JP7420336B2 - Method for manufacturing composite particles - Google Patents

Description

The present invention relates to composite particles containing micronized chitin/core particles and a method for producing the composite particles.

Living organisms produce highly crystalline nanofibers such as cellulose and chitin during the biosynthetic process. Highly crystalline nanofibers such as cellulose and chitin are the most abundant biologically produced nanofibers on earth. These nanofibers are structural polysaccharides essential for maintaining living organisms and exhibit high strength.

Chitin nanofibers (micronized chitin) are nanofibers made by pulverizing chitin/chitosan collected from crab shells and the like into ultrafine fibers. Chitin nanofiber is a recyclable resource with antibacterial and biodegradable properties, and is expected to be used as an addition to foods and cosmetics, as reinforcing fiber for films, as agricultural resources, and for medical purposes. be done.

However, since chitin/chitosan are closely bonded to each other through strong hydrogen bonds, it is not easy to prepare individual nanofibers from chitin/chitosan. According to the chitin nanofibers and the method for producing the same described in Patent Document 1, a dispersion containing chitin nanofibers separated into individual fibers can be obtained through a simple process.

Japanese Patent Application Publication No. 2010-180309

However, according to the chitin nanofibers and the method for producing the same described in Patent Document 1, it is possible to obtain a dispersion containing chitin nanofibers separated one by one. If the solvent of a dispersion containing fibers is removed, the ultrafine fibers will aggregate, become keratinized, or form a film. Furthermore, since the solid content concentration of chitin nanofibers is low, the process of removing the solvent by drying requires a large amount of energy, which is another factor that impairs business viability.

As described above, handling chitin nanofibers in the form of a dispersion itself can be a cause of impairing business viability, so it is strongly desired to provide a new handling mode that allows chitin nanofibers to be handled easily. .

The present invention has been made in view of such circumstances, and aims to provide a new handling mode for chitin nanofibers that is easy to handle while maintaining the characteristics of chitin nanofibers.

In order to solve the above problems, the present invention proposes the following means.
The composite particle according to the first aspect of the present invention is a composite particle that includes a core particle containing at least one type of polymer, and has a fine chitin layer made of fine chitin on the surface of the core particle, and The core particles and the fine chitin are bonded and inseparable, and the fine chitin layer is coated with fine chitin to a uniform thickness .

The method for producing composite particles according to the second aspect of the present invention includes a first step of defibrating chitin and/or chitosan raw materials in a solvent to obtain a fine chitin dispersion, and a monomer liquid and or a second step of coating the surface of the droplet containing the polymer liquid with the finely divided chitin and stabilizing it as an emulsion, and a second step of solidifying the droplet to obtain composite particles coated with the polymer with the finely divided chitin. 3 steps, the second step is a step of adding a polymerizable monomer liquid to the micronized chitin dispersion to form an emulsion, and the third step is a step of polymerizing the polymerizable monomer. This is a step of solidifying the droplets to obtain composite particles, and in the second step, the amount of the polymerizable monomer is 1 part by mass or more and 50 parts by mass or less with respect to 100 parts by mass of the micronized chitin .

According to one embodiment of the composite particles of the present invention, it is possible to provide a new handling mode that allows easy handling while maintaining the characteristics of chitin nanofibers (micronized chitin).

FIG. 1 is a schematic diagram of composite particles according to an embodiment of the present invention. 1 is a schematic diagram of an O/W Pickering emulsion using finely divided chitin and a method for producing composite particles in which monomers inside the emulsion are polymerized and solidified according to an embodiment of the present invention. FIG. 2 is a schematic diagram of a method for producing composite particles in which an organic solvent inside an O/W Pickering emulsion using micronized chitin is removed to solidify a dissolved polymer according to an embodiment of the present invention. 1 is a schematic diagram of an O/W Pickering emulsion using micronized chitin and a method for producing composite particles in which a molten polymer inside the emulsion is solidified according to an embodiment of the present invention. This is an optical micrograph of composite particles made from raw material obtained by crushing red king crab shell into pieces of about 5 mm. This is an optical micrograph of composite particles made from raw material obtained by crushing the soft carapace of a squid into pieces of about 1 cm. It is a graph showing the measurement results of the light transmittance of the micronized chitin dispersion. FIG. 2 is an electron microscope observation diagram of composite particles.

Hereinafter, one embodiment of the present invention will be described using the drawings. However, in each of the figures described below, mutually corresponding parts are given the same reference numerals, and descriptions of overlapping parts will be omitted as appropriate. Further, this embodiment is an example of a configuration for embodying the technical idea of the present invention, and the material, shape, structure, arrangement, dimensions, etc. of each part are not specified as described below. The technical idea of the present invention can be modified in various ways within the technical scope defined by the claims.

<Composite particle 5>
First, composite particles 5 of finely divided chitin and resin particles according to an embodiment of the present invention will be described. Note that the resin is also referred to as a polymer. Figure 1 shows an O/W Pickering emulsion using micronized chitin 1, and solidification of polymerizable monomer droplets and/or polymer droplets 2 (hereinafter also simply referred to as "droplets 2") inside the emulsion. It is a schematic diagram of composite particle 5 obtained by this.

The composite particle 5 includes a core particle 3 having at least one type of resin (polymer), has a fine chitin layer 10 composed of a fine chitin 1 on the surface of the core particle 3, and has a fine chitin layer 10 composed of a fine chitin 1, and has a fine chitin layer 10 composed of a fine chitin 1. It is a composite particle in which chitin-1 is bound and inseparable.

The method for producing the composite particles 5 is not particularly limited, and any known method can be used. For example, polymerization granulation methods (emulsion polymerization method, suspension polymerization method, seed polymerization method, radiation polymerization method, etc.) in which particles are formed during the polymerization process from polymerizable monomers, and particles are formed from polymer solutions that have been turned into microdroplets. Examples include dispersion granulation methods (spray drying method, in-liquid curing method, solvent evaporation method, phase separation method, solvent dispersion cooling method, etc.). Details of the manufacturing method will be described later.
For example, by adsorbing the fine chitin 1 to the interface of the droplets 2 of core particles dispersed in the hydrophilic solvent 4, the O/W Pickering emulsion is stabilized, and the liquid inside the emulsion remains stable. By solidifying the droplets 2, composite particles 5 using the emulsion as a template can be produced.
Note that solidifying the polymerizable monomer droplets and/or the polymer droplets 2 means (1) polymerizing the polymerizable monomer droplets, (2) solidifying the polymer droplets, (3) polymerizable including solidifying monomer droplets and polymer droplets.

"Inseparable" here refers to the operation of purifying and washing the composite particles 5 by centrifuging the dispersion containing the composite particles 5 to remove the supernatant, and then adding a solvent and redispersing the composite particles 5, or using a membrane filter. Even after repeating the operation of washing with a solvent by filtration washing using It means that. The coating state can be confirmed by observing the surface of the composite particles 5 using a scanning electron microscope. The bonding mechanism between fine chitin 1 and core particles 3 in composite particles 5 is not certain, but since composite particles 5 are created using an O/W type emulsion stabilized by fine chitin 1 as a template, the inside of the emulsion Because the solidification of the droplet 2 progresses while the finely divided chitin 1 is in contact with the droplet 2 of It is presumed that 3 and micronized chitin 1 reach an inseparable state.
Here, the O/W emulsion is also called an oil-in-water emulsion, in which water is the continuous phase and oil is dispersed therein as oil droplets (oil particles). .

Furthermore, since the composite particles 5 are produced using the O/W type emulsion stabilized by the micronized chitin 1 as a template, the shape of the composite particles 5 is characterized by a true spherical shape derived from the O/W type emulsion. be. Specifically, the fine chitin layer 10 made of the fine chitin 1 is formed on the surface of the true spherical core particle 3 with a relatively uniform thickness. The average thickness of the fine chitin layer 10 is determined by cutting the composite particles 5 fixed with embedding resin using a microtome and observing them with a scanning electron microscope. It can be calculated by measuring the thickness at 100 random locations on the image and taking the average value. Further, it is preferable that the composite particles 5 are uniformly covered with a fine chitin layer 10 having a relatively uniform thickness, and specifically, the coefficient of variation of the thickness value of the fine chitin layer 10 mentioned above is 0.5. It is preferably 0.4 or less, more preferably 0.4 or less.

In this embodiment, the chitin nanofibers (micronized chitin) in the micronized chitin 1 are nanofibers obtained by pulverizing chitin/chitosan collected from crab shells or the like into ultrafine fibers. Micronized chitin 1 has biodegradability.

Although not particularly limited, it is preferable that the micronized chitin 1 contains an ionic functional group. It is preferable that the ionic functional group that the micronized chitin 1 has is cationic. The ionic functional group content of the fine chitin 1 constituting the fine chitin layer 10 is 0.1 mmol/g or more and 3.0 mmol based on the dry weight of the fine chitin 1 constituting the fine chitin layer 10. /g or less is preferable. When the ionic functional group content of the micronized chitin 1 is within this range, highly dispersible composite particles 5 with uniform particle diameters can be obtained.
Further, the ionic functional group content of the micronized chitin 1 constituting the micronized chitin layer 10 is preferably 0.0002 mmol/g or more and 0.2 mmol/g or less based on the dry weight of the composite particles 5. preferable.

