High-drug-loading tumor liquid embolism system and application thereof

Abstract

The invention discloses a high-drug-loading tumor liquid embolism system and application thereof, and belongs to the technical field of medical instruments. The system comprises an embolism polymer solution and a solvent used for dissolving a drug, the polymer can be dissolved at a high concentration by regulating the molecular weight of the block polymer, the solvent used for dissolving the drug can dissolve the high-concentration drug, and high-concentration drug loading is achieved after the solvent used for dissolving the drug is mixed with the embolism polymer solution. The requirements of some disease treatment on high-dose medicines are met.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, in particular to a high-drug-loading liquid embolization system for tumors and application thereof. BACKGROUND

[0002] Chemotherapy is a systemic treatment method. No matter what route of administration is used (oral, intravenous, and body cavity administration, etc.), the chemotherapy drug will block the blood flow and release the chemotherapy drug at the same time to kill the tumor. TACE can improve the local drug concentration, prolong the contact time of the drug with the tumor, and achieve the effect of slow drug release. Due to its good treatment effect, minimally invasive, repeatability and low risk of systemic side effects, TACE has been used to treat various malignant tumors, including hepatocellular carcinoma (HCC), cholangiocarcinoma, liver metastasis, lung cancer and cervical cancer. However, the traditional embolic TACE drug has certain limitations, such as low drug loading capacity and low local drug concentration.

[0003] Drug-loaded microspheres as a new type of embolic material have been gradually applied in liver cancer TACE surgery in recent years. However, according to relevant literature, drug-loaded microspheres also have certain problems, such as relatively low drug loading capacity, which cannot meet the demand for high-dose drugs for the treatment of some diseases. Although the existing microspheres such as DC / LC-Beads have achieved a high drug loading capacity, the theoretical maximum doxorubicin loading capacity can reach 45 mg / mL, but in actual application, too high drug loading capacity may affect the drug adsorption efficiency, for example, when the drug loading capacity exceeds a certain threshold, the time for the drug to be adsorbed onto the microspheres significantly increases. In addition, the drug loading performance of the drug-loaded microspheres needs to be balanced with the embolic effect, such as optimizing the material formula and preparation process to improve the drug loading efficiency while ensuring the accuracy and stability of embolization. Peplum is a new type of temperature-sensitive liquid embolic agent, and the maximum drug loading capacity of a single bottle of peplum is the maximum drug amount that can be dissolved in 2 ml of solvent. The mass concentration of the polymer in the formula product is not higher than 2%, and more product is needed to meet the embolization demand in clinical application.

[0004] Current research is exploring methods to improve drug loading concentration, but the balance between drug loading capacity and embolic material concentration is still a key problem that needs to be continuously solved to meet the demand for high-dose drug treatment and ensure the embolic effect. SUMMARY

[0005] The present application aims to provide a high-drug-loading liquid embolization system for tumors and application thereof. The present application uses PEG-PCL-I as an embolic polymer, which has the characteristics of high concentration dissolution, and after mixing with another part of DMSO, a suitable embolic concentration of 30-50% is achieved; and another part of DMSO can also dissolve drugs, and after mixing with the embolic polymer solution, high-concentration drug loading is achieved.

[0006] One of the technical solutions of the present application is to provide a high drug-loading tumor liquid embolization system, which comprises an embolization polymer solution and a solvent for dissolving drugs, and in the embolization polymer solution, the mass concentration of the embolization polymer is 50-70%; the embolization polymer is an iodinated copolymer, and the solvent is a mixed solution of DMSO and ethanol. The solvent for dissolving drugs is DMSO.

[0007] The embolization polymer comprises hydrophilic segments PEG and hydrophobic segments PCL; the molecular weight of the hydrophilic segment PEG is 1000-1500, and the molecular weight ratio of the hydrophilic segment PEG to the hydrophobic segment PCL is 0.3-1.5:1.

