JP7295559B2 - Chitosan-based composite composition and method for producing chitosan-based composite - Google Patents

Description

TECHNICAL FIELD The present invention relates to a chitin/chitosan-based composite composition and a method for producing a chitin/chitosan-based composite.

Chitin and chitosan are polysaccharides obtained from crustaceans such as shrimp and crab, and are known to have biocompatibility and antibacterial properties. Therefore, the use of chitin/chitosan as a medical material, such as a scaffold material for regenerative medicine and a wound dressing material, has been studied. However, the material using chitin/chitosan alone lacks flexibility and is therefore brittle.

Therefore, the development of composite materials in which chitin/chitosan is chemically combined with other compounds is being developed (for example, Patent Document 1). In order to use it for medical materials that require flexibility, such as wound dressings, it has low stretchability and elasticity, and needs to be improved.

Japanese Patent Application Laid-Open No. 2005-281425

The problem to be solved by the present invention is to obtain a chitin/chitosan-based composite which is excellent in stretchability and elasticity in addition to flexibility.

The first aspect of the present invention, which has been made to solve the above problems,
at least one polysaccharide selected from the group consisting of chitin, chitosan, chitin derivatives, and chitosan derivatives;
and a trimethylene carbonate-based polymer comprising at least one of trimethylene carbonate and a trimethylene carbonate derivative.

The chitin/chitosan-based composite is obtained by dissolving the chitin/chitosan-based composite composition in a solvent to form a solution or suspension, and heating to remove the solvent. In the complex, the trimethylene carbonate-based polymer and chitin/chitosan or chitin/chitosan derivative are not chemically bonded, but chitin/chitosan or chitin/chitosan derivative is contained in the network structure formed by the trimethylene carbonate-based polymer. It becomes a state in which a chain structure consisting of Therefore, it is possible to obtain a composite having both the excellent stretchability and elasticity of the trimethylene carbonate-based polymer and the properties of chitin/chitosan (antibacterial properties and biocompatibility). Moreover, since the trimethylene carbonate-based polymer is excellent in biocompatibility, the chitin-chitosan-based composite is useful as a medical material. In addition, since the composite has antibacterial properties derived from chitin and chitosan, it can be used not only as a medical material but also as a material for nursing care products, infant products, and the like.

The polysaccharide contained in the chitin/chitosan-based composite composition may be of one type or plural types. Similarly, the trimethylene carbonate-based polymer contained in the chitin/chitosan-based composite composition may be of one type or a plurality of types.

The physical properties (elasticity, stretchability, etc.) of the composite obtained from the chitin/chitosan composite composition are determined by the ratio of the polysaccharide to the trimethylene carbonate polymer in the chitin/chitosan composite composition. In other words, by adjusting the ratio, it is possible to obtain a composite with appropriate physical properties according to the application.

A second aspect of the present invention is a method for producing a chitin/chitosan-based composite,
At least one polysaccharide selected from the group consisting of chitin, chitosan, chitin derivatives, and chitosan derivatives, and a trimethylene carbonate-based polymer comprising at least one of trimethylene carbonate and trimethylene carbonate derivatives are mixed in a solvent. It is characterized by forming a solution or suspension and heating said solution or said suspension to remove solvent from said solution or said suspension.

In the above production method, by including glycerol in the solvent, it is possible to suppress the generation of air bubbles when the solution or suspension is heated to remove the solvent. This increases the transparency of the chitin-chitosan composite. Moreover, improvement of tensile strength can be aimed at.

Moreover, in the above production method, it is preferable that the polysaccharide is positively charged and the trimethylene carbonate-based polymer is negatively charged, and both are mixed in the solvent. By doing so, the polysaccharide and the polymer can be efficiently mixed in the solvent.

In this case, the method of positively charging the polysaccharide includes a method of quaternary amination of the polysaccharide. Moreover, as a method of negatively charging the trimethylene carbonate-based polymer, a method of introducing a carboxylic acid into the polymer can be mentioned.

According to the present invention, a chitin-chitosan or chitin-chitosan derivative is combined with a trimethylene carbonate-based polymer, so that a chitin-chitosan-based composite having excellent flexibility, stretchability, and elasticity can be obtained. Chitin/chitosan and chitin/chitosan derivatives are excellent in antibacterial properties and biocompatibility, and trimethylene carbonate-based polymers are excellent in biocompatibility. It is particularly useful for sutures and wound dressings that require excellent stretchability and elasticity.