Furthermore, it is preferable that the micronized chitin 1 has a fiber shape derived from a microfibril structure. Specifically, the micronized chitin 1 is fibrous, and has a number average minor axis diameter of 1 nm or more and 1000 nm or less, a number average major axis diameter of 50 nm or more, and a number average major axis diameter of 1 nm or more and 1000 nm or less, and a number average major axis diameter of 50 nm or more. It is preferable that it is 5 times or more. The degree of crystallinity of the micronized chitin 1 is preferably 50% or more.
The number average short axis diameter of the micronized chitin 1 is determined by measuring the short axis diameter (minimum diameter) of 100 fibers by transmission electron microscopy and atomic force microscopy, and finding the average value thereof. On the other hand, the number average long axis diameter of the micronized chitin 1 is determined by measuring the long axis diameter (maximum diameter) of 100 fibers by transmission electron microscopy and atomic force microscopy, and finding the average value thereof.

In particular, it is preferable that the micronized chitin 1 consists of alpha chitin with a degree of N-acetylation of 60% or more and 85% or less. When the degree of N-acetylation is within this range, narrow, individually separated nanofibers with a number average short axis diameter of 5 nm or more and 50 nm or less and a number average long axis diameter of 300 nm or more and 5 μm or less are produced. can be obtained.

The polymer is not particularly limited, and examples thereof include acrylic polymers, epoxy polymers, polyester polymers, amino polymers, silicone polymers, fluorine polymers, urethane/isocyanate polymers, and the like.

Although not particularly limited, the polymer is preferably a biodegradable polymer. Biodegradable refers to polymers that decompose and disappear in the earth's environment such as soil and seawater, and/or polymers that decompose and disappear in living organisms. In general, polymers are degraded in soil or seawater by enzymes possessed by microorganisms, whereas in living organisms they are degraded by physicochemical hydrolysis without the need for enzymes.
Biodegradable polymers include naturally derived natural polymers and synthetic polymers. Examples of natural polymers include polysaccharides produced by plants (cellulose, starch, alginic acid, etc.) and polysaccharides produced by animals (chitin, alginic acid, etc.). Examples include chitosan, hyaluronic acid, etc.), proteins (collagen, gelatin, albumin, etc.), polyesters produced by microorganisms (poly(3-hydroxyalkanoate)), polysaccharides (hyaluronic acid, etc.). The biodegradable polymer will be described later.

<Method for manufacturing composite particles 5>
Next, a method for manufacturing composite particles 5 according to this embodiment will be explained. The method for producing composite particles 5 according to the present embodiment includes a step (first step) of defibrating chitin and/or chitosan raw materials in a solvent to obtain a dispersion of micronized chitin 1, and dispersion of micronized chitin 1. A step (second step) of coating the surface of the polymerizable monomer droplets and/or polymer droplets 2 with finely divided chitin 1 in the liquid and stabilizing them as an emulsion (second step); and solidifying the droplets 2 to form finely divided chitin 1. This is a method for producing composite particles 5, comprising: obtaining composite particles 5 coated with core particles 3 (third step).

FIG. 2 is a schematic diagram of an O/W Pickering emulsion using micronized chitin 1 and a method for producing composite particles 5 in which monomers inside the emulsion are polymerized and solidified.
FIG. 3 is a schematic diagram of a method for producing composite particles 5 in which the organic solvent inside an O/W Pickering emulsion using micronized chitin 1 is removed to solidify the dissolved polymer.
FIG. 4 is a schematic diagram of an O/W type Pickering emulsion using micronized chitin 1 and a method for producing composite particles 5 that solidify the molten polymer inside the emulsion.

The composite particles 5 obtained by the above manufacturing method are obtained as a dispersion. Further, by removing the solvent, it is obtained as a dry solid. The method for removing the solvent is not particularly limited, and for example, a dry solid can be obtained by removing excess water by centrifugation or filtration, and then heat drying in an oven. At this time, the obtained dry solid does not become film-like or aggregate-like, but is obtained as a fine-textured powder. Although the reason for this is not certain, it is known that when the solvent is removed from a dispersion of finely divided chitin 1, the finely divided chitin 1 strongly aggregates and forms a film. On the other hand, in the case of a dispersion containing composite particles 5, since the fine chitin 1 is a truly spherical composite particle fixed on the surface, even if the solvent is removed, the fine chitin 1 does not aggregate with each other, and the composite Since the particles are in contact only at points, it is thought that the dry solid is obtained as a fine-textured powder. As described above, the composite particles of the present invention can be used in cosmetics and medical applications, such as powder-type foundation compositions, because micronized chitin, which is biodegradable and biocompatible, can be used as a fine-textured powder. suitable for
In addition, since there is no aggregation of the composite particles 5, it is easy to redisperse the composite particles 5 obtained as a dry powder in a solvent again, and even after redispersion, fine particles bonded to the surface of the composite particles 5 remain. The dispersion stability derived from chitin 1 is shown. At this time, if an ionic functional group is introduced into the crystal surface of the micronized chitin 1 used, the ionic functional group will be selectively arranged on the surface of the composite particle, and the osmotic pressure will cause the gap between the composite particles. This is preferable because it allows the solvent to easily penetrate into the resin and further improves dispersion stability.

The dry powder of the composite particles 5 is a dry solid that contains almost no solvent and can be redispersed in the solvent, and specifically, the solid content can be set to 80% or more. It can be increased to 90% or more, furthermore it can be increased to 95% or more. Since most of the solvent can be removed, favorable effects can be obtained from the viewpoints of reducing transportation costs, preventing spoilage, and increasing the addition rate. In addition, when the solid content percentage is increased to 80% or more by drying treatment, since the micronized chitin 1 easily absorbs moisture, there is a possibility that the solid content percentage will decrease over time due to adsorption of moisture in the air. However, considering the technical idea of the present invention, which is characterized in that the composite particles 5 can be easily obtained as a dry powder and can be redispersed, the solid content of the dry powder containing the composite particles 5 should be 80% or more. It is defined that any dry solid material that includes the steps described above falls within the technical scope of the present invention.

Each step will be explained in detail below.

(1st step)
The first step is a step of defibrating chitin and/or chitosan raw materials in a solvent to obtain a dispersion of micronized chitin 1. Although not particularly limited, a dispersion containing chitin nanofibers separated into individual fibers can be obtained by using the following method. By using such chitin nanofibers, composite particles 5 with good dispersibility and uniform particle diameter can be obtained.
Specifically, a dispersion of micronized chitin 1 was prepared through the steps of (1) purification of chitin and/or chitosan raw materials and introduction of ionic functional groups, (2) immersion treatment, and (3) fibrillation treatment.

(1) Purification of chitin and/or chitosan raw materials and introduction of ionic functional groups First, chitin and/or chitosan raw materials are prepared. For example, antiparallel chain alpha chitin found in crustaceans such as crabs and shrimp, and parallel chain beta chitin found in the shells of squids can be used.
Chitin and/or chitosan are polysaccharides whose molecular structure is similar to cellulose. Cellulose has a hydroxyl group, chitin has an N-acetyl group, and chitosan has an amino group bonded to the 2nd carbon of the pyranose ring, and the other parts have the same structure. In chitin and/or chitosan, N-acetyl groups and amino groups are not 100% bound to the C2 position of the pyranose ring, but are generally mixed.
Chitin and/or chitosan raw materials are linear structural polysaccharides that support and protect the bodies of animals such as crustaceans such as crabs and shrimp, insects, spiders, arthropods, and squid tendons. (there are parts where the molecules are arranged regularly), and some are bound to proteins. Chitin is a polysaccharide whose main constituent sugar is N-acetylglucosamine. When chitin and/or chitosan raw materials are isolated and purified, there is hardly any purified chitin that consists of 100% N-acetylglucosamine, and chitin and/or chitosan that partially contains glucosamine as a component can be obtained.

For example, two types of chitin and/or chitosan raw materials can be used: raw material a made by crushing dry red king crab shell into pieces of about 5 mm, and raw material b made by crushing the soft carapace of a wet squid into pieces about 1 cm.

Chitin and/or chitosan raw materials can be purified by the following method. First, chitin and/or chitosan raw materials are degreased, then demineralized, deproteinized and bleached several times, and finally washed.

Chitin and/or chitosan raw materials are immersed in a chloroform/methanol (2/1) solution for one day to degrease them.

Next, the defatted raw material is treated with 1M hydrochloric acid for 3 hours to demineralize it. The treated raw material is treated overnight with a 10% aqueous sodium hydroxide solution under a nitrogen purge to effect deproteinization. Thereafter, the treated raw material is bleached by immersing it in a 0.3% aqueous sodium chlorite solution and stirring for 4 hours using a magnetic stirrer in an oil bath set at 70°C.
After a series of demineralization, deproteinization, and bleaching processes are repeated four times, the defatted raw material is washed with a 1M aqueous sodium hydroxide solution to deproninate the amino groups on the surface, and then washed with water. .

After purifying the chitin and/or chitosan raw materials, ionic functional groups are introduced as necessary. Purified chitin and/or chitosan raw materials are called purified chitin. The ionic functional group to be introduced is not particularly limited, and known methods can be used. For example, an amino group, a carboxy group, etc. can be introduced. In particular, the method of introducing amino groups by partial deacetylation treatment is safe and is therefore suitable for use in cosmetics and medical applications.

