WO2023035384A1

WO2023035384A1 - Hydrogel embolization microsphere and preparation method therefor

Info

Publication number: WO2023035384A1
Application number: PCT/CN2021/128171
Authority: WO
Inventors: 郭平
Original assignee: 苏州浩微生物医疗科技有限公司
Priority date: 2021-09-10
Filing date: 2021-11-02
Publication date: 2023-03-16
Also published as: CN113975453B; CN113975453A

Abstract

Disclosed is a method for preparing a hydrogel embolization microsphere. The microsphere is formed by means of cross-linking polymerization of an acrylate monomer and a vinyl alcohol carboxylic acid derivative monomer via a cross-linking agent. The method comprises the following steps: adding a dispersant to deionized water to form an aqueous phase solution; mixing an acrylate monomer, a vinyl alcohol carboxylic acid derivative monomer, a cross-linking agent and an initiator to form a first mixture; mixing the first mixture with the aqueous phase solution, and generating a microsphere intermediate by means of a polymerization reaction; and mixing the microsphere intermediate with a sodium hydroxide solution, and reacting same to generate a hydrogel microsphere. Provided in the present invention is a hydrogel microsphere having good elasticity and vascular fit and relatively high elastic deformation and recovery performance. The provided hydrogel microsphere can efficiently adsorb a large number of drugs in a short period of time when used for loading a hydrophilic drug.

Description

Hydrogel embolization microspheres and preparation method thereof

technical field

The invention relates to the technical field of medical materials, in particular to hydrogel embolic microspheres and a preparation method thereof.

Background technique

According to statistics, in 2020, more than 410,000 people in China will be newly diagnosed with liver cancer, and more than 390,000 people will die of liver cancer. Since most patients with liver cancer are already in the middle or advanced stage or complicated with liver cirrhosis when they are diagnosed, only about 20%-30% of the patients have the chance of surgical resection. For patients with liver cancer who cannot receive surgery, transcatheter arterial embolization (TACE) is a very important treatment method. It mainly injects embolism into the blood vessels of the target organ through the artery to occlude the blood vessels and interrupt the blood supply. , and finally achieve the purpose of treatment. TACE has the advantages of less trauma, quick curative effect, and less side effects. This method has played an increasingly important role in clinical cancer treatment, especially in the treatment of advanced liver cancer.

Embolic agents are the core material for TACE treatment. Existing embolic agents include polyvinyl alcohol particles, gelatin sponge particles, polyvinyl alcohol microspheres, sodium alginate microspheres, and triplyl gelatin microspheres, among which polyvinyl alcohol particles and gelatin Sponge particles are irregular products, which are easy to block the catheter during clinical use and affect the operation process; polyvinyl alcohol microspheres and sodium alginate microspheres are regular in shape, which solves the problem of blocked catheters; swelling, which limits its clinical application; when polyvinyl alcohol microspheres embolize blood vessels, the fit between the microspheres and blood vessels is not good, and there are still large gaps between the microspheres. In addition, the production process of polyvinyl alcohol microspheres Complex, long production cycle, more "three wastes" produced.

Contents of the invention

The purpose of the present invention is to provide hydrogel embolic microspheres and a preparation method thereof, which can solve one or more of the above-mentioned problems in the prior art.

In the first aspect, the present invention provides a method for preparing hydrogel embolic microspheres, which comprises acrylic ester monomers and vinyl alcohol carboxylic acid derivative monomers cross-linked and polymerized by a cross-linking agent to form microspheres.

In some embodiments, the following steps are included:

Add the dispersant to deionized water to form an aqueous phase solution;

mixing an acrylate monomer, a vinyl alcohol carboxylic acid derivative monomer, a crosslinking agent and an initiator to form a first mixture;

The first mixture is mixed with the aqueous phase solution to form a microsphere intermediate through polymerization reaction.

In some embodiments, it also includes mixing the microsphere intermediate with sodium hydroxide solution to react to form hydrogel microspheres.

Among them: by reacting the microsphere intermediate with sodium hydroxide solution, the acrylate structural units and vinyl alcohol carboxylic acid derivative structural units in the microspheres can be hydrolyzed to generate sodium acrylate and vinyl alcohol structural units, thus preparing the The hydrogel microspheres with good elasticity and vascular adhesion also enable the hydrogel microspheres to efficiently adsorb a large amount of drugs in a short time when they are loaded with hydrophilic drugs.

