Embolism microsphere capable of loading platinum drugs, drug-loaded embolism microsphere and preparation method of drug-loaded embolism microsphere

Abstract

The embodiment of the invention provides an embolism microsphere capable of loading platinum drugs, a drug-loaded embolism microsphere and a preparation method, and relates to the technical field of medical instruments. The structural main chain of the embolism microsphere capable of loading the platinum medicine contains adjacent carboxyl groups, and the two adjacent carboxyl groups and platinum ions in the platinum medicine can form an annular structure. The embolism microsphere provided by the embodiment of the invention can be used for efficiently loading platinum drugs.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular to an embolic microsphere capable of loading platinum drugs, a drug-loaded embolic microsphere, and a preparation method thereof. Background Art

[0002] Platinum drugs are an important class of chemotherapy drugs, which are widely used in the treatment of various cancers, including lung cancer, nasopharyngeal carcinoma, ovarian cancer, breast cancer, etc. The main mechanism of action of these drugs is to form adducts with DNA, inhibit DNA replication and transcription of tumor cells, and thus induce cell apoptosis.

[0003] D-TACE aims to reduce the systemic side effects of chemotherapy and increase the duration of action by loading chemotherapy drugs onto embolic microspheres. However, the embolic microspheres currently prepared generally load drugs through ion action, and the types of drugs loaded are limited, mainly anthracyclines (doxorubicin or epirubicin, etc.), especially unable to achieve effective loading of platinum drugs such as cisplatin and oxaliplatin. Summary of the invention

[0004] The purpose of the embodiments of the present application is to provide an embolic microsphere capable of loading platinum drugs, a drug-loaded embolic microsphere and a preparation method, which can efficiently load platinum drugs.

[0005] In a first aspect, the embodiments of the present application provide an embolic microsphere capable of loading a platinum drug, wherein the main chain of the microsphere structure contains adjacent carboxyl groups, and two adjacent carboxyl groups can form a ring structure with platinum ions in the platinum drug.

[0006] In the above technical solution, the embolic microspheres can efficiently load platinum drugs. Specifically, the main chain of the embolic microsphere structure contains adjacent carboxyl groups, which can form a relatively stable ring structure with platinum drugs. This ring structure will be converted into platinum drugs and released under the action of chloride ions in the body, thereby taking effect.

[0007] In a possible implementation, the structure of the embolic microspheres includes a three-dimensional network structure formed by cross-linking polymerization of polymaleic anhydride, a monomer copolymerizable with maleic anhydride and containing electron-rich double bonds, and a cross-linking agent containing multiple polymerizable double bonds.

[0008] In the above technical scheme, maleic anhydride and monomers are copolymerized under the action of a cross-linking agent to form embolic microspheres. Maleic anhydride provides adjacent carboxyl groups after hydrolysis, which can be loaded with cationic drugs like ordinary microspheres, as well as platinum drugs. The monomers can form alternating copolymers with maleic anhydride to solve the problem that maleic anhydride is difficult to copolymerize, while also increasing the hydrophilicity and biocompatibility of the microspheres.

[0009] In a possible implementation, the monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether, and butyl vinyl ether.

[0010] In the above technical solution, the above monomers can form an alternating copolymer with maleic anhydride.

[0011] In a possible implementation, the cross-linking agent includes at least one of p-phenylene glycol, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether, and 1,4-cyclohexyl dimethanol divinyl ether.

[0012] In a second aspect, an embodiment of the present application provides a method for preparing embolic microspheres capable of loading platinum drugs according to the first aspect, wherein maleic anhydride, a monomer copolymerizable with maleic anhydride and containing electron-rich double bonds, and a cross-linking agent containing multiple polymerizable double bonds are subjected to suspension polymerization.

[0013] In a possible implementation, the monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether, and butyl vinyl ether;

[0014] The cross-linking agent includes at least one of terephthalene, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether, and 1,4-cyclohexyl dimethanol divinyl ether.

