JP2011099107A - Method for producing composite molded product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a composite molded product in which various active substances are supported on a polyion complex excellent in biodegradability and biological affinity and formed of a polysaccharide material including a component monosaccharide having a definite chemical structure. <P>SOLUTION: In the method for producing a composite molded product containing an anionic polymer and a cationic polymer, the anionic polymer is an anionic polymer obtained by oxidation of any one polysaccharide of cellulose, starch and chitin, and the molded product is formed by adding an aqueous solution of the cationic polymer to an aqueous solution of the anionic polymer. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a composite molded body, a composite molded body encapsulating various active substances and a capsule, and a method for immobilizing various active substances, and is a composite molded article composed of a natural product-derived polysaccharide having excellent biodegradability and biocompatibility. It is about the body.

  In various fields, various microcapsules have been developed for the purpose of containing various drugs, microorganisms, bacteria, nucleic acids, enzymes, or magnetic substances, catalysts, pigments, dyes, etc. for sustained release or as immobilization carriers. .

  Some of these carrier materials require biodegradability, biocompatibility, and the like.

  Many of these microcapsules use natural polymers such as gelatin, agarose and alginic acid. Furthermore, since polyion complex materials composed of polycationic substances and polyanionic substances can be easily prepared in an aqueous system and the resulting carrier is insoluble in water, various proposals have conventionally been made as these carrier substances. (Japanese Patent Laid-Open Nos. 6-100468, 7-33682, 11-1130697, 2002-638, etc.).

  For example, natural products such as hyaluronic acid, chondroitin, chitin, chitosan, sodium alginate, pectin, dextran, etc., and other derivatives such as carboxymethylcellulose, gelatin, polyamino acids and polypeptides and proteins, There are polyion complexes using synthetic polymers such as acrylic acid.

  However, the synthetic polymer can control the cationic group or anionic group in the molecule, and it is easy to prepare polyion complexes with various physical properties, but it is poor in biodegradability and biocompatibility, and its application range is limited. Is done.

  In addition, natural materials with excellent biodegradability and biocompatibility, protein materials have the risk of viral infections derived from humans and animals, and natural polysaccharides have cationic or anionic functional groups due to natural products. Cannot be controlled, and it is difficult to form a polyion complex corresponding to various required physical properties.

  Furthermore, with conventional polysaccharide derivatives such as carboxymethylcellulose, the degree of substitution can be controlled, but the distribution of substituents within the molecule or between molecules is disjoint, and the mechanism of degradation and metabolism in vivo is not clear. Had the problem of not.

  At the same time, the polyion complex formed by using conventional natural resources for the anionic polymer is a dense polyion complex due to the non-uniform structure and high molecular weight of the anionic polymer and gelation derived from the high viscosity of the aqueous solution. It was not possible to encapsulate various active substances.

Japanese Patent Laid-Open No. 6-100468 JP 7-33682 A JP-A-11-130697 JP 2002-638 A

  An object of the present invention is to provide a composite molded article in which various active substances are supported on a polyion complex formed from a polysaccharide material composed of monosaccharides having excellent biodegradability and biocompatibility and a clear chemical structure, and composite molding The object is to provide a method for immobilizing various active substances by the body.

  Furthermore, an object of the present invention is to use a linear polysaccharide-derived anionic polymer having a uniform structure, thereby forming a dense polyion complex composite membrane to fix the inclusion, It is an object to provide a semipermeable membrane-like capsule in which a low-molecular substance such as a salt can freely enter and exit and an immobilization method using the capsule.

  The invention according to claim 1 is a method for producing a composite molded article containing an anionic polymer and a cationic polymer, wherein the anionic polymer is obtained by oxidation of a polysaccharide of cellulose, starch, or chitin. A method for producing a composite molded body, wherein the anionic polymer is formed by adding an aqueous solution of the cationic polymer to an aqueous solution of the anionic polymer.