BRIEF DESCRIPTION OF THE DRAWINGS The figure which shows the procedure which manufactures the chitin chitosan type|system|group composite (film) which concerns on Example 1 of this invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the chemical structures of chitosan, quaternary aminated chitosan and N,N,N-trimethylchitosan, which are chitosan derivatives, and synthetic conditions. ³ H-NMR spectra of chitosan (a), quaternary aminated chitosan (b) and N,N,N-trimethylchitosan (c), which are chitosan derivatives. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing synthesis routes and synthesis conditions for polytrimethylene carbonate, its derivative polyMBC, and a copolymer of TMC and MBC. 1 is a schematic diagram of one step of obtaining a film from solution (A) and solution (C) of Production Example 1, an external photograph of the film, and a schematic diagram of the internal structure of the film. FIG. FT-IR spectra (a) of films obtained from solutions (A) to (C), stress-strain curves (b) from tensile tests of films obtained from solutions (A) and (C). 1 is a schematic diagram of one step of obtaining a film from the solution (D) and the solution (E) of Production Example 2, and an appearance photograph of the film. FT-IR (Fourier transform infrared spectrophotometer) spectra (a) of films obtained from solutions (D) and (E), stress from tensile tests of films obtained from solutions (D) and (E) - Distortion curve (b). Schematic diagram of one step from solutions (F) to (H) of Production Example 3 to obtain a film, photograph of external appearance of the film, and schematic diagram of the internal structure of the film. FT-IR (Fourier transform infrared spectrophotometer) spectrum (a) of films obtained from solutions (F) to (H), stress by tensile test of films obtained from solutions (F) to (H) - Distortion curve (b). FIG. 2 shows a procedure for producing a chitin/chitosan-based composite (film) according to Example 2 of the present invention. Appearance photograph (a) of the film obtained by heating at 40 degreeC in procedure (4), and appearance photograph (b) of the film obtained by heating at 25 degreeC. FIG. 10 is a photograph of the external appearance of a film that is a chitin/chitosan-based composite according to Example 3 of the present invention, wherein the mixing ratio of CS, PTMC, and glycerol (CS:PTMC:glycerol) is 90:0:10 (a); Photographs taken at 75:25:0 (b), 67.5:22.5:10 (c), and 60:20:20 (d). Stress-strain curves obtained by tensile tests of four types of films obtained in Example 3. Stress-strain curves by compression test of four types of films obtained in Example 3. A diagram showing a schematic synthetic pathway of the CS-g-PTMC complex. ³ H-NMR spectra of intermediate products in the synthetic route of FIG.

EXAMPLES The chitin/chitosan-based composite composition and the method for producing the chitin/chitosan-based composite according to the present invention will be described below with reference to examples.

[Example 1]
1. 1. Production of chitin/chitosan-based composite FIG. 1 is a diagram schematically showing the procedure of the method for producing a chitin/chitosan-based composite according to Example 1 of the present invention. In this example, a film composed of a chitin/chitosan composite is produced.

Procedure (1): adding a composition comprising chitosan (CS) or a CS derivative and polytrimethylene carbonate (PTMC) or a PTMC derivative to a container containing water or N,N-dimethylformamide (DMF), By mixing, a solution or turbid liquid (hereinafter collectively referred to as "solution") is obtained.
Procedure (2): Put a predetermined amount of the solution obtained in Procedure (1) into a Teflon dish with a diameter of 50 mm.
Step (3): Heat the Teflon dish to 40°C-80°C for 1-2 days to remove the solvent in the solution.
Step (4): Subsequently, the Teflon dish is heated to 40°C-80°C under reduced pressure, and the solvent in the solution is removed.
Step (5): Peel off the film from the Teflon dish.

As a CS derivative, quaternary aminated chitosan (QCS) or N,N,N-trimethylchitosan (TMCS) can be used. FIG. 2 shows the structural formulas of CS, QCS and TMCS. Also, conditions for synthesizing QCS and TMCS from CS are shown. Specifically, QCS was obtained by adding glycidyltrimethylammonium chloride and 0.5% acetic acid to CS and leaving overnight. TMCS was obtained by adding sodium iodide (NaI), iodomethane (CH3I), 15% sodium hydroxide, and N-methyl-2-pyrrolidone (NMP) to CS and allowing to stand at room temperature for 4 days.

The physical property values of the obtained QCS and TMCS are shown in Table 1 below. Also, (a) to (c) of FIG. 3 are ³ H-NMR spectra of CS, QCS and TMCS, respectively.

As the PTMC derivative, polyMBC (5 -methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one) and a copolymer of TMC and MBC can be used. FIG. 4 shows synthetic routes of poly-TMC, poly-MBC, and copolymers of TMC and MBC, and synthetic conditions in each process. Table 2 below shows the physical properties of these polyMBCs and copolymers of TMC and MBC.

