JP2008280407A - Production method of sphere-shaped composite gel particles - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple production method of polymer composite gel particles having a uniform sphere shape in which a particle diameter can be controlled. <P>SOLUTION: This production method of sphere-shaped polymer composite gel particles comprises a step of producing polymer composite gel particles by mixing anionic polymers and cationic polymers in an aqueous solvent. This production method preferably further contains a step of reacting the above sphere-shaped composite gel particles with a crosslinker after the above step. This production method preferably further contains a step of purifying the above sphere-shaped composite gel particles by performing the dialysis after the above step. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a gel, particularly a spherical polymer composite gel particle that is easy to produce.

Conventionally, various gel compositions using polymers have been widely used in various fields such as foods, pharmaceuticals, and cosmetics, and further development of functional gel compositions has been attempted. The gel composition that can be used for such a living body is generally formed from a natural product or a processed product thereof in consideration of the influence on the living body.
For example, as a method for producing a gel using hyaluronic acid having high biocompatibility, a method in which hyaluronic acid is reacted with trisodium trimetaphosphate (STMP) as a crosslinking agent in an emulsion to form a hydrogel has been reported ( Non-patent document 1).
Carbohydrate Polymers, Vol. 57, Issue 1, p. 1-6, 2004 Abstracts of the 53rd Annual Meeting of the Polymer Society of Japan (2004)

However, when a gel is formed in an emulsion as in the above technique, it is necessary to add an organic solvent. However, in order to obtain a final gel, these must be removed, and the manufacturing process tends to be complicated. Met. In addition, in the production method, it is difficult to control the particle diameter of the formed gel, and the desired form of gel may not be obtained.
In addition, as a method for producing a gel that can solve such complexity of production, carboxymethyl cellulose (CMC), which is an anionic polymer, is molecularly accumulated by DTAB, which is a cationic surfactant, and has pH responsiveness. It has been disclosed that a spherical cross-linked gel can be synthesized (Non-patent Document 2).
However, the gel composition by this method has low biocompatibility, and is unsuitable for application to pharmaceuticals, cosmetics and the like that are currently required.
The present invention has been made in view of the above-mentioned problems of the prior art, and an object of the present invention is to provide a simple method for producing polymer composite gel particles having a uniform spherical shape capable of controlling the particle diameter. .

As a result of intensive studies by the present inventors in order to achieve the above object, an anionic polymer and a cationic polymer are aggregated using an electrostatic attractive force in an aqueous solvent, and both polymers are It was found that by forming uniform spherical composite particles and further crosslinking the particles with a crosslinking agent, it is possible to easily obtain strong and functional spherical gel particles, thereby completing the present invention.
That is, the method for producing spherical composite gel particles according to the present invention includes a step of mixing an anionic polymer and a cationic polymer in an aqueous solvent to form spherical composite particles.
Moreover, it is preferable that after the said process, the process of making a crosslinking agent act on the said spherical composite particle is included.
Furthermore, it is preferable to include a step of purifying the spherical composite particles by performing dialysis after the step.
In addition, it is preferable that the step of causing the crosslinking agent to act is performed under stationary conditions.

  According to the production method of the present invention, spherical composite gel particles having a uniform spherical shape and excellent functionality can be easily obtained. Moreover, according to this manufacturing method, the particle size of the spherical composite gel particles can be easily controlled. Furthermore, the spherical composite gel particles obtained by the production method of the present invention are highly safe and can be widely applied to foods, pharmaceuticals, cosmetics and the like.

Hereinafter, the configuration of the present invention will be described in more detail.
Formation of polymer spherical composite particles The inventors of the present invention have studied the characteristics of anionic polymers and cationic polymers. Using the phase separation that occurs when an aqueous cationic polymer solution is added to an aqueous anionic polymer solution. And found that uniform polymer aggregates can be obtained. This aggregate has a uniform spherical shape and forms gel particles composed of a composite of an anionic polymer and a cationic polymer.

  That is, the method for producing spherical composite gel particles according to the present invention comprises a step of mixing an anionic polymer and a cationic polymer in an aqueous solvent to form an aggregate of the polymer, that is, a spherical composite gel particle. Including. Since gel formation in the present invention agglomerates molecules using electrostatic attraction between both polymers in an aqueous system, an aqueous solution of an anionic polymer and a cationic polymer is mixed in an aqueous solvent. This can be easily achieved.