When the raw material a (alpha chitin) obtained by crushing dry red king crab shell into pieces of about 5 mm is subjected to the above purification treatment, it is preferable to introduce an ionic functional group after the above purification treatment.
On the other hand, when raw material b (beta chitin), which is obtained by crushing the soft shell of a squid in a wet state into pieces of about 1 cm, is subjected to the above purification process, the amino groups are exposed on the chitin crystal surface due to the above purification process. , it can be easily defibrated without further introducing an ionic functional group after purification.

The method of partial deacetylation treatment is not particularly limited, but partial deacetylation can be performed by the following method. Purified chitin is preferably kept at a temperature of 0°C or more and 140°C or less, more preferably 87°C to 99°C, and is preferably kept in a 20% or more and 50% aqueous sodium hydroxide solution, preferably for 0.5 hours or more and 48 hours or less. , more preferably for a time of 1 hour or more and 5 hours or less, and is subjected to partial deacetylation treatment. Thereafter, the partially deacetylated purified chitin is thoroughly washed by filtration and water washing until the filtrate becomes neutral. Raw material a has a lower degree of N-acetylation due to partial deacetylation, and becomes suitable for forming into nanofibers. Chitin contained in raw material a partially becomes a chitosan structure due to partial deacetylation and has an amino group.

(2) Immersion treatment Next, the purified chitin and/or chitosan obtained in the step (1) above is immersed in a pH-adjusted liquid. By immersing the chitin microfibrils in a liquid with a pH appropriate for the introduced ionic functional groups, the chitin microfibrils are easily defibrated due to charge repulsion between them.
When amino groups are introduced by partial deacetylation treatment, it is preferable to immerse purified chitin and/or chitosan in an acidic liquid whose pH is adjusted to 5 or less.

As the acidic liquid, any acid can be used as long as a desired pH range can be obtained. That is, the acid may be an organic acid or an inorganic acid, and is not particularly limited. Furthermore, the solvent for the acidic liquid is not particularly limited, and solvents other than water may be used.

Examples of organic acids include formic acid, acetic acid, citric acid, malic acid, oxalic acid, salicylic acid, ascorbic acid, tartaric acid, gluconic acid, lactic acid, fumaric acid, succinic acid, sodium succinate, phytic acid, adipic acid, and propionic acid. , glyoxylic acid, pyruvic acid, acetoacetic acid, levulinic acid, heptanoic acid, caprylic acid, capric acid, lauric acid, glycolic acid, glyceric acid, acrylic acid, benzoic acid, paranitrobenzoic acid, paratoluenesulfonic acid, picric acid, maleic acid Acids, etc. Examples of inorganic acids include phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, and disodium dihydrogen pyrophosphate.

However, when using the obtained chitin nanofibers for medical purposes, foods, drugs, and other applications in which they are taken into living organisms, edible acids such as acetic acid, citric acid, and malic acid should be used, and water should be used as the solvent. is preferred. This is because it becomes unnecessary or extremely easy to remove acids and solvents used in the production of nanofibers, and it is also effective in terms of safety.

In this embodiment, pH adjustment of the liquid to be immersed is extremely important. Purified chitin into which amino groups have been introduced can be easily separated into individual chitin nanofibrils by fibrillation when the pH of the acidic liquid in which it is immersed is 5 or less. This is thought to be because the glucosamine constituting chitin is sufficiently charged and becomes easier to defibrate due to charge repulsion between chitin microfibrils.
Further, it is preferable that the solid content concentration in the acidic liquid in which purified chitin is immersed is 5% or less. This is to avoid insufficient charging of glucosamine.

(3) Defibration treatment Next, the liquid in which the purified chitin is immersed is subjected to defibration treatment. By this defibration treatment, a dispersion of finely divided chitin (micronized chitin 1) is obtained. The chitin nanofibers contained in the dispersion obtained by partially deacetylating purified chitin, immersing it in a pH-adjusted acidic liquid, and defibrating it are made of chitin that has not been chemically modified, and have a width of 5 nm to 5 nm. It is a chitin nanofiber having a length of 50 nm and a length of 300 nm or more.

The defibration treatment can be performed using a defibration and pulverization device such as a household mixer (propeller mixer, cutter mixer), an ultrasonic application device, an ultrasonic homogenizer, a high-pressure homogenizer, a twin-screw kneader, and the like. Further, a plurality of defibration treatments using these devices may be combined. For example, defibration processing using an ultrasonic application device may be performed after defibration processing using a household mixer.

Since nanofiber formation is performed using charge repulsion between chitin nanofibrils, the energy applied to chitin purified through fibrillation can be kept low. Therefore, even a simple device such as a household mixer can be sufficiently applied. Furthermore, since the fibrillation process only takes a few minutes, nanofibers can be produced with extremely high efficiency.

Note that during the defibration treatment, the pH-adjusted liquid in which purified chitin is immersed may be diluted. When purified alpha chitin is converted into nanofibers by defibration treatment, it becomes a highly viscous dispersion, so it is preferable to lower the solid content concentration in advance by diluting it. This allows for smooth stirring during the defibration process. The solid content concentration after dilution is preferably 1% or less, more preferably 0.5% or less, and still more preferably 0.2% or less.

For dilution, a solvent such as water or an acid solution is added to the acidic liquid. Adding a solvent will change the pH of the pH-adjusted liquid, such as an acidic liquid, but if the glucosamine component of the purified chitin is sufficiently charged during the immersion process, it will have little effect on the yield of the fibrillation process. . Moreover, a solvent other than water may be included. As the solvent other than water, a hydrophilic solvent is preferred. The hydrophilic solvent is not particularly limited, but alcohols such as methanol, ethanol, and isopropanol; and cyclic ethers such as tetrahydrofuran are preferred.
Further, if necessary, it is preferable to remove purified chitin that remains undispersed in the defibration treatment by filtration, centrifugation, or the like.

Through steps (1) to (3) above, chitin and/or chitosan raw materials are defibrated in a solvent to obtain a dispersion of micronized chitin 1.
In particular, the purified chitin is partially deacetylated to reduce the degree of N-acetylation, immersed in a pH-adjusted acidic liquid, and then defibrated, making each piece one by one. A dispersion containing chitin nanofibers can be obtained. By using such chitin nanofibers, composite particles 5 with good dispersibility and uniform particle diameter can be obtained.

The resulting chitin nanofibers are made of chitin and/or chitosan that have not been chemically modified and do not require safety confirmation, so they are particularly useful for use in the food, medical, pharmaceutical, and healthcare fields when taken into the body. It will be much easier to develop applications in the applications in which it will be used. The chitin nanofiber dispersion obtained in the above process is also a transparent, highly viscous liquid, and depending on the type of acid added, it can be used as is in foods and medical materials.

Further, the dispersion of micronized chitin 1 may contain other components as necessary within a range that does not impair the effects of the present invention. The other components mentioned above are not particularly limited, and can be appropriately selected from known additives depending on the use of the composite particles 5 and the like. Specifically, organometallic compounds such as alkoxysilanes or their hydrolysates, inorganic layered compounds, inorganic acicular minerals, antifoaming agents, inorganic particles, organic particles, lubricants, antioxidants, antistatic agents, UV absorbers, stabilizers, magnetic powders, orientation promoters, plasticizers, crosslinking agents, magnetic materials, pharmaceuticals, agricultural chemicals, fragrances, adhesives, enzymes, pigments, dyes, deodorants, metals, metal oxides, inorganic oxidation Examples include things.

(Second process)
The second step is a step in which the surfaces of the polymerizable monomer droplets and/or polymer droplets 2 are coated with the micronized chitin 1 in the dispersion 4 of the micronized chitin 1 to stabilize them as an emulsion.

Specifically, as shown in FIGS. 2 to 4, a polymerizable monomer and/or polymer liquid is added to the dispersion 4 of the finely divided chitin 1 obtained in the first step, and the polymerizable monomer and/or polymer The liquid is dispersed as droplets 2 in a dispersion 4 of micronized chitin 1, and the surface of the droplets 2 is further coated with micronized chitin 1 to produce an O/W emulsion stabilized by micronized chitin 1. This is the process of The polymer liquid is not particularly limited, but can be obtained by melting or dissolving the polymer in a solvent.

The method for producing the O/W emulsion is not particularly limited, but general emulsification treatments, such as various homogenizer treatments and mechanical stirring treatments, can be used. Specifically, high-pressure homogenizers, ultra-high-pressure homogenizers, all-purpose homogenizers, Mechanical treatments include ball mills, roll mills, cutter mills, planetary mills, jet mills, attritors, grinders, juicer mixers, homomixers, ultrasonic homogenizers, nanogenizers, underwater counter-impingement, paint shakers, and the like. Further, a combination of a plurality of mechanical treatments may be used.

For example, when using an ultrasonic homogenizer, a polymerizable monomer and/or polymer liquid is added to the dispersion 4 of the micronized chitin 1 obtained in the first step to form a mixed solvent, and the tip of the ultrasonic homogenizer is added to the mixed solvent. Insert and perform ultrasonic treatment. The processing conditions of the ultrasonic homogenizer are not particularly limited, but for example, the frequency is generally 20 kHz or higher, and the output is generally 10 W/cm ² or higher. Although the processing time is not particularly limited, it is usually about 10 seconds to 1 hour.

