JP4918665B2 - Method for producing polysaccharide fine particles - Google Patents

Description

This invention is particularly useful as a material for medical materials and chemical fields, for example a process for producing a fine particles composed of polysaccharides such as chitosan.

  Polysaccharides formed by glycosidic bonding of many monosaccharides are indispensable materials for living organisms. They are abundant in nature and do not become depleted, and are biodegradable. There will be no environmental pollution problems. For example, chitosan obtained by deacetylating chitin with high chemical stability is mentioned as an example of polysaccharide. In this chitosan, the acetyl group of chitin is substituted with an amino group that has a high chemical activity and is positively charged. For this reason, chitosan has a property of easily binding to a negatively charged substance having, for example, a carboxyl group. On the other hand, the carboxyl group is also a substance constituting a part of various bacteria, viruses and bacteria.

  For this reason, chitosan exhibits effects such as anti-allergic properties and antibacterial properties, in which the above-mentioned various bacteria, viruses and bacteria can be made harmless by incorporating them into a molecule through amino-carboxyl bond. Therefore, for example, in the medical field, oral dressings such as wound dressings and toothpaste (antibacterial effect against mutans streptococci and cell activity effect on oral mucosa, effective for oral inflammation, gum edema and bleeding, etc.) Can be suitably used. Other polysaccharides also have the advantages of high biocompatibility and easy disposal, as described above. For example, cleaning applications for metal parts, chemical physical polishing cleaning agents for silicon wafers, etc., powder characteristics in the cosmetics field. Applications to improver applications and thickening / dispersion / film-former applications in the paint field are expected.

  There is a strong demand for particulate polysaccharides in the aforementioned applications, especially in the cosmetics field. When chitosan typical as a polysaccharide is made into fine particles, the following method is used. In other words, chitosan is dissolved in an acid, and a surfactant and an organic solvent are added to form a so-called Water / Oil emulsion. Further, water is removed by heat evaporation, use of a poor solvent such as alcohol, and solidification by mixing with a specific solution. This is a method of making fine particles. However, with this method, (1) it is difficult to produce fine particles below the μm level, and (2) it is inevitable to use substances with high environmental loads such as surfactants and organic solvents. It does not match today's demanded situation.

In addition, the following [Patent Document 1] to [Patent Document 4] also disclose a method for producing chitosan fine particles, which requires the use of expensive reagents and complicated operations, and is inexpensive and simple. It is hard to say that it is a manufacturing method. This has been proposed. However, these methods require the use of expensive reagents and complicated operations, and the problem of manufacturing costs has not been solved.
JP 60-215033 A Japanese Patent Laid-Open No. 61-040337 JP 62-062827 A Japanese Unexamined Patent Publication No. 1-140961

On the other hand, the invention “Method for producing chitosan fine particles” described in [Patent Document 5] below is an inexpensive and simple method. However, it has been difficult to produce chitosan having a particle size of μm level and a nano-level particle size.
JP 58-057401 A

That is, the present invention has been proposed to solve these problems in view of the problems involved in the conventional technology, and can be manufactured inexpensively and easily. Further, the particle size of submicron or less can be arbitrarily set. and to provide a method for producing a polysaccharide fine particles capable of controlling.

In order to overcome the above problems and achieve the intended purpose, the invention according to claim 1
A polysaccharide solution is prepared by adding and dissolving a polysaccharide in an acid solvent.
With respect to 100 parts by volume of this polysaccharide solution, the polysaccharide solution is dropped into water as a dispersion medium having a volume of 100 parts by volume or more,
By removing and at least excess hydrogen ions from the mixed solution of the polysaccharide solution and the dispersion medium, the polysaccharide is associated and precipitated,
The gist of the invention is to produce an arbitrarily controlled polysaccharide having a particle size of 2 μm or less.

Therefore, according to the invention which concerns on Claim 1 , a fine polysaccharide particle can be manufactured cheaply and simply, and suppressing an environmental load. Moreover, the particle size can be easily controlled.

