JPH01299639A - Microcapsule and its production - Google Patents

Abstract

PURPOSE:To prepare microcapsules having no fluctuation of the quality and contg. no impurities by crosslinking a shell material consisting of polyvinyl alcohol having anionic groups in a molecule and gelatin with an aldehydric crosslinking agent. CONSTITUTION:A soln. of polyvinyl alcohol having anionic groups in a molecule is mixed with a soln. of gelatin having a pH adjusted to a pH near an isoelectric point of gelatin. When the temp. is elevated to above the gelling temp. of the gelatin and the pH is reduced to below the isoelectric point of the gelatin by adding an acid thereto, particles of coacervate are formed. When the coacervate particles are then treated with an aldehydric crosslinking agent, the positions of OH groups in the polyvinyl alcohol are crosslinked forming microcapsules. The microcapsules obtd. by this method consist of very firm and stable shell material.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides microcapsules for protecting drugs, cosmetics, adhesives, etc. and adjusting the rate at which they elute into the external environment.
The present invention also relates to microcapsules useful for diagnostic reagents, artificial carriers for tissue culture, carriers for liquid chromatography, adhesive particles for liquid crystal display elements, colored particles for liquid crystal display elements, and methods for producing the same.

(Prior art) "Microcapsule" is a microcapsule with a size of micrometer (
A microcapsule is a microparticle with a microscopic container on the order of .mu.-), and is composed of a content called a core material and a container called a wall material that covers the core material.

In order to produce microcapsules, a method is adopted in which the core material is first made into fine particles and dispersed in an appropriate medium, and then each of the fine particles is coated with a wall material. The membrane-spreading operation when manufacturing microcapsules is called microencapsulation, and a number of methods have been proposed so far, and can be roughly divided into: ■ chemical method, ■ physicochemical method, and ■
There are three methods: physical and mechanical.

The present invention relates to a novel microcapsule using a complex coacervation (phase fraction m> method) belonging to a physicochemical method, and a method for manufacturing the same.

Generally, when an electrolyte or an organic solvent is added to a polymer solution, the solubility of the polymer decreases. Composite coacervage gin is
A combination of a polycation solution and a polyanion solution is used as the polymer solution, and the concentrated colloidal phase produced when these are mixed is utilized for the encapsulation film. That is, when a polycation solution and a polyanion solution are mixed, phase separation occurs due to electrical interaction and a concentrated colloidal phase is produced, and this concentrated colloidal phase is utilized for the encapsulation film.

Coacervation with gelatin as a polycation component and gum arabic as a polyanionic component is
It is most commonly used because of its excellent film-forming ability.

Gelatin is a protein obtained by partially hydrolyzing animal collagen, and has been produced and used in large quantities for food, photography, medicine, etc., and its quality is relatively stable.

In addition, the proteins in gelatin contain all essential amino acids except tryptophan, have the property of reversible sol-gel transformation by heating and cooling, and have excellent film-forming ability, as well as the ability to change amino acids at the isoelectric point. Because the charges of acidic and basic groups are reversed, it has excellent properties as a polycation component in complex coacervation.

On the other hand, in addition to the above-mentioned gum arabic, the polyanion components used in complex coacervation include sodium alginate, carrageenan, carboxymethyl cellulose, agar, and many others. , polyvinylbenzenesulfonic acid, polyvinyl methyl ether-maleic anhydride copolymer, anionic surfactants, and the like are known. Among them, gum arabic is less affected by pH, has excellent compatibility with gelatin, and has excellent film-forming ability, so gum arabic has traditionally been used for complex coacervation.
Gum arabic is widely used.

For example, JP-A-57-153658, JP-A-57-153658,
-160465 publication and JP-A-59-195161
The publication proposes a microcapsule containing a water-soluble polymer such as gum arabic and gelatin, and a method for producing the same.

(Problem to be solved by the invention) However, gum arabic is a resin collected from trees of the genus Acacia, and its component is arabic acid, which is a multi-KM group. However, its quality is not necessarily constant, and its aqueous solution contains small amounts of impurities. Therefore, when using this gum arabic, operations such as filtration are required prior to use, and there are also drawbacks such as precipitation of insoluble matter over time and thickening due to enzyme activity.