By the above-mentioned ultrasonic treatment, the polymerizable monomer droplets and/or polymer droplets 2 are dispersed in the dispersion 4 of the micronized chitin 1, and emulsion progresses, and the droplets 2 and the dispersion of the micronized chitin 1 By selectively adsorbing the micronized chitin 1 to the liquid/liquid interface of 4, the droplets 2 are coated with the micronized chitin 1, forming a stable structure as an O/W emulsion. An emulsion that is stabilized by adsorption of solid matter at the liquid/liquid interface is academically referred to as a "Pickering emulsion." As mentioned above, the mechanism by which Pickering emulsion is formed by micronized chitin 1 fibers is not clear, but chitin and chitosan have hydrophilic sites derived from hydroxyl groups and hydrophobic sites derived from hydrocarbon groups in their molecular structures. Because it has amphiphilic properties, it is thought that it adsorbs to the liquid/liquid interface between the hydrophobic monomer and the hydrophilic solvent due to its amphiphilic properties.

The O/W emulsion structure can be confirmed by optical microscopic observation. The particle size of the O/W emulsion is not particularly limited, but is usually about 0.1 μm to 1000 μm.

In the O/W emulsion structure, the thickness of the fine chitin layer 10 formed on the surface layer of the droplet 2 is not particularly limited, but is usually about 3 nm to 1000 nm. The thickness of the fine chitin layer 10 can be measured using, for example, cryo-TEM.

The types of polymerizable monomers that can be used in the second step shown in Figure 2 include polymer monomers that have a polymerizable functional group in their structure, are liquid at room temperature, and are It is not particularly limited as long as it is incompatible with the polymer and can form a polymer (high molecular polymer) through a polymerization reaction. The polymerizable monomer has at least one polymerizable functional group. A polymerizable monomer having one polymerizable functional group is also referred to as a monofunctional monomer. Furthermore, a polymerizable monomer having two or more polymerizable functional groups is also referred to as a polyfunctional monomer. The type of polymerizable monomer is not particularly limited, but examples include (meth)acrylic monomers and vinyl monomers. It is also possible to use a polymerizable monomer (for example, ε-caprolactone, etc.) having a cyclic ether structure such as an epoxy group or an oxetane structure.
Note that the expression "(meth)acrylate" includes both "acrylate" and "methacrylate."

Examples of monofunctional (meth)acrylic monomers include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, n-butyl (meth)acrylate, and isobutyl. (meth)acrylate, t-butyl (meth)acrylate, glycidyl (meth)acrylate, acryloylmorpholine, N-vinylpyrrolidone, tetrahydrofurfuryl acrylate, cyclohexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, isobornyl ( meth)acrylate, isodecyl(meth)acrylate, lauryl(meth)acrylate, tridecyl(meth)acrylate, cetyl(meth)acrylate, stearyl(meth)acrylate, benzyl(meth)acrylate, 2-ethoxyethyl(meth)acrylate, 3 -Methoxybutyl (meth)acrylate, ethyl carbitol (meth)acrylate, phosphoric acid (meth)acrylate, ethylene oxide modified phosphoric acid (meth)acrylate, phenoxy (meth)acrylate, ethylene oxide modified phenoxy (meth)acrylate, propylene oxide Modified phenoxy (meth)acrylate, nonylphenol (meth)acrylate, ethylene oxide modified nonylphenol (meth)acrylate, propylene oxide modified nonylphenol (meth)acrylate, methoxydiethylene glycol (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, methoxypropylene glycol (meth)acrylate, 2-(meth)acryloyloxyethyl-2-hydroxypropyl phthalate, 2-hydroxy-3-phenoxypropyl (meth)acrylate, 2-(meth)acryloyloxyethyl hydrogen phthalate, 2-(meth)acryloyl Oxypropyl hydrogen phthalate, 2-(meth)acryloyloxypropyl hexahydrohydrogen phthalate, 2-(meth)acryloyloxypropyl tetrahydrohydrogen phthalate, dimethylaminoethyl (meth)acrylate, trifluoroethyl (meth)acrylate, tetrafluoropropyl ( meth)acrylate, hexafluoropropyl (meth)acrylate, octafluoropropyl (meth)acrylate, octafluoropropyl (meth)acrylate, adamantyl acrylate with monovalent mono(meth)acrylate derived from 2-adamantane and adamantane diol Examples include adamantane derivative mono(meth)acrylates such as.

Examples of difunctional (meth)acrylic monomers include ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, butanediol di(meth)acrylate, hexanediol di(meth)acrylate, and nonanediol di(meth)acrylate. ) acrylate, ethoxylated hexanediol di(meth)acrylate, propoxylated hexanediol di(meth)acrylate, diethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate Di(meth)acrylate, neopentyl glycol di(meth)acrylate, ethoxylated neopentyl glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, neopentyl hydroxypivalate di(meth)acrylate, etc. Examples include meth)acrylate.

Examples of trifunctional or higher-functional (meth)acrylic monomers include trimethylolpropane tri(meth)acrylate, ethoxylated trimethylolpropane tri(meth)acrylate, propoxylated trimethylolpropane tri(meth)acrylate, and tris-2-hydroxy. Tri(meth)acrylates such as ethyl isocyanurate tri(meth)acrylate, glycerin tri(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol tri(meth)acrylate, ditrimethylolpropane tri(meth)acrylate, etc. Trifunctional (meth)acrylate compounds, pentaerythritol tetra(meth)acrylate, ditrimethylolpropane tetra(meth)acrylate, dipentaerythritol tetra(meth)acrylate, dipentaerythritol penta(meth)acrylate, ditrimethylolpropane penta( Trifunctional or higher functional (meth)acrylate compounds such as meth)acrylate, dipentaerythritol hexa(meth)acrylate, ditrimethylolpropane hexa(meth)acrylate, and some of these (meth)acrylates with alkyl groups or ε- Examples include polyfunctional (meth)acrylate compounds substituted with caprolactone.

As monofunctional vinyl monomers, liquids that are incompatible with water at room temperature are preferred, such as vinyl ethers, vinyl esters, aromatic vinyls, and especially styrene and styrene monomers.
Among monofunctional vinyl monomers, (meth)acrylates include methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, t-butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, lauryl ( meth)acrylate, alkyl(meth)acrylate, tridecyl(meth)acrylate, stearyl(meth)acrylate, cyclohexyl(meth)acrylate, benzyl(meth)acrylate, isobornyl(meth)acrylate, glycidyl(meth)acrylate, tetrahydrofurfuryl( meth)acrylate, allyl(meth)acrylate, diethylaminoethyl(meth)acrylate, trifluoroethyl(meth)acrylate, heptafluorodecyl(meth)acrylate, dicyclopentenyl(meth)acrylate, dicyclopentenyloxyethyl(meth)acrylate , tricyclodecanyl (meth)acrylate, and the like.
In addition, monofunctional aromatic vinyl monomers include styrene, α-methylstyrene, o-methylstyrene, m-methylstyrene, p-methylstyrene, ethylstyrene, isopropenyltoluene, isobutyltoluene, tert-butylstyrene, vinyl Examples include naphthalene, vinylbiphenyl, 1,1-diphenylethylene and the like.

Examples of the polyfunctional vinyl monomer include polyfunctional groups having an unsaturated bond such as divinylbenzene. A liquid that is incompatible with water at room temperature is preferred.
For example, specific examples of polyfunctional vinyl monomers include (1) divinyls such as divinylbenzene, 1,2,4-trivinylbenzene, and 1,3,5-trivinylbenzene, (2) ethylene glycol Dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, 1,3-propylene glycol dimethacrylate, 1,4-butylene glycol dimethacrylate, 1,6-hexamethylene glycol dimethacrylate, neopentyl glycol dimethacrylate Dimethacrylates such as methacrylate, dipropylene glycol dimethacrylate, polypropylene glycol dimethacrylate, 2,2-bis(4-methacryloxydiethoxyphenyl)propane, (3) trimethylolpropane trimethacrylate, triethylolethane trimethacrylate, etc. Trimethacrylates, (4) Ethylene glycol diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, polyethylene glycol diacrylate, 1,3-dipropylene glycol diacrylate, 1,4-dibutylene glycol diacrylate, 1,6 -Hexylene glycol diacrylate, neopentyl glycol diacrylate, dipropylene glycol diacrylate, polypropylene glycol diacrylate, 2,2-bis(4-acryloxypropoxyphenyl)propane, 2,2-bis(4-acryloxydiacrylate) diacrylates such as (ethoxyphenyl)propane, (5) triacrylates such as trimethylolpropane triacrylate and triethylolethane triacrylate, (6) tetraacrylates such as tetramethylolmethanetetraacrylate, (7) others, Examples include tetramethylene bis(ethyl fumarate), hexamethylene bis(acrylamide), triallyl cyanurate, and triallyl isocyanurate.
For example, specific examples of functional styrenic monomers include divinylbenzene, trivinylbenzene, divinyltoluene, divinylnaphthalene, divinylxylene, divinylbiphenyl, bis(vinylphenyl)methane, bis(vinylphenyl)ethane, bis(vinylphenyl)ethane, phenyl)propane, bis(vinylphenyl)butane, and the like.

In addition to these, polyether resins, polyester resins, polyurethane resins, epoxy resins, alkyd resins, spiroacetal resins, polybutadiene resins, polythiol polyene resins, etc. having at least one polymerizable functional group can be used. Yes, the material is not particularly limited.

The above polymerizable monomers may be used alone or in combination of two or more types.

