding, tumor embolization treatment, and intracranial aneurysm embolization treatment.

[0003] There are many types of embolic agents currently used in clinical practice, but they are generally PVA (polyvinyl alcohol), gelatin, sodium alginate microspheres or particles with fixed particle size and shape, which are delivered to the tumor site of blood vessels of matching size through microcatheters to achieve mechanical closure of these blood vessels. The PVA (polyvinyl alcohol) microsphere structure has certain pores, which can adsorb chemotherapy drugs through positive charges and are non-degradable. The advantage of this type of embolic agent is high embolic strength, but the disadvantage is that it does not degrade or degrades too quickly, cannot be embolized step by step, and has the risk of non-targeted embolism.

[0004] Whether it is liquid embolic agents or solid embolic agents, there are the following problems in clinical application: (1) Degradation problem: Currently available embolic agents have the problem of not degrading or degrading too quickly. For example, solid embolic agents PVA (polyvinyl alcohol) microspheres, liquid embolic agents ethylene-vinyl alcohol, acrylamide copolymers, etc. are not degradable. After permanent embolization of the target blood vessel, it is easy to cause vascular necrosis, collateral capillary regeneration and foreign body inflammatory reaction. Even if gelatin particles or sodium alginate particles can be degraded, because their degradation cycle is too short (2-3 months), the embolization effect is not enough and causes secondary embolism; (2) The risk of non-targeted embolism, especially solid embolic agents, which have a fixed particle size and need to match the size of the blood vessel for embolization. Once small microspheres or particles are mistakenly used to embolize large blood vessels during surgery, Blood vessels, microspheres or particles will flow with the blood to other locations to form non-targeted emboli; (3) They cannot meet the dual requirements of drug delivery and contrast imaging. Solid embolic agents mostly contain hydrophilic groups and are wrapped with positive charges, which can better absorb drugs, but are not easy to absorb contrast agents such as iohexol. Liquid embolic agents such as iodized oil and acrylamide copolymers (mixed tantalum powder contrast imaging) are all hydrophobic structures and are not easy to absorb tumor drugs. (4) They cannot effectively embolize step by step. The minimum particle size of solid embolic agent microspheres is 40μm, and they cannot embolize blood vessels below 40μm. Although liquid embolic agents can achieve step-by-step embolism by flowing into blood vessels of different sizes, they still cannot achieve effective embolism due to poor adhesion (such as iodized oil) and ectopic precipitation (such as acrylamide copolymers).

[0005] Regarding the improvement scheme of embolic agents, a patent document discloses a manufacturing process of a gelatin sponge granule embolic agent, in which the gelatin sponge is crushed and dried, sieved and graded, and then packed into cleaned and sterilized vials for subpackaging and capping. However, this embolic agent has the defects of too short degradation cycle (1-2 months), poor embolic effect, easy to cause secondary embolism, and no drug loading function.

[0006] The patent document also discloses a preparation process of a microsphere embolic agent, which forms functionalized macromolecules by covalently linking cross-linkable small molecules with acrylic acid structures to polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecules. Subsequently, these functionalized macromolecules are subjected to reverse suspension polymerization with 2-acrylamide-2-methylpropanesulfonic acid monomers to finally obtain cross-linked polymerized microsphere embolic agents. However, this microsphere embolic agent has the problem of not degrading or degrading too quickly, and does not have the ability of step-by-step embolization. It needs to be mixed with contrast agents for contrast imaging, and there is a risk of non-targeted embolism.

[0007] After comprehensive analysis, it is concluded that safe and effective embolic agents currently used for tumor embolization should have the following four key characteristics: first, they must have a suitable degradation time; second, they must effectively avoid the occurrence of non-targeted embolism; third, they must meet the dual requirements of drug loading and contrast imaging; and fourth, they must achieve effective step-by-step embolization. Therefore, it is necessary to improve the embolic agents and their preparation methods to ensure that they meet all of the above characteristics. Summary of the invention

[0008] In order to solve the above technical problems, the present invention provides an embolic hydrogel that can be imaged, loaded with drugs, and has moderate degradation, and the embolic hydrogel is composed of powder I, powder II, solution I, solution II, and supporting tools. The embolic hydrogel provided by the present invention can be cross-linked in situ during use to achieve the effects of step-by-step embolism and targeted embolism.