[0015] In a possible implementation, the following steps are included:

[0016] Dropping a mixed solution containing the maleic anhydride, the monomer and the cross-linking agent into a sodium chloride solution, and performing a suspension polymerization reaction to generate microspheres;

[0017] The microspheres are hydrolyzed.

[0018] In the above technical solution, suspension polymerization in sodium chloride solution can reduce solubility and inhibit hydrolysis.

[0019] In a possible implementation, the mixed solution further contains a catalyst, and the catalyst includes azobisisobutyronitrile;

[0020] and / or, adding a dispersant to the sodium chloride solution, wherein the mass concentration of the sodium chloride solution is 10%-30%; the dispersant comprises polyvinyl alcohol;

[0021] and / or, the reaction temperature is 50-70°C and the reaction time is 15-25h;

[0022] And / or, the microspheres are mixed with a sodium hydroxide solution for hydrolysis, wherein the mass concentration of the sodium hydroxide solution is 3%-10%.

[0023] In a third aspect, the present application provides a drug-loaded embolic microsphere, the structural formula of which is as follows:

[0024] R is ammonia or an amino group.

[0025] In a fourth aspect, the present application provides a method for preparing the drug-loaded embolic microspheres according to the third aspect, which comprises the following steps:

[0026] The platinum drug is dissolved in a glucose solution and mixed with the embolic microspheres of the first aspect, and samples are taken until the concentration of the platinum drug in the solution no longer decreases. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments of the present application will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0028] Figure 1 is a Mirco CT image of the embolic microspheres of Example 4;

[0029] Figure 2 This is the Micro CT image of the embolic microspheres of Example 5. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0031] The embolic microspheres capable of loading platinum drugs, the drug-loaded embolic microspheres and the preparation method of the embodiments of the present application are described in detail below.

[0032] The present application embodiment provides an embolic microsphere capable of loading a platinum drug, wherein the main chain of the microsphere structure contains adjacent carboxyl groups, and two adjacent carboxyl groups can form a ring structure with platinum ions in the platinum drug. In the present application embodiment, the carboxyl group can be -COOH or a carboxylate group (such as -COONa).

[0033] Exemplarily, the structural formula of the embolic microspheres is as follows:

[0034]

[0035] In some embodiments of the present application, the structure of the embolic microspheres includes a three-dimensional network structure formed by cross-linking polymerization of polymaleic anhydride, a monomer copolymerizable with maleic anhydride and containing electron-rich double bonds, and a cross-linking agent containing multiple polymerizable double bonds.

[0036] In some embodiments of the present application, the monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether (HBVE), and butyl vinyl ether (BVE); optionally, the monomer includes 4-iodostyrene.

[0037] In some embodiments of the present application, the cross-linking agent includes at least one of terephthalene, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether (DVE-3), and 1,4-cyclohexyl dimethanol divinyl ether (CHVE).

[0038] As an embodiment, the structural formula of the embolic microspheres that can be loaded with platinum drugs is as follows:

[0039]

[0040] The structure of the embolic microsphere can be a three-dimensional network structure formed by cross-linking polymerization of polymaleic anhydride, monomer vinyl acetate and cross-linking agent p-phenylene vinyl, and the main chain of the structure contains adjacent sodium carboxylate groups.

[0041] The embolic microspheres of the present application can also be self-imaging embolic microspheres, and the structure of the self-imaging embolic microspheres contains iodine. As an embodiment, the structure of the self-imaging embolic microspheres is as follows:

[0042]

[0043] The present application also provides a method for preparing embolic microspheres capable of loading platinum drugs according to the aforementioned embodiment, comprising suspension polymerizing maleic anhydride, a monomer copolymerizable with maleic anhydride and containing electron-rich double bonds, and a cross-linking agent containing multiple polymerizable double bonds.