The invention according to claim 2 is obtained by a method in which the anionic polymer is obtained by oxidizing a polysaccharide dissolved or dispersed in water in an aqueous system using an oxidizing agent in the presence of a catalyst of an N-oxyl compound, The method for producing a composite molded article according to claim 1, which is polyuronic acid or a salt thereof obtained by selectively oxidizing the primary hydroxyl group at the 6-position in the pyranose ring of a natural polysaccharide.

  Invention of Claim 3 is a manufacturing method of the composite molded object in any one of Claim 1 thru | or 2, The said anionic polymer consists of polyuronic acid which oxidized the cellulose.

According to a fourth aspect of the invention, the cationic polymer is chitosan, polyallylamine, claim 1, polyethyleneimine and derivatives thereof, cationic derivatives of Po Rimmer, characterized in that it consists of cationic derivatives of polysaccharides It is a manufacturing method of the composite molded object in any one of thru | or 3 .

Claim The invention according to claim 5, before Symbol cationic polymer is a chitosan, the ratio of glucosamine for N- acetylglucosamine of the chitosan, characterized in that in the range of 100% or less than 90% It is a manufacturing method of the composite molded object in any one of Claim 1 thru | or 3.

  The invention described in claim 6 is characterized in that pH adjustment is not performed after the aqueous solution of the cationic polymer is added to the aqueous solution of the anionic polymer. It is a manufacturing method of a composite molded object.

  The invention according to claim 7 is the method for producing a composite molded body according to any one of claims 1 to 6, wherein the composite molded body has a capsule shape.

  The invention according to claim 8 is characterized in that an active substance is included in the composite molded body, and the active substance is a microorganism, a cell, an enzyme, a nucleic acid, a protein, a magnetic substance, a catalyst, a pigment, and a dye. A method for producing a composite molded body according to any one of claims 1 to 7.

  The composite molded body obtained by the production method of the present invention is composed of an anionic polymer derived from a natural polysaccharide having a uronic acid structure with a controlled chemical structure and various cationic polymers. It has become possible to improve biocompatibility and safety for the living body.

  In addition, it is characterized by encapsulating the complex and encapsulating various active substances, and has a semipermeable membrane property that allows free entry and exit of low molecular weight substances such as water and salt. The composite molded body can be used for various uses for medical materials, agricultural chemicals, foods, and cosmetics.

  In addition, the composite molded product obtained by the production method of the present invention can be immobilized, sustained-released and stabilized by encapsulating microorganisms, enzymes, nucleic acids, proteins, magnetic materials, catalysts, pigments, dyes, etc. in the composite. It has become possible.

  In addition, the production method of the present invention makes it possible to form a dense complex by using linear polyuronic acid having a clear structure as the acidic polysaccharide.

  In addition, the composite molded product obtained by the production method of the present invention can change the sustained release property by controlling the semipermeable membrane property and molecular weight of the composite.

  The composite molded article of the present invention is a polyion complex of an anionic polymer and a cationic polymer.

  In the composite molded body of the present invention, as the anionic polymer, (a) cellulose which is a homopolymer of β-1,4-glucopyranose is oxidized, and a carboxyl group is selectively introduced into the 6-position of the pyranose ring. Polyuronic acid having β-1,4-polyglucuronic acid as a basic skeleton, (b) α-1,4-poly obtained by oxidizing starch with continuous α-1,4-glucopyranose, although there is branching in the middle Polyuronic acid having glucuronic acid as a basic skeleton, (U) β-1,4-N-acetylglucosamine and β-1,4-polyN obtained by oxidizing chitin consisting of a part of β-1,4-glucosamine -Polyuronic acid etc. which have acetylglucosaminuronic acid as a basic skeleton can be used.

  As the selective oxidation method, an aqueous system that can control the degree of oxidation and can oxidize almost all the 6-positions of the pyranose ring to a carboxyl group without oxidizing the 2nd or 3rd position of the pyranose ring. Thus, a method of oxidizing using an oxidizing agent in the presence of an N-oxyl compound catalyst can be used.