[0009] The technical solution of the present invention is:

[0010] The embolic hydrogel capable of imaging, loading drugs and moderate degradation provided by the present invention is composed of powder I, powder II, solution I and solution II.

[0011] Among them, powder I is a multi-arm polyethylene glycol derivative with double bond groups (acrylate or methacrylate groups), the number of arms is 2-8, and the molecular weight is 3000-15,000;

[0012] Powder II is an iodine-containing contrast agent; the contrast agent is selected from any one of iopromide, iopamidol, iomeprol, diatrizolan, ioversol, iohexol and iodixanol.

[0013] Solution I is a reducing agent and acidity regulator;

[0014] Preferably, the reducing agent is selected from2+ Cr 2+ 、V 2+ 、Ti 3+ 、Co 2+ , Cu + Any one of the compounds, further selected from any one or two or more of ferrous sulfate, ferrous lactate, and ferrous gluconate;

[0015] Preferably, the acidity regulator is selected from any one of hydrochloric acid and sulfuric acid.

[0016] Solution II is an initiator, which is selected from any one of tert-butyl hydroperoxide, peracetic acid, sodium peracetate, sodium persulfate, and hydrogen peroxide.

[0017] When in use, powder I and solution I are mixed and dissolved to form a first component, and powder II and solution II are mixed and dissolved to form a second component. The first component and the second component are transported to the tumor embolization site through matching tools to form an embolic hydrogel.

[0018] Preferably, the supporting tools include a coaxial double-lumen catheter, an adapter and a push injection tool;

[0019] The coaxial double-lumen catheter comprises an inner catheter and an outer catheter; the inner catheter has a size of 1.2F to 1.8F and a length of 110 to 170cm; the outer catheter has a size of 1.8F to 3.0F and a length of 105 to 165cm;

[0020] The adapter has a three-way structure, connecting two male Luers and one female Luer via a catheter;

[0021] The push tool is a push gun that can be equipped with two syringes side by side and can push quantitatively.

[0022] Preferably, the amount of powder I in the first component is 10% to 60% of the mass of solution I;

[0023] The amount of powder II in the second component is 30% to 300% of the mass of solution II;

[0024] The iodine content of the second component is 15% to 35% of the mass of the embolic hydrogel;

[0025] The first component is delivered through the inner conduit of the accessory tool, and the second component is delivered through the outer conduit of the accessory tool;

[0026] The volume ratio of the first component: the second component is 1:0.5-10.

[0027] Among them, powder I is directly packaged and sterilized together with the supporting tools with ethylene oxide at 40-50°C and 40-80% humidity for 5-7 hours, and powder II, solution I and solution II are sterilized by radiation.

[0028] In the present invention, the components of powder I are selected from multi-arm polyethylene glycol derivatives with double bond groups, the number of arms is 2-8, and the molecular weight is 3000-15,000. The reason why polyethylene glycol is selected as the structural main chain of the polymer is that the molecular weight range of polyethylene glycol is relatively wide, and it has a multi-arm branched structure, which is convenient for modification of multiple functional groups. After the gel is formed, it is hydrolyzed again at the cross-linking point position. Since the cross-linking point distances are different for different molecular weights and the cross-linking numbers are different for different arm numbers, the degradation time of the prepared hydrogel is different.

[0029] The present invention utilizes this structural feature of polyethylene glycol, selects polyethylene glycol with 2-8 arms, performs terminal double bond group modification, and performs in situ cross-linking under initiation conditions to form an interventional tumor embolization hydrogel. The cross-linking point position gradually undergoes ester hydrolysis in the body and is completely degraded in 3-12 months, making the degradation time of the hydrogel relatively moderate, between the non-degradable PVA microspheres and the gelatin microspheres that degrade too quickly, which not only meets the function of drug loading, but also meets the clinical demand for ablation after degradation.

[0030] The reason why the present invention selects multi-arm polyethylene glycol derivatives as the single active component of the embolic hydrogel to achieve self-crosslinking is based on the following considerations: the hydrogel needs to achieve instant crosslinking at the tumor embolization site. If two active components are selected for mutual crosslinking and delivered to the tumor embolization site through the inner and outer catheters, the gelation effect will be affected if there is a difference in the delivery speed of the inner and outer tubes; or, if any of the inner and outer tubes cannot be effectively delivered, the entire system will not be able to form a hydrogel, and once this happens, no secondary remedy will be possible.