In certain embodiments, the reaction temperature of the first mixture and the aqueous phase solution is 35-75° C., and the reaction time is 1-10 h.

In certain embodiments, the reaction temperature of the microsphere intermediate and the sodium hydroxide solution is 25-80° C., and the reaction time is 1-24 h.

Among them: for the above two reactions, by setting the reaction temperature within a reasonable range, the low temperature reaction time is long; the high temperature reaction time is short, and the reaction is too violent.

In certain embodiments, the dispersant includes but is not limited to one or more of polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone; the acrylate monomer includes but is not limited to methyl acrylate, One or more of ethyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, ethylene glycol methyl ether acrylate, propyl methacrylate, tert-butyl methacrylate; the Vinyl carboxylic acid derivative monomers include but not limited to one or more of vinyl formate, vinyl acetate, vinyl benzoate, allyl formate, vinyl butyrate; the crosslinking agent includes but not Limited to N,N'-methylenebisacrylamide, N,N'-ethylenebisacrylamide, ethylene glycol dimethacrylate, tetraethylene glycol diacrylate, 1,6-hexanediol dimethyl Acrylate, polyethylene glycol diacrylate, polypropylene glycol dimethacrylate; said initiators include, but are not limited to, azobisisobutylcyanide, benzoyl peroxide, dimethyl azobisisobutyrate, One or more of benzoyl tert-butyl peroxide.

In certain embodiments, the sodium hydroxide solution comprises an aqueous sodium hydroxide solution, a methanolic sodium hydroxide solution, or an ethanolic sodium hydroxide solution.

In some embodiments, the mass percentage of the dispersant is 0.1 wt.%-10 wt.%.

In certain embodiments, the mass percentages of acrylate monomers, vinyl alcohol carboxylic acid derivative monomers, crosslinking agents, and initiators are 10wt.%-90wt.%, 10wt.%-90wt.%, respectively. %, 0.1wt.%-5wt.%, 0.1wt.%-5wt.%.

In some embodiments, the mass percentage of sodium hydroxide is 0.1 wt.%-5 wt.%, and the mass percentage of the microsphere intermediate is 1 wt.%-30 wt.%.

In the second aspect, the hydrogel embolic microspheres provided by the present invention and the preparation method of the hydrogel embolic microspheres comprise the following steps:

Add the dispersant to deionized water to form an aqueous phase solution;

mixing the first mixture with an aqueous phase solution to generate a microsphere intermediate through a polymerization reaction;

Mixing the microsphere intermediate with sodium hydroxide solution to react to generate hydrogel microspheres; and

Cleaning, sieving, filling steps.

Among them: acrylate monomers, vinyl alcohol carboxylic acid derivatives and cross-linking agents are reacted and connected together to form macromolecular chains, and many macromolecular chains are intertwined and cross-linked to form microspheres.

In certain embodiments, the hydrogel embolic microspheres are capable of compression set of greater than 50%.

In certain embodiments, the size of the hydrogel microspheres is between 30-1200 μm.

Among them: the hydrogel microsphere has the characteristics of regular shape and uniform size, and the particle size distribution of the microsphere is narrower, and the particle size range is between 30-1200 μm and the particle size is adjustable. In most applications it will be desirable to have microspheres with a narrow particle size distribution in order to provide predictable embolization. The method used to prepare the microspheres can be manipulated to achieve a particular desired size range of microspheres. Methods such as sieving can be used to control the size range of the microspheres.

In the third aspect, the application of the hydrogel embolic microspheres provided by the present invention in hydrophilic soluble drugs, the hydrophilic drugs include doxorubicin hydrochloride or irinotecan hydrochloride.

Compared with prior art, the beneficial effect that the present invention produces is:

1. The present invention provides a hydrogel microsphere with good elasticity and vascular adhesion, and has relatively large elastic deformation and recovery performance;

2. The present invention provides a hydrogel microsphere with a narrower particle size distribution;

3. When the hydrogel microspheres provided by the present invention are used to load hydrophilic drugs, they can efficiently adsorb a large amount of drugs in a short period of time. The microspheres have higher drug loading and better slow-controlled release capabilities, solving It solves the problem of low drug loading of similar products in the prior art, and has a good application prospect in the field of liver cancer interventional therapy.