The weight ratio of the dispersion 4 of micronized chitin 1 and the polymerizable monomer that can be used in the second step is not particularly limited, but the proportion of the polymerizable monomer of 1 part by mass or more to 100 parts by mass of micronized chitin 1 is 50 parts by mass or more. It is preferably less than parts by mass. If the amount of the polymerizable monomer is less than 1 part by mass, the yield of composite particles 5 will decrease, which is undesirable, and if it exceeds 50 parts by mass, it will be difficult to uniformly coat the polymerizable monomer droplets 2A with the finely divided chitin 1, which is not preferred. .

Further, the polymerizable monomer may contain a polymerization initiator in advance. General polymerization initiators include radical initiators such as organic peroxides and azo polymerization initiators.

Examples of organic peroxides include peroxyketals, hydroperoxides, dialkyl peroxides, diacyl peroxides, peroxycarbonates, and peroxyesters.

Examples of the azo polymerization initiator include ADVN and AIBN.
For example, 2,2-azobis(isobutyronitrile) (AIBN), 2,2-azobis(2-methylbutyronitrile) (AMBN), 2,2-azobis(2,4-dimethylvaleronitrile) (ADVN) , 1,1-azobis(1-cyclohexanecarbonitrile) (ACHN), dimethyl-2,2-azobisisobutyrate (MAIB), 4,4-azobis(4-cyanovaleric acid) (ACVA), 1, 1-azobis(1-acetoxy-1-phenylethane), 2,2-azobis(2-methylbutyramide), 2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2- Azobis(2-methylamidinopropane) dihydrochloride, 2,2-azobis[2-(2-imidazolin-2-yl)propane], 2,2-azobis[2-methyl-N-(2-hydroxyethyl) propionamide], 2,2-azobis(2,4,4-trimethylpentane), 2-cyano-2-propylazoformamide, 2,2-azobis(N-butyl-2-methylpropionamide), 2,2 -azobis(N-cyclohexyl-2-methylpropionamide) and the like.

If a polymerizable monomer containing a polymerization initiator is used in the second step, the polymerization initiator will be included in the polymerizable monomer droplets 2A inside the emulsion particles when an O/W emulsion is formed. The polymerization reaction progresses more easily when the monomers inside the emulsion are polymerized and solidified in the third step described below.

The weight ratio of the polymerizable monomer and polymerization initiator that can be used in the second step is not particularly limited, but usually the amount of the polymerizable initiator is 0.1 part by mass or more per 100 parts by mass of the polymerizable monomer. is preferred. If the amount of the polymerizable monomer is less than 0.1 part by mass, the polymerization reaction will not proceed sufficiently and the yield of composite particles 5 will decrease, which is not preferable.

Further, as shown in FIG. 3, as the droplet 2 that can be used in the second step, it is also possible to use a dissolved polymer droplet 2B in which an existing polymer is dissolved using various solvents. For example, an existing polymer is dissolved in a solvent with low compatibility with the dispersion liquid 4 of the micronized chitin 1 to form a dispersion liquid, and the dissolved liquid is mechanically treated with an ultrasonic homogenizer or the like as described above to form the dispersion liquid 4. It is preferable to stabilize the polymer droplets in the dispersion liquid 4 as an O/W emulsion by adding it.

Specific polymers include, for example, cellulose acetate, cellulose acetate derivatives such as cellulose acetate butyrate, and cellulose acetate propionate, polysaccharides such as chitin and chitosan, polylactic acid, and copolymers of lactic acid and other hydroxycarboxylic acids. Polylactic acids such as polybutylene succinate, polyethylene succinate, dibasic acid polyesters such as polybutylene adipate, polycaprolactones such as polycaprolactone, a copolymer of caprolactone and hydroxycarboxylic acid, polyhydroxybutyrate, Polyhydroxybutyrates such as copolymers of polyhydroxybutyrate and hydroxycarboxylic acids, aliphatic polyesters such as polyhydroxybutyric acid, copolymers of polyhydroxybutyric acid and other hydroxycarboxylic acids, polyamino acids, Examples include polyester polycarbonates, natural resins such as rosin, and these can be used alone or in combination of two or more.

Although not particularly limited, the polymer is preferably a biodegradable polymer. Biodegradable refers to polymers that decompose and disappear in the earth's environment such as soil and seawater, and/or polymers that decompose and disappear in living organisms. In general, polymers are degraded in soil or seawater by enzymes possessed by microorganisms, whereas in living organisms they are degraded by physicochemical hydrolysis without the need for enzymes.
Polymer decomposition means that the polymer becomes lower in molecular weight or becomes water-soluble and loses its form. Decomposition of the polymer is not particularly limited, but occurs by hydrolysis of the main chain, side chains, and crosslinking points, and oxidative decomposition of the main chain.

Biodegradable polymers include natural polymers derived from nature and synthetic polymers.
Examples of natural polymers include polysaccharides produced by plants (cellulose, starch, alginic acid, etc.), polysaccharides produced by animals (chitin, chitosan, hyaluronic acid, etc.), proteins (collagen, gelatin, albumin, etc.), and polysaccharides produced by microorganisms. Examples include polyesters (poly(3-hydroxyalkanoate)) and polysaccharides (hyaluronic acid, etc.).
Examples of synthetic polymers include aliphatic polyesters, polyols, and polycarbonates.
Examples of fatty acid polyesters include glycol/dicarboxylic acid polycondensation systems (polyethylene succinate, polybutylene succinate, etc.), polylactides (polyglycolic acid, polylactic acid, etc.), polylactones (β-caprolactone, ε-caprolactone, etc.) and others (polybutylene terephthalate adipate, etc.).
Examples of the polyol include polyvinyl alcohol.
Examples of the polycarbonate include polyester carbonate.
Other biodegradable synthetic polymers include polyacid anhydrides, polycyanoacrylates, polyorthoesters, and polyphosphazenes.
Among these, polylactides and polylactones, which are biodegradable and are also used as medical materials, are preferred.

Moreover, as a solvent for dissolving the polymer, a solvent having low compatibility with the dispersion liquid 4 of the micronized chitin 1 is preferable. When the solubility in water is high, emulsification becomes difficult because the solvent easily dissolves from the dissolved polymer droplet layer into the water phase. On the other hand, in the case of a solvent that is not soluble in water, composite particles cannot be obtained because the solvent cannot move from the dissolved polymer droplet phase to the dispersion phase of micronized chitin 1. Further, the boiling point of the solvent is preferably 90°C or lower. When the boiling point is higher than 90°C, the dispersion liquid 4 of the finely divided chitin 1 evaporates before the solvent, making it impossible to obtain composite particles. Specific examples of solvents that can be used include dichloromethane, chloroform, 1,2-dichloroethane, and benzene.

Furthermore, as shown in FIG. 4, it is also possible to use molten polymer droplets 2C in which the polymer itself is melted without using a solvent in the second step. For example, a polymer that is solid at room temperature is melted into a liquid, and the melt is mechanically treated with an ultrasonic homogenizer or the like as described above, while being heated to a temperature at which the polymer can maintain its molten state. It is preferable to stabilize the polymer droplets in the dispersion liquid 4 as an O/W emulsion by adding it.

The molten polymer droplets 2C that can be used in the second step are preferably those that have low solubility in the aqueous dispersion 4 of the micronized chitin 1. If the solubility in water is high, the polymer easily dissolves from the molten polymer droplet layer into the aqueous phase, making emulsion formation difficult. Further, the melting point of the molten polymer is preferably 90°C or lower. If the melting point is higher than 90° C., water in the dispersion 4 of the micronized chitin 1 will evaporate, making it difficult to form an emulsion. Specifically, pentaerythritol tetrastearate, pentaerythritol distearate, pentaerythritol tristearate, stearyl stearate, batyl stearate, stearyl stearate, myristyl myristate, cetyl palmitate, ethylene glycol distearate, behenyl alcohol, Microcrystalline wax, paraffin wax, hydrocarbon wax, fatty acid alkyl ester, polyol fatty acid ester, mixture of fatty acid ester and wax, mixture of fatty acid ester, glycerin monopalmitate (/stearic acid monoglyceride), glycerin mono-distearate (/glycerin stearate) rate), glycerin monoacetomonostearate (/glycerin fatty acid ester), succinic acid aliphatic monoglyceride (/glycerin fatty acid ester), citric acid saturated aliphatic monoglyceride, sorbitan monostearate, sorbitan fatty acid ester, sorbitan tribehenate, Propylene glycol monobehenate (/propylene glycol fatty acid ester), stearate of pentaerythritol adipate polymer, pentaerythritol tetrastearate, dipentaerythritol hexastearate, stearyl citrate, pentaerythritol fatty acid ester, glycerin fatty acid ester, ultra-light color Rosin, rosin-containing diol, ultra-light colored rosin metal salt, hydrogenated petroleum resin, rosin ester, hydrogenated rosin ester, special rosin ester, novolak, crystalline polyα-olefin, polyalkylene glycol, polyalkylene glycol ester, polyoxyalkylene ether , polylactic acid, polylactic acids such as copolymers of lactic acid and other hydroxycarboxylic acids; dibasic acid polyesters such as polybutylene succinate, polyethylene succinate, polybutylene adipate, polycaprolactone, caprolactone and hydroxycarboxylic acids Polycaprolactones such as copolymers with polyhydroxybutyrate, polyhydroxybutyrates such as copolymers of polyhydroxybutyrate and hydroxycarboxylic acids, polyhydroxybutyric acid, polyhydroxybutyric acid and other hydroxycarboxylic acids Aliphatic polyesters such as copolymers with , polyamino acids, polyester polycarbonates, natural resins such as rosin, etc. can be used.