In addition, in order to make the wall substance of the coacervate particles obtained by coacervagedin exist strongly and stably, conventionally, the coacervate particles are treated with an aldehyde crosslinking agent such as glyoxal or glutardehyde to cause crosslinking. It is common practice to do so. However, in the reaction between coacervate particles and an aldehyde crosslinking agent, many IJ! Crosslinking of the hydroxyl groups in the gelatin group is difficult to occur, and the reaction between the amino groups contained in gelatin and the crosslinking agent takes priority, and as a result, most of the amino groups may be consumed by the crosslinking reaction. Therefore, the obtained microcapsules are
For example, it is not preferable to use it for biochemical purposes that utilize the reactivity of amino groups.

Furthermore, as mentioned above, the reaction between the amino groups contained in gelatin and the crosslinking agent causes crosslinking by producing aldehyde amine (azomethine), but it is said that about 8% of the amino acids in gelatin have amino groups. Even if all of these amino acids react with a crosslinking agent, it is difficult to form a strong crosslinked structure.

The present invention is intended to solve the above-mentioned drawbacks, and its purpose is to provide a homogeneous and stable substitute for gum arabic, to have excellent film-forming ability, and to be able to form a relatively strong wall material. An object of the present invention is to provide microcapsules and a method for producing the microcapsules by a complex coacervation method.

Furthermore, in applications such as artificial blood cells, artificial carriers for diagnosis, and colored beads, gelatin-gum arabic microcapsules are used after being colored with direct dyes or acid dyes. It has the disadvantage that dye elution is observed in physiological saline).

In order to eliminate such drawbacks, the present invention provides novel colored microcapsules that enable strong binding of reactive dyes such as mono(di)chlorotriazine and dye molecules through covalent bonds, and a method for producing the same. This is also another purpose.

(Means for Solving the Problems) In the microcapsule of the present invention, the wall substance contains polyvinyl alcohol having an anionic group in the molecule and gelatin, and the polyvinyl alcohol is treated with an aldehyde crosslinking agent at its hydroxyl group. It is characterized by being crosslinked, thereby achieving the above object.

The method for producing microcapsules of the present invention is a gelatin solution obtained by dissolving gelatin in a polyvinyl alcohol solution having an anionic group in the molecule, and the pH of the solution is adjusted to be at or near the isoelectric point of the gelatin. to form a homogeneous system by heating above the gelation temperature of gelatin, and then add acid to bring the PTT of the system below the isoelectric point of gelatin to produce coacervate particles. It is characterized in that the particles are treated with an aldehyde-based crosslinking agent, thereby achieving the above object.

The present invention will be explained in detail below.

In producing the microcapsules of the present invention, first, a polyvinyl alcohol solution and a gelatin solution having an anion group in the molecule are prepared.

A polyvinyl alcohol solution is obtained by dissolving polyvinyl alcohol having an anionic group in the molecule in a solvent such as water. As the polyvinyl alcohol having an anion group in the molecule, polyvinyl alcohol having a sulfonic acid group or a carboxylic acid group as an anion group in the molecule can be used. Particularly suitable is polyvinyl alcohol having a carboxylic acid group in the molecule. A method for producing polyvinyl alcohol having a carboxylic acid group in the molecule is known. That is, a method of copolymerizing vinyl acetate and maleic acid or maleic anhydride in an organic solvent (in the presence of an alkali) and saponifying the resulting copolymer (for example, as disclosed in Japanese Patent Publication No. 38753/1983) reference)
Alternatively, a method in which a saponified vinyl ester polymer is reacted with a cyclic acid anhydride in an anhydrous state in the presence of a hydroxide or alkoxide of a -valent metal (for example, JP-A-53
-143691) etc. can be adopted. The concentration of the polyvinyl alcohol solution containing these anionic groups can be 0.1 to 3.0% by weight, preferably 0.2 to 1.5% by weight.