[0031] In addition, the multi-arm structure of polyethylene glycol can form multiple cross-linking points. Experimental verification shows that the more arms of polyethylene glycol, the greater the cross-linking density of the hydrogel, and the better the sustained release effect of contrast agents and tumor drugs. Specifically, the retention time of contrast agents in hydrogels is prolonged, which is convenient for postoperative follow-up observation; at the same time, the release rate of tumor drugs is slowed down, which helps to improve the effect of chemotherapy.

[0032] The concentration of powder I in solution I is 10% to 60% (i.e., 100 to 600 mg / mL). Too low a concentration will affect the cross-linking effect and thus the embolization effect, while too high a concentration will affect the delivery effect of the gel precursor in the catheter. Therefore, the concentration range provided by the present invention satisfies that the formed hydrogel has an effective cross-linking effect and can achieve effective push injection to the embolization site.

[0033] The present invention has been experimentally verified that the multi-arm polyethylene glycol derivatives of double bond groups are sterilized by irradiation, and the double bond groups are easily self-crosslinked, causing the powder to be inactivated, and the melting point of the powder cannot meet the temperature requirements of wet heat and dry heat sterilization, so the powder is sterilized by ethylene oxide. The present invention also found that the structural law of the powder, the more branches the powder has, the lower its melting point, when the number of arms is 2-4, the conventional sterilization temperature of ethylene oxide is 50±3℃, and the powder can be sterilized. When the number of arms is 6-8, the sterilization temperature of ethylene oxide needs to be reduced to 40℃±3℃ to achieve the sterilization of the powder. In addition, the more arms the powder has, the better the sustained release effect of the contrast agent and tumor drug. The technician can combine the demand for sustained release effect and the choice of ethylene oxide sterilization conditions, and make a compromise to select a suitable hydrogel formula.

[0034] The solution system of the present invention is a Fenton reagent, because the initiator and the reductant can form a Fenton chain reaction through oxidation and reduction after being mixed in a slightly acidic environment, that is, a large amount of hydroxyl free radicals ·OH are formed in the system, and the hydroxyl free radicals ·OH trigger the opening of the double bond groups of the multi-arm polyethylene glycol derivative, which are continuously polymerized to form a solid hydrogel.

[0035] Solution I is the reducing agent of Fenton's reagent, which contains Fe 2+ Cr 2+ 、V 2+ 、Ti 3+ 、Co 2+ , Cu + Any one of the compound raw materials is used as a reducing agent, and the concentration of the initiator in the first component solution is 0.2% to 5%. The present invention found in the experimental process that the low-valent metal ions used as reducing agents are more active and can be easily oxidized to form high-valent ions, especially after irradiation sterilization, which brings problems to the stability of solution I. Therefore, the present invention adds an acidity regulator to solution I to control the pH value of solution I between 2.5 and 3.5. Within this pH range, the low-valent metal in solution I can exist stably without affecting the redox effect of solution I and solution II. For example, Fe 2+ As a reducing agent, the Fenton reagent system, when the system pH is less than 3, most of the Fe 2+ When the system pH is greater than 3, most of them exist in the form of Fe 3+ exists in the form of Fe 2+ The pH value of solution I is generally 4.0-4.5. It is necessary to add an acidity regulator to adjust the pH value of solution I to 2.5-3.5 before mixing solution I with solution II. 2+ The pH value of the mixed system is closer to 3, releasing more Fe 3+ , which facilitates the redox reaction.

[0036] In addition, the present invention proposes that hydrochloric acid and sulfuric acid can be selected as acidity regulators, and phosphoric acid, nitric acid, and lactic acid cannot be selected. Because the N in nitrate is oxidizing, and its strength is higher than that of cuprous and ferrous ions, nitrate and cuprous and ferrous ions cannot exist at the same time, and phosphoric acid and ferrous ions will also form precipitation, and lactic acid is oxidized to generate pyruvic acid under slow conditions, which is also unstable. Therefore, the present invention only selects hydrochloric acid and sulfuric acid as acidity regulators to prepare solution I.