Description of drawings

Fig. 1 is the optical microscope photograph of microsphere after filling in the embodiment of the present invention 1;

Fig. 2 is a schematic diagram of microspheres before and after compression deformation in Example 2 of the present invention (Fig. a is a schematic diagram before compression deformation test, and Fig. b is a schematic diagram after compression deformation (50%) test);

Fig. 3 is the optical microscope photograph (figure A is the optical microscope photograph before microsphere compressive deformation test before microsphere compressive deformation in the embodiment 2 of the present invention and after compressive deformation, and Fig. B is after microsphere compressive deformation (50%) test optical microscope photographs).

Detailed ways

The present invention will be further described in detail through embodiments below.

Example 1

(1) First add polyethylene glycol to deionized water to form a water phase solution, then mix ethyl acrylate, vinyl acetate, N,N'-ethylene bisacrylamide, and benzoyl peroxide to form a mixed solution, in which poly The mass percentage of ethylene glycol is 10wt.%, the mass percentages of ethyl acrylate, vinyl acetate, N,N'-ethylene bisacrylamide, and benzoyl peroxide are 89.8wt.%, 10wt.% respectively .%, 0.1wt.%, 0.1wt.%. Then drop the mixed solution into the aqueous phase solution under stirring conditions, and react at 35°C for 10 hours to form a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 0.1wt.%, the mass percentage of the microsphere intermediate is 1wt.%, and react at 25°C 24h, generating hydrogel microspheres;

(3) Washing, sieving and filling the hydrogel microspheres to obtain an embolism microsphere product with a particle size of 30-60um.

Among them: as shown in Figure 1, it can be seen that the particle size of the hydrogel microspheres is uniform and the dispersion is good.

Example 2

(1) First, polyvinyl alcohol is added to deionized water to form a water phase solution, and methyl acrylate, vinyl formate, N,N'-methylenebisacrylamide, and azobisisobutylcyanide are mixed to form a mixed solution. The mass percentage of vinyl alcohol is 1wt.%, and the mass percentages of methyl acrylate, vinyl formate, N,N'-methylenebisacrylamide, and azobisisobutylcyanide are 30wt.% and 68wt.%, respectively. %, 1wt.%, 1wt.%. Then drop the mixed solution into the water phase solution under stirring conditions, and invert for 6 hours at 45°C to generate a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 1wt.%, the mass percentage of the microsphere intermediate is 10wt.%, and react at 50°C for 6h , generate hydrogel microspheres;

(3) Cleaning, sieving, and filling the hydrogel microspheres to obtain an embolism microsphere product with a particle size of 70-100 um.

Example 3

(1) First, polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and butyl acrylate, vinyl benzoate, ethylene glycol dimethacrylate, and dimethyl azobisisobutyrate are mixed to form a mixed solution, Wherein the mass percentage of polyvinylpyrrolidone is 5wt.%, and the mass percentages of butyl acrylate, vinyl benzoate, ethylene glycol dimethacrylate, and dimethyl azobisisobutyrate are respectively 50wt.%. , 42wt.%, 3wt.%, 5wt.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 65°C for 3 hours to form a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 5wt.%, the mass percentage of the microsphere intermediate is 20wt.%, and react for 1h at 80°C , generate hydrogel microspheres;

(3) The hydrogel microspheres are cleaned, sieved, and filled to obtain an embolism microsphere product with a particle size of 100-150 um.

Example 4

(1) first polyvinyl alcohol is added into deionized water to form an aqueous phase solution, methyl methacrylate, allyl formate, tetraethylene glycol diacrylate, benzoyl tert-butyl peroxide are mixed to form a mixed solution, Wherein the mass percent composition of polyvinyl alcohol is 0.1wt.%, the mass percent composition of methyl methacrylate, allyl formate, tetraethylene glycol diacrylate, benzoyl tert-butyl peroxide is 80wt respectively .%, 10wt.%, 5wt.%, 5wt.%. Then drop the mixed solution into the aqueous phase solution under stirring conditions, and react at 75°C for 1 hour to generate a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 5wt.%, the mass percentage of the microsphere intermediate is 20wt.%, and react for 3h at 70°C , generate hydrogel microspheres;

(3) The hydrogel microspheres are cleaned, sieved, and filled to obtain an embolism microsphere product with a particle size of 200-250um.