Furthermore, the polymerizable monomer droplets and/or the polymer droplets 2 may contain a functional component other than the polymerization initiator in advance. Specific examples include magnetic substances, pharmaceuticals, agricultural chemicals, fragrances, adhesives, enzymes, pigments, dyes, deodorants, metals, metal oxides, and inorganic oxides. When the polymerizable monomer contains a functional component other than the polymerization initiator in advance, the above-mentioned functional component can be contained inside the particle when it is formed as the composite particle 5, and it can be used in accordance with the application. Function expression becomes possible.

Furthermore, it is also possible to form the droplets 2 using a combination of a polymerizable monomer and a dissolved/molten polymer to form an emulsion. In addition, when a biodegradable resin is selected as the polymer species that forms the core of this composite particle, the resulting composite particle is composed of a biodegradable resin in the inner core and nanofibers in the outer shell, making it a biodegradable material. It is also possible to provide composite particles with high environmental friendliness.

(3rd step)
The third step is a step of solidifying the polymerizable monomer droplets and/or the polymer droplets 2 to obtain composite particles 5 in which the core particles 3 are coated with the finely divided chitin 1.

The method for solidifying the polymerizable monomer droplets is not particularly limited and can be appropriately selected depending on the type of polymerizable monomer and polymerization initiator used, and examples include suspension polymerization.

The specific suspension polymerization method is not particularly limited either, and any known method can be used. For example, this can be carried out by heating the O/W emulsion prepared in the second step, in which monomer droplets containing a polymerization initiator are coated with finely divided chitin 1 and stabilized, while stirring. The stirring method is not particularly limited, and any known method can be used, and specifically, a disperser or a stirrer can be used. Alternatively, only heat treatment may be performed without stirring. Further, the temperature conditions during heating can be appropriately set depending on the type of polymerizable monomer and the type of polymerization initiator, but preferably 20 degrees or more and 150 degrees or less. If it is less than 20 degrees, the reaction rate of polymerization will decrease, which is not preferable, and if it exceeds 150 degrees, the fine chitin 1 may be denatured, which is not preferable. The time for the polymerization reaction can be appropriately set depending on the type of polymerizable monomer and the type of polymerization initiator, but is usually about 1 hour to 24 hours. Further, the polymerization reaction may be carried out by ultraviolet irradiation treatment, which is a type of electromagnetic wave. In addition to electromagnetic waves, particle beams such as electron beams may also be used.

Furthermore, the method of solidifying the polymer droplets is not particularly limited. For example, when using dissolved polymer droplets 2B using a solvent, after forming an O/W type emulsion in the dispersion 4 of micronized chitin 1, the solvent with low solubility in water will gradually dissolve over time as described above. By diffusing into the aqueous phase, the dissolved polymer can precipitate and solidify as particles. For example, when using the molten polymer droplets 2C obtained by heating the polymer and liquefying it, it is possible to form an O/W type emulsion in the dispersion 4 of the micronized chitin 1 and then cool the emulsion to make the molten polymer liquid. Droplets 2C can be solidified as particles.

In addition, the state immediately after the solidification process of the droplets 2 is such that a large amount of water is present in the dispersion of the composite particles 5 and free fine chitin 1 that does not contribute to the formation of the fine chitin layer 10 of the composite particles 5 is present. It is in a mixed state. Therefore, it is necessary to collect and purify the produced composite particles 5, and as a method of collection and purification, washing by centrifugation or washing by filtration is preferable. As a washing method using centrifugation, a known method can be used. Specifically, the composite particles 5 are sedimented by centrifugation, the supernatant is removed, and the operation of redispersing in a water/methanol mixed solvent is repeated. The composite particles 5 can be recovered by removing residual solvent from the sediment obtained by centrifugation. Known methods can be used for filtration and cleaning, for example, repeating suction filtration with water and methanol using a PTFE membrane filter with a pore size of 0.1 μm, and finally removing residual solvent from the paste remaining on the membrane filter. The composite particles 5 can be recovered by doing so.

It is preferable to adjust the pH of the collected composite particles 5 to make them easier to disperse. When using micronized chitin 1 having amino groups, the pH is adjusted to a range of 2 to 7 using acetic acid or the like. By ionic bonding between the added acid and the amino groups on the surface of the micronized chitin 1, the amino groups tend to have a positive charge, and the composite particles 5 become easier to disperse. In particular, by adjusting the pH to about 3.3, the composite particles 5 can be suitably dispersed.

Through the above-described steps, true spherical composite particles 5 in which the core particles 3 are coated with the micronized chitin 1 can be produced. FIG. 5 is an optical micrograph of composite particles 5 made from raw material a obtained by crushing dry king crab shells into pieces of about 5 mm. FIG. 6 is an optical micrograph of composite particles 5 made from raw material b obtained by crushing the soft shell of a squid in a wet state into pieces of about 1 cm.

The method for removing the residual solvent is not particularly limited, and can be carried out by simple heat drying such as air drying or oven drying. The dry solid material containing the composite particles 5 obtained in this manner does not form a film or aggregate as described above, but is obtained as a finely textured powder.

Note that the composite particles 5 can be provided as a composition containing the composite particles 5.
For example, the composite particles 5 can be provided as a dispersion liquid in which the composite particles 5 are dispersed in a suitable dispersion medium. Further, the dispersion liquid may contain components other than the composite particles 5, such as an organic metal compound such as an alkoxysilane or a hydrolyzate thereof, an inorganic layered compound, an inorganic acicular mineral, an antifoaming agent, an inorganic particle, an organic particle. , lubricants, antioxidants, antistatic agents, ultraviolet absorbers, stabilizers, magnetic powders, alignment promoters, plasticizers, crosslinking agents, magnetic substances, pharmaceuticals, agricultural chemicals, fragrances, adhesives, enzymes, pigments, dyes, Examples include deodorants, metals, metal oxides, and inorganic acids.

For example, the composite particles 5 can be provided as a fine-textured powder containing no solvent for application to the skin. More specifically, it can be provided as a powder-type foundation composition for cosmetics. Furthermore, the powder may contain components other than the composite particles 5, such as organometallic compounds such as alkoxysilanes or their hydrolysates, inorganic layered compounds, inorganic acicular minerals, antifoaming agents, inorganic particles, and organic particles. , lubricants, antioxidants, antistatic agents, ultraviolet absorbers, stabilizers, magnetic powders, alignment promoters, plasticizers, crosslinking agents, magnetic substances, pharmaceuticals, agricultural chemicals, fragrances, adhesives, enzymes, pigments, dyes, Examples include deodorants, metals, metal oxides, and inorganic acids.
Note that the composition containing the composite particles 5 can be used not only as a product applied to the skin, but also as a component of products such as toothpaste used in the oral cavity, and hair care products used for the hair.

The composite particles 5 according to the present embodiment provide novel composite particles that are derived from the fine chitin 1 on the surface of the composite particles 5 and have high biocompatibility and good dispersion stability without agglomeration even in a solvent. be able to.

Further, the dry solid material containing the composite particles 5 according to the present embodiment is obtained as a fine-textured powder and there is no aggregation of particles, so the composite particles 5 obtained as a dry powder are redispersed in a solvent again. Even after redispersion, the dispersion stability derived from the fine chitin layer 10 of chitin nanofibers bonded to the surface of the composite particles 5 is exhibited. It is possible to provide novel composite particles that solve the problem.

Although one embodiment of the present invention has been described above in detail with reference to the drawings, the specific configuration is not limited to this embodiment, and may include design changes without departing from the gist of the present invention. Moreover, the components shown in the above-described embodiment and modified examples can be appropriately combined and configured.

Hereinafter, the present invention will be explained in detail based on Examples, but the technical scope of the present invention is not limited to these Examples. In each of the following examples, "%" indicates mass % (w/w%) unless otherwise specified.

<Example>
(First step: Step of obtaining micronized chitin dispersion)
Chitin and/or chitosan raw materials were defibrated in a solvent to obtain a dispersion of micronized chitin 1. Specifically, a dispersion of micronized chitin 1 was prepared through the following steps: (1) purification and partial deacetylation treatment of chitin and/or chitosan raw materials, (2) soaking treatment, and (3) fibrillation treatment.

(1-1) Purification of chitin and/or chitosan raw materials First, as raw materials for chitin and/or chitosan, raw material a was prepared by crushing dry red king crab shell into pieces of about 5 mm and wet squid soft carapace was crushed into pieces about 1 cm. Two types of raw material b were prepared. In order to degrease raw material a and raw material b, they were immersed in a chloroform/methanol (2/1) solution for one day.

Next, the defatted raw material was treated with 1M hydrochloric acid for 3 hours in order to demineralize it. The treated raw material was treated overnight with a 10% aqueous sodium hydroxide solution under a nitrogen purge to perform deproteinization. Thereafter, the treated raw material was bleached by immersing it in a 0.3% aqueous sodium chlorite solution and stirring for 4 hours using a magnetic stirrer in an oil bath set at 70°C.
After repeating a series of treatments of demineralization, deproteinization, and bleaching four times, the defatted raw material was washed with a 1M aqueous sodium hydroxide solution to deproninate the amino groups on the surface, and then washed with water.