  As the N-oxyl compound, 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (hereinafter referred to as TEMPO) or the like can be used.

  Examples of the oxidizing agent include halogens, hypohalous acids, halous acids, perhalogen acids or salts thereof, oxides that can promote the target oxidation reaction, such as halogen oxides, nitrogen oxides, and peroxides. Any oxidizing agent can be used as long as it is an agent.

  In addition, when oxidation is performed in the presence of bromide or iodide, the oxidation reaction can proceed smoothly even under mild conditions, and the introduction efficiency of carboxyl groups can be greatly improved.

  Further, it is particularly preferable to use TEMPO as the N-oxyl compound and sodium hypochlorite as an oxidizing agent in the presence of sodium bromide.

  Here, the N-oxyl compound may be used in an amount as a catalyst, for example, 10 ppm to 5% is sufficient relative to the number of moles of the constituent monosaccharide of the polysaccharide, but 0.05% to 3% is preferable. Moreover, the usage-amount of a bromide or iodide can be selected in the range which can accelerate | stimulate an oxidation reaction, for example, is 0-100% with respect to the number of moles of the constituent monosaccharide of a polysaccharide, More preferably, it is 1-50%.

  Further, for the purpose of increasing the selectivity of oxidation of the constituent monosaccharides to primary hydroxyl groups and suppressing side reactions, the reaction temperature is desirably room temperature or lower, more preferably 5 ° C. or lower. Furthermore, it is preferable to keep the inside of the system alkaline during the reaction. The pH at this time may be kept at 9 to 12, more preferably pH 10 to 11.

  In this oxidation method, the degree of oxidation can be controlled by the amount of the oxidant and the amount of alkali added when the pH is kept constant. For example, when an alkali is added in an equimolar amount with a sugar residue, almost all primary hydroxyl groups at the 6-position of the pyranose ring are oxidized to carboxyl groups, and water-soluble polyuronic acid is obtained.

  As the raw material polysaccharide for this oxidation reaction, water-soluble polysaccharides such as starch, pullulan and hyaluronic acid, water-insoluble cellulose, chitin and the like can be used.

  When a highly crystalline polysaccharide such as cellulose or chitin is used as a raw material, it is preferable to perform a regeneration treatment for reducing the crystallinity as a pretreatment.

  As the regeneration treatment of cellulose, a known regeneration treatment method such as a cupra ammonium method or a viscose method can be used.

  Moreover, as a regeneration process of chitin, an alkali regeneration process is mentioned, for example. After dipping chitin in a high-concentration alkali, it becomes a viscous liquid by diluting under low temperature while adding ice. When hydrochloric acid is added thereto for neutralization, flake-like chitin precipitates, but an almost amorphous chitin is obtained, which is subjected to the above oxidation reaction without being sufficiently washed with water and dried to obtain a molecular weight. The decrease is suppressed as much as possible, and almost all primary hydroxyl groups at the 6-position of the pyranose ring can be oxidized to carboxyl groups.

  Alternatively, a chitosan that is a deacetylated product of chitin may be used as a raw material, and a material N-acetylated under a uniform reaction may be subjected to the oxidation reaction.

  For example, after dissolving chitosan in acetic acid and diluting with methanol, it is easily N-acetylated by adding 1.5 to 3 times the molar amount of acetic anhydride relative to the amount of amino groups in the chitosan, and again chitin The chemical structure can be restored.

  Through this operation, the product washed sufficiently with water is subjected to the oxidation reaction without drying or freeze-drying, whereby only the primary hydroxyl group at the 6-position is oxidized with high selectivity as in the case of alkali-regenerated chitin.

  Furthermore, in this case, it is also possible to control the degree of N-acetylation of the oxidation raw material by the amount of acetic anhydride added.