In FIG. 1, the photographs shown in steps (2), (3), and (4) are respectively a solution obtained by mixing a composition consisting of CS and PTMC and water, and a solution obtained by heating the solution. The composite removed from the Teflon dish while it was being heated, and the state of the inside of the Teflon dish when the heating of the solution was completed. As can be seen from the photographs of steps (3) and (4), the composite had a cloudy color during heating, but was substantially transparent at the end of heating.

An example of actually producing a film by the above procedures (1) to (5) will be described .
<Production Example 1>
Solution (A) consisting of 40 mL of 1 v/v % acetic acid and 0.4 g of CS, solution (B) consisting of 40 mL of 1 v/v % acetic acid and 0.4 g of polyMBC, 1 v/v % acetic acid: A solution (C) consisting of 20 mL, 0.2 g of CS and 0.2 g of polyMBC was prepared (procedure (1)) and films were produced by procedures (2)-(5). FIG. 5 shows a diagram showing one process of obtaining a film from solution (A) and solution (C), a photograph of the appearance of the film, and a schematic diagram of the internal structure of the film.
The exterior photograph of FIG. 5 was taken by placing the film on paper on which characters and pictures were drawn in order to confirm the transparency. As can be seen from the photograph of appearance in FIG. 5, the films obtained from solutions (A) and (C) both had high transparency, and characters and pictures could be confirmed through the films.

FIG. 6(a) is the FT-IR (Fourier transform infrared spectrophotometer) spectrum of the films obtained from solutions (A) to (C), and (b) is obtained from solutions (A) and (C). It is a stress-strain curve obtained by a tensile test of the film.
As can be seen from FIG. 6(a), the FT-IR spectrum of the film obtained from solution (C) is the sum of the FT-IR spectra of the films obtained from each of solutions (A) and (B). It had a similar shape.
Moreover, from FIG. 6(b), compared with the film obtained from the solution (A), the film obtained from the solution (C) needs to be stretched by applying a strong force and has low stretchability. It turned out that it is hard to elastically deform.

<Production Example 2>
Solution (D) consisting of 20 mL of water and 0.4 g of QCS, solution (D) of 20 mL of water, 1 mL of 15% sodium hydroxide, 0.2 g of QCS and 0.2 g of TMC (7)-MBC (3) ( E) was used to produce a film according to procedures (2) to (5). FIG. 7 shows a diagram showing one process of obtaining a film from the solution (D) and the solution (E), and a photograph of the appearance of the film. As can be seen from the appearance photograph of FIG. 7, the film obtained from the solution (D) had high transparency, and characters and pictures could be confirmed through the film. On the other hand, the film obtained from the solution (E) was in a round and shrunk state and had low transparency.

FIG. 8(a) shows the FT-IR (Fourier transform infrared spectrophotometer) spectra of the films obtained from the solutions (D) and (E), and (b) shows the spectra obtained from the solutions (D) and (E). It is a stress-strain curve obtained by a tensile test of the film.

<Production Example 3>
Solution (F) consisting of 20 mL of N,N-dimethylformamide (DMF) and 0.4 g of TMCS, solution (G) consisting of 20 mL of DMF, 0.2 g of TMCS and 0.2 g of PTMC, and 20 mL of DMF and a solution (H) consisting of 0.2 g of TMCS and 0.2 g of TMC(7)-MBC(3) to prepare a film according to procedures (2)-(5).
FIG. 9 shows a diagram showing one process until the film is obtained, a photograph of the appearance of the film, and a schematic diagram of the internal structure of the film. As can be seen from the appearance photograph of FIG. 9, the film obtained from the solution (F) had transparency to the extent that letters and pictures could be confirmed through the film, but was in a round and hardened state. . On the other hand, no film-like composite was obtained from the solutions (G) and (H).
FIG. 10(a) is the FT-IR (Fourier transform infrared spectrophotometer) spectrum of the film obtained from the solutions (F) to (H), and (b) is the solution obtained from the solutions (F) to (H). It is a stress-strain curve obtained by a tensile test of the film.

Table 3 below shows the evaluation results of the flexibility of the films obtained in Production Examples 1 to 3.

[Example 2]
1. Production of chitin/chitosan-based composite This example was used to examine the difference in the mixing ratio of chitosan (CS) and polytrimethylene carbonate (PTMC) and the difference in the appearance of the composite (film) due to the difference in heating temperature. gone.