(1-2) Partial deacetylation of purified chitin The purified chitin raw material obtained by performing the above purification treatment on raw material a is immersed in a 33% sodium hydroxide aqueous solution kept at 90°C for 1 hour or 4 hours, and then partially deacetylated. Deacetylated. Thereafter, the partially deacetylated raw material a was thoroughly washed by filtration and water washing until the filtrate became neutral. Raw material a has a lower degree of N-acetylation due to partial deacetylation, and becomes suitable for forming into nanofibers. Chitin contained in raw material a partially becomes a chitosan structure upon deacetylation.
On the other hand, the purified chitin obtained by performing the above purification treatment on raw material b was not subjected to partial deacetylation.

(2) Soaking treatment Next, water was added to the purified chitin obtained above to prepare a purified chitin aqueous dispersion having a solid content concentration of 0.1%. Thereafter, an aqueous dispersion sample was prepared in which the pH was adjusted to 3.3 by adding acetic acid to the above aqueous dispersion.

(3) Defibration treatment Next, the obtained 0.25% purified chitin aqueous dispersion sample was defibrated for 1 minute using a household mixer, and then defibrated for 1 minute using an ultrasonic homogenizer.
Through the above steps (1) to (3), a nanofiber aqueous dispersion using purified chitin as a raw material was obtained.

(Evaluation of micronized chitin 1)
Regarding the obtained purified chitin and micronized chitin 1, the amount of amino groups, degree of crystallinity, number average axis diameter of major axis, and light transmittance were measured and calculated as follows. Table 1 shows the evaluation results of the obtained micronized chitin.

(Amino group amount measurement)
Regarding purified chitin before dispersion treatment, the amount of amino groups was calculated by the following method.
0.2 g of purified chitin in terms of dry weight was placed in a beaker, and 80 mL of ion-exchanged water was added.
While stirring, 0.1 mol/L aqueous sodium hydroxide solution was added thereto to adjust the pH of the whole to 8.
Using an automatic titrator (trade name: AUT-701, manufactured by DKK Toa), 0.1 mol/L hydrochloric acid was injected at 0.05 mL/30 seconds, and the conductivity and pH value were measured every 30 seconds. Measurement was continued until pH 2.0.
From the obtained conductivity curve, the titration amount of hydrochloric acid was determined, and the amount of amino groups (mmol/g) was calculated.

(Calculation of crystallinity)
The X-ray diffraction pattern of the purified chitin was measured using a sample horizontal multipurpose X-ray diffraction device (trade name: Ultima III, manufactured by Rigaku). The crystallinity of purified chitin was calculated from the X-ray diffraction pattern.

(Calculation of number average axis diameter of long axis of micronized chitin 1)
The number average axis diameter of the long axis of the micronized chitin was calculated using an atomic force microscope.
First, the micronized chitin aqueous dispersion was diluted to 0.001%, and then 20 μL each was cast onto a mica plate and air-dried.
After drying, the shape of the micronized chitin was observed in DFM mode using an atomic force microscope (trade name: AFM5400L, manufactured by Hitachi High-Technologies).
The number average axis diameter of the long axis of the micronized chitin was determined by measuring the long axis diameter (maximum diameter) of 100 fibers from an image observed using an atomic force microscope, and determining the average value thereof.

(Measurement of light transmittance of micronized chitin 1 aqueous dispersion)
Light transmittance was measured for a 0.25% aqueous dispersion of micronized chitin.
One side of the quartz sample cell is filled with water as a reference, and the other side is filled with a micronized chitin aqueous dispersion to prevent air bubbles from entering. Measurement was performed using a meter (trade name: NRS-1000, manufactured by JASCO Corporation). FIG. 5 shows the light transmittance measurement results.

As is clear from Table 1, the micronized chitin 1 aqueous dispersion exhibited high transparency. Further, the number average minor axis diameter of the fine chitin contained in the aqueous dispersion of fine chitin 1 was 50 nm or less, and the crystallinity was as high as 50% or more.

(Second process)
Next, 1 g of 2,2-azobis-2,4-dimethylvaleronitrile (hereinafter also referred to as ADVN), which is a polymerization initiator, is added to 10 g of divinylbenzene (hereinafter also referred to as DVB), which is a polymerizable monomer. Dissolved.

When the entire amount of the polymerizable monomer mixture was added to 40 g of a fine chitin dispersion with a fine chitin concentration of 0.25%, the polymerizable monomer mixture and the fine chitin dispersion were both highly transparent. Separated into phases.

Next, the shaft of an ultrasonic homogenizer was inserted from the liquid level of the upper phase of the mixed liquid in a state where the two phases were separated, and ultrasonic homogenizer treatment was performed for 3 minutes at a frequency of 24 kHz and an output of 400 W. The appearance of the mixed solution after treatment with an ultrasonic homogenizer was that of a cloudy emulsion. When a drop of the mixed solution was placed on a slide glass, sealed with a cover glass, and observed under an optical microscope, countless emulsion droplets of about 1 to several μm were formed, indicating that the dispersion was stabilized as an O/W emulsion. was confirmed.

(Third step: Step of obtaining composite particles 5)
The O/W type emulsion dispersion was placed in a water bath at 70°C and treated for 8 hours while stirring with a stirrer to carry out a polymerization reaction. After 8 hours of treatment, the dispersion was cooled to room temperature. There was no change in the appearance of the dispersion before and after the polymerization reaction. When the resulting dispersion was treated with a centrifugal force of 75,000 g for 5 minutes, a precipitate was obtained. The supernatant was removed by decantation to collect the sediment, which was then washed repeatedly with pure water and methanol using a PTFE membrane filter with a pore size of 0.1 μm.
The purified and recovered product thus obtained was made into a 1% concentration, the pH was adjusted to 3.3 using acetic acid, and the particle size was evaluated using a particle size distribution analyzer (NANOTRAC UPA-EX150, Nikkiso Co., Ltd.). did.
Next, the purified and collected product was air-dried and further subjected to vacuum drying treatment at a room temperature of 25 degrees Celsius for 24 hours to obtain a fine-textured dry powder (composite particles 5).

<Example 1>
In the above example, raw material a prepared by crushing dry king crab shell into pieces of about 5 mm was used as a raw material for chitin and/or chitosan, and was partially deacetylated by immersing it in a 33% sodium hydroxide aqueous solution kept at 90°C for 1 hour. Composite particles 5 were produced using the treated micronized chitin 1A.

<Example 2>
Composite particles 5 were produced under the same conditions as in Example 1, except that diethylene glycol diacrylate (trade name FA-222A, Hitachi Chemical, hereinafter also referred to as FA-222A) was used instead of DVB in Example 1. did.

<Example 3>
The same procedure as in Example 1 was used except that hexanediol diacrylate (trade name A-HD-N, Shin Nakamura Chemical Industries, hereinafter also referred to as A-HD-N) was used instead of DVB in Example 1. Composite particles 5 were produced under the following conditions.

<Example 4>
Composite particles were prepared under the same conditions as in Example 1, except that micronized chitin 1B, which was prepared by immersing it in a 33% sodium hydroxide aqueous solution maintained at 90°C for 4 hours and undergoing partial deacetylation treatment, was used in Example 1. 5 was produced.

<Example 5>
In Example 1, raw material b (beta chitin), which is made by crushing squid cartilage (wet) into pieces of about 1 cm, was used instead of raw material a, which was made by crushing dried red king crab shell into pieces of about 5 mm, as a raw material for chitin and/or chitosan. Composite particles 5 were produced under the same conditions as in Example 1, except that micronized chitin 1C, which was produced without performing partial deacetylation treatment of purified chitin, was used.

<Example 6>
In the same manner as in the first step of Example 1, a finely divided chitin dispersion was obtained.
Next, in the second step, 10 g of polylactic acid (PLA) was dissolved in 100 g of dichloroethane, and 2 g of fenitrothion (Sumithion, MEP) was added and mixed to prepare a dissolved polymer liquid.
When the entire amount of the polymer liquid was added to 500 g of a fine chitin dispersion having a fine chitin 1 concentration of 0.25%, the dissolved polymer liquid and the fine chitin dispersion were separated into two phases with high transparency.

Next, in the same manner as in the third step of Example 1, an ultrasonic homogenizer was applied to the liquid surface of the upper layer of the mixed liquid in a state where the two phases were separated. Using an optical microscope, it was confirmed that countless emulsion droplets of about 1 to several micrometers were produced, and the dispersion was stabilized as an O/W emulsion.

Next, in the third step, the O/W emulsion was dried under reduced pressure of 700 mgHg at 40° C. for 3 hours to completely volatilize dichloroethane. There was no change in the appearance of the dispersion before and after volatilization of dichloroethane.
The obtained dispersion liquid was separated and purified under the same conditions as in Example 1. The average particle diameter of the obtained composite particles 5 was 1.8 μm. When the recovered material was dried under the same conditions as in Example 1, fine-textured dry powder (composite particles 5) was obtained.

<Example 7>
In Example 6, a micronized chitin 1 dispersion was prepared under the same conditions as in the first step, and in the second step, 10 g of poly-ε-caprolactone (PCL, manufactured by Wako Pure Chemical Industries, Ltd.) was heated to form a molten polymer liquid. After preparing an O/W type emulsion liquid under the same conditions as in the third step, the O/W type emulsion liquid was cooled in the 4th step b. Composite particles 5 were obtained under the same conditions as in Example 6 except for the above.

