JPS6233263B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a spherical gelatin gel, and more particularly to a method for producing a spherical gelatin gel that can be applied to a carrier for impregnating vascular embolic substances or pharmaceuticals.

In recent years, research on arterial embolization, selective intraarterial injection of drugs, etc. has become active in the field of radiology.
In other words, this involves embolizing the feeding artery of the tumor as a pretreatment for surgical removal of the tumor to reduce blood loss during surgery, or embolizing the feeding artery for malignant tumors for which radical surgery is not possible. The aim is to shrink the tumor by occluding it or selectively injecting drugs through the feeding artery. Currently, the vascular embolization materials used for this purpose include gelatin dissolved in water, foamed, freeze-dried to form a sponge, cut into several mm squares, or powdered, or gelatin. Formaldehyde is added to the mixture, heated to polymerize it, and air bubbles are blown in to form a sponge, which is then cut into pieces of several millimeters or powdered. These are used by impregnating them with chemicals. However, since these are all crushed, they have drawbacks such as difficulty in adhering closely to blood vessels compared to spherical ones.

In addition, currently available spherical materials include polystyrene, polyacrylate,
There are polymers such as polyvinyl alcohol, silica, and glass, but all of them have safety issues when injected into the body.

The present invention solves these problems.

That is, in the present invention, an aqueous solution of gelatin and a water-soluble compound that crosslinks with gelatin is dispersed in a dispersion medium prepared by dissolving water-insoluble ethyl cellulose in a non-polar organic solvent that is incompatible with water, and the crosslinking reaction is carried out. The present invention relates to a method for producing gelatin spherical gel characterized by the following.

There are various types of gelatin depending on the molecular weight, raw material, etc., and any gelatin may be used. Gelatin has _-NH2 groups, -OH groups and
It has COOH groups, and these serve as reaction sites for crosslinking reactions.

A water-soluble compound that crosslinks with gelatin (hereinafter referred to as
Crosslinking agents) that are reactive with _-NH2 groups include aliphatic dials such as gluoxal, propane dial, butane dial, pentan dial (glutaraldehyde), and hexane dial, and ethylene glycol diglycidyl ether. , polyethylene glycol diglycidyl ether, glycerol polyglycidyl ether, diglycerol polyglycidyl ether, sorbitol polyglycidyl ether, diglycidyl methyl dantoin, and other water-soluble polyvalent epoxides. These crosslinking agents are preferably used in an amount of 1/20 to 10 equivalents, particularly preferably 1/10 to 5 equivalents, per equivalent of NH ₂ group in gelatin.

In addition, aliphatic dibasic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, and adipic acid can also be used as the crosslinking agent.

The dispersion medium of the present invention is incompatible with water, and non-polar organic solvents such as alicyclic hydrocarbons are used, and polar solvents such as esters, ketones, alkyl halides, ethers, and alcohols, aromatic Used in combination with group hydrocarbons, etc. Among these, those that do not react with the above-mentioned crosslinking agent are used.

The alicyclic compound preferably has 5 to 10 carbon atoms or an alkyl-substituted alicyclic compound, such as cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, cyclooctane, and decalin.

Examples of aromatic hydrocarbon compounds include aromatic hydrocarbons having 6 to 8 carbon atoms and halogen-substituted aromatic hydrocarbons, such as benzene, toluene, xylene,
Examples include ethylbenzene, chlorobenzene, dichlorobenzene, bromobenzene, and dibromobenzene.

The esters include fatty acids having 1 to 8 carbon atoms or aromatic carboxylic acids having 7 to 8 carbon atoms and 1 to 8 carbon atoms.
Preferred are esters with alkanols such as methyl acetate, ethyl acetate, n-butyl acetate,
Examples include benzyl acetate, methoxyethyl acetate, methyl cabroate, methyl benzoate, diethyl phthalate, and the like.

As the ketone, aliphatic ketones having 3 to 8 carbon atoms, aromatic ketones having 8 to 13 carbon atoms, etc. are preferable.
Specific examples include methyl isobutyl ketone, cyclohexanone, methyl amyl ketone, hexyl methyl ketone, acetophenone, and benzophenone.

The halogenated alkyl is preferably an alkyl substituted with 1 to 4 halogens on carbon, such as methylene chloride, hydrogen tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane,
Examples include pentachloroethane, 1,2-dichloropropane, 1,2-dichlorobutane, and 1,2-dibromoethane.

The ether is preferably a linear or cyclic ether having 4 to 8 carbon atoms, such as di-n-propyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, and the like.

The alcohol is preferably an alkanol having 2 to 8 carbon atoms or an alkoxy-substituted alkanol, such as ethanol, n-propanol, n-
-Butanol, n-octanol, methoxyethanol, ethoxyethanol, butoxyethanol, diethylene glycol monomethyl ether, etc.