  Here, polyuron containing β-1,4-glucopyranose and β-1,4-glucuronic acid as constituent monosaccharides, in which regenerated cellulose is oxidized by the above oxidation method and a carboxyl group is introduced at the 6-position of D-glucose. The acid will be called celouronic acid.

  Polyuronic acid containing α-1,4-glucopyranose and α-1,4-glucuronic acid, which is obtained by oxidizing starch and introducing a carboxyl group at the 6-position of D-glucose, is called amylouronic acid. I will decide.

  In addition, polyuronic acid having β-1,4-N-acetylglucosaminouronic acid obtained by oxidizing chitin as a constituent monosaccharide is called chitouronic acid.

  The 6-position carboxyl group of these polyuronic acids is more stable when present in a salt such as sodium or calcium salt, and monovalent salts such as sodium salt are particularly highly water-soluble.

  Further, desalted COOH-type synthetic polyuronic acid can be obtained by adding an acid such as hydrochloric acid to an aqueous solution of these synthetic polyuronic acids or treating with an ion exchange resin.

  In particular, the chitouronic acid and amylouronic acid described above are water-soluble even in the COOH type, and are highly water-soluble in a wide pH range of pH 1-14.

  Furthermore, in the composite molded body of the present invention, the above polyuronic acid can be used as a single anionic polymer, but several types of polyuronic acid may be mixed and used.

  For example, a composite molded body in which a polyion complex is formed by using chitouronic acid alone as an acidic polysaccharide and chitosan as a cationic salt polymer is easily decomposed by the action of lysozyme. When a polyion complex is formed, the resistance to lysozyme increases, so that the degradation rate in vivo is slowed, and the remaining period in and outside the organism can be controlled.

  As described above, the anionic polymer used in the composite molded body of the present invention is different from natural polyuronic acids such as alginic acid, pectin, and hyaluronic acid, has a clear structure, is a uniform polyuronic acid, has no branching, Since it is close to a linear homopolymer, it has a feature that it is easy to form a more uniform polyion complex.

  Furthermore, these polyuronic acids are highly water-soluble, especially water-soluble in a wide pH range of pH 1 to 14, and the viscosity of the aqueous solution is low compared to other polymers. It is difficult to cause gelation, and the capsule outer shell composite membrane can be densified.

  Next, the cationic polymer of the composite molded body of the present invention will be described.

  The cationic polymer of the composite molded body of the present invention is not particularly limited as long as it forms the anionic polymer of the present invention and a polyion complex, but chitosan, polyallylamine, polyethyleneimine and derivatives thereof, and cations of various polymers One kind or two or more kinds of cationized derivatives of various polysaccharides such as cationized derivatives and cationized starches can be selected.

  In particular, when chitosan or cationized derivatives of various polysaccharides are used, all the composite molded products produced are derived from polysaccharides, which are extremely excellent in biodegradability, biocompatibility, etc., and are derived from sugar structures. There is also a possibility of imparting high functionality, which is more preferable.

  In particular, chitosan is similar in structure to the anionic polymer of the present invention, and the spacing and size of the cationic groups are almost equal to the spacing of the anionic groups, and the composite membrane is formed when a polyion complex or a composite molded body is formed. Densification can be performed, which is more preferable.

  When chitosan is used as the cationic polymer of the composite molded article of the present invention, general chitosan is applicable, and the raw material, purification method, degree of polymerization and the like are not particularly limited.

However, considering the workability of forming a composite film that prevents gelation, chitosan having a weight average molecular weight in the range of 1 × 10 ⁴ to 2 × 10 ⁶ is preferably used.

The ratio of glucosamine and N-acetylglucosamine in the constituent monosaccharide is not particularly limited, but is preferably in the range of 40:60 to 100: 0 from the viewpoint of solubility in water or acid.

  However, for the purpose of densifying the composite membrane, so-called highly deacetylated chitosan having a high ratio of glucosamine that is closest to the structure of the polyuronic acid of the present invention is preferably used.

