JPS6020934A - Production of spherical gelatin particle - Google Patents

Abstract

PURPOSE:To produce spherical gelatin gel particles applicable to a blood vessel plugging material or an impregnation carrier for medicines, by subjecting an aqueous solution containing gelatin and a crosslinking agent to a crosslinking raction in a specified dispersing medium. CONSTITUTION:An aqueous solution of gelatin and a water-soluble compound which can crosslink gelatin (e.g., glutaraldehyde) is subjected to a crosslinking reaction in a dispersing medium formed by dissolving water-insoluble ethylcellulose (ethoxy group content of 43-50%) in a water-immiscible nonpolar organic solvent (e.g., cyclohexane or toluene). Spherical gelatin gel particles can be obtained. The formed particles can be recovered by filtration or decantation, and purified by washing them with a relatively low-boiling solvent and drying them at atmospheric pressure or in vacuum. These particles can be used as a blood vessel plugging material or an impregnation carrier for medicines.

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 impregnated with vascular embolic substances or pharmaceuticals.

In recent years, research on arterial embolization and selective drug kinetics has become active in the field of radiology.

In other words, as a pretreatment for surgical removal of the tumor, embolization of the feeding artery of the tumor is performed to reduce the amount of blood loss during the surgery, or occlusion of the feeding artery is performed for malignant tumors for which radical surgery is not possible. The aim is to shrink the tumor by selectively injecting drugs from the feeding artery. Currently, the vascular embolization substances used for this purpose include gelatin dissolved in water, foamed, lyophilized to form a sponge, cut into several cubes, powdered, or gelatin. Add formaldehyde, heat it and polymerize it, blowing out all the air bubbles and making it into a sponge shape.
This can be cut into several cubes or powdered, and when selectively injecting a drug, these are impregnated with the drug. However, since these are all crushed, they have drawbacks such as difficulty in adhering closely to blood vessels compared to single spherical ones.

Also, as a spherical substance that is currently easily available.

There are polymers such as polystyrene, polyacrylic acid ester, and polyvinyl alcohol, silica, and glass, but all of them have problems in terms of safety 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 noethyl 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 C0OH groups as functional groups, and these serve as reaction points for crosslinking reactions.

A water-soluble compound that crosslinks with gelatin (see below).

Examples of the crosslinking agent include aliphatic dials that are reactive with -Ni42 groups, butane dials, pentan dials (glutaraldehyde), hexane dials, ethylene glycol diglycidyl needles, and polynigelyl gelicols. Examples include water-soluble polyepoxides such as diglycidyl ether, glycerol polyglycidyl ether, diglycerol polyglycidyl ether, sorbitol polyglycidyl ether, and diglycidyl methyl hydantoin. These crosslinking agents are preferably used in an amount of 1/lt, 1/20 to 10 NH2 group equivalent of gelatin.
It is preferable to use 1/10 to 5 equivalents for L<,%.

Other crosslinking agents include oxalic acid and malonic acid.

Aliphatic dibasic acids such as succinic acid, glutaric acid, and adipic acid can also be used.

The dispersion medium of the present invention is incompatible with water.

Non-polar organic solvents such as alicyclic hydrocarbons are used.

As appropriate, esters, ketones, alkyl halides.

Used in combination with polar solvents such as ether and alcohol, aromatic hydrocarbons, etc. Among these, those that do not react with the above-mentioned crosslinking agent are used.

The alicyclic compound preferably has 5 to 1 carbon atoms or an alkyl-substituted alicyclic compound, such as tatoeba/clopentane, cyclohexane, cyclohebutane, methylcyclohexane, chlorooctane, and decalin.

Examples of aromatic hydrocarbon compounds include aromatic hydrocarbons having 6 to 8 carbon atoms, halogen-substituted aromatic hydrocarbons, and the like, such as benzene, toluene, and chlorine.

Ethylbenzene, chlorobenzene, dichlorobenzene,
Examples include bromobenzene and cyfurombenzene.

As esters, fatty acids with 1 to 8 carbon atoms or 7 carbon atoms
Esters of ~8 aromatic carboxylic acids and alkanols having 1 to 8 carbon atoms are preferred, specifically methyl acetate, ethyl acetate, and n-butyl acetate.

Benzyl acetate, methoxyethyl acetate, caprone (
Examples include p-methyl, methyl benzoate, diethyl phthalate, and the like.

The ketone is an aliphatic ketone having 3 to 8 carbon atoms.

Aromatic ketones having 8 to 13 carbon atoms are preferred, and specific examples include methylinobutylketone, cyclohexanone, methylamylketone, hegysylmethylketone, 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-dichlorobutane, 1,
1.2-) Lichloroethane, pentachloroethane, 1
．． 2-) Chlorpropane, 1,2-dichlorobutane,
Examples include '1,2-dibromoethane.

The ether is preferably a straight-chain cyclic needle 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.

Alcohol is an alkanol with 2 to 8 carbon atoms! Bamboo alkoxy-substituted alkanols are preferred.

7'c,! : Ekeethanol, n-propertool, n
-7'tanol, n-octatool, methoxyethanol, ethoxyethanol, Butkin Ep/-le.

Examples include diethylene glycol monomethyl ether.

In the present invention, water-insoluble ethylhirulose is used as a dispersant. As such ethyl cellulose, those having 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 9, 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 described above, ethyl cellulose has poor solubility in non-polar organic solvents, so it is preferable to use the above-mentioned polar solvent or aromatic hydrocarbon compound as a dispersion medium.