[0044] In some embodiments of the present application, the monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether (HBVE), and butyl vinyl ether (BVE); the cross-linking agent includes at least one of terephthalate, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether (DVE-3), and 1,4-cyclohexyl dimethanol divinyl ether (CHVE).

[0045] In some embodiments of the present application, it includes the following steps:

[0046] (1) A mixed solution containing maleic anhydride, a monomer and a cross-linking agent is formed.

[0047] In some embodiments of the present application, the mixed solution further contains a catalyst, and the catalyst includes azobisisobutyronitrile (AIBN).

[0048] (2) dropping the mixed solution into a sodium chloride solution and performing a suspension polymerization reaction to generate microspheres;

[0049] In some embodiments of the present application, a dispersant is added to a sodium chloride solution, and the mass concentration of the sodium chloride solution is 10%-30%; the dispersant includes polyvinyl alcohol.

[0050] In some embodiments of the present application, the reaction temperature is 50-70° C., and the reaction time is 15-25 h.

[0051] (3) Hydrolyzing the microspheres.

[0052] In some embodiments of the present application, the microspheres are mixed with a sodium hydroxide solution for hydrolysis, and the mass concentration of the sodium hydroxide solution is 3%-10%.

[0053] As an implementation method, embolic microspheres are mainly prepared by reacting three raw materials, namely: maleic anhydride, vinyl acetate and terephthalene. Maleic anhydride provides adjacent carboxyl groups after hydrolysis, and vinyl acetate can form alternating copolymers with maleic anhydride. Terephthalene acts as a crosslinking agent and can copolymerize with vinyl acetate and maleic anhydride. The microspheres obtained by the reaction are hydrolyzed with sodium hydroxide solution to obtain embolic microspheres that can load platinum drugs. The overall reaction process is as follows:

[0054]

[0055] In order to make the embolization microspheres self-radioscopic, the method may further include reacting the prepared embolization microspheres with an iodine-containing developer to introduce iodine.

[0056] As an embodiment, the reaction process of the self-imaging embolization microspheres is as follows:

[0057]

[0058] The present application embodiment provides a drug-loaded embolic microsphere, the structural formula of which is as follows:

[0059] R is ammonia or an amino group.

[0060] In the present application, two Rs may be the same or different and are generally ortho-amino groups.

[0061] The present application provides a method for preparing the drug-loaded embolic microspheres of the aforementioned embodiment, which comprises the following steps:

[0062] The platinum drug is dissolved in a glucose solution and mixed with the embolic microspheres of the aforementioned example, and samples are taken until the concentration of the platinum drug in the solution no longer decreases.

[0063] In some embodiments of the present application, the platinum drug may be cisplatin, lobaplatin, nedaplatin, etc. The platinum drug chelates with the embolic microspheres to form a relatively stable ring structure, which is similar to oxaliplatin.

[0064] The features and performance of the present application are further described in detail below in conjunction with the embodiments.

[0065] Example 1

[0066] This embodiment provides an embolic microsphere, and the preparation process thereof is as follows:

[0067] 9.8g maleic anhydride (molecular weight 98), 8.6g vinyl acetate (molecular weight 86), 0.57g ethylene glycol divinyl ether (molecular weight 114), 0.1g AIBN were dissolved in 50mL toluene, added dropwise to 300mL 20% sodium chloride solution containing 3g polyvinyl alcohol, dispersed at 200rpm with mechanical stirring, heated to 60 degrees for 20h, filtered, washed three times with ethanol, and washed three times with purified water to obtain microspheres.

[0068] The microspheres were added into 500 mL of 5% sodium hydroxide, stirred for 4 h, and washed with purified water.

[0069] Example 2

[0070] This embodiment provides an embolic microsphere, and the preparation process thereof is as follows:

[0071] 9.8g maleic anhydride (molecular weight 98), 10.4g styrene (molecular weight 104), 0.57g ethylene glycol divinyl ether (molecular weight 114), 0.1g AIBN were dissolved in 50mL toluene, added dropwise to 300mL sodium chloride solution containing 3g polyvinyl alcohol 20%, dispersed by mechanical stirring at 200rpm, heated to 60 degrees for 20h, filtered, washed three times with ethanol, and washed three times with purified water to obtain microspheres.