  The ratio of glucosamine and N-acetylglucosamine in this chitosan is generally expressed as deacetylation degree or N-acetylation degree (N-acetylation degree (%)) = 100%-(deacetylation degree (%)). As shown, it can be determined by elemental analysis, colloid titration, infrared spectroscopy (IR) by the KBr tablet method, or nuclear magnetic resonance spectroscopy (NMR) dissolved in an acidic solution.

  The compounding ratio of the anionic polymer and the cationic polymer of the composite molded body of the present invention is not particularly limited, but in general, the anionic and cationic valences are ion-bonded at about 1: 1, A polyion complex is formed.

  However, the compounding ratio in the composite molded body is slightly different depending on the structure of each polymer, particularly the interval between ionic groups, the solid content concentration, the type of counterion, pH, etc., and the physical properties of the composite molded body vary greatly.

  Therefore, it can be set arbitrarily within a range that satisfies the required physical properties.

  Furthermore, the shape of the composite molded body of the present invention can be a gel, a sheet, a powder, or a capsule.

  Various active substances can be encapsulated, and immobilization or sustained release can be arbitrarily selected according to the intended use.

  In particular, when various active substances are immobilized by encapsulation, a composite coating can be formed even when the size is on the order of several nanometers to several centimeters, and the inclusions can be stabilized.

  Thereby, an inclusion can be protected from an external influence or the influence can be reduced.

  These capsules can be used as active substances as they are, but can also be used by dispersing in various solvents, mixing or coating fibers, nonwoven fabrics, paper, sheets, films, glass, metals, and the like.

  Various active substances to be encapsulated in the composite molded body include microorganisms, cells, enzymes, nucleic acids, proteins, magnetic substances, catalysts, pigments, dyes, seeds, eggs, resins, oils and fats, solvents, etc. , Protection, sustained release, etc. can be performed.

  Moreover, the composite molded body of the present invention may contain at least one kind of additive such as a crosslinking agent.

  In particular, it has many relatively reactive functional groups such as aldehydes and carboxyl groups present in the aforementioned anionic polymers, amino groups and imide groups of cationic polymers, and can be modified efficiently. is there.

  Next, a method for producing the composite molded body of the present invention will be described.

  The composite molded body of the present invention comprises a composite system of an anionic polymer and a cationic polymer.

  In order to form the most functional and strong dense film, it is efficient to form a polyion complex.

  A method of forming a polyion complex by adjusting the pH of an aqueous solution in which both polymers are dissolved to a pH range where the polyion complex is most easily formed is also mentioned.

  In this method, it is also possible to adjust the pH from the mixed aqueous solution and form a polyion complex precipitated in water to form a capsule, flake, lump, thread, or sheet polyion complex.

  Alternatively, the polyion complex can be formed by contacting an ionized anionic polymer and a cationic polymer.

  For example, an aqueous solution of each polymer can be mixed and brought into contact, and at the same time, polyion complex formation and molding can be performed simultaneously.

  As the simplest method, for example, a capsule of a polyion complex is formed by dropping a cationic polymer aqueous solution into an anionic polymer aqueous solution. The order of dripping may be reversed.

  In particular, regarding the capsule formation method and the method of encapsulating the active substance, various methods can be selected according to the use and structure.

  Here, the inclusion means that the inclusion is taken into the composite film including the surface layer or the capsule, and the inclusion may have a structure that protrudes out of the composite molded body.

  The inclusion is dispersed or dissolved in one or both of an anionic polymer and a cationic polymer, and is encapsulated using a method such as a simple coacervation method or a secondary emulsion method.

  With regard to this encapsulation, the shape, size, outer wall thickness, particle size distribution, capsule physical properties, etc. can be controlled by various conditions such as the configuration of each device and solution, stirring, and temperature.

  First, production examples of acidic polysaccharides and basic polysaccharides as raw materials used in Examples and Comparative Examples will be described.