The invention according to claim 2 is the invention according to claim 1 ,
The gist is that a cationic polysaccharide having a positively charged functional group in the structure of the pyranose ring constituting the polysaccharide is used as the polysaccharide. Therefore, according to the invention which concerns on Claim 2 , the highly usable polysaccharide microparticles | fine-particles can be manufactured.

The invention according to claim 3 is the invention according to claim 1 or 2 ,
The dripping of the polysaccharide solution with respect to the water is performed at a rate of 0.1 ml / second or less. Therefore, according to the invention which concerns on Claim 3 , the miniaturization of a polysaccharide can be achieved more suitably.

The invention according to claim 4 is the invention according to any one of claims 1 to 3 ,
The gist is that hydrochloric acid is used as the acid solvent. Therefore, according to the invention which concerns on Claim 4 , the polysaccharide fine particle which can be used more widely can be manufactured.

The invention according to claim 5 is the invention according to any one of claims 1 to 4 ,
The gist is that the salt constituting the acid solvent is removed together with the removal of the hydrogen ions. Therefore, according to the invention which concerns on Claim 5 , precipitation of polysaccharide microparticles | fine-particles can be implemented more suitably.

In order to overcome the above-mentioned problems and achieve the intended purpose, the invention according to claim 6 provides:
A polysaccharide solution is prepared by adding and dissolving a polysaccharide in an acid solvent.
With respect to 100 parts by volume of the polysaccharide solution, the polysaccharide solution is dropped into a metal salt aqueous solution of a monovalent or divalent anion as a dispersion medium having a volume of 100 parts by volume or more,
By removing and at least excess hydrogen ions from the mixed solution of the polysaccharide solution and the dispersion medium, the polysaccharide is associated and precipitated,
The gist of the invention is to produce an arbitrarily controlled polysaccharide having a particle size of 2 μm or less.

Therefore, according to the invention which concerns on Claim 6 , it can manufacture fine polysaccharide particle | grains cheaply and simply, and suppressing an environmental load. Moreover, the particle size can be easily controlled.

The invention according to claim 7 is the invention according to claim 6 ,
The gist is that a cationic polysaccharide having a positively charged functional group in the structure of the pyranose ring constituting the polysaccharide is used as the polysaccharide. Therefore, according to the invention which concerns on Claim 7 , highly usable polysaccharide microparticles | fine-particles can be manufactured.

The invention according to claim 8 is the invention according to claim 6 or 7 ,
The gist is that the dropping of the polysaccharide solution to the metal salt solution is performed at a rate of 0.1 ml / second or less. Therefore, according to the invention which concerns on Claim 8 , miniaturization of a polysaccharide can be achieved more suitably.

The invention according to claim 9 is the invention according to any one of claims 6 to 8 ,
The gist is that an aqueous solution of a metal halide is used as the dispersion medium. Therefore, according to the invention which concerns on Claim 9 , the polysaccharide fine particle which can be used more widely can be manufactured.

The invention according to claim 10 is the invention according to any one of claims 6 to 9 ,
The gist is that lactic acid is used as the acid constituting the acid solvent. Therefore, according to the invention which concerns on Claim 10 , polysaccharide microparticles | fine-particles can be manufactured more suitably.

The invention according to claim 11 is the invention according to any one of claims 6 to 10 ,
The gist is that, together with the removal of the hydrogen ions, the salt constituting the acid solvent and the salt constituting the dispersion medium are also removed. Therefore, according to the invention concerning Claim 11 , precipitation of polysaccharide microparticles | fine-particles can be implemented more suitably.

The invention according to claim 12 is the invention according to any one of claims 1 to 11 ,
The gist is that a dialysis membrane is used to remove the hydrogen ions and the like. Therefore, according to the invention which concerns on Claim 12 , while being able to manufacture a polysaccharide microparticles | fine-particles more suitably, the precipitation can also be made more suitable.