[0072] The microspheres were added into 500 mL of 5% sodium hydroxide, stirred for 4 h, and washed with purified water.

[0073] Example 3

[0074] This embodiment provides an embolic microsphere, and the preparation process thereof is as follows:

[0075] 9.8g maleic anhydride (molecular weight 98), 23.3g 4-iodostyrene (molecular weight 230), 0.65g p-phenylene (molecular weight 130), 0.1g AIBN were dissolved in 50mL toluene, added dropwise to 300mL sodium chloride solution containing 3g polyvinyl alcohol 20%, dispersed by mechanical stirring at 200rpm, heated to 60 degrees for 20h, filtered, washed three times with ethanol and washed three times with purified water to obtain microspheres.

[0076] The microspheres were added into 500 mL of 5% sodium hydroxide, stirred for 4 h, and washed with purified water.

[0077] Example 4

[0078] This embodiment provides an embolic microsphere, and the preparation process thereof is as follows:

[0079] 9.8g maleic anhydride (molecular weight 98), 7.2g ethyl vinyl ether (molecular weight 72), 0.57g ethylene glycol divinyl ether (molecular weight 114), 0.1g AIBN were dissolved in 50mL toluene, added dropwise to 300mL sodium chloride solution containing 3g polyvinyl alcohol 20%, dispersed by mechanical stirring at 200rpm, heated to 60 degrees for 20h, filtered, washed three times with ethanol, and washed three times with purified water to obtain microspheres.

[0080] The microspheres were added into 500 mL of 5% sodium hydroxide, stirred for 4 h, and washed with purified water.

[0081] Example 5

[0082] This embodiment provides an embolic microsphere, and the preparation process thereof is as follows:

[0083] 9.8g maleic anhydride (molecular weight 98), 23.3g 4-iodostyrene (molecular weight 230), 0.79g diethylene glycol divinyl ether (molecular weight 158), 10g methyl methacrylate, 0.1g AIBN were dissolved in 50mL toluene, added dropwise to 300mL sodium chloride solution containing 3g polyvinyl alcohol 20%, dispersed by mechanical stirring at 200rpm, heated to 60 degrees for reaction for 20h, filtered, washed three times with ethanol, and washed three times with purified water to obtain microspheres.

[0084] The microspheres were added into 500 mL of 5% sodium hydroxide, stirred for 4 h, and washed with purified water.

[0085] Comparative Example 1

[0086] Comparative Example 1 provides an embolic microsphere, which is a commercially available microsphere HepaSphere.

[0087] 1. Drug loading experiment

[0088] 100 mg of cisplatin was dissolved in 10 mg of glucose solution, mixed with 2 ml of embolic microspheres, and sampled until the concentration of cisplatin no longer decreased. The concentration of cisplatin was tested using high performance liquid chromatography, and the drug loading of the embolic microspheres was calculated.

[0089] 2. Development Experiment

[0090] HU value test method: The developed microspheres obtained in each embodiment and comparative example were subjected to Micro CT test (Bruker skyscan1276).

[0091] The strength and elasticity test method is: use the TA.XT.plus C texture analyzer system for testing, select a 6mm probe, a trigger force of 0.1g, compress the microspheres to 50% and hold for 60 seconds.

[0092] Figure 1 and Figure 2 The images of the embolic microspheres of Example 4 and Example 5 under Micro CT are shown respectively. By comparison, it can be seen that the embolic microspheres of Example 5 can be visualized.