In the present invention, water-insoluble ethylcellulose is used as a dispersant. Such ethyl cellulose has an ethoxy group content of 43 to 50%.
are known. Here, the ethoxy group content is the weight ratio (% by weight) of ethoxy groups in ethylcellulose. Among the above, those having a relatively small ethoxy group content, for example, those having an ethoxy group content of 43 to 46% by weight, are poorly soluble in the above nonpolar organic solvent. Therefore, when using the above-mentioned nonpolar organic solvent alone as a dispersion medium, it is preferable to use one having an ethoxy group content of 47 to 50% by weight.

Ethylcellulose, which is insoluble in water, forms a particularly good dispersion medium when combined with the above-mentioned cycloaliphatic compounds. However, as mentioned above, since ethyl cellulose has poor solubility in non-polar organic solvents, it is preferable to use the above-mentioned polar solvent or aromatic hydrocarbon compound as a dispersion medium.

When an aromatic hydrocarbon compound is mixed with a non-polar organic solvent to form a dispersion medium, it is preferable to use the aromatic hydrocarbon compound in an amount of 400% by weight or less, preferably 200% by weight or less based on the non-polar organic solvent. good. When a dispersion medium is prepared by mixing an ester, a ketone, and an alkyl halide with a nonpolar organic solvent, the amount of the compound such as the ester, ketone, and alkyl halide is preferably 200% by weight or less based on the nonpolar organic solvent, and especially 150% by weight or less. It is preferable to use less than % by weight. Further, when a dispersion medium is prepared by mixing ether, alcohol, etc. with a non-polar organic solvent, it is preferably used in an amount of 30% by weight or less, particularly preferably 20% by weight or less, based on the non-polar organic solvent. When aromatic hydrocarbons, ketones, esters, alkyl halides, ethers, and alcohols are mixed with a nonpolar organic solvent, if they are used in an amount exceeding the above-mentioned amount, a good dispersion system tends not to be obtained.

The water-insoluble ethylcellulose is preferably used in an amount of 0.05 to 10% by weight, preferably 0.5 to 5% by weight, based on the total amount of dispersion medium.

The dispersion medium is preferably used in an amount of 50 to 2000% by weight, particularly 100 to 1000% by weight, based on the total amount of gelatin, crosslinking agent, and water (hereinafter referred to as the amount of aqueous phase).
It is preferable to use If the amount of the dispersion medium is too large, the productivity will be poor, and if the amount of the dispersion medium is too small, the stability of the dispersion system will be poor.

In addition, gelatin is 5% by weight based on the amount of aqueous phase.
The concentration may be appropriately selected between . If the proportion of gelatin is too low, productivity will decrease.

An aqueous solution of gelatin and a crosslinking agent can be dispersed in a dispersion medium by adding an aqueous solution of gelatin and a crosslinking agent dissolved in water to a liquid that is not compatible with water, and stirring the mixture. However, since gelatin and a crosslinking agent tend to react, it is preferable to disperse an aqueous solution of gelatin in a liquid that is incompatible with water and then add the crosslinking agent or its aqueous solution. The crosslinking reaction is carried out in a dispersed state, and in this case, the reaction temperature is preferably above room temperature and below the boiling point of water or the dispersion medium.

Stirring methods used in the reaction include stirring methods involving high-speed shearing using an emulsifier, mechanical cutting of particles using a propeller-type stirrer or magnetic stirrer, and stirring methods that do not involve pulverization. These stirring methods can be selected depending on the required particle size. When stirring by high-speed shearing, it is preferable to stir before the crosslinking reaction in order to avoid destroying the crosslinked particles.

The polypeptide spherical gel obtained in the present invention is recovered by filtration or decantation, further washed with a relatively low boiling point solvent, and purified by drying under normal pressure or reduced pressure.

Moreover, by classifying, only the required particle size can be obtained.

The present invention will be explained below with reference to Examples and Comparative Examples.

Example 1 6 g of ethyl cellulose (ethoxy group content: 49%) is dissolved in a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, and the solution is introduced into a 500 ml flask equipped with a condenser and a Teflon stirring blade. The stirring speed was 400 rpm and the temperature was 70°C. Next, 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight was added, and then
4 g of 50% glutaraldehyde aqueous solution (4 g of glutaraldehyde per 1 equivalent of amino group of gelatin)
equivalent amount) and reacted for 5 minutes to obtain brown and colored particles. The particles were collected by filtration and washed with ethyl acetate and then acetone. When these particles are observed under a microscope, they are spherical and the particle size is
It was 0.1 to 1 mm.