The invention according to claim 13 is the invention according to any one of claims 1 to 12 ,
The gist is that dissolution of the polysaccharide in an acid solvent is achieved by heating, and precipitation of polysaccharide fine particles is achieved by cooling. Therefore, according to the invention which concerns on Claim 13 , more various polysaccharides can be refined | miniaturized suitably.

As described above, according to the manufacturing method of the polysaccharide fine particles according to the present invention, inexpensive and simple, microscopic polysaccharide particles submicron can be prepared while controlling the particle diameter.

Next, the manufacturing method of the polysaccharide fine particles according to the present invention, by way of preferred embodiments will be described below with reference to the accompanying drawings. The inventor of the present application has a polysaccharide solution obtained by dissolving a polysaccharide such as chitosan with an acid solvent (in a state in which the association is released) with respect to the dispersion medium having a required amount or more and a required speed or less. In addition, the polysaccharide is dissolved from the mixed solution of the polysaccharide solution and the dispersion medium, and by removing excessive hydrogen ions existing in the system, the particle size is 2 μm or less. In addition, it was found that polysaccharide fine particles that can be controlled to an arbitrary numerical value can be obtained. The polysaccharide used in the present invention is considered to have a particle size that increases as the average molecular weight increases in association with the average molecular weight. Therefore, in the present invention, it is preferably carried out by using a polysaccharide having an average molecular weight of about 20,000 or less.

  Further, by using an acid and / or an aqueous solution containing a monovalent metal halide such as hydrochloric acid or sodium chloride, for example, a metal chloride, as an acid and / or a dispersion medium that forms an acid solvent for dissolving the polysaccharide, It was also found that polysaccharide fine particles having a particle size of nano (nm) order level can be obtained. In the examples described below, chitosan, which is a cationic polysaccharide having a high usefulness as a polysaccharide and having a positively charged functional group in the structure of the pyranose ring forming the polysaccharide, was used. This will be described using an example. Here, there are anionic polysaccharides and nonionic polysaccharides other than the above-mentioned cationic as polysaccharides. However, these charged properties and the acidity that can dissolve the polysaccharides that can be linked regardless of this are also present. By adopting it as a salt derived from a solvent or a salt derived from a dispersion medium, it is possible to make polysaccharides fine particles by the same mechanism. Moreover, dripping in this invention means supplying gradually by the controlled speed | rate.

  As shown in FIG. 1, the polysaccharide fine particle manufacturing process includes a dissolving process S1 in which a polysaccharide as a raw material of the polysaccharide fine particle 10 and a specific acid solvent are mixed and dissolved to obtain a polysaccharide solution, and a polysaccharide solution Is dripped into a dispersion medium of a predetermined amount or more within a predetermined speed range to develop a sea-island effect (details will be described later [0042]), and when it becomes an associated state, polysaccharide fine particles having a required particle diameter are formed. From the dropping step S2 in which the polysaccharides in the dissociated state are divided into particles so that the amount of the polysaccharide is dissociated, and a mixed solution of the polysaccharide solution and the dispersion medium, at least in the system, The polysaccharide fine particles to be obtained in the dropping step S2 by removing excess hydrogen ions dissolving the polysaccharide (in the case of cationic polysaccharides, excess hydrogen ions with respect to the cationic group) For example, polysaccharides divided into spheres corresponding to the particle size of This is basically composed of a precipitation step S3 in which a kind is associated.

  In the dissolving step S1, as shown in FIG. 2, the polysaccharide M and the acid solvent A are mixed and sufficiently stirred to dissolve the polysaccharide M to form a polysaccharide fine particle 10. This is a step of making the sugar solution MAq. By performing this dissolution step S1, chitosan (see FIG. 2 (a)) in an associated state has been dissociated by hydrogen bonds within and between the molecules forming the chitosan (hereinafter simply referred to as molecules). The state, that is, the dissolved state (see FIG. 2B). In addition, about this process S1, when melt | dissolution at room temperature is difficult, what is necessary is just to heat to the temperature which can melt | dissolve chitosan suitably. Further, after the chitosan is dissolved, the insoluble matter may be removed by any means such as filtration. In addition, the broken line in FIG. 2 represents the hydrogen bond.