FIG. 11 schematically shows the procedure of the method for producing a chitin/chitosan-based composite according to Example 2. As shown in FIG. In procedure (1) of the production method of Example 1, a composition comprising CS or a CS derivative and PTMC or a PTMC derivative was added to the solvent, whereas in procedure (1) of the production method of Example 2, , a solution of 1 v/v % of CS in an acidic solution and a solution of 1 w/w % of PTMC in tetrahydrofuran (THF) were mixed to obtain a solution. At this time, the mixed amounts of the CS solution and the PTMC solution were adjusted so that the ratio of CS to PTMC (CS:PTMC) in the mixed solution was 100:0 to 25:75.

In addition, in both procedures (3) and (4) of Example 1, the Teflon dish was heated to 40°C-80°C, but in procedure (3) of Example 2, the Teflon dish was heated to 25°C or 40°C. However, in step (4), the Teflon dish was left at room temperature.
The following formula (1) shows the structural formula of PTMC used in this example, and Table 4 shows its physical properties.

The three photographs on the left side of FIG. 12 are photographs of the appearance of the film when heated at 40° C. in procedure (4), and the four photographs on the right side are photographs of the appearance of the film when heated at 25° C. in procedure (4). All the ratios described in each appearance photograph indicate CS:PTMC.
As can be seen from the comparison of these appearance photographs, the transparency of the obtained film was higher when heated at 25°C than when heated at 40°C. This is probably because heating at a lower temperature suppresses the generation of air bubbles when the solvent evaporates from the mixed solution. In addition, when the ratio of PTMC in the composite increased, the shape of the film collapsed. In particular, a composite with a PTMC ratio of 75% heated at 25° C. could not form a film.

[Example 3]
In this example, changes in appearance and tensile strength of composites produced by adding glycerol to a mixed solution of CS solution and PTMC solution were investigated. In this example, the composite (film) was basically produced by the same procedure as the production method shown in Example 2, but in this example, procedure (1) of the production method shown in Example 2 , glycerol was added to the CS solution. Also in procedure (3), the Teflon dish was heated to 25°C.

FIG. 13 shows photographs of the appearance of films when the mixing ratios of CS:PTMC:glycerol were 90:0:10, 75:25:0, 67.5:22.5:10, and 60:20:20. ing. As can be seen from FIG. 13 and a comparison with FIG. 12 described in Example 2, the addition of glycerol increased the transparency of the film.

14 and 15 are stress-strain curves obtained by tensile tests and stress-strain curves obtained by compression tests of the films shown in (a) to (d) of FIG. 13, respectively. From these figures, it was found that the film (d), which had the largest amount of glycerol added, stretched greatly with a small force compared to the other films.

FIG. 16 shows a schematic synthetic pathway for glycerol-added conjugates (CS-g-PTMC conjugates). Table 5 below shows physical properties of PTMC-Allyl and PTMC-Epoxy, which are intermediate products in the synthetic route shown in FIG. 16, and FIG. 17 shows ³ H-NMR spectra.

Claims (5)

at least one polysaccharide of chitosan and N,N,N-trimethylchitosan ;
At least one trimethylene selected from the group consisting of polyTMC (trimethylene carbonate), polyMBC (5-methyl-5-benzyloxybenzylcarbonyl-1,3-dioxan-2-one), and copolymers of TMC and MBC a carbonate-based polymer;
or
a polysaccharide consisting of quaternary aminated chitosan;
a trimethylene carbonate-based polymer composed of a copolymer of TMC and MBC having a composition ratio of TMC and MBC of 7:3;
A chitosan- based composite composition comprising: At least one polysaccharide of chitosan and N,N,N-trimethylchitosan , polyTMC (trimethylene carbonate), polyMBC (5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one), and TMC at least one trimethylene carbonate-based polymer selected from the group consisting of copolymers of and MBC; in a solvent to form a solution or suspension, and heating the solution or suspension to remove the solvent from the solution or suspension A method for producing a chitosan -based composite , comprising: 3. The method for producing a chitosan -based composite according to claim 2, wherein the solvent contains glycerol. In the manufacturing method according to claim 2 or 3,
Polysaccharide consisting of N,N,N-trimethylchitosan and at least one trimethylene carbonate system of polyMBC (5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one) and copolymer of TMC and MBC Mixing a polymer, or a polysaccharide composed of quaternary aminated chitosan, and a trimethylene carbonate-based polymer composed of a copolymer of TMC and MBC in which the composition ratio of TMC and MBC is 7:3 in the solvent. A method for producing a chitosan- based composite, characterized by: In the production method according to any one of claims 2 to 4,
A method for producing a chitosan-based composite, wherein the solvent is a polar solvent.

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