<Comparative example 1>
In Example 1, an attempt was made to produce composite particles under the same conditions as in Example 1, except that pure water was used instead of the micronized chitin dispersion.

<Comparative example 2>
In Example 1, an attempt was made to produce composite particles under the same conditions as in Example 1, except that an aqueous carboxymethyl chitin solution was used instead of the finely divided chitin dispersion.

<Comparative example 3>
In Example 6, in step b1, instead of the micronized chitin dispersion, an aqueous solution of 8 parts by mass of an aqueous carboxymethyl chitin solution and 0.5 parts by mass of polyglyceryl laurate (PGLE ML10) dissolved in 500 g of pure water was used. An O/W emulsion liquid was prepared under the same conditions as in Example 6 in the second and third steps. The obtained O/W emulsion liquid was spray-dried using a spray dryer at a drying temperature of 100° C. to produce particles.

<Comparative example 4>
In Comparative Example 3, an attempt was made to produce particles under the same conditions as Comparative Example 4, except that polyglyceryl-10 laurate (PGLE ML10) was not added.

<Evaluation method>

(Evaluation of droplet stabilization)
Whether or not the droplets could be stably formed was determined visually and by shape observation using an optical electron microscope. The resulting composite particle dispersion was dropped onto a slide glass, covered with a cover glass, and observed under an optical microscope.
Whether or not the emulsion could be stabilized in the second step was determined as follows.
○: Fine droplets were observed under an optical microscope without visual separation of the two phases.
×: The two phases were visually separated, or the average diameter of the droplets was 50 μm or more under an optical microscope.

(Evaluation of whether composite particles can be formed)
The formation of composite particles was determined by shape observation using a scanning electron microscope. The obtained dry powder was observed using a scanning electron microscope. The formation of composite particles was determined as follows.
Good: Particles were obtained, and the particle surfaces were coated with finely divided chitin.
Δ: Particles were obtained, but the particle surfaces were not coated with micronized chitin.
x: The above particles were not obtained.

(Evaluation of redispersibility)
The redispersibility was evaluated by comparing the particle size distribution of the composite particles obtained in the fourth step with the particle size distribution after drying and redispersion.
The composite particles obtained in the fourth step were adjusted to a 1% concentration, adjusted to pH 3.3 using acetic acid, dispersed, and measured using a particle size distribution meter (NANOTRAC UPA-EX150, Nikkiso Co., Ltd.). The particle size was taken as the average particle size (D1) before redispersion, and the dry powder of composite particles 5 was added to pure water at a concentration of 1%, and while stirring with a stirrer, an acetic acid aqueous solution was added to adjust the pH to 3. The particle size measured after adjusting the particle size to .3 and redispersing the particles is defined as the average particle size after redispersion (D2). Evaluation of redispersibility was determined as follows.
〇: 0.5 ≦ D2/D1 ≦1.5
×: D2/D1 < 0.5, 1.5 < D2/D1

(Evaluation of redispersibility)
Biodegradability was evaluated according to the JIS standard "JIS K6950:2000 Plastics - How to determine the ultimate aerobic biodegradability in an aqueous culture medium - Method by measuring oxygen consumption using a closed respirator." Composite particles 5 and activated sludge were added to an inorganic salt medium at a concentration of 100 mg/L and 30 mg/L, respectively, and the amount of oxygen consumed was measured. , the mass concentration of dissolved oxygen consumed by aerobic biological oxidation in water under specified conditions.
As a control, an inorganic salt medium containing no composite particles 5 is used. The amount of oxygen (theoretical oxygen demand, ThOD) required for all of the composite particles 5 excluding the functional components to be converted to water and carbon dioxide was calculated from the polymer composition formula. The biodegradation degree was calculated as the biochemical oxygen demand relative to the theoretical oxygen demand (biodegradation=BOD/ThOD×100). Evaluation of redispersibility was determined as follows.
○: Biodegradation degree 28 days after the start of the test was 80% or more.
×: The degree of biodegradation 28 days after the start of the test was less than 80%.

Evaluation results using the above Examples and Comparative Examples are shown in FIGS. 7, 8, and Table 2. FIG. 7 is an optical microscope observation diagram of composite particles obtained in Example 1 and Example 4. FIG. 8 shows the results of observing the dry powder of composite particles 5 using an operating electron microscope. In Table 2, the droplet stabilizer refers to an additive used to stabilize the O/W type emulsion in the second step, and corresponds to, for example, the micronized chitin 1 in the present invention. Furthermore, the diagonal lines in each cell in Comparative Examples in Table 2 indicate that the process became impossible to perform during each process, and the subsequent process was not performed.

As is clear from FIGS. 7 and 8, by solidifying the droplets using the O/W emulsion droplets as a template, countless true spherical composite particles 5 derived from the shape of the emulsion droplets are formed. Furthermore, as shown in FIG. 8, it was confirmed that the surface was uniformly covered with fine chitin 1 having a width of several nm. Furthermore, even though the surfaces of the composite particles 5 were repeatedly washed by filtration and washing, the surfaces of the composite particles 5 were evenly and uniformly coated with the fine chitin 1. Therefore, in the composite particles 5 of the present invention, the monomer inside the composite particles and the fine chitin Chitin-1 was shown to be bound and inseparable.

As is clear from the evaluation results of Examples 1 to 7 in Table 2, regardless of the type of micronized chitin 1, droplets can be stabilized, and polymers of various monomers, biodegradable polymers, and various functional components can be used as the core. It was confirmed that composite particles 5, which are particles 3, could be produced. The obtained composite particles 5 had good redispersibility. Furthermore, by using a biodegradable polymer, biodegradable composite particles 5 were obtained.

On the other hand, in Comparative Example 1, it was impossible to perform the second step. Specifically, even if the ultrasonic homogenizer treatment was carried out, the monomer phase and the finely divided chitin dispersion liquid phase remained separated into two phases, making it impossible to produce an O/W emulsion itself.
In Comparative Example 4 as well, it was impossible to perform the second step. Specifically, even if the ultrasonic homogenizer treatment was carried out, the polymer phase and the micronized chitin dispersion liquid phase remained separated into two phases, making it impossible to produce an O/W emulsion itself.

Furthermore, in Comparative Example 2 and Comparative Example 4, it was possible to form an O/W emulsion in the a2 step. This is thought to be because carboxymethyl chitin, like finely divided chitin, exhibited amphipathic properties and thus functioned as a stabilizer for the emulsion. However, when the droplets were solidified in the subsequent third step, the emulsion collapsed, making it impossible to obtain composite particles using the O/W emulsion as a template. The reason for this is not certain, but since carboxymethyl chitin is water-soluble, it is likely to be weak as the fine chitin layer 10 that maintains the emulsion shape even during the solidification of droplets, and therefore It is thought that the emulsion collapsed due to the solidification of the droplets.

Further, in Comparative Example 3, particles were produced, but the surfaces were not coated with micronized chitin 1.

The composite particles of the present invention have favorable effects from the viewpoint of industrial implementation, such as improved addition efficiency as an additive and kneading efficiency with resin, and contributing to cost reduction from the viewpoint of improving transportation efficiency and preventing spoilage. It will be done.
The composite particles of the present invention can be further manufactured by incorporating functional materials such as magnetic substances, pharmaceuticals, agricultural chemicals, fragrances, adhesives, enzymes, pigments, and dyes into the core particles 3, and then microcapsulating them. , it becomes possible to protect the functional material and control its release behavior. It is also possible to further provide a functional material to the fine chitin layer 10 covering the core particles 3.
Since the micronized chitin 1 has biodegradability and biocompatibility, the composite particles 5 of the present invention can be used in drug delivery systems, etc. by using biodegradable polymers and biocompatible polymers in the core particles 3. It is suitable for medical applications, health care applications such as cosmetics and patches, and food applications.

1 Micronized chitin (chitin nanofiber)
10 Micronized chitin layer 2 Droplet 2A Droplet (monomer droplet)
2B Droplet (dissolved polymer droplet)
2C droplet (molten polymer droplet)
3 Core particles (polymer, resin)
4 Dispersion liquid 5 Composite particles

Claims (3)

A first step of defibrating chitin and/or chitosan raw materials in a solvent to obtain a finely divided chitin dispersion;
A second step of coating the surface of droplets containing the monomer liquid and/or polymer liquid in the dispersion liquid with the finely divided chitin and stabilizing it as an emulsion;
a third step of solidifying the droplets to obtain polymer-coated composite particles with the finely divided chitin;
The second step is a step of adding a polymerizable monomer liquid to the micronized chitin dispersion to form an emulsion,
The third step is a step of solidifying the droplets by polymerizing the polymerizable monomer to obtain composite particles,
In the second step, the amount of the polymerizable monomer is 1 part by mass or more and 50 parts by mass or less with respect to 100 parts by mass of the micronized chitin.
Method for producing composite particles. The second step is a step of adding a dissolved polymer obtained by dissolving a polymer in a solvent having low compatibility with the fine chitin dispersion to the fine chitin dispersion to form an emulsion.
A method for producing composite particles according to claim 1 . The second step is a step of adding a molten polymer obtained by heating and melting a polymer that is solid at room temperature above its melting point to the finely divided chitin dispersion to form an emulsion.
A method for producing composite particles according to claim 1 .

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