  In the present embodiment, chitosan is used as the polysaccharide M, but in addition to this, it is a high molecular compound produced by glycosidic bonding of a large number of monosaccharides such as chitin, cellulose and pullulan. A typical polysaccharide M can be used, so that these microparticles can also be produced. Here, the concentration of chitosan is not particularly limited, but is usually in the range of about 0.1 to 30% by weight from the viewpoint of handling.

  Examples of the acid solvent A include water-soluble organic acids such as acetic acid, formic acid, lactic acid, salicylic acid, succinic acid, and benzoic acid (in the case where the polysaccharide M is chitosan, an organic acid having one anionic group in the molecule). Alternatively, inorganic acids of monovalent anions such as hydrochloric acid or nitric acid are used alone or in combination of two or more. Since these acids are used as an aqueous solution, when the property is solid, such as lactic acid, it is used by dissolving in a solvent such as water. Moreover, in order to express the sea-island effect (described later [0042]) more efficiently, it is preferable to use lactic acid or the like that develops viscosity when the solution is used. Further, the concentration of the acid solvent A is not particularly limited. However, as described above ([0038]), it is possible to supply hydrogen ions to the extent that the intramolecular and intermolecular hydrogen bonds derived from the hydroxyl groups and the like of the mixed polysaccharide M are inhibited and chitosan is dissolved. In general, it is within the range of about 0.1 to 30% by weight. The selection of the acid solvent A greatly affects the dissolution and precipitation (association) of the polysaccharide M, which will be described later in detail ([0048]).

  In the dropping step S2, as shown in FIG. 3 and FIG. 4, the polysaccharide solution MAq is dropped onto the dispersion medium DS under control to develop a sea-island effect while making a mixed solution. Dispersing the polysaccharides M in the dissociated state for each required amount so that the amount of the polysaccharide fine particles 10 having the required particle size can be formed when the associated state is reached in the DS. It is. Specifically, the polysaccharide solution MAq is dropped into the dispersion medium DS (see FIG. 3 (a)), and this is a dropping step S21 (see FIG. 3 (b)) to form a fine droplet in the dispersion medium DS. ), And a total amount of the polysaccharide solution MAq added dropwise to the dispersion medium DS, and a coalescence step S22 to obtain a required size by coalescing the microdroplets of the polysaccharide solution MAq present in the dispersion medium DS; (See FIGS. 4A and 4B).

  Here, the sea-island effect means that when there is a two-component system in which one is a major component and the other is a minor component, the minor component present between the major components (see FIG. 3 (a)) This is a phenomenon in which a force that a large amount of component tends to shift to a continuous phase is used as a driving force to gradually become smaller lumps (see FIG. 3B). Therefore, if a small amount of the polysaccharide solution MAq is added to a sufficiently large amount of the dispersion medium DS, the polysaccharide solution MAq will continue to change autonomously into smaller chunks due to this effect. And it reaches the minimum size determined by the ratio of the total amount of each of the dispersion medium DS and the saccharide solution MAq, the viscosity and other physical properties.

  In order to suitably achieve such a sea-island effect, the dropping of the polysaccharide solution MAq to the dispersion medium DS is set to 0.1 ml / second or less. When this value exceeds 0.1 ml / sec, a large amount of the polysaccharide solution MAq is present at a local site of the dispersion medium DS to which the polysaccharide solution MAq is dropped, which is preferable for the sea-island effect. Will not be expressed. The dripping step S21 proceeds and is completed by the expression of the sea-island effect. The amount of the dispersion medium DS is 100 volumes with respect to 100 parts by volume of the polysaccharide solution MAq in order to continuously develop the aforementioned sea-island effect until the dropping of the whole amount of the polysaccharide solution MAq is completed. Set to more than When this numerical value is less than 100 parts by volume, the abundance of the polysaccharide solution MAq in the dispersion medium DS increases as the dropping of the polysaccharide solution MAq proceeds, so that the polysaccharide solution MAq is suitable. It becomes difficult to form fine droplets, and it becomes difficult to achieve a particle size of 2 μm or less in the polysaccharide fine particles 10. In addition, if it is 100 parts by volume or more and the dropping rate of the polysaccharide solution MAq is 0.1 ml / second or less, it is at most regardless of the type and amount of the other acid solvent A and the type of the dispersion medium DS. A particle size of 2 μm or less is achieved. In addition, such fine saccharide fine particles 10 are easily aggregated by a treatment such as drying. Therefore, in order to take advantage of the fineness of the particles, they are generally used in a state of being dispersed in moisture.