[0037] The powder II of the present invention is an iodine-containing contrast agent, such as any one of iopromide, iopamidol, iomeprol, diatrizolar, ioversol, iohexol and iodixanol. Solution II selects raw materials such as hydrogen peroxide, alkyl peroxide, persulfate, perborate and the like as initiators, because these raw materials contain peroxide groups, which form a large amount of hydroxyl free radicals OH under the action of a reducing agent, providing an initiator for the system; the initiator is specifically tert-butyl hydroperoxide, peracetic acid, sodium peracetate, sodium persulfate and hydrogen peroxide. The concentration of the reducing agent in solution II is 0.2% to 5%, and when used, the powder II and solution II containing the contrast agent are mixed to form a second component.

[0038] The powder I and the supporting tools of the present invention are sterilized by EO. The solutions I and II contain relatively active ions, which are not easy to be sterilized by wet heat or dry heat, and EO cannot penetrate the solutions. The powder II is an iodine-containing contrast agent and is also sterilized by irradiation. Therefore, the powder II and the solutions I and II are sterilized by irradiation.

[0039] The supporting tool of the present invention is a double-lumen microcatheter composed of an inner and outer catheter. The first component is transported through the inner catheter. The size of the inner catheter is 1.2F to 1.8F. Since the inner catheter has a small aperture, it is necessary to control the concentration of the first component, that is, the concentration of powder I in solution I. The outer catheter mainly transports the second component. The size of the catheter can be selected according to clinical application, and the size is 1.8F to 3.0F. According to the formula of the embolic agent, the volume ratio of the first component and the second component is not necessarily 1:1, so the inner and outer volumes of the combination of the inner and outer catheters are not necessarily 1:1. The volume ratio of the first component V1 and the second component V2 of the present invention is 1:0.5 to 10. In addition, considering that the inner catheter enters the outer catheter through the adapter, there will be a certain bend at the front end. After entering the human body, it is ensured that the lengths of the inner and outer catheters are basically the same, so the inner catheter is 5 to 10 cm longer than the outer catheter.

[0040] The use of the above-mentioned embolic agent as a tumor embolization treatment material is also within the protection scope of the present invention.

[0041] The embolic hydrogel is composed of two powders, two solutions and supporting tools. Powder I is a multi-arm polyethylene glycol derivative with a double bond group, with 2-8 arms and a molecular weight of 3000-15,000. Powder II is an iodine-containing contrast agent, such as any one of iopromide, iopamidol, iomeprol, diatrizolam, ioversol, iohexol and iodixanol. Solution I is a reducing agent and an acidity regulator, wherein the reducing agent is one or more of ferrous sulfate, ferrous lactate, and ferrous gluconate, and the acidity regulator is hydrochloric acid or sulfuric acid. Solution II contains an aqueous solution of a peroxide initiator, such as hydroperoxide, alkyl peroxide, persulfate, such as tert-butyl hydroperoxide. Powder I and supporting tools of the present invention are sterilized by EO, and powder II, solution I and solution II are sterilized by irradiation.

[0042] Compared with the prior art, the present invention has the following advantages and effects:

[0043] (1) The present invention utilizes this structural feature of polyethylene glycol, selects polyethylene glycol with 2-8 arms, modifies the terminal double bond groups, and performs in situ cross-linking under initiation conditions to form an interventional tumor embolization hydrogel. The cross-linking point position gradually undergoes ester hydrolysis in vivo and is completely degraded within 3-12 months, making the degradation time of the hydrogel relatively moderate, between the non-degradable PVA microspheres and the gelatin microspheres that degrade too quickly, which not only meets the function of drug loading, but also meets the clinical demand for ablation after degradation;

[0044] (2) The reason why the multi-arm polyethylene glycol derivative is selected as the single active component for self-crosslinking in the embolic hydrogel of the present invention is that the hydrogel is instantaneously crosslinked at the tumor embolization site. If two active components are selected to crosslink each other and delivered to the tumor embolization site through the inner and outer catheters, the gelation effect will be affected if the delivery speeds of the inner and outer tubes are different. If one of the inner and outer tubes cannot be effectively delivered, the entire system cannot form a hydrogel and secondary remedy is not possible.