A gelatin solution is obtained by dissolving gelatin in a solvent such as water, and the pH of the solution is adjusted to be at or near the isoelectric point of the gelatin. Adjusting the pH of the gelatin solution to be at or near the isoelectric point of the gelatin means that the gelatin solution in which gelatin is uniformly dissolved is prepared to the extent that it is visually recognized as transparent.

Gelatin can be used either by acid treatment (type A) or lime treatment (type B), both of which are industrially produced. Among them, type A gelatin has an isoelectric point of 6 to 6.
The one as high as 9 is good. If the pi when gelatin is dissolved in water is not at or near the isoelectric point of gelatin, for example, an alkali such as sodium hydroxide may cause the ptt of the solution to be at or near the isoelectric point of the gelatin. It will be adjusted so that The concentration of gelatin in the gelatin solution can be from 0.05 to 3.0% by weight, preferably from 0.1 to 1.5% by weight.

The polyvinyl alcohol solution and gelatin solution prepared in this way are generally mixed in a mixed solution for complex coacervation prepared in advance, and heated to a temperature higher than the gelation temperature of gelatin to form a homogeneous system. shall be. In order to facilitate complex coacervation, it is preferable to add a conventionally known inorganic salt and a hydrophilic organic solvent to the mixed solution.

Examples of inorganic salts include ammonium sulfate, sodium sulfate, sodium metaphosphate, and sodium pyrophosphate. Among these, metaphosphates exhibiting metaphosphate ions, which are known to have the effect of coagulating and precipitating protein solutions such as silver nitrate solutions, barium nitrate solutions, and albumin, are preferred. These inorganic salts can be added in an amount of 5 to 60% by weight based on the solid amount of the polymer in the mixed system.

Hydrophilic organic solvents that are added to reduce the solubility of polymer solutions include methanol, ethanol, isopropanol, acetone, etc. Examples include IEK, and methanol and ethanol are particularly preferably used. The amount of these hydrophilic organic solvents added is in the range of 5 to 50% by volume based on the entire mixed system, but the amount of these hydrophilic organic solvents added should be determined depending on the particle size of the target microcapsules. It can be determined from a trigonometric phase diagram depending on the desired physical properties.

Next, while preferably stirring the mixed solution made into a homogeneous system in this way, an acid is added to the mixed solution to adjust the pH of the system.
below the isoelectric point of gelatin. Here, the acid used to adjust the pH may be an organic acid or an inorganic acid, but acetic acid is preferably used. When the pH of the system is lowered to below the isoelectric point of gelatin by adding an acid in this way, coacervate particles are generated and the liquid becomes cloudy and slurry-like.

Thereafter, the temperature of the system is cooled to below the gelation temperature of gelatin, preferably around 5° C., and then the obtained coacervate particles are treated with an aldehyde crosslinking agent to firmly crosslink the wall material. Here, only the coacervate particles are collected by separating the mother liquor by centrifugation or precipitation, and then the coacervate particles are redispersed and suspended in water at around 15°C, and the above-mentioned aldehyde-based crosslinking is carried out under an acid catalyst such as hydrochloric acid. Preferably, the agent is allowed to react. Examples of the aldehyde crosslinking agent used include formaldehyde, acetaldehyde, crotonaldehyde, acrolein, glyoxal, and gluculdehyde.

The amount of aldehyde crosslinking agent used is preferably 5 to 50% by weight based on the solid amount of the polymer, and the reaction time is 1 to 5% by weight.
The time is selected accordingly.

By treating the coacervate particles with the aldehyde crosslinking agent in this manner, the hydroxyl groups of polyvinyl alcohol, which is a constituent component of the wall material of the coacervate particles, react with the aldehyde crosslinking agent, and the polyvinyl alcohol is crosslinked. Here, since polyvinyl alcohol can have 90% or more of hydroxyl groups, although it varies depending on its degree of saponification, a strong wall material is formed by the acetalization reaction.