<Production Example 1>
(Preparation of N-acetylated chitosan (1))
Daiichi Seika Kogyo Co., Ltd. Daichitosan 100D (VL) was used as 100% deacetylated chitosan. 10 g of this chitosan was dissolved in 190 g of 10% acetic acid, diluted with 1 L of methanol, and acetic anhydride with stirring. When 12.68 g (2 eq.) Was added, it gelled in a few minutes.

  After leaving this for 15 hours, add 1 L of methanol and stir with a homogenizer, add 2N-NaOH aqueous solution to neutralize to pH 7, filter this, wash thoroughly with methanol and deionized water, freeze-dry To obtain 11.6 g of N-acetylated chitosan. The degree of N-acetylation by elemental analysis was 95%.

<Production Example 2>
(Preparation of N-acetylated chitosan (2))
Daiichi Seika Kogyo Co., Ltd. Daichitosan 100D (VL) was used as 100% deacetylated chitosan. 10 g of this chitosan was dissolved in 190 g of 10% acetic acid, diluted with 1 L of methanol, and acetic anhydride with stirring. 3.17 g (0.5 eq.) Was added, and the mixture was stirred at room temperature for 15 hours.

  When 2N-NaOH aqueous solution is added to neutralize to pH 7, flaky chitosan is precipitated. This is filtered, washed thoroughly with a solution of methanol and water: acetone = 1: 7, and then washed with acetone. It dehydrated and dried under reduced pressure at 40 ° C. to obtain 10.3 g of N-acetylated chitosan.

  This chitosan was water-soluble and had a pH of 8.2 with a 1 wt% aqueous solution.

  Furthermore, even if acid or alkali was added and pH was changed, it was dissolved.

  From the result of 1H-NMR analysis measured by dissolving in an aqueous deuterated chlorohydrochloride solution, the degree of N-acetylation was 45%.

<Production Example 3>
(Preparation of sodium chitouronic acid salt)
10 g of N-acetylated chitosan prepared in Production Example 1 was suspended in 400 g of distilled water, a solution prepared by dissolving 0.15 g of TEMPO and 2.0 g of sodium bromide was added to 100 g of distilled water, and the mixture was cooled to 5 ° C. or lower.

  84 g of an aqueous 11% sodium hypochlorite solution was added dropwise thereto to initiate the oxidation reaction.

  The reaction temperature was always kept below 5 ° C.

  During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.

  When the amount of alkali added corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position is reached, ethanol is added to stop the reaction, and the reaction solution is poured into 2 L of ethanol. The product was precipitated, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, and dried under reduced pressure at 40 ° C. to obtain 10.8 g of white powdery sodium chitouronic acid salt. .

<Production Example 4>
(Preparation of calcium chitouronic acid salt)
10 g of chitin manufactured by Wako Pure Chemical Industries, Ltd. was immersed in 150 g of 45% aqueous sodium hydroxide solution and stirred at room temperature or lower for 2 hours.

  The aqueous solution was cooled with ice water or the like, and 850 g of crushed ice was added with stirring.

  Chitin was almost dissolved by this alkali treatment.

  The aqueous solution was neutralized with hydrochloric acid, sufficiently washed with water, and then not dried, which was used as an oxidation raw material.

  A solution prepared by dissolving 0.08 g of TEMPO and 1.0 g of sodium bromide in 50 g of distilled water was added to 200 g of this 5% regenerated chitin suspension and cooled to 5 ° C. or lower.

  An 11% sodium hypochlorite aqueous solution (35 g) was added dropwise thereto to initiate the oxidation reaction.

  The reaction temperature was always kept below 5 ° C.

  During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.

  Then, when the alkali addition amount corresponding to 100% of the number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction.

  To this solution, 150 g of a 10% calcium chloride aqueous solution was added and precipitated as a calcium salt of chitouronic acid.

  This precipitate was washed several times with water to remove reagents and generated salts.

<Production Example 5>
(Preparation of calcium amylouronate)
10 g of starch was dissolved by heating in 400 g of distilled water and cooled.