[0008] The preparation method of the embolization polymer is as follows: a block copolymer is obtained by copolymerization of a hydrophobic monomer under the initiation of an initiator PEG; an iodinated copolymer is obtained by covalent bonding of an iodine-containing small molecule and the block copolymer. The copolymer segment formed by the hydrophobic monomer is a PCL segment.

[0009] Specifically, the initiator PEG and caprolactone monomers are mixed, heated, vacuumed to remove water for 1 h, and then a catalyst is added for reaction. After the reaction is completed, precipitation is performed with n-hexane, and vacuum drying is performed to obtain a block copolymer. The block copolymer is taken out, dissolved in super-dry dichloromethane at room temperature, and stirred. Triiodobenzoic acid is dissolved in N,N-dimethylformamide, and DCC (dicyclohexyl carbodiimide) and DMAP (4-dimethylaminopyridine) are dissolved in super-dry dichloromethane. The three solutions are mixed in a single-neck flask of 250 mL for reaction. After the reaction is completed, the product is further purified with n-hexane, the precipitate is collected, and then placed in a vacuum oven for drying for 24-72 h to obtain the final product, an iodinated copolymer (embolization polymer).

[0010] Further, the mass ratio of ethanol to DMSO in the solvent of the embolization polymer solution is 0-2.4:1. Preferably, the initiator PEG is PEG1000 or PEG1500.

[0011] The embolization polymer of the present application is a block copolymer obtained by copolymerization of a hydrophobic monomer under the initiation of an initiator PEG; wherein the hydrophobic monomer forms a hydrophobic segment, and PEG constitutes a hydrophilic segment; by adjusting the molecular weight of the initiator and the ratio of the block monomers, the hydrophilic and hydrophobic properties of the copolymer are adjusted, so as to optimize the compatibility of the copolymer and the drug / DMSO mixed solution.

[0012] The second technical solution of the present application is to provide a drug-loading method of the above-mentioned high drug-loading tumor liquid embolization system, wherein a therapeutic drug is dissolved in a solvent for dissolving drugs, and then mixed with an embolization polymer solution; the concentration of the embolization polymer is 40-60 wt%.

[0013] The present application has the advantages that a high drug loading tumor liquid embolization system is ingeniously designed, PEG-PCL-I is used as the embolic polymer, the polymer has the characteristics of high concentration dissolution, and after being mixed with another part of DMSO, a suitable embolic concentration of 30-50% is reached; and another part of DMSO can also dissolve drugs, and after being mixed with the embolic polymer solution, high concentration drug loading is achieved. The drug loading of the system is not less than 50 mg, and can be as high as 200 mg. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1 Drug release of system 2 after drug loading; Figure 2 Embolization effect of 1 mL embolic agent of system 2 after drug loading; Figure 3 Embolization effect of 1 mL embolic agent of the comparative example temperature-sensitive liquid embolic agent. DETAILED DESCRIPTION

[0015] The following examples are used to further illustrate the present application, and the purpose is to illustrate the present application, and should not be interpreted as limiting the scope of the present application. The following uses weight parts and weight percentages unless otherwise specified.

[0016] The raw materials used in the present application are conventional commercially available products unless otherwise specified; the methods used in the present application are conventional methods in the art unless otherwise specified.

[0017] The preparation method of the PEG-PCL-I block copolymer described in the present application is the same as CN 118755063 B.

[0018] The following examples are used to further illustrate the present application, and the purpose is to illustrate the present application, and should not be interpreted as limiting the scope of the present application. The following uses weight parts and weight percentages unless otherwise specified.

[0019] It should be clear that the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0020] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0021] Example 1: High concentration formula test Mix PEG initiator and caprolactone monomer, heat up, vacuum to remove water for 1h, then add catalyst to react. After the reaction, precipitate with n-hexane, vacuum dry to get block copolymer. Take the block copolymer above, add to super dry dichloromethane to stir and dissolve at room temperature, take triiodobenzoic acid to dissolve in N, N dimethylformamide, take DCC (dicyclohexyl carbodiimide) and DMAP (4 dimethylamino pyridine) to dissolve in super dry dichloromethane. Put the above three solutions in a single port bottle 250mL to react. After the reaction, further purify the product obtained above with n-hexane, collect the precipitate, and then put it into a vacuum oven to dry for 24 ~ 72h to get the final product iodinated copolymer (embolization polymer).