  The coalescence step S22 is a step of increasing the size of the micro-droplets of the polysaccharide solution MAq, all of which are present in the dispersion medium DS, colliding with each other and coalescing. The size of the droplet of the polysaccharide solution MAq finally reached in this step S22 basically varies depending on the force to be miniaturized by the sea-island effect and the amount present in the dispersion medium DS. It is determined by the balance with the number of collisions. This is because the amount of the polysaccharide solution MAq dropped onto the dispersion medium DS is proportional to the size of the droplets in the dispersion medium DS of the polysaccharide solution MAq, that is, dropped onto the dispersion medium DS. This means that the size of the polysaccharide fine particles 10 to be obtained can be controlled by the total amount of the polysaccharide solution MAq.

Examples of the dispersion medium DS used in the dropping step S2 include (a) water, (b) a metal salt aqueous solution of a monovalent anion (including an aqueous solution of a metal halide), or (c) a divalent or higher anion. An aqueous metal salt solution is used. Since these have different effects on the polysaccharide solution MAq, they will be described below. In order to contribute to this understanding, the dissolution and precipitation (association) of chitosan will be described first. Chitosan is basically a polymer in which glucosamine, which is a monosaccharide, is continuous by glycosidic bonds, and a hydroxyl group and an amino group are present in the glucosamine, which is the smallest unit. And (1) hydrogen bonds by polarization of O (δ−) and H (δ +) of hydroxyl groups and (2) ionic bonds between positively charged amino groups via anions, and / or The state of association (degree) between molecules has been determined. When the degree of association becomes a certain value or more (large), it becomes insoluble and precipitates in water, and when it becomes less than a certain value (small), it dissolves in water. Here, in order to bond a plurality of amino groups, it is necessary to interpose an anion having at least a charge of −2 or more, for example, a divalent or more anion such as SO ₄ ²⁻ .

  First, (a) when water is used as the dispersion medium DS, the amount of hydrogen ions derived from the acid solvent A, which basically inhibits hydrogen bonding and reduces the degree of association of chitosan, decreases. The bond is restored, and as a result, the degree of association increases and chitosan precipitates. In the case of (b), in addition to the action of (a), since the monovalent anion that will be ionized in the dispersion medium DS binds to the hydrogen ion, the degree of association of chitosan is considered to be further increased. The monovalent anion binds to an amino group. In this case, since the anion has a charge of -1, it binds only to one amino group and does not bind to another amino group. Will not fluctuate.

  Furthermore, in the case of (c), the action on hydrogen ions is considered to be substantially the same as (b). However, on the other hand, it exists between a plurality of amino groups, and a complex of a polyvalent anion may be generated via the amino group, so that the degree of association of chitosan becomes larger and the association is larger than (b). It is considered to be a degree. Therefore, the degree of association of chitosan increases in the order of (a) <(b) <(c). This means that the particle diameter of the polysaccharide fine particles 10 can be controlled also by the selection of the dispersion medium DS. In practice, when (a) water or (b) a metal salt aqueous solution of a monovalent anion is used as the dispersion medium DS, several tens of fine particles observed without being clouded in the dispersion medium DS are observed. It has been confirmed that polysaccharide fine particles 10 of around nm are obtained.