[0045] (3) In addition, the present invention selects multi-arm polyethylene glycol derivatives, considering that the multi-arm structure of polyethylene glycol can form multiple cross-linking points. Experimental verification shows that the more arms the polyethylene glycol has, the greater the cross-linking density of the hydrogel, and the better the sustained release effect of the contrast agent and tumor drug, that is, the contrast agent stays in the hydrogel for a longer time, which is convenient for postoperative follow-up observation. The release of tumor drugs will also be slower, improving the chemotherapy effect;

[0046] (4) adding an acidity regulator to solution I to ensure the stability of solution I after sterilization and to ensure that the reducing agent is effectively oxidized and the low-valent metal ions are fully converted into high-valent metal ions when reacting with the second component;

[0047] (5) The present invention discloses a sterilization method for preparing embolic hydrogels, and the prepared hydrogels can be effectively and safely used in clinical practice. Technicians can consider the requirements for sustained-release effects and the selection of ethylene oxide sterilization conditions and choose a suitable hydrogel formula. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 is the DSC result of AA-PEG-AA-3.4K in Example 2;

[0049] Figure 2 The DSC results of 4-arm PEG-AA, 5K in Example 2;

[0050] Figure 3 The DSC results of 6-arm PEG-AA, 7K in Example 2;

[0051] Figure 4 The DSC results of 8-arm PEG-AA, 10K in Example 2;

[0052] Figure 5 The zebra pig kidney was dissected 24 hours after surgery in Example 5;

[0053] Figure 6 This is the DSA spectrum of the hydrogel observed 24 hours after surgery in Example 5;

[0054] Figure 7 This is the DSA spectrum of PVA microspheres observed 24 hours after surgery in Example 5;

[0055] Figure 8 is the drug epirubicin release curve of Example 6;

[0056] Fig. 9 This is the release curve of the contrast agent iohexol in Example 6. DETAILED DESCRIPTION

[0057] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in conjunction with specific implementation methods.

[0058] Example 1 Selection of concentration of powder Ⅰ

[0059] Powder I has 2-8 acrylate or methacrylate groups with double bond groups, a molecular weight of 3000Da-15000Da, and a concentration of powder I in solution I of 10%-60% (i.e. 100-600mg / mL); powder I and solution I constitute the first component and are transported through a 1.7F, 150cm inner catheter.

[0060] Table 1 below summarizes the gelation, swelling (24h), and catheter push injection of powders with different structures or dosages during the experiment.

[0061] Table 1 Concentration screening of powder I

[0062]

[0063] As shown in Table 1 above, when the molecular weight is lower than 2000Da, the amount of 100mg cannot form a hydrogel. When the amount of 8-arm PEG-15K is 800mg, it is too viscous to be injected after adding 1mL of solution I, which is not conducive to clinical use. The swelling rate of the hydrogel prepared with 100mg and 600mg in different powders I is similar, and the swelling rate of 600mg is slightly lower. This is because the cross-linking density of the hydrogel increases with the increase of the powder concentration, and the gel network structure is denser, so the swelling rate is slightly lower. However, when the concentration is increased to 800mg, the gel effect is worse. This is because when the viscosity of the first component is too large, the solution of the second component is not easy to enter the first component, so the cross-linking effect is not good, the gel has fewer cross-linking points, and the swelling rate is greater, or even unable to form a gel.

[0064] Example 2 Sterilization method of powder Ⅰ

[0065] AA-PEG-AA-3.4K powder I was selected for sterilization experiments using irradiation sterilization and ethylene oxide sterilization. After sterilization, the gelation effect was verified. The results showed that the powder I after irradiation sterilization could not form a gel. This is because the acrylate or methacrylate group in the powder I contains double bonds. Under the irradiation of radiation, the double bonds are opened for self-crosslinking and aggregation, and it cannot form a gel. However, the powder I after ethylene oxide sterilization can still form a gel, so we chose ethylene oxide sterilization.

[0066] In addition, powders I with different numbers of arms, AA-PEG-AA, 3-arm PEG-AA, 4-arm PEG-AA, 6-armPEG-AA, and 8-arm PEG-AA, were selected for sterilization with ethylene oxide at a conventional temperature of 50°C. The results showed that 6-arm PEG-AA and 8-armPEG-AA powder I melted. When the temperature of ethylene oxide was further lowered to 40°C, the 6-arm PEG-AA and 8-arm PEG-AA powder I no longer melted, thus achieving sterilization.