[0022] The specific parameters are as follows: Common liver cancer chemotherapy drugs such as anthracyclines such as irinotecan hydrochloride and doxorubicin hydrochloride, and mitomycin such as mitomycin C, of which doxorubicin hydrochloride is a commonly used representative drug in tumor embolization. The solubility experiment shows that 0.5mL DMSO can dissolve more than 500mg of doxorubicin hydrochloride, 0.5mL DMSO can dissolve more than 150mg of irinotecan hydrochloride, and 0.5mL DMSO can dissolve more than 100mg of mitomycin C. Since the conventional drug loading amount of drug-loaded microspheres commonly used in actual clinical practice is 30-50mg, the present application preliminarily uses the conventional drug loading amount of 50mg and the maximum drug loading amount to verify the compatibility of the above material formula (PECL1-PECL12) and the drug.

[0023] Take any 0.50g of the above composite copolymer, add 0.50g of DMSO, and stir to dissolve at room temperature to get 2.5mL in bottle A and 0.5mL DMSO solution in bottle B. As can be seen from the above experimental cases, when the conventional drug loading amount in clinical practice is 50mg, it has good compatibility with the system. When the drug dosage is increased, the larger the molecular weight of PEG-PCL-I, the worse the compatibility, which is due to the increase of the proportion of hydrophobic segment, which competes with the solubility of the drug in DMSO.

[0024] Based on the above experiments, high concentration formula research is carried out: in order to meet the basic function of development, the iodine content of more than 20% of the polymer is preferred, in order to meet the high solubility requirement, the relative molecular weight is as low as possible, the invention selects PECL-5 (PEG1000-PCL-I) and PECL-11 (PEG1500-PCL-I) to carry out high concentration formula test. DMSO is the key solvent for dissolving PECL, and PECL-1 to PECL-12 raw materials can be used with pure DMSO high concentration (50-70%), in order to reduce the vascular irritation, part of DMSO is replaced by ethanol, and excessive ethanol will cause PECL to be insoluble, therefore, in the case of meeting the formula solubility, the amount of DMSO is as low as possible. From the above experimental cases, it can be seen that the low molecular weight polymer can be dissolved to 50-70%, the DMSO can be controlled at a low concentration of 15%, and the ethanol content can be controlled at 35% without affecting the solubility of the formula.