The anionic polymer that can be applied to the production method according to the present invention is not particularly limited as long as it is a polymer having an anionic group in the molecule. Application of sugars is preferred.
Furthermore, synthetic polymers such as carboxyvinyl polymer, acrylic acid / methacrylic acid copolymer, polyacrylic acid, carboxymethylcellulose, acrylic acid / alkyl methacrylate copolymer, and the like can also be used.
The concentration of the anionic polymer in the present invention is preferably 0.0005 to 5% by weight in the reaction system in the aqueous solvent, although it depends on the charge ratio with the cationic polymer mixed at the same time. More preferably, it is 0.001-1 weight%, More preferably, it is 0.05-0.5 weight%.

The cationic polymer applicable to the production method according to the present invention is not particularly limited as long as it is a polymer having a cationic group in the molecule. Examples of such cationic polymer include poly (dimethyldiallylammonium halide) type cationic polymer, dimethyldiallylammonium halide and acrylamide copolymer cationic polymer, quaternary nitrogen-containing cellulose ether, or polyethylene glycol. Is a condensation product of taroylamine obtained from epichlorohydrin, propyleneamine and beef tallow fatty acid, or a cationized vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer, and the poly (dimethyldiallylammonium halide) type cationic polymer is a marcoat. Examples include those sold by Merck & Co. Inc. under the trade name 100 (Merquat100). Examples of the copolymer type cationic polymer of dimethyldiallylammonium halide and acrylamide include Merquat 550 (Merquat & Co., Inc.). An example of a condensation product of polyethylene glycol, epichlorohydrin, propyleneamine and taroylamine or cocoylamine is the product name Polyquat H, under the trade name Henkel
International Co.) can be listed. Quaternary nitrogen-containing cellulose is a product name of polymer JR-400 (Polymer JR-400), polymer JR-125 (Polymer JR-125), polymer JR-30M (Polymer JR-30M), and US Union Carbide ( Such as those sold by Union Carbide Corp.). The cationized vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer is sold by GAF Corp. in the United States under the trade names of Gafquat 755 and Gafquat734.
In addition, cationized polysaccharides such as cationized cellulose, cationized hydroxyethyl cellulose, cationized starch, cationized guar gum, cationized locust bean gum, cationized tamarind gum, and cationized fenucreak gum can also be suitably used. .

  The concentration of the cationic polymer in the present invention is preferably 0.0005 to 5% by weight in the reaction system in the aqueous solvent, although it depends on the charge ratio with the anionic polymer mixed at the same time. More preferably, it is 0.001-1 weight%, More preferably, it is 0.05-0.5 weight%.

The production method according to the present invention can control the size of the produced spherical gel particles by the charge ratio of the anionic polymer and the cationic polymer in an aqueous solvent. That is, since the electrostatic attractive force that serves as the starting force for aggregating both polymers can be adjusted by the ratio of the anionic group of the anionic polymer to the cationic group of the cationic polymer, it is formed by the aggregation. The size of the spherical gel particles is controlled. Therefore, at a concentration at which the charge of the anionic polymer and the cationic polymer is neutral, the electrostatic attraction becomes the smallest and the particle size becomes small.
In the production method according to the present invention, the charge ratio of the cationic group of the cationic polymer to the anionic group of the anionic polymer is preferably 0.1 to 10 times.

Crosslinking of spherical composite gel particles In addition, in the method for producing spherical composite crosslinked gel particles according to the present invention, after forming the spherical composite gel particles of the anionic polymer and the cationic polymer by the above steps, a crosslinking agent is further added. The particles can be added to crosslink the particles to form strong gel particles. For the addition of the crosslinking agent, a system in which spherical particles are formed can be used as it is. Although spherical particles may be separated from the system and reacted separately with a crosslinking agent, it is preferable to use the same system in terms of production efficiency.