In addition, in the process of forming coacervate particles by the above-mentioned complex coacervation, in order to disperse the solid substance as a part of the core substance into single particles, and to prevent coalescence of coacervate particles or microcapsules in the process of forming microcapsules. Therefore, it is preferable to add a surfactant to the mixed solution. The surfactants used include alkyl sulfates, alkylbenzenesulfonates, alkylnaphthalenesulfonates, alkylsulfosuccinates, polyoxyethylene alkyl or alkylaryl sulfates, and special polycarboxylic acid type polymers. Anionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, oxyethylene, oxypropylene block copolymer, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene fatty acid ester There are nonionic surfactants such as
The concentration of these surfactants used is appropriately selected within the range of o, oot to 5.0% by weight.

It is also possible to obtain colored microcapsules by treating the thus obtained microcapsules with a reactive dye. The reactive dye has a sulfonic acid group in its molecular structure to impart water solubility, and one or two active chlorine atoms as a reactive group to covalently bond to the hydroxyl group of the microcapsule wall material. So-called monochloro or dichloro-3-)riazinyl dyes can be used. In particular, dichloro-3-triazinyl dyes that react at low temperatures are preferably used.

As described above, the microcapsules produced in this manner are composed of a core material and a wall material covering the core material, and the wall material contains polyvinyl alcohol having an anion group in its molecule and gelatin. , the polyvinyl alcohol is crosslinked at a large number of hydroxyl sites contained therein with an aldehyde crosslinking agent. Therefore, a wall material having a strong crosslinked structure is formed by acetalization, and the amino groups contained in gelatin are not completely eliminated during the acetalization reaction.

The obtained microcapsules or colored microcapsules can be used, for example, as microcapsules for protecting drugs, cosmetics, adhesives, etc. and adjusting the rate of elution into the external environment, or for diagnostic reagents, artificial carriers for tissue culture, and liquids. It is used as carriers for chromatography, adhesive particles for liquid crystal display elements, colored particles for liquid crystal display elements, etc.

(Examples) The present invention will be described in more detail below based on Examples.

Preparation of polyvinyl alcohol solution containing an anionic group> Polyvinyl alcohol having an anionic group in the molecule is obtained by copolymerizing 97 mol% of vinyl acetate and 3 mol% of maleic anhydride, and then saponifying this copolymer. Maleated polyvinyl alcohol having a degree of polymerization of 1050 and a degree of saponification of 95 mol% was used.

11 Put 470 g of ion-exchanged water in a beaker and warm it to 40°C. While stirring with a magnetic stirrer, gradually add 30 g of the above maleated polyvinyl alcohol into the ion-exchanged water, and continue stirring for 1 hour to completely stir. A 6% maleated polyvinyl alcohol aqueous solution was obtained. The pH of this aqueous solution was 6.1. This maleated polyvinyl alcohol aqueous solution is hereinafter referred to as "Liquid A".

<Preparation of gelatin solution> 30 g of commercially available A type gelatin with an isoelectric point of 9 was weighed out.

Meanwhile, put 470 g of ion-exchanged water in a 1ffi beaker, warm it to 40°C, and gradually add the above gelatin while stirring with a magnetic cooler. Continue stirring for 1.5 hours to completely dissolve the gelatin. An aqueous gelatin solution was obtained.

Since the pH of this aqueous gelatin solution was 4.1, 10% NaOH was added to it to reach pi, which is the isoelectric point of gelatin.
(=9.0) was prepared. This gelatin aqueous solution is hereinafter referred to as rG solution. This "G solution" was kept in a constant temperature bath at 40°C and used in the following experiment.

Preparation of microcapsules> 50% by volume ethanol aqueous solution 18 in a 500d beaker
6ml was taken and stirred with a magnetic cooler while heating to 40"C. To this solution was added 15g of sodium sulfate.
was added and dissolved, and 10% of a nonionic surfactant (polyoxyethylene alkyl ether; manufactured by Daiichi Kogyo Seiyaku ■, trade name: Neugen ET135) 3- was added. Furthermore, microspheres formed from a crosslinked copolymer of 60 parts by weight of tetraethylene glycol dimethacrylate and 40 parts by weight of methacrylic acid and having an average particle size of 2 to 4 μm were added to this solution and colored with a red dye. 2 g of microspheres were added and stirred to disperse the colored microspheres into single particles. A mixture of the above A liquid 60d and G liquid 54rd was added to this mixed solution, and 10% by volume acetic acid was gradually added dropwise while stirring, and the p
Addition of acetic acid was stopped when H reached 4.5, and the solution was then cooled to 5°C.