[0025] Example 2: Tumor embolization system (high drug loading formula) The formula of example 1 is A bottle (in turn formula 1, formula 2, formula 7, formula 8, formula 9), the volume is 2.5 mL, 0.5 mL DMSO is used as B bottle, 100 mg of drug is dissolved in B bottle DMSO, and the drug compatibility of several liver cancer chemotherapy drugs is verified, and the results show that the system in the invention is suitable for common chemotherapy drugs. Example 3: Tumor embolization system (high drug loading formula) The formula of example 1 is A bottle, the volume is 2.0 mL, 1 mL DMSO is used as B bottle, 200 mg of doxorubicin hydrochloride is dissolved in B bottle DMSO, and the compatibility is verified after mixing with the embolization polymer solution A bottle. The results show that the DMSO solution after mixing with the drug has good compatibility with the A bottle. Example 4: Tumor embolization system (high drug loading formula) The formula of example 1 is A bottle, the volume is 5.0 mL, 0.5 mL DMSO is used as B bottle, 100 mg of doxorubicin hydrochloride is dissolved in B bottle DMSO, and the compatibility is verified after mixing with the embolization polymer solution A bottle. The results show that the DMSO solution after mixing with the drug has good compatibility with the A bottle. Example 5: Tumor embolization system (high drug loading formula) Take the formulation of Example 1 as A bottle, volume 5.0 mL, take 1.0 mL DMSO as B bottle, use 200 mg doxorubicin hydrochloride dissolved in DMSO in B bottle to mix with the embolization polymer solution A bottle to verify the compatibility. The results show that the DMSO solution after mixing with the drug has good compatibility with the A bottle. Example 6: Clinical configuration of tumor embolization system In order to facilitate the convenience and flexibility of drug loading for clinical operation, under the condition of meeting the basic embolization and drug loading, the embolization effect of the drug-loaded embolization agent after mixing the drug (100 mg doxorubicin hydrochloride) loaded by system 2 with different DMSO amounts with A bottle is studied: the mechanical properties and whether it has the ability of distal embolization of the drug-loaded embolization agent are judged by rabbit ear embolization experiment; the mechanical property evaluation standard: whether the embolization material is lost from the rabbit ear; the distal embolization evaluation standard: whether it reaches the distal ear artery; the drug solubility is judged: take an appropriate amount of liquid in B bottle, add 100 mg of drug powder, shake manually, and record the dissolution time. In order to reduce the vascular irritation, as much as possible, use less DMSO, the results show that taking 0.5-0.8 mL is most suitable for clinical application. Example 7: Drug release property of system 2 after drug loading Take 100 mg of doxorubicin drug and place it in a centrifuge tube, use a 1 mL syringe to extract 0.5 mL of DMSO solution from B bottle and inject it into the centrifuge tube, shake manually for 1 min, then the drug is completely dissolved, then use the syringe to extract and inject the drug solution into A bottle, shake manually for 1 min to mix evenly, and get the drug-loaded embolization agent. Drug release experiment: place a 50 mL centrifuge tube on an electronic balance and set it to zero, use a flat 100 μL microsyringe to add 20 μL of drug-loaded embolization agent to the conical bottom of the centrifuge tube, and record the mass. Add 20 mL of preheated release medium (PBS or normal saline) to the centrifuge tube, then place the centrifuge tube in a 37°C shaking bed, set the rotation speed to 100 rpm. The parallel control sample is not less than 3 groups. Time starts from the moment when the release medium is added, and at the set time point, the result is analyzed using a UV-vis spectrophotometer. The drug release property of system 2 is as Figure 1 The drug is slowly released within 24 h, and the release rate is more than 90% at 24 h.

[0026] Example 8: Embolization effect of system 2 after drug loading Take 100 mg of doxorubicin drug and place it in a centrifuge tube. Use a 1 mL syringe to extract 0.5 mL of DMSO solution from bottle B and inject it into the centrifuge tube. Shake the tube manually for 1 min until the drug is completely dissolved. Then use the syringe to extract the drug solution and inject it into bottle A. Shake the mixture manually for 1 min to obtain the drug-loaded embolization agent. Perform a rabbit renal artery embolization experiment: fix the rabbit with a fixator, remove the hair from the ears, abdomen, and groin, spray the ear margin vein with alcohol to dilate the ear margin vein, inject 10 mL of prepared urethane solution, clamp the rabbit's leg skin with hemostatic forceps, and confirm complete anesthesia of the rabbit. If there is still a reaction, continue to supplement the appropriate amount of urethane. After the rabbit is completely anesthetized, proceed to the next step; fix the rabbit in a supine position on an acrylic plate. Wrap the limbs with masking tape and then fix them to the acrylic plate. Touch the groin to find the arterial pulsation point. After confirming the pulsation point, make a linear incision 2-3 cm to the left of the groin. Use blunt dissection to separate the femoral bundle including the femoral vein, femoral artery, and nerve, and completely separate the femoral artery using a surgical curved forceps. Use a puncture needle to thread the femoral artery, and after seeing arterial blood flow out of the tube, perform interventional catheterization. After successful catheterization, perform catheterization. After the catheter is inserted into the renal artery, perform contrast imaging using a DSA surgical operating table. After confirming successful catheterization, flush the catheter with normal saline. After flushing, inject 1 mL of embolization solution at a rate of 1 mL / min. Use PEG300 to continue pushing the remaining embolic agent in the catheter into the blood vessel at a rate of 1 mL / min. After injection is complete, wait for 30 min, and inject contrast agent to observe the vascular embolization. The results show that the drug-loaded embolic agent prepared by mixing system 2 can achieve distal embolization, and the real-time imaging effect is good (a), and after 30 min of reexamination, the contrast agent cannot enter the kidney, indicating that 1 mL of embolic solution is sufficient to embolize the entire kidney (b). Figure 2 Figure 2