Any crosslinking agent may be used as long as it can crosslink between the polymer chains constituting the spherical composite gel particles by chemical bonding.
As the cross-linking agent, for example, a polyfunctional compound having two or more functional groups capable of forming a covalent bond by reacting with a reactive functional group such as a carboxyl group, a hydroxyl group, or an acetamide group possessed by an anionic polymer can be used. . Specific examples of the crosslinking agent applicable to the present invention include alkyl diepoxy compounds such as 1,3-butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadiene diepoxide, Examples include diglycidyl ethers such as ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, and bisphenol A diglycidyl ether, divinyl sulfone, and epichlorohydrin. Among these, divinyl sulfone, 1,4-butanediol diglycidyl ether, and ethylene glycol diglycidyl ether can be preferably used. Moreover, in this invention, you may use in combination of 2 or more types of crosslinking agents suitably.

The concentration of the crosslinking agent is preferably 0.000001 to 5% by weight in a system containing an anionic polymer and a cationic polymer, although it depends on the type of the crosslinking agent used. More preferably, it is 0.00001 to 0.5 weight%, More preferably, it is 0.0001 to 0.05 weight%.
As the concentration of the crosslinking agent increases, the particle diameter of the spherical composite gel particles increases. This is considered to be because the higher the concentration of the cross-linking agent, the higher the cross-linking rate of the polymer in the system, thereby forming larger particles. Therefore, in the present invention, it is also possible to control the particle diameter of the spherical composite gel particles formed by the concentration of the crosslinking agent. However, if the concentration of the cross-linking agent is too high, the particles become too large to maintain a spherical shape, which is not preferable because precipitation may occur.

In the method for producing a spherical composite crosslinked gel particle according to the present invention, a mixture containing the polymer, the crosslinking agent, and water is mixed under acid or alkaline conditions, and the reactive functional group of the polymer is included. Are reacted with the cross-linking agent to cross-link the polymer chains constituting the polymer composite gel particles by chemical bonds, thereby generating cross-linked spherical cross-linked composite gel particles.
In the present invention, for the purpose of increasing the reactivity of the polymer chain during the crosslinking reaction, acids such as hydrochloric acid and sulfuric acid, bases such as sodium hydroxide and potassium hydroxide, phosphates, quaternary ammonium salts, etc. The pH of the mixture is appropriately adjusted with an appropriate buffer solution, and the mixture is stirred and mixed under acid or alkaline conditions. Specifically, for example, it is preferable to adjust the pH of the mixture so that the pH is 1 to 5 under acid conditions and the pH is 10 to 14 under alkaline conditions. When the crosslinking reaction is performed using the same system as that for forming the spherical particles, the pH of the system may be adjusted in the step of forming the particles. That is, it is possible to adjust the pH by dissolving an acid, a base, or the like in addition to an anionic polymer and a cationic polymer in an aqueous solvent.

  Moreover, in the manufacturing method concerning this invention, it is suitable to perform the said crosslinking reaction on stationary conditions. In ordinary polymer cross-linking techniques, a cross-linking agent is often added to the system under stirring conditions in order to promote the cross-linking reaction uniformly. In the case of the spherical composite gel particles according to the present invention, the cross-linking agent is added under stirring conditions. Addition may cause precipitation. This is because the reaction frequency between the spherical composite gel particles and the crosslinking agent and the collision frequency between the particles increase by stirring, and the crosslinking reaction occurs not only within the particles but also between the particles, and the particles aggregate and precipitate. it is conceivable that. On the other hand, if the cross-linking reaction is allowed to proceed slowly in a stationary state, it is possible to suppress cross-linking between particles as described above and to cross-link only within the particles, thereby obtaining a uniform dispersion of spherical cross-linked composite gel particles. be able to.

  In the production method according to the present invention, the time for performing the crosslinking reaction may be appropriately adjusted according to the type and concentration of the crosslinking agent. That is, when the concentration of the cross-linking agent is high, if the cross-linking time is increased, the cross-linking proceeds between the spherical composite gel particles, and precipitation may occur. On the other hand, when the concentration of the crosslinking agent is low, the crosslinking reaction does not proceed sufficiently if the crosslinking time is short, but if the crosslinking time is lengthened, spherical crosslinked composite gel particles can be obtained.

In the production method of the spherical composite gel particles according to the purification invention spherical composite gel particles, after crosslinked spherical particles made of a polymer complex by the above process, further dialyzed spherical composite crosslinked gel particles that dispersion Is preferably purified.
It is possible to easily remove the crosslinking agent remaining in the system by dialysis and obtain only gel particles.