In addition, as described above, the kind of the acid solvent A used in the previous dissolution step S1 also affects the precipitation of the polysaccharide M, as the valence of the anion greatly affects the particle size of the polysaccharide fine particles 10. It has a particularly big impact. That is, as the acid solvent A, for example, when using a sulfuric acid with SO ₄ ^2-a is a divalent anion, it would not at all dissolve in a mixture of polysaccharide M. This is because the amount of association expressed due to complex formation with a plurality of amino groups is larger than the amount of dissolution expressed by releasing the association state resulting from inhibition of hydrogen bonding by hydrogen ions. When the production of finer polysaccharide particles 10 is considered in this way, it is preferable to use a monovalent anionic acid or metal salt. Regarding the valence of the anion in the aforementioned acid, not only the number but also the acid dissociation constant (pKa) is an important index. Specifically, an inorganic acid such as sulfuric acid having a low pKa is not suitable for use as the acid solvent A as described above. On the other hand, even if it is the same inorganic acid, substances having a high pKa such as carbonic acid or phosphoric acid or various organic acids can be employed.

  In the precipitation step S3, hydrogen ions or hydrogen ions and anions (hereinafter referred to as association inhibitors) that are present in the mixed solution and inhibit the association of chitosan are removed. It is the process of making it precipitate. Any known method can be used for this precipitation step S3 as long as it can remove the association inhibitor from the mixed solution. However, until the association-inhibiting substance is removed from the mixed solution, the association of chitosan, that is, precipitation is not complete, and the particle size may vary.

  Therefore, it is not preferable to apply a physical force, for example, filtration or decantation, or removal of specific components such as moisture from a mixed solution that affects the sea-island effect. Therefore, it is preferable to use a dialysis membrane or the like that can remove only the association inhibitor. Further, if the dialysis rate is too high, it becomes a driving force to move each substance that affects the association of chitosan, so that the rate is preferably 0.1 ml / second or less.

  As can be seen from the above description, in the polysaccharide fine particles and the production method thereof according to the present invention, (1) the polysaccharide fine particles 10 can be made fine from the viewpoint of raw materials (polysaccharide M) by the sea-island effect. (2) Further, by adjusting the dropping amount of the polysaccharide solution MAq to the dispersion medium DS, it is possible to control the particle size of the polysaccharide fine particles 10 from the viewpoint of raw materials, and (3) the polysaccharide M is finally associated. By controlling the state, the polysaccharide fine particles 10 can be made fine and the particle size can be controlled from a method viewpoint.

  Further, as in this example, when chitosan is employed as the polysaccharide M, the binding of the anion to the amino group, which is one factor that determines the degree of association, inhibits the high chemical activity of the chitosan. . Therefore, it is desirable that the anion is dissociated from the amino group when chitosan is used (in the presence of water (see [0043])). For this reason, as the acid solvent A, it is preferable to use hydrochloric acid or the like whose anion is chloride ion and pKa is high. Specifically, hydrochloric acid whose anion is chloride ion is used as acid solvent A, or metal halide such as sodium chloride, magnesium chloride, lithium chloride, lithium bromide such as chloride ion or bromide ion is used. It is conceivable to use an aqueous solution as the dispersion medium DS.

  In addition, when using halides such as chlorine in this way, when used (in the presence of water (see [0043])), ammonium ions and halide (chlorine) ions, which are ionization products of amino groups and chlorine, are used. Neutralizes and becomes neutral in charge. For this reason, compared with chitosan (solution) that has been acidic in the same use so far, it is possible to remarkably expand its usage.

(Experimental example)
The experiment example about the polysaccharide microparticles | fine-particles obtained with the manufacturing method which concerns on this invention below is shown. In all the experiments, in the dissolution step S1, the polysaccharide solution was chitosan as the polysaccharide, and an aqueous lactic acid solution (concentration: 1.3% by weight) as the acid solvent. A 5 wt% aqueous chitosan lactic acid solution was used. Moreover, in precipitation process S3, the salt which concerns on the hydrogen ion and dispersion medium in an excess mixed solution is removed by the salting-out method using a dialysis membrane.