Example 2 6 g of ethyl cellulose (ethoxy group content: 49%) is dissolved in a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, and the solution is introduced into a 500 ml flask equipped with a condenser and a Teflon stirring blade. The stirring speed was 400 rpm and the temperature was 70°C. Next, 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, followed by 0.15 g of a 50% aqueous glutaraldehyde solution (0.15 g of glutaraldehyde per amino group of gelatin).
equivalent amount) and reacted for 5 minutes to obtain colored particles. The particles were collected by filtration and washed with ethyl acetate and then acetone. When this particle is observed under a microscope, it is spherical and the particle size is 0.1
It was ~1 mm.

Example 3 Ethyl cellulose (ethoxy group content: 49
%) and introduced into a 500 ml flask equipped with a condenser tube and Teflon stirring blade. The stirring speed was 400 rpm and the temperature was 70°C. Next, 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, and then
Add 4 g of 50% glutaraldehyde aqueous solution (4 equivalents of glutaraldehyde per 1 equivalent of amino group of gelatin) and react for 5 minutes to obtain brown particles. The particles were collected by filtration and washed with ethyl acetate and then acetone. When this particle is observed under a microscope, it is spherical and the particle size is 0.1
It was ~1 mm.

Example 4 6 g of ethyl cellulose (49% ethoxy group content) is dissolved in a dispersion medium consisting of 150 g of cyclohexane and 50 g of ethyl acetate, and the solution is introduced into a 500 ml flask equipped with a condenser and a Teflon stirring blade.
The stirring speed was 400 rpm and the temperature was 70°C. Next, add 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C, and then add 4 g of a 50% aqueous glutaraldehyde solution (4 equivalents of glutaraldehyde per 1 equivalent of the amino group of gelatin). After adding it and reacting for 5 minutes, brown and colored particles are obtained. The particles were collected by filtration and washed with ethyl acetate and then acetone. When these particles are observed under a microscope, they are spherical and the particle size is
It was 0.1 to 1 mm.

Example 5 6 g of ethyl cellulose (ethoxy group content 49%) was dissolved in a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, and introduced into a 500 ml flask equipped with a cooling tube and a Teflon stirring blade.The stirring speed was set to 400 rpm, and the temperature was lowered. The temperature was set to 70℃. Next, 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight was added, and then 5 g of ethylene glycol diglycidyl ether (4 equivalents of epoxy groups per 1 equivalent of amino groups in gelatin) was added. After reacting at 70°C for 5 hours, colored particles were obtained. The particles were collected by filtration and washed with ethyl acetate and then acetone. When these particles are observed under a microscope, they are spherical and the particle size is
It was 0.1 to 1 mm. Also, the beads were insoluble in water.

Example 6 6 g of ethyl cellulose (ethoxy group content 49%) was dissolved in a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, and introduced into a 500 ml flask equipped with a cooling tube and a Teflon stirring blade.The stirring speed was set to 400 rpm, and the temperature was lowered. The temperature was set to 70℃. Next, 40 g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight was added, and then 5 g of polyglycerol polyglycidyl ether (trade name: Denacol EX512, manufactured by Nagase Kasei) (1 equivalent of the amino group of gelatin) was added. 4 equivalents of epoxy groups) was added and reacted at 70°C for 5 hours to obtain colored particles. The particles were collected by filtration and washed with ethyl acetate and then acetone. When these particles are observed under a microscope, they are spherical and the particle size is 0.1~
It was 1mm thick. Also, the beads were insoluble in water.

Comparative Example 1 6 g of polyoxyethylene nonyl phenyl ether as a dispersant was dissolved in 200 g of cyclohexane, and 500 ml was prepared using a cooling tube equipped with a Teflon stirring rod.
into the flask. Stirring speed 400r.p.
m and the temperature to 70℃. 40g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, followed by 4g of a 50% glutaraldehyde aqueous solution, and the mixture was allowed to react for 5 minutes. The product obtained here was in the form of a lump, and no spherical product was obtained.

Comparative Example 2 6 g of ethyl cellulose (ethoxy group content: 49% by weight) was dissolved in 200 g of toluene and introduced into a 500 ml flask equipped with a cooling tube and a Teflon stirring bar. Stirring speed is 400r.pm and temperature is 70.
℃. 40g of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, followed by 4g of a 50% glutaraldehyde aqueous solution, and the mixture was reacted for 5 minutes. The product obtained here was in the form of a lump, and no spherical product was obtained.

According to the present invention, crosslinked gelatin spherical particles can be efficiently obtained.

Claims (1)

[Claims] 1. A crosslinking reaction is carried out by dispersing an aqueous solution of gelatin and a water-soluble compound crosslinking with gelatin in a dispersion medium prepared by dissolving water-insoluble ethyl cellulose in a non-polar organic solvent that is incompatible with water. Method for producing gelatin spherical gel.