  To this solution was added a solution prepared by dissolving 0.18 g of TEMPO and 2.5 g of sodium bromide in 100 g of distilled water, and 104 g of an aqueous 11% sodium hypochlorite solution was added dropwise to initiate the oxidation reaction.

  The reaction temperature was always kept below 5 ° C.

  During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.

  When the amount of alkali added reaches 100% of the total number of moles of the primary hydroxyl group at the 6-position, ethanol is added to stop the reaction, and 200 mL of 10% aqueous calcium chloride solution is added. The precipitated calcium amylouronate was washed several times with water and dried to isolate the calcium amylouronate.

<Production Example 6>
(Preparation of sodium cellulonate)
As the regenerated cellulose, Benise manufactured by Asahi Kasei Kogyo Co., Ltd. is used. 10 g of regenerated cellulose is suspended in 400 g of distilled water. did.

  To this, 104 g of an aqueous 11% sodium hypochlorite solution was added dropwise to initiate the oxidation reaction.

  The reaction temperature was always kept below 5 ° C.

  During the reaction, the pH in the system was lowered, but a 0.5 N NaOH aqueous solution was sequentially added to adjust the pH to 10.75.

  When the amount of alkali added corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position is reached, ethanol is added to stop the reaction, and the reaction solution is poured into 2 L of ethanol. Then, the product was precipitated, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, dried under reduced pressure at 40 ° C., and white powdery 100% cerulouronic acid sodium salt 11 0.6 g was obtained.

<Example 1>
Next, the composite molded body of Example 1 will be described.

  2 g of N-acetylated chitosan prepared in Production Example 2 was dissolved in a dilute hydrochloric acid solution to obtain a cationic polymer aqueous solution having a solid concentration of 3% and pH 1.

  In this chitosan aqueous solution, 0.5 g of lipase, 70 mL of benzene and 2 g of tween 80 as a surfactant were added and stirred.

  1 g of chitouronic acid sodium salt prepared in Production Example 4 was dissolved in distilled water to obtain an aqueous anionic polymer solution having a solid content concentration of 5%.

  A cationic polymer emulsion was added to this aqueous solution with stirring, and stirring was continued for several minutes.

The produced capsule was lightly washed with water and treated with 1% aqueous CaCl ₂ solution and acetone to obtain a capsule of Example 1.

<Example 2>
Commercially available highly deacetylated chitosan was dissolved in 0.2 M aqueous acetic acid solution to prepare 100 g of 2% aqueous chitosan solution. Here, 2 g of fine powder of iron oxide (Fe ₃ O ₄ ) was suspended and dispersed.

  The chitosan / iron oxide suspension was dropped into an aqueous solution in which sodium celolone of Production Example 6 was dissolved at a concentration of 2% to prepare capsules containing magnetic powder.

  Even when stored in water for 1 month, the capsule contained magnetic powder, and it was confirmed that it was reacting to a magnetic field.

<Reference Example 1>
Commercially available highly deacetylated chitosan was dissolved in 0.2 M aqueous acetic acid solution to prepare 100 g of 2% aqueous chitosan solution.

  Here, 2 g of hydroxyapatite fine powder was dispersed by a homogenizer.

  A 2% aqueous solution of sodium celolone of Production Example 6 was added to the chitosan / hydroxyapatite mixture, and further stirred.

  When this hydroxyapatite paste was coated on a glass substrate, a uniform coating film was obtained.

  The dried membrane was stable in water and did not disintegrate for 3 days even in acidic and alkaline atmospheres.

  The coded glass substrate prepared in Reference Example 1 was placed in physiological saline.

  When observed after 14 days, the coating film did not appear to collapse.

This suggests that the coating agent of Reference Example 1 may be used as a coating material for biomaterials.

<Example 3>
10 g of carbon black pigment, 20 g of ethylene glycol, 5 g of glycerin and 15 g of a surfactant were mixed and dispersed in 50 g of a 10% aqueous solution of polyallylamine (molecular weight: 100,000).