[0067] Table 2 Phase transition temperature of powder Ⅰ

[0068] Name of powderⅠ Melting point / ℃ AA-PEG-AA, 3.4K 54.88 3-arm PEG-AA, 5K 53.39 4-arm PEG-AA, 7K 50.74 6-arm PEG-AA, 10K 48.20 8-arm PEG-AA, 15K 44.37 3-arm PEG-AA, 1.5K 39.44

[0069] It can be seen that the more branches the powder I has, the lower its melting point. When the number of arms is 2-4, the conventional sterilization temperature of ethylene oxide is 50°C, which can achieve the sterilization of powder I. When the number of arms is 6-8, the sterilization temperature of ethylene oxide needs to be reduced to 40°C to achieve the sterilization of powder I. The conventional sterilization time is generally 8h to 10h. We have verified that under the premise of ensuring the sterility of powder I, in order to reduce the impact of ethylene oxide on the activity of powder I, the sterilization time is reduced to 6h±1h. Technicians need to select the sterilization temperature according to actual conditions.

[0070] Example 3 Solution I Stability and Sterilization

[0071] 1% ferrous gluconate, ferrous sulfate and ferrous lactate were prepared as solution I respectively for direct sampling. In addition, phosphoric acid, sulfuric acid, nitric acid and hydrochloric acid were used to adjust the pH of solution I to 3 respectively. The state of the solution before and after pH adjustment was observed, see Table 3.

[0072] Table 3 Acidity regulator for solution I

[0073]

[0074] This is because when the pH value is greater than 3, the trivalent iron ions in the system are more stable, and the divalent iron ions in the solution are gradually converted into trivalent iron ions, and iron hydroxide precipitates. Therefore, a certain acidity regulator is used to adjust the pH to avoid the precipitation of trivalent iron ions.

[0075] When phosphoric acid is used as an acidity regulator to adjust the pH, solution I immediately produces precipitation. On the contrary, after nitric acid is used to adjust the pH, solution I produces precipitation after being left for a period of time. Therefore, phosphoric acid and nitric acid are not suitable for adjusting the pH of solution I. From the above table, it can be seen that sulfuric acid and hydrochloric acid are suitable acidity regulators.

[0076] Table 4 Preparation of hydrogels after adjusting the pH of solution I using an acidity regulator

[0077]

[0078] From the above table, we can see that the pH value of solution I is better at 2.5-3.5 for gelation.

[0079] The solution I (1% ferrous gluconate solution) after the pH was adjusted by the acidity regulator was sterilized by E electron beam irradiation sterilization. The content of divalent iron ions was tested before and after sterilization, and the solution was left for a certain period of time to observe whether there was precipitation. The results are as follows.

[0080] Table 5 Content detection of solution I before and after sterilization

[0081]

[0082] It can be seen from the above table that the content of divalent iron ions is more stable after adjusting the pH with an acidity regulator. Even after irradiation sterilization, the content of divalent iron ions will not change and no precipitation will occur in the solution.

[0083] Example 4 Preparation of powder, solution and embolic hydrogel

[0084] Powder I: Powder I was purchased from Xiamen Sinobond, packaged in a glove box at 300 mg / bottle, and then sterilized with ethylene oxide for later use.

[0085] Powder II: Take powder II, package it into 1200 mg / bottle, and sterilize it by irradiation for later use.

[0086] Solution I: Weigh 1 g of ferrous gluconate solution and add water to make up to 100 mL. Use 1% hydrochloric acid to adjust the pH value to 3.0. Dispense 100 mL of the above solution into 100 1 mL syringes and sterilize by irradiation for later use.

[0087] Solution II: Dissolve 0.15 g of tert-butyl hydroperoxide in 100 mL of purified water. Divide 100 mL of the above solution evenly into 100 1 mL syringes and sterilize by irradiation for later use.

[0088] The supporting tools include a coaxial double-lumen catheter, an adapter and an injection tool, which are sterilized with ethylene oxide and are ready for use.

[0089] The coaxial double-lumen catheter includes an inner catheter and an outer catheter. The catheter size is 1.2F to 1.8F and the length is 110 to 170cm. The outer catheter size is 1.8F to 3.0F and the length is 105 to 165cm.

[0090] The adapter consists of a three-way structure that connects two male Luers and one female Luer via a catheter.