Example 5

(1) First add polyethylene glycol to deionized water to form a water phase solution, mix ethyl methacrylate, vinyl butyrate, 1,6-hexanediol dimethacrylate, and azobisisobutylcyanide Form a mixed solution, wherein the mass percentage of polyethylene glycol is 0.1wt.%, ethyl methacrylate, vinyl butyrate, 1,6-hexanediol dimethacrylate, azobisisobutyrocyanide The mass percentages are respectively 90wt.%, 5wt.%, 2wt.%, 3wt.%. Then drop the mixed solution into the aqueous phase solution under stirring condition, and react at 60°C for 3 hours to form a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 5wt.%, the mass percentage of the microsphere intermediate is 20wt.%, and react for 3h at 65°C , generate hydrogel microspheres;

Example 6

(1) First, polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and ethylene glycol methyl ether acrylate, vinyl benzoate, polyethylene glycol diacrylate, and dimethyl azobisisobutyrate are mixed to form Mixed solution, wherein the mass percent of polyvinylpyrrolidone is 10wt.%, the mass percent of ethylene glycol methyl ether acrylate, vinyl benzoate, polyethylene glycol diacrylate, dimethyl azobisisobutyrate The component contents are 10wt.%, 89.8wt.%, 0.1wt.%, 0.1wt.%. Then drop the mixed solution into the aqueous phase solution under stirring conditions, and react at 35°C for 10 hours to form a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 0.1wt.%, the mass percentage of the microsphere intermediate is 1wt.%, and react at 25°C 20h, generating hydrogel microspheres;

Example 7

(1) First, polyvinyl alcohol is added to deionized water to form an aqueous phase solution, and propyl methacrylate, vinyl acetate, polypropylene glycol dimethacrylate, and dimethyl azobisisobutyrate are mixed to form a mixed solution, Wherein the mass percentage content of polyvinyl alcohol is 1wt.%, the mass percentage content of propyl methacrylate, vinyl acetate, polypropylene glycol dimethacrylate, dimethyl azobisisobutyrate is 30wt. %, 68wt.%, 1wt.%, 1wt.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 45°C for 6 hours to form a microsphere intermediate;

Example 8

(1) First, polyvinylpyrrolidone is added to deionized water to form an aqueous phase solution, and tert-butyl methacrylate, allyl formate, tetraethylene glycol diacrylate, and benzoyl tert-butyl peroxide are mixed to form a mixed solution , wherein the mass percentage of polyvinylpyrrolidone is 5wt.%, and the mass percentages of tert-butyl methacrylate, allyl formate, tetraethylene glycol diacrylate, and benzoyl tert-butyl peroxide are respectively 50wt.%, 42wt.%, 3wt.%, 5wt.%. Then drop the mixed solution into the water phase solution under stirring condition, and react at 65°C for 3 hours to form a microsphere intermediate;

(2) Add the microsphere intermediate to the sodium hydroxide methanol solution, wherein the mass percentage of sodium hydroxide is 5wt.%, the mass percentage of the microsphere intermediate is 20wt.%, and react at 60°C for 4h , generate hydrogel microspheres;

Performance Testing

1. Elastic deformation test

The elastic deformation of the microspheres is tested by a strain gauge, and the specific method is as follows:

Spread the filled hydrogel microspheres on the test platform, and when the probe of the deformation meter moves down the contacted microspheres, it moves down a distance of 50% of the diameter of the microspheres, and then withdraws the probe after keeping it for a certain period of time. Take out the microspheres and observe whether they are broken. If the microspheres return to a spherical shape without breaking, it means that the microspheres can withstand 50% compression deformation test.

According to the above method, the hydrogel microspheres in Example 2 were taken to perform a 50% compression set test, and the schematic diagram of the test is shown in FIG. 2 .

The test results are shown in Figure 3. It can be seen that after the test, the microspheres all recovered to a spherical shape without breaking, indicating that the above-mentioned hydrogel microspheres have good elasticity.

2. Test of drug loading

The 30-50 μm embolic microspheres prepared in Example 1 were added to the 25 mg/mL doxorubicin hydrochloride solution, and samples were taken at the load times of 0 min, 5 min, 15 min, 30 min, and 60 min respectively, and HPLC (ultraviolet detection wavelength was 254 nm , chromatographic column is Waters C18) measure the content of doxorubicin in the sample of above-mentioned different loading time.