Further, a cationic polymer aqueous solution in which a carbon black pigment is dispersed in a suspension in which 5 g of calcium amylouronate prepared in Production Example 5 is dispersed in 50 g of water is added dropwise with stirring, and the capsule encapsulating the pigment of Example 3 Got.

<Example 4>
Commercially available highly deacetylated chitosan was dissolved in 0.2N hydrochloric acid to prepare 20 g of a 2% chitosan aqueous solution.

  Here, 0.2 g of hemoglobin was added and stirred well to disperse.

  This aqueous solution was added dropwise to the 2% aqueous solution of sodium ceuronate in Production Example 6 to obtain hemoglobin-encapsulated capsules.

  The produced capsules were collected by filtration and washed with a buffer.

  This capsule contains hemoglobin, and the size of the capsule is different when it is poured into water with different salt concentrations, so it was confirmed that low molecular weight substances such as water entered and exited.

<Comparative Example 1>
The anionic polymer of Example 4 was changed from sodium celouronate of Production Example 6 to a 2% aqueous solution of sodium alginate (1% viscosity 100 to 150 mPaS), and an aqueous chitosan solution was added dropwise.

  However, the composite molded body of chitosan and alginic acid did not form a dense film, gelled, and did not encapsulate.

<Comparative example 2>
Furthermore, the sodium alginate aqueous solution was adjusted to 0.5% concentration, and capsules with chitosan were formed in the same manner as in Comparative Example 1, but the capsules collapsed during washing.

  According to the present invention, it becomes possible to produce a composite molded body comprising an anionic polymer derived from a natural polysaccharide having a uronic acid structure with a controlled chemical structure and various cationic polymers, and these composite molded bodies can be easily produced. Biodegradable and highly biocompatible.

  In addition, it is characterized by encapsulating and encapsulating various active substances, and has a semipermeable membrane property that allows free entry and exit of low-molecular substances such as water and salt. It can be used for various applications such as industrial materials, agricultural chemicals, foods, hygiene products, and cosmetics.

Claims (8)

A method for producing a composite molded article comprising an anionic polymer and a cationic polymer, wherein the anionic polymer is an anionic polymer obtained by oxidation of a polysaccharide of cellulose, starch, or chitin,
A method for producing a composite molded body, comprising forming the aqueous solution of the cationic polymer by adding the aqueous solution of the cationic polymer to the aqueous solution of the anionic polymer.   The anionic polymer is obtained by a method in which a polysaccharide dissolved or dispersed in water is oxidized in an aqueous system using an oxidizing agent in the presence of an N-oxyl compound catalyst, and in the pyranose ring of a natural polysaccharide The method for producing a composite molded article according to claim 1, which is polyuronic acid or a salt thereof obtained by selectively oxidizing the primary hydroxyl group at the 6-position.   The method for producing a composite molded article according to any one of claims 1 to 2, wherein the anionic polymer comprises polyuronic acid obtained by oxidizing cellulose. The cationic polymer, chitosan, polyallylamine, polyethyleneimine and derivatives thereof, cationic derivatives of polymers, according to any one of claims 1 to 3, characterized in that it consists of a polysaccharide cationic derivatives A method for producing a composite molded body.   The cationic polymer is chitosan, and the ratio of glucosamine to N-acetylglucosamine in the chitosan is in the range of 90% or more and 100% or less. A method for producing a composite molded article.   The method for producing a composite molded article according to any one of claims 1 to 5, wherein the pH is not adjusted after the aqueous solution of the cationic polymer is added to the aqueous solution of the anionic polymer. The method for producing a composite molded body according to any one of claims 1 to 6 , wherein the composite molded body has a capsule shape.   The active substance is encapsulated in the composite molded body, and the active substance is a microorganism, a cell, an enzyme, a nucleic acid, a protein, a magnetic substance, a catalyst, a pigment, and a dye. The manufacturing method of the composite molded object in any one.