The spherical composite cross-linked gel particles obtained by the production method according to the present invention described above are excellent in terms of functionality such as uniform spherical particles, salt resistance and pH responsiveness.
In addition, in the production of the spherical composite crosslinked gel particles according to the present invention, in addition to the above-described components, components that are usually used in medicines, cosmetics and the like in advance do not affect the purpose and effect of the present invention. May be blended as appropriate. Alternatively, the obtained spherical composite crosslinked gel particles can be blended into various products such as foods, pharmaceuticals, and cosmetics.

The spherical composite crosslinked gel particles obtained by the production method according to the present invention can be used as a pH-responsive material, a salt-resistant material, and a humectant by utilizing the characteristics. In addition, the gel of the present invention can be used as a single layer film and used as a coating agent for skin and hair.
Furthermore, when a polymer with high biocompatibility is used, the gel is difficult to be metabolized in vivo and has salt resistance and pH responsiveness, so that wrinkles, depressions and breast augmentation in cosmetic surgery are performed. Infusions for use, therapeutic agents for osteoarthritis (intra-articular injections) that exhibit high in vivo retention, lubrication and pharmacological effects, dry eye drops that exhibit high moisturizing action, retention in tears and pharmacological effects, Expected to be used for preventive and therapeutic agents for gastric ulcer, hay fever preventive agent, anti-oral dry agent and the like.
Since the formation of the spherical composite gel particles according to the present invention utilizes the electrostatic interaction between the anionic polymer and the cationic polymer as described above, if the stability of the gel particles in the product is taken into consideration It is preferable to blend the gel particles into various products after producing the spherical composite gel particles according to the present invention. That is, even if an anionic polymer and a cationic polymer are simply added to the product as a component, the gel particles may not be stably generated due to the influence of electrostatic interaction due to other components in the product. is there.

Also, utilizing the hydrophobic nature of the gel particles, encapsulating hydrophobic drugs or cationic drugs in the particles, and using them as carriers for drug delivery systems (DDS), gel compositions can be applied. It can be used in all possible fields.
EXAMPLES Hereinafter, although the Example of this invention is shown and this invention is demonstrated in more detail, this invention is not limited to this.

  An attempt was made to form spherical composite gel particles by combining anionic polymers and cationic polymers shown in Table 1 below. That is, the presence or absence of gel particle generation was evaluated according to the following evaluation criteria for the polymer dispersion after the crosslinking reaction produced according to the following method. The results are shown in Table 1.

<Production example of spherical composite crosslinked gel particles>
Production Method A 0.25 wt% aqueous anionic polymer solution, 1.6 wt% sodium hydroxide and distilled water for adjusting the concentration were added to a 50 ml sample tube and mixed. To this was added a 0.25 wt% cationic polymer aqueous solution as the final concentration under stirring conditions, and the mixture was stirred for 5 minutes for molecular accumulation / phase separation. Further, divinyl sulfone (DVS) was added as a cross-linking agent. After stirring to such an extent that the inside of the system became uniform, stirring was stopped and a cross-linking reaction was carried out under standing conditions. The crosslinking reaction was stopped by adding 1M hydrochloric acid to make the pH in the system neutral to weakly acidic, and a dispersion of crosslinked spherical composite gel particles was obtained. Thereafter, the dispersion was subjected to centrifugation and dialysis to purify the crosslinked spherical composite gel particles.

Evaluation criteria ( circle): It was the dispersion liquid of the uniform gel particle in which precipitation was not seen.
(Triangle | delta): It was the dispersion liquid which fibrous precipitation floated.
X: Gel particles were not generated.

(Table 1)
* 1 Marquat 100 (Merck): Poly N, N'-dimethyl-3,5-methylenepiperidinium chloride solution * 2 Cationized locust bean gum: O- [2-hydroxy-3- (trimethylammonio) chloride ) Propyl] locust bean gum * 3 Cationized guar gum M: Chloride O- [2-hydroxy-3- (trimethylammonio) propyl] guar gum * 4 Polymer JR400 (manufactured by Union Carbide): O- [2-hydroxy-chloride] 3- (Trimethylammonio) propyl] hydroxyethylcellulose * 5 Marquat 550 (Merck): Dimethyldiallylammonium chloride / acrylamide copolymer solution

As shown in Table 1, it was found that uniform cross-linked spherical gel particles were formed by mixing polymers having opposite charges and cross-linking in that state. Further, as a result of measuring the particle diameter of the particles, it was 24 μm in the combination of gum arabic / Mercoat 100 and 4 μm in the combination of sodium chondroitin sulfate / Mercoat 100. From this, it was presumed that the particle diameter of the gel particles slightly increased as the molecular weight of the anionic polymer used increased. This is considered to be because a complex of polymers is difficult to take a compact molecular form.
From the above results, it was confirmed that spherical composite gel particles were obtained by the production method of the present invention. Further, it was suggested that the particle size of the gel particles can be controlled by a combination of an anionic polymer and a cationic polymer.