[0091] The push injection tool is a push injection gun that can be installed with two side-by-side syringes and can push quantitatively. Preparation of embolic hydrogel: 300 mg of powder I is dissolved in 1 mL of solution I as the first component, and 1200 mg of powder II is dissolved in 1 mL of solution II as the second component. The first component and the second component are installed on the push injection gun, and the first component and the second component are simultaneously delivered to the embolization site through the coaxial double-lumen catheter of the matching tool through the inner catheter and the outer catheter, respectively. The first component and the second component are mixed and solidified to form an embolic hydrogel.

[0092] Example 5: Porcine renal artery embolization experiment

[0093] Using zebra pigs to test the effectiveness of embolic medical glue.

[0094] Test sample: the embolic hydrogel prepared in Example 4, specification 2 mL.

[0095] Reference substance: PVA microspheres, specification: 40-90μm

[0096] Experimental steps:

[0097] Preparation method of embolization medical glue: 1mL solution I is mixed with powder I and then drawn into a 2mL syringe, 1mL solution II is mixed with 1mL powder II and then drawn into a 2mL syringe, two 2mL syringes are placed in a double stand, and the injection speed is about 0.2mL / min.

[0098] Preparation method of PVA microspheres: draw the microspheres into a 20mL syringe, invert the syringe and wait for the microspheres to settle to push out the supernatant, then add 1 volume of iohexol.

[0099] In the same zebra pig, the catheter delivery system was placed into the secondary branch of the renal artery through the femoral artery under DSA fluoroscopy, the syringe containing the embolic material was connected to the microcatheter, the left kidney was embolized with embolic hydrogel, and the right kidney was embolized with PVA microspheres. DSA angiography was performed after surgery to examine the embolization. The animals were dissected at 12 months, and pathological observation showed that the hydrogel in the left kidney had degraded in the body, while the PVA microspheres in the right kidney had not degraded.

[0100] Depend on Figure 5 , Figure 6 , Figure 7 Animal experiments showed that both embolic hydrogel and PVA microspheres achieved effective embolization. Tissue dissection after 24 hours showed that small blood vessels were embolized at the site of hydrogel embolization, while no embolized small blood vessels were observed with PVA. Similarly, DSA also showed that embolic hydrogel was more effective than PVA microspheres in embolization. All small blood vessels in the lower part of the left kidney were embolized, while only the main large blood vessels were observed in the right kidney with PVA microspheres, and small blood vessels were still imaged.

[0101] Note: The animal experiments of this patent were conducted with both kidneys filled with blood, in order to compare the differences between hydrogels and microspheres. In some animal experiments, the blood in the kidneys was deliberately drained before embolization, although this could also be achieved. Figure 6 The DSA spectrum effect can be simulated, but it cannot simulate the actual clinical status.

[0102] Example 6 Comparison of contrast agent loading and epirubicin release in embolic hydrogel

[0103] Three different powders, AA-PEG-AA-3.4K, 3-arm PEG-5K, and 4-arm PEG-7K, were used to prepare drug-loaded or iohexol-containing hydrogels and compared with PVA microspheres.

[0104] Table 6 Drug epirubicin release rate

[0105]

[0106]

[0107] Table 7 Dissolution rate of contrast agent iohexol

[0108] Time / h Microspheres / % 3.4K / ％ 5K / ％ 7K / ％ 1 0 23 20 19 4 0 46 40 30 24 0 80 59 52 48 0 86 69 66 72 0 88 72 67 84 0 89 72 67

[0109] Depend on Figure 8 , Fig. 9 Combining Tables 6 and 7, it can be seen that as the number of powder I arms increases, the molecular weight increases, and the number of acrylate groups increases, which slows the release of epirubicin, but the release rate is not affected. The dissolution of hydrogel iohexol slows down with the increase of molecular weight, and the dissolution rate decreases with the increase of molecular weight. The presence of undissolved iohexol in the gel is convenient for subsequent clinical review to increase the imaging effect. PVA microspheres cannot load iohexol, so no iohexol is dissolved.