The solution became cloudy and slurry-like, so next, one drop of this slurry was sampled and examined under a microscope with a magnification of 400 times. As a result, the center diameter including the colored microspheres was 8 to 15 mm.
Coacervate particles of μm size were observed. Next, the slurry containing coacervate particles was centrifuged at 1500 rpm for 5 minutes to sediment the particles, and the mother liquor was separated to remove the coacervate particles. The coacervate particles were then redispersed in 300 grit water containing 0.1% Neugen ET135. The temperature of this system was maintained at 15°C, and 0.3 d of 35% hydrochloric acid and 25% glutaldehyde 2 were added thereto, and after stirring for 2 hours,
Neutralized to pH 1 with 10% NaOH. Thereafter, this liquid was centrifuged at 1500 rpm+ for 5 minutes to sediment the particles, and the mother liquid was separated to obtain microcapsules.

Tip I: 50 parts by weight of divinylbenzene with a particle size of 6 to 15 μm;
Porous microspheres obtained by copolymerizing with 50 parts by weight of methacrylic acid were impregnated with Rose oil, which is a type of fragrance, to obtain fragrance-impregnated porous microspheres. 1 g of this fragrance-impregnated porous microspheres was mixed with 240 ml of a 40% ethanol aqueous solution containing 3d of 10% Neugen ET135! dispersed in l,
This dispersion was kept at 40°C. Next, add 4 parts of liquid A to this liquid.
2 lines and G liquid 18ad! After adding 3 ml of 10% sodium pyrophosphate, the pH of the system was adjusted to 4.5 with 10% acetic acid, coacervation was performed, and the mixture was cooled to 5°C. When a portion of the obtained slurry was sampled and the sampled sample was examined under a microscope in the same manner as in Example 1, coacervate particles with a center diameter of 10 to 30 μm were observed.

To this slurry, 35% hydrochloric acid (0.2%) and 25% gluculdehyde (3d) were added, and the temperature was raised to 50°C. It was kept in this condition for 1 hour. Thereafter, the system was centrifuged to separate the mother liquor in the same manner as in Example 1, and the resulting particles were washed with methanol to obtain perfume-impregnated microcapsules.

A portion of the perfume-impregnated microcapsules obtained here and the perfume-impregnated porous microspheres were placed in petri dishes, and after being left at room temperature for - months, their fragrance retention properties were compared. As a result, the fragrance-impregnated porous microspheres lost the fragrance odor, whereas the fragrance-impregnated microcapsules retained the fragrance odor.

Example 1 - 30% by volume ethanol aqueous solution 3 in a 500Id beaker
Take 20 d of liquid, heat it to 40℃, and while stirring with a magnetic cooler, add 56 ml of liquid A and 24 ml of liquid G! Add a mixture of 10% sodium hexametaphosphate and 3d
added. 10% acetic acid was added dropwise to this mixed solution while stirring to adjust the pH of the system to 4.5 and cause coacervation. After that, 10% Neugen ET135 was added to the system, the system was cooled to 5°C, a part of it was sampled, and when the sampled sample was examined with a microscope in the same manner as in Example 1, the center diameter was 6 to 8 μm. Uniformly spherical coacervate particles were observed.

Next, the slurry containing coacervate particles was heated at 150°r
pm - The particles were sedimented by centrifugation for 5 minutes, and the mother liquor was separated to take out the coacervate particles. Next, the coacervate particles were redispersed in 300 rnl of water containing 0.1% Neugen ET135 and the temperature of the system was maintained at 15°C.
d and 25% glutaldehyde 3d were added, stirred for 3 hours to carry out the acetalization reaction, and then added with 10% N.
Neutralize to pH 7 by adding aOH. Thereafter, this liquid was centrifuged in the same manner as in Example 1 to sediment the particles, and the mother liquid was separated to obtain microcapsules.