[0093] The results of the above experiments are shown in the following table:

[0094] Table 1 Drug loading and imaging results of different embolic microspheres

[0095] serial number Drug loading mg / ml Drug loading rate Drug loading time Hu value Strength g Example 1 85 85％ 40min N / A 270.6 Example 2 90 90％ 30min N / A 641.7 Example 3 93 93％ 40min 2540 507.4 Example 4 95 95％ 40min N / A 460.5 Example 5 90 90％ 30min 2300 283.8 Comparative Example 1 10 10％ 40min N / A 89.4

[0096] It can be seen from the above results that the embolic microspheres of the embodiments of the present application can be loaded with platinum drugs, and the drug loading amount meets the application requirements; in addition, the embolic microspheres can also be combined with developer monomers to form developing microspheres.

[0097] In summary, the embolic microspheres capable of loading platinum drugs, drug-loaded embolic microspheres, and preparation methods of the embodiments of the present application can load cationic drugs as well as platinum drugs.

[0098] The above description is only an embodiment of the present application and is not intended to limit the protection scope of the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. An embolic microsphere capable of loading a platinum drug, characterized in that: The main chain of the structure contains adjacent carboxyl groups, and two adjacent carboxyl groups can form a ring structure with platinum ions in platinum drugs.

2. The embolic microspheres capable of loading platinum drugs according to claim 1, characterized in that: The structure of the embolic microspheres comprises a three-dimensional network structure formed by cross-linking polymerization of polymaleic anhydride, a monomer copolymerizable with maleic anhydride and containing electron-rich double bonds, and a cross-linking agent containing multiple polymerizable double bonds.

3. The embolic microspheres capable of loading platinum drugs according to claim 2, characterized in that: The monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether, and butyl vinyl ether.

4. The embolic microspheres capable of loading platinum drugs according to claim 2, characterized in that: The cross-linking agent includes at least one of terephthalene, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether, and 1,4-cyclohexyl dimethanol divinyl ether.

5. A method for preparing embolic microspheres capable of loading platinum drugs according to any one of claims 1 to 4, characterized in that: Maleic anhydride, a monomer copolymerizable with maleic anhydride and containing an electron-rich double bond, and a crosslinking agent containing a plurality of polymerizable double bonds are subjected to suspension polymerization.

6. The method for preparing embolic microspheres capable of loading platinum drugs according to claim 5, characterized in that: The monomer includes at least one of vinyl acetate, ethyl vinyl ether, styrene, 4-iodostyrene, methyl vinyl ether, hydroxybutyl vinyl ether, and butyl vinyl ether; The cross-linking agent includes at least one of terephthalene, diethylene glycol divinyl ether, ethylene glycol divinyl ether, triethylene glycol divinyl ether, and 1,4-cyclohexyl dimethanol divinyl ether.

7. The method for preparing embolic microspheres capable of loading platinum drugs according to claim 5, characterized in that: It includes the following steps: Dropping a mixed solution containing the maleic anhydride, the monomer and the cross-linking agent into a sodium chloride solution, and performing a suspension polymerization reaction to generate microspheres; The microspheres are hydrolyzed.

8. The method for preparing embolic microspheres capable of loading platinum drugs according to claim 7, characterized in that: The mixed solution also contains a catalyst, and the catalyst includes azobisisobutyronitrile; and / or, adding a dispersant to the sodium chloride solution, wherein the mass concentration of the sodium chloride solution is 10%-30%; the dispersant comprises polyvinyl alcohol; and / or, the reaction temperature is 50-70°C and the reaction time is 15-25h; And / or, the microspheres are mixed with a sodium hydroxide solution for hydrolysis, wherein the mass concentration of the sodium hydroxide solution is 3%-10%.

9. A drug-loaded embolic microsphere, characterized in that: Its structural formula is as follows: R is ammonia or an amino group.

10. A method for preparing drug-loaded embolic microspheres according to claim 9, characterized in that: It includes the following steps: The platinum drug is dissolved in a glucose solution and mixed with the embolic microspheres as claimed in claim 1, and samples are taken until the concentration of the platinum drug in the solution no longer decreases.

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