(Experiment 1) Regarding the relationship between the total amount of the polysaccharide solution dripped onto the dispersion medium and the particle size of the resulting polysaccharide fine particles Using the polysaccharide solution, a sodium sulfate aqueous solution having a concentration of 14% by weight as the dispersion medium was used. Was used by heating to 40 ° C., and a total amount of the polysaccharide solution according to Examples 1 to 4 described in Table 1 was added dropwise to 150 ml of the dispersion medium at a rate of 0.1 ml / second. Thereafter, the aqueous solution was rapidly cooled to 5 ° C., and the aforementioned salting out (rate: 0.1 ml / second) was performed to obtain polysaccharide fine particles. And the particle size of the obtained polysaccharide microparticles | fine-particles was measured with the distribution by the light-scattering (DLS) method.

(Raw material)
・ Chitosan: Wako Pure Chemical ・ Lactic acid: Wako Pure Chemical ・ Sodium sulfate: Wako Pure Chemical
(Device used)
・ DSL particle size distribution analyzer: Trade name Zeta Sizer Nano; manufactured by JEOL)

(Result of Experiment 1)
The results of Experiment 1 are shown in FIG. As can be seen from the figure and the table, the polysaccharide fine particles according to Example 1 have a particle size that is reduced to a submicron size as the bath ratio, that is, the ratio of the dripping amount to the salt aqueous solution decreases, and the total dripping amount. It was confirmed that and the particle size had a positive correlation.

(Experiment 2) Regarding the relationship between the type of dispersion medium and the particle size of the obtained polysaccharide fine particles The following polysaccharide solution was used, and the concentration was adjusted to 3.125% by weight as the dispersion medium ([0059 ] From the mixed solution obtained by using the monovalent anion metal salt aqueous solution or (c) the divalent or higher anion metal salt aqueous solution, respectively, to Examples 5 to 14 under the conditions according to Experiment 1 Such polysaccharide fine particles were prepared. And the state of the obtained polysaccharide fine particle was confirmed by visual observation. Further, for Example 8 and Example 1 of Experiment 1 described above for reference, the outer shape and the like of the obtained polysaccharide fine particles were observed with a transmission electron microscope (TEM).

(Raw material)
Example 5: NaCl (manufactured by Wako Pure Chemical Industries)
Example 6: NaPH ₂ O ₂ (Wako Pure Chemical Industries)
Example 7: MgCl ₂ (manufactured by Wako Pure Chemical Industries)
Example 8: NaH ₂ PO ₄ (Wako Pure Chemical Industries)
Example 9: Na ₂ SO ₃ (manufactured by Wako Pure Chemical Industries)
Example 10: Na ₂ SO ₄ (manufactured by Wako Pure Chemical Industries)
Example 11: K ₂ SO ₄ (manufactured by Wako Pure Chemical Industries)
Example 12: MgSO ₄ (manufactured by Wako Pure Chemical Industries)
Example 13: Na ₂ HPO ₄ (Wako Pure Chemical Industries)
Example 14: Na ₃ PO ₃ (manufactured by Wako Pure Chemical Industries)
(Device used)
・ Transmission electron microscope (TEM): trade name 2000FX; manufactured by JEOL)

(Result of Experiment 2)
As a result of Experiment 2, in the monovalent anion system, the production of fine polysaccharide fine particles on the order of several nanometers that shine without being clouded was observed. On the other hand, white turbidity was observed in the polyanion system. This is thought to be due to the fact that cross-linking occurs between sugar chains due to the complex of the amino group of chitosan and the polyvalent anion, and the association of the chitosan is increased. It was confirmed that the particle size of the polysaccharide fine particles can also be controlled by appropriately selecting the type of the dispersion medium from here, and that very fine particles can be generated.