[0110] In summary, the embolic hydrogel provided by the present invention includes 2 powders and 2 solutions. When used, the powders and solutions are used in combination with corresponding tools. Powder I selects a multi-arm polyethylene glycol derivative with a double bond group, powder II selects an iodine-containing contrast agent, solution I includes a reducing agent and an acidity regulator, and solution II is an initiator. The embolic agent prepared by the present invention not only avoids the problem of secondary embolism caused by the embolic agent with a fast degradation time and insufficient embolic effect, but also realizes targeted step-by-step embolism, and can simultaneously meet the dual requirements of contrast imaging and drug loading. The above is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equal changes and modifications made within the scope of the present invention should still be within the scope of the present invention.

Claims

1. An embolic hydrogel capable of imaging, drug loading and moderate degradation, characterized in that: The components of the embolic hydrogel mainly include: Powder I, powder II, solution I, solution II; Powder I is a multi-arm polyethylene glycol derivative with double bond groups, the number of arms is 2 to 8, and the molecular weight is 3000-15000Da; Powder II is an iodine-containing contrast medium; the contrast medium is selected from any one of iopromide, iopamidol, iomeprol, diatrizolan, ioversol, iohexol and iodixanol; Solution I includes a reducing agent and an acidity regulator; The reducing agent is selected from a 2+ Cr 2+ 、V 2+ 、Ti 3+ 、Co 2+ , Cu + Any compound of The acidity regulator is selected from any one of hydrochloric acid and sulfuric acid; Solution II is an initiator, which is selected from any one of tert-butyl hydroperoxide, peracetic acid, sodium peracetate, sodium persulfate, and hydrogen peroxide.

2. The imaging, drug-carrying, moderately degradable embolic hydrogel as claimed in claim 1, characterized in that: Powder I is sterilized with ethylene oxide at 40-50°C and 40-80% humidity for 5-7 hours; The reducing agent is selected from any one or any two or more of ferrous sulfate, ferrous lactate and ferrous gluconate.

3. The imaging, drug-carrying, moderately degradable embolic hydrogel as claimed in claim 1, characterized in that: The embolic hydrogel also includes supporting tools used in conjunction with powder I, powder II, solution I and solution II; the supporting tools include a coaxial double-lumen catheter, an adapter and a push injection tool.

4. The imaging, drug-carrying, moderately degradable embolic hydrogel as claimed in claim 3, characterized in that: The coaxial double-lumen catheter comprises an inner catheter and an outer catheter; the inner catheter has a size of 1.2F to 1.8F and a length of 110 to 170cm; The outer catheter has a size of 1.8F~3.0F and a length of 105~165cm.

5. The imaging, drug-carrying, moderately degradable embolic hydrogel as claimed in claim 3, characterized in that: The adapter has a three-way structure, and is connected to two male Luers and one female Luer via a catheter.

6. The imaging, drug-carrying, moderately degradable embolic hydrogel as claimed in claim 3, characterized in that: The push injection tool is a push injection gun which can be equipped with two syringes arranged side by side and can perform quantitative push injection.

7. A method for preparing an embolic hydrogel capable of imaging, loading drugs and moderate degradation as claimed in claim 1, comprising the following steps: (1) Preparation of powder I: Weigh a multi-arm polyethylene glycol derivative with 2 to 8 arms and a molecular weight of 3000 to 15000 Da, and sterilize with ethylene oxide; (2) Preparation of powder II: Weigh an iodine-containing contrast agent, any one of iopromide, iopamidol, iomeprol, diatrizolan, ioversol, iohexol and iodixanol, and sterilize by irradiation; (3) Preparation of Solution I: Weigh the reducing agent and dissolve it in water for injection, adjust the pH to 2.5-3.5 with an acidity regulator, and sterilize by irradiation; (4) Preparation of solution II: Weigh the initiator and dissolve it in water for injection, and sterilize it by irradiation; (5) Preparation of embolic hydrogel: dissolving powder I in solution I as the first component; Dissolve powder II in solution II as the second component; The first component and the second component are delivered to the embolization site through the matching tool, and the first component and the second component are mixed and solidified to form the embolization hydrogel.

8. The preparation method as claimed in claim 7, characterized in that The amount of powder I in the first component of (5) is 10% to 60% of the mass of solution I; The dosage of powder II in the second component is 30%~300% of the mass of solution II; The iodine content of the second component is 15% to 35% of the mass of the embolic hydrogel; The first component is delivered through the inner conduit of the accessory tool, and the second component is delivered through the outer conduit of the accessory tool; The volume ratio of the first component: the second component is 1:0.5~10.

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