[0027] Comparative Example 1 A commercially available temperature-sensitive liquid embolic agent (Pepisense) was used to perform embolization experiments. A kidney of similar size to Example 8 was selected, and the embolic material was injected at a rate of 1 mL according to the above injection method. After injection was complete, a 30 min contrast was performed, and it was found that the distal embolization was successful, and the contrast agent was visible from the distal to the proximal blood vessels, indicating that 1 mL of the embolic agent of Comparative Example 1 was difficult to embolize the entire kidney (a). The polymer concentration in the product of Comparative Example 1 is not higher than 2%; therefore, the embolic solution prepared using a high-concentration dissolved polymer in the present patent formulation can achieve better embolization effects with less volume. Figure 3

[0028] Comparative Example 2 The preparation method of Example 1 was further used to obtain other hydrophilic-hydrophobic ratio PEG-PCL-I block copolymers, and the specific parameters are as follows: ​​​ Take 0.50g of any of the above composite copolymer, add 0.50g of DMSO, and stir to dissolve at room temperature to obtain 2.5mL of A bottle and 0.5mL of B bottle DMSO solution. Verify the above material formula and different content of doxorubicin hydrochloride drug compatibility. From the above experimental results, it can be seen that as the molecular weight of PEG-PCL-I increases, the hydrophilic-hydrophobic ratio decreases, resulting in a decrease in compatibility with the drug. This is mainly due to the increase in the proportion of hydrophobic segments, which competes with drug molecules for solvent environment in the DMSO system, thereby weakening the drug loading capacity.

[0029] The above examples illustrate the structure, features and effects of the present application. The above description is only the preferred embodiment of the present application. Any changes or modifications made in accordance with the concept of the present application, or equivalent embodiments with equivalent changes, shall be within the scope of the present application.

Claims

1. A high-drug-loaded tumor liquid embolization system, characterized in that, Includes embolizing polymer solutions and solvents used to dissolve drugs; In the embolization polymer solution, the mass concentration of the embolization polymer is 50-70%; the embolization polymer is an iodinated copolymer, and the solvent is a mixed solution of DMSO and ethanol; The solvent used to dissolve the drug is DMSO.

2. The high-drug-loaded tumor liquid embolization system according to claim 1, characterized in that, The embolic polymer includes hydrophilic segment PEG and hydrophobic segment PCL; the molecular weight of hydrophilic segment PEG is 1000~1500, and the molecular weight ratio of hydrophilic segment PEG to hydrophobic segment PCL is 0.3~1.5:

1.

3. The high-drug-load tumor liquid embolization system according to claim 2, characterized in that, The preparation method of the embolic polymer is as follows: a block copolymer is obtained by copolymerizing hydrophobic monomers under the initiation of PEG; an iodinated copolymer is obtained by covalently bonding iodine-containing small molecules to the block copolymer; The copolymer segments formed by the hydrophobic monomers are PCL segments.

4. The high-drug-loaded tumor liquid embolization system according to claim 1, characterized in that, In the solvent of the embolic polymer solution, the mass ratio of ethanol to DMSO is not greater than 2.

34.

5. A drug delivery method for the high-drug-load tumor liquid embolization system as described in claim 1, characterized in that, The therapeutic drug is dissolved in a solvent used to dissolve the drug, and then mixed with the embolic polymer solution; the concentration of the embolic polymer after mixing is 33~60wt%.

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