When a dispersion medium is prepared by mixing an aromatic hydrocarbon compound with a non-polar organic solvent, the amount of the aromatic hydrocarbon compound is 400% by weight or less based on the non-polar organic solvent.

Preferably, it is used in an amount of 200% by weight or less.

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 particularly 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.

Non-polar organic solvents, aromatic hydrocarbons, and ketones.

When mixing esters, alkyl halides, ethers, and alcohols, there is a tendency that a good dispersion system cannot be obtained when used on the above-mentioned leaf blade.

The amount of water-insoluble ethyl cellulose is preferably 0.05 to 10% by weight based on the total amount of the dispersion medium.

Preferably it is used in an amount of 0.5 to 5% by weight.

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

Further, the gelatin may be appropriately selected from a concentration of 5% by weight to a saturation concentration based on the amount of the aqueous phase. 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. Because gelatin and a crosslinking agent tend to react easily, 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 two-dispersed state, and in this case, the two-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 to avoid destroying the crosslinked particles.

The polypeptide spherical gel obtained in the present invention is recovered by filtration or decanting.

It is further purified by washing with a relatively low boiling point solvent and drying under normal pressure or reduced pressure.

Further, by performing one classification, only the required particle size can be obtained.

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

Example 1 Ethyl cellulose (ethoxy group content 49%) was added to a dispersion medium consisting of cyclohexane 15 (l) and toluene 50 J.
69- is dissolved and introduced into a 500 ml flask equipped with a condenser and a Teflon stirring blade. Stirring speed 4
0 Or, p, m, and the temperature was set to 70°C. Then,
To this was added 40y of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight, and then 4y of a 50% aqueous tiglutaraldehyde solution (4 equivalents of glutaraldehyde per 1 equivalent of amine group in gelatin) was added. After reacting for 5 minutes, brown and colored particles were obtained. The particles were collected by PA, washed with ethyl acetate, and then washed with acetone. When the particles were observed under a microscope, they were spherical and had a particle size of 0.1 to 1 mm.

Example 2 Ethyl cellulose (ethoxy group content 49%) was added to the dispersion medium consisting of cyclohexane 150ψ and hydrene 501
6y- is dissolved and introduced into a 500 ml flask equipped with a condenser and a Teflon stirring blade. Stirring speed 4
0 Or, I), m, and the temperature was 70°C. Next, 40% of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added to this, and then 50% of an aqueous solution of tiglutaraldehyde and 15P (0% of glutaraldehyde was added to the amine group of gelatin). .15 J%-)
' and react for 5 minutes to obtain colored particles. The particles were collected by filtration, washed with ethyl acetate, and then with acetone. When the particles were observed under a microscope, they were spherical and the particle size was 0.1 to 1 nm+.

Example 3 Ethylcellulose (49% ethoxy group content) 6P was dissolved in a dispersion medium consisting of 150 g of decalin and 501 toluene, and a cooling tube of 500
m1. into the flask.

The stirring speed was set to 40°, Or, p, m, and the temperature was set to 70°.
'C. Next, 402 of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, and then 402 of an aqueous solution of 50 tiglutaraldehyde (4 equivalents of glutaraldehyde per 1 equivalent of amine group of gelatin) was added. ) and react for 5 minutes to obtain brown colored particles. The particles were collected by fj filtration and washed with ethyl acetate and then acetone. When the particles were observed under a microscope, they were spherical and the particle size was 0.1-1.

Example 4 Ethylcellulose (ethoxy group content 49%) was added to a dispersion medium consisting of cyclohexane 1501 and ethyl acetate 502
h) Melt 6Z and introduce into a 500M flask equipped with a condenser and Teflon stirring blade. Stirring speed 4
0 Or, 1), m, and the temperature was 70°C. Next, 40 P of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C was added, and then 4 g of an aqueous glutaraldehyde solution (4 equivalents of glutaraldehyde per 1 equivalent of the amino group of gelatin) was added. ) and react for 5 minutes to obtain brown colored particles. The particles were collected by filtration and washed with ethyl acetate and then with acetone. When the particles were observed under a microscope, they were spherical and the particle size was 0.1 to 1 mm.

Comparative Example 1 6ψ of polyoxyethylene nonylphenyl ether as a dispersant was dissolved in 200 g of cyclohexane and introduced into a 500 ml flask equipped with a condenser and a Teflon stirring bar. The stirring speed is set to 400 r, p, m, and the temperature is set to 70°C. Add 401 of an aqueous solution obtained by dissolving gelatin in water at a concentration of 30% by weight at 50°C, and then
A 0% glutaraldehyde aqueous solution was added to a 4J gold plate and reacted for 5 minutes. The product obtained here was in the form of a lump, and a single sphere was not obtained.

Comparative Example 2 Ethyl cellulose (ethoxy group content: 49% by weight) 6P was dissolved in 20 (l) of toluene, and a cooling tube was prepared.

Introduce into a 500 flask equipped with a Teflon stir bar. The stirring speed is set to 40 Or, p, In and the temperature is set to 70°C. Dissolve gelatin in water at a concentration of 30% by weight at 50°C, add 40 g of the resulting aqueous solution, and then dissolve to 50%
A glutaraldehyde aqueous solution 47- was added and reacted for 5 minutes. The product obtained here was in the form of a lump, and a single sphere was not obtained.

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

Claims (1)

[Claims] 1. Dispersing an aqueous solution of gelatin and a water-soluble compound that crosslinks with gelatin in a dispersion medium made by dissolving water-insoluble ethyl cellulose in a non-polar organic solvent that is incompatible with water to cause a crosslinking reaction. A method for producing gelatin spherical gel.