<Concentration of anionic polymer and cationic polymer>
Using the system of gum arabic / merquat 100 in the above production example, the marcoat 100 was adjusted so as to have a final concentration of 0.04, 0.4, 0.8% by weight in a 0.25% by weight aqueous solution of gum arabic under alkaline conditions. Was added to cause molecular accumulation, and then crosslinked with DVS to obtain gel particles. FIG. 1 shows the results of measuring the particle diameter of gel particles at each concentration of the Marquat 100 by performing the above test using water and physiological saline as solvents.

  As shown in FIG. 1, the particle diameter of the spherical gel particles changed depending on the concentration of the marcoat 100, and showed a minimum value at a marcoat concentration of 0.4% by weight. This is considered to be because the gel particles contracted because the charges of the marcoat 100 and the gum arabic were neutralized and the electrostatic repulsion due to the dissociating group was suppressed. If the particle size changes depending on the charge ratio between the anionic polymer and the cationic polymer, the concentration of the anionic polymer can be adjusted by adjusting the concentration of the anionic polymer in the same manner as the cationic polymer in this test. It is considered that the particle diameter can be controlled.

Moreover, according to FIG. 1, when the solvent in the production | generation of a gel particle was used as the physiological saline, the particle diameter change substantially the same as the case where water was used as the solvent was shown.
From the above results, it was confirmed that in the production method of the present invention, the particle diameter of the spherical composite gel particles can be controlled by adjusting the concentration based on the charge ratio of the anionic polymer and / or the cationic polymer. . It was also recognized that the gel particles according to the present invention have salt resistance.

<Concentration of crosslinking agent>
In the gum arabic / mercoat 100 system in the above production example, the particle diameter of the spherical composite crosslinked gel particles when the DVS concentration was changed was measured. The results are shown in FIG.
As shown in FIG. 2, the particle size of the spherical gel particles increased with increasing DVS concentration. This is presumably because more polymer was cross-linked as the DVS concentration increased, and larger gel particles were formed accordingly.
From the above results, it was confirmed that the particle diameter can be controlled by the concentration of the crosslinking agent in the production method of the present invention.

<Observation of particles by scanning electron microscope (SEM)>
The form of the spherical composite gel particles obtained by the production method according to the present invention was confirmed using a scanning electron microscope (SEM).
That is, the gel particles obtained from the gum arabic / Mercoat 100 system in the above test example were diluted to an appropriate concentration and deposited and fixed on the cover glass. This was vacuum-deposited with platinum (Pt) and then fixed to a sample table with carbon tape. This was photographed with a scanning electron microscope (VE8800: manufactured by KEYENCE) at an appropriate magnification, and the particle morphology and surface appearance were observed. A photomicrograph obtained by the above operation is shown in FIG.
As shown in FIG. 3, the gel particles produced by the production method of the present invention had a uniform spherical shape.
From the above test results, it was confirmed that spherical composite gel particles having functional and particle size control can be easily obtained by the production method according to the present invention.

It is the graph which showed the change of the particle diameter by the density | concentration of the cationic polymer in this invention. It is the graph which showed the change of the particle diameter by the change of the crosslinking agent concentration in this invention. 2 is a SEM photograph of spherical composite crosslinked gel particles according to the present invention.

Claims (4)

  A method for producing spherical composite gel particles, comprising a step of mixing an anionic polymer and a cationic polymer in an aqueous solvent to form spherical composite particles.   After the process of Claim 1, the manufacturing method of the spherical composite gel particle characterized by including the process of making a crosslinking agent act on the said spherical composite particle.   A method for producing spherical composite gel particles, comprising the step of purifying the spherical composite particles by dialysis after the step according to claim 2.   The manufacturing method of the spherical composite gel particle characterized by performing the process of Claim 2 on stationary conditions.