The obtained microcapsules were redispersed in 100 ml of ion-exchanged water, and the liquid was then heated to 50°C and visually observed. No aggregation of the microcapsules was observed, and the particle morphology was stable. was held.

111 (In a 300 d beaker, add a low temperature reactive dichlorotriazine red dye (Kayaract Red, manufactured by Nippon Kayaku).
3B) Add 0.1 g to 200 Ill of ion-exchanged water.
Dissolve at 0°C and add 10% soda carbonate to reduce the ρ■
was set as 7. 4 2 ml (sedimentation volume) of the microcapsules obtained in Example 3 were added to this solution, and the mixture was reacted at 40°C for 3 hours with stirring. Thereafter, the dye bath was filtered off using a 4G-glass filter, and the microcapsules were washed with water to obtain colored microcapsules dyed red.

Next, the colored microcapsules were dispersed in 10 trtll of PbS and left at room temperature for one week. When observed, the colored microcapsules sedimented and the supernatant PbS
The bS solution was colorless and transparent, and no dye elution was observed.

n-Example - 30% by volume methanol aqueous solution 1 in a 500ml beaker
Add 80'iji and Neugen ET1353 g, 4
The mixture was heated to 0°C and stirred using a magnetic cooler.

Add to this 60 ml of liquid A, 60 ml of liquid G, and aqueous dispersion-processed titanium oxide with a solid content of 50% (manufactured by Dainippon Seika Kogyo ■, trade name E).
P232 White) 4g was added and mixed uniformly. next,
While stirring this mixed solution, 3 ml of 10% sodium hexametaphosphate was added, and then 10% acetic acid was gradually added dropwise to bring the pH of the system to 4.5, followed by cooling to 5°C. When a portion of this liquid was sampled and examined under a microscope in the same manner as in Example 1, one particle was observed in the core cell with a center diameter of 10 to 20 μm. After allowing the obtained slurry to settle naturally,
The mother liquor was separated by decantation, and then the coacervate particles were crosslinked by acetalization reaction in the same manner as in Example 3 to obtain microcapsules.

(Effects of the Invention) As described above, according to the present invention, since polyvinyl alcohol having an anion group in the molecule is used as a constituent component of the wall material of the microcapsules, there is no variation in quality and no impurities are contained. It is possible to obtain microcapsules of excellent quality.

Furthermore, unlike the conventional case where gum arabic is used as a polyanion component, there is no need for a filtration operation to remove impurities, and productivity is also excellent.

Furthermore, the wall material of the microcapsules contains polyvinyl alcohol having anionic groups in the molecule and gelatin, and since the polyvinyl alcohol is crosslinked with an aldehyde crosslinking agent, the hydroxyl groups present in large numbers in the polyvinyl alcohol can be converted into acetals. By taking part in the chemical reaction,
Microcapsules having a strong and stable wall material can be obtained, and the amine groups contained in gelatin, which is another component of the wall material, can remain, and the resulting microcapsules can be It can also be used for biochemical purposes utilizing its reactivity.

In addition, the microcapsules of the present invention can chemically bond reactive dyes to hydroxyl groups contained in polyvinyl alcohol, so they are useful for products that do not elute dyes, such as artificial blood cells, artificial carriers for diagnosis, and colored beads. Colored microcapsules can also be obtained.

that's all

Claims (1)

[Claims] 1. The wall material contains polyvinyl alcohol having an anion group in the molecule and gelatin, and the polyvinyl alcohol is crosslinked at its hydroxyl group with an aldehyde crosslinking agent. microcapsules. 2. Obtained by dissolving gelatin in a polyvinyl alcohol solution that has anionic groups in the molecule, and the pH of the solution
A gelatin solution adjusted to or near the isoelectric point of the gelatin is mixed with the gelatin solution, heated above the gelation temperature of the gelatin to form a homogeneous system, and then acid is added to adjust the pH of the system to that of the gelatin. A method for producing microcapsules, which comprises producing coacervate particles by lowering the temperature to below the electric point, and then treating the coacervate particles with an aldehyde-based crosslinking agent.