The drug loading efficiency of the degradable embolization microspheres was calculated by the difference method.

Wherein: microsphere drug-loading efficiency=(1-the content of doxorubicin in the sample/doxorubicin feeding amount) * 100%

When the loading time is 5min, the drug loading efficiency has reached about 90%. It shows that the embolic microspheres prepared by the present invention have rapid drug-loading property for doxorubicin.

In summary: the present invention provides a hydrogel microsphere with good elasticity and vascular adhesion, and has greater elastic deformation and recovery performance; the present invention provides a hydrogel microsphere with a narrower particle size distribution. Glue microspheres; when the hydrogel microspheres provided by the present invention are used to load hydrophilic drugs, they can efficiently absorb a large amount of drugs in a short time, and the microspheres have higher drug loading and better slow-controlled release capabilities , which solves the problem of low drug loading of similar products in the prior art, and has good application prospects in the field of liver cancer interventional therapy.

The above statement is only the preferred mode of the present invention. It should be pointed out that those skilled in the art can make some modifications and improvements without departing from the inventive concept of the present invention, and these should also be regarded as the protection of the invention. within range.

Claims

The preparation method of hydrogel embolic microspheres is characterized in that the microspheres are formed by cross-linking polymerization of acrylate monomers and vinyl alcohol carboxylic acid derivative monomers through a cross-linking agent.
The preparation method of hydrogel embolic microspheres according to claim 1, is characterized in that, comprises the following steps:

Add the dispersant to deionized water to form an aqueous phase solution;

mixing an acrylate monomer, a vinyl alcohol carboxylic acid derivative monomer, a crosslinking agent and an initiator to form a first mixture;

The first mixture is mixed with the aqueous phase solution to form a microsphere intermediate through polymerization reaction.
The preparation method of hydrogel embolic microspheres according to claim 2, further comprising mixing the microsphere intermediate with sodium hydroxide solution to react to generate hydrogel microspheres.
The preparation method of hydrogel embolic microspheres according to claim 2, wherein the dispersant includes but not limited to one or more of polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone; The acrylate monomers include but are not limited to methyl acrylate, ethyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, ethylene glycol methyl ether acrylate, propyl methacrylate, methyl One or more of tert-butyl acrylate; said vinyl alcohol carboxylic acid derivative monomers include but not limited to vinyl formate, vinyl acetate, vinyl benzoate, allyl formate, vinyl butyrate One or more; the cross-linking agent includes but not limited to N,N'-methylene bisacrylamide, N,N'-ethylene bisacrylamide, ethylene glycol dimethacrylate, tetraethylene glycol Diacrylate, 1,6-hexanediol dimethacrylate, polyethylene glycol diacrylate, polypropylene glycol dimethacrylate; the initiators include but are not limited to azobisisobutylcyanide, peroxide One or more of benzoyl, dimethyl azobisisobutyrate, and tert-butyl benzoyl peroxide.
The method for preparing hydrogel embolic microspheres according to claim 3, wherein the sodium hydroxide solution comprises sodium hydroxide aqueous solution, sodium hydroxide methanol solution or sodium hydroxide ethanol solution.
The method for preparing hydrogel embolic microspheres according to claim 5, characterized in that the mass percentage of the dispersant is 0.1wt.%-10wt.%.
The preparation method of hydrogel embolic microspheres according to claim 5, wherein the mass percentages of acrylate monomers, vinyl alcohol carboxylic acid derivative monomers, crosslinking agents, and initiators are respectively 10wt.%-90wt.%, 10wt.%-90wt.%, 0.1wt.%-5wt.%, 0.1wt.%-5wt.%.
The preparation method of hydrogel embolic microspheres according to claim 5, wherein the mass percentage of sodium hydroxide is 0.1wt.%-5wt.%, and the mass percentage of the microsphere intermediate It is 1wt.%-30wt.%.
The hydrogel embolic microspheres prepared by the preparation method according to any one of claims 1 to 8, characterized in that the preparation method of the hydrogel embolic microspheres also includes cleaning, sieving, and filling step.
The application of the hydrogel embolic microspheres in claim 9 in hydrophilic soluble drugs, characterized in that the hydrophilic drugs include doxorubicin hydrochloride or irinotecan hydrochloride.