It is process drawing which shows the manufacturing process of the polysaccharide microparticles | fine-particles based on the suitable Example of this invention. It is a state figure showing dissolution process S1 concerning an example. It is a state figure showing dropping stage S21 (sea-island effect) in dropping process S2 concerning an example. It is a state figure showing unification stage S22 in dropping process S2 concerning an example. It is a graph which shows the result of the DLS particle size distribution of the polysaccharide microparticles | fine-particles which concern on each of Examples 1-4 in Experiment 1. FIG. It is a TEM photograph of polysaccharide fine particles concerning Example 8 in Experiment 2. 4 is a TEM photograph of polysaccharide fine particles according to Example 1 in Experiment 1. FIG.

Explanation of symbols

10 Polysaccharide fine particles, A acid solvent, M polysaccharide. MAq polysaccharide solution, DS dispersion medium

Claims (13)

Add polysaccharide (M) to acid solvent (A) and dissolve to make polysaccharide solution (MAq),
With respect to 100 parts by volume of this polysaccharide solution (MAq), the polysaccharide solution (MAq) is dropped into water as a dispersion medium (DS) having a volume of 100 parts by volume or more,
By removing at least excess hydrogen ions from the mixed solution of the polysaccharide solution (MAq) and the dispersion medium (DS), the polysaccharide (M) is associated and precipitated,
A method for producing polysaccharide microparticles, characterized in that an arbitrarily controlled polysaccharide having a particle size of 2 μm or less is produced. Examples polysaccharide (M), the method of producing a polysaccharide particulate of claim 1 wherein the cationic polysaccharide comprising functional groups that positively charged charge within the structure of the pyranose ring constituting the polysaccharide (M) is used . The method for producing polysaccharide fine particles according to claim 1 or 2 , wherein the dropping of the polysaccharide solution (MAq) to the water is performed at a rate of 0.1 ml / second or less. The method for producing polysaccharide fine particles according to any one of claims 1 to 3 , wherein hydrochloric acid is used as the acid solvent (A). The method for producing polysaccharide fine particles according to any one of claims 1 to 4 , wherein the salt constituting the acid solvent (A) is removed together with the removal of the hydrogen ions. Add polysaccharide (M) to acid solvent (A) and dissolve to make polysaccharide solution (MAq),
To 100 parts by volume of this polysaccharide solution (MAq), the polysaccharide solution (MAq) is dropped into a metal salt aqueous solution of a monovalent or divalent anion as a dispersion medium (DS) having a volume of 100 parts by volume or more. ,
By removing at least excess hydrogen ions from the mixed solution of the polysaccharide solution (MAq) and the dispersion medium (DS), the polysaccharide (M) is associated and precipitated,
A method for producing polysaccharide microparticles, characterized in that an arbitrarily controlled polysaccharide having a particle size of 2 μm or less is produced. The method for producing polysaccharide microparticles according to claim 6, wherein a cationic polysaccharide having a positively charged functional group in the structure of a pyranose ring forming the polysaccharide (M) is used as the polysaccharide (M). . The method for producing polysaccharide fine particles according to claim 6 or 7 , wherein the dropping of the polysaccharide solution (MAq) to the metal salt solution is performed at a rate of 0.1 ml / second or less. The method for producing polysaccharide fine particles according to any one of claims 6 to 8 , wherein an aqueous solution of a metal halide is used as the dispersion medium (DS). The method for producing polysaccharide fine particles according to any one of claims 6 to 9 , wherein lactic acid is used as the acid forming the acid solvent (A). The production of polysaccharide fine particles according to any one of claims 6 to 10 , wherein together with the removal of the hydrogen ions, the salt constituting the acid solvent (A) and the salt constituting the dispersion medium (DS) are also removed. Method. The method for producing polysaccharide fine particles according to any one of claims 1 to 11 , wherein a dialysis membrane is used for removing the hydrogen ions and the like. The dissolution in acid solvent (A) polysaccharide (M) is accomplished by heating, and precipitation of the polysaccharide particles (10) according to any one of claims 1 to 12 is accomplished by cooling A method for producing polysaccharide fine particles.