JP2011099029A - Polysaccharide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a polysaccharide derivative which becomes a hydrogel holding high viscoelasticity even when it is subjected to high pressure steam sterilization after mixture with water and is useful as an antiadhesive material, and to provide a method for producing the same. <P>SOLUTION: In the polysaccharide derivative, both a β-alanine derivative and -CH<SB>2</SB>CONHY (Y denotes an alkyl group which has the number of carbons of 70 or less and may be substituted) are bonded to a side chain. There is also provided the method for producing the same. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention is a polysaccharide derivative in which both a β-alanine derivative and phosphatidylethanolamine are bonded as side chains to the polysaccharide, a method for producing the same, and a hydrogel thereof. When the polysaccharide derivative of the present invention is mixed with water, it becomes a gel that retains high viscoelasticity even after high-pressure steam sterilization, and is used as a medical material.

  Chemically modified polysaccharides are widely used in food applications, daily necessities applications, cosmetic applications, etc. due to their hydrogel properties and biocompatibility, and their applications extend to the medical field. For example, a composition comprising a compound obtained by crosslinking hyaluronic acid and carboxymethylcellulose, which was developed based on Patent Document 1 and Patent Document 2, and a film-like adhesion preventing material “Seprafilm” (registered trademark, manufactured by Genzyme) is commercially available. Has been.

  Among them, polysaccharide hydrogels that have fluidity can be injected into the body using a syringe, and can be used under minimally invasive conditions even during endoscopic surgery. It can be. In addition, a wide range of applications in the medical field such as a wound dressing that keeps the wound site moist, a filler for tissue repair, a cell culture medium, and a carrier for a drug delivery system are expected.

  When using gel as a medical material, it must be sterilized. Sterilization methods include dry heat method, high pressure steam method (autoclave method), flow steam method, boiling method, intermittent method, filtration method, γ ray method, electron beam method, ultraviolet ray method, high frequency method, gas method (ethylene oxide) Method, formaldehyde method) and the like are also described in the Japanese Pharmacopoeia. Among these, the high pressure steam method is excellent as a sterilization method that can be directly applied to the gel in the final form and does not cause a chemical change. For example, Patent Document 3 describes that a composition comprising sodium alginate and water is subjected to high-pressure steam sterilization and used as an adhesion preventing material. However, the viscosity of the composition after high-pressure steam sterilization is low, and in order for the viscosity after high-pressure steam sterilization to be 1 Pa · s or more, the weight concentration of sodium alginate had to be increased to 5%. For this reason, it has been a problem to produce a gel having sufficient retention in the body from a polysaccharide derivative having a low weight concentration.

  Patent Document 4 describes a reaction in which carboxymethylcellulose and phosphatidylethanolamine are condensed using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide as a condensing agent. However, in Patent Document 4, the side chain introduced into the polysaccharide is only the phosphatidylethanolamine site, and there is no description about the viscoelasticity of the hydrogel.

  Non-Patent Document 1 describes a reaction in which dicyclohexylcarbodiimide and N-hydroxysuccinimide are added to Sepharose or Trisacryl, and a β-alanine derivative is introduced as a side chain by the Losen rearrangement reaction. However, in this reaction, hydrophobic groups are not introduced at the same time, and there is no description about the viscoelasticity of polysaccharide derivative hydrogels.

Japanese National Patent Publication No. 5-508161 JP-T 6-508169 JP 2003-24431 A US Pat. No. 5,064,817

Biochemistry, 1987; 26: 2155-2161.

The problem to be solved by the present invention is to provide a polysaccharide derivative that becomes a hydrogel that retains high viscoelasticity even when autoclaved after mixing with water.
It is another object of the present invention to provide an efficient method for producing such polysaccharide derivatives.

  The inventors of the present invention, as a result of intensive research under the above object, have found that a specific polysaccharide derivative forms a hydrogel having high viscoelasticity even after high-pressure steam sterilization. completed.

  That is, this invention is the polysaccharide derivative which consists of a repeating unit represented by following formula (1), and its hydrogel.

式（１）中、Ｒ^１、Ｒ^２、およびＲ^３は、それぞれ独立に、下記式（１−ａ）、（１−ｂ）、（１−ｃ）、および（１−ｄ）からなる群より選ばれる基を表す。ただし、多糖類誘導体中には、式（１−ｃ）で表される基、および式（１−ｄ）で表される基がいずれも存在する。

In formula (1), R ¹ , R ² , and R ³ are each independently a group consisting of the following formulas (1-a), (1-b), (1-c), and (1-d) Represents a group selected from However, in the polysaccharide derivative, both a group represented by the formula (1-c) and a group represented by the formula (1-d) are present.

式（１−ｂ）および（１−ｄ）中、Ｘは水素またはアルカリ金属を表し、式（１−ｃ）中、Ｙは炭素数７０以下の置換されていてもよいアルキル基を表す。

In the formulas (1-b) and (1-d), X represents hydrogen or an alkali metal, and in the formula (1-c), Y represents an optionally substituted alkyl group having 70 or less carbon atoms.

  Further, the present invention provides a carboxymethyl cellulose composed of a repeating unit represented by the following formula (2) and an amine represented by the following formula (3), a condensing agent represented by the following formula (4), and N-hydroxy. The method for producing a polysaccharide derivative, wherein the reaction is carried out in the presence of succinimide or a derivative thereof.

式（２）中、Ｒ^１１、Ｒ^２１、およびＲ^３１はそれぞれ独立に、下記式（２−ａ）および（２−ｂ）からなる群より選ばれる。

In formula (2), R ¹¹ , R ²¹ and R ³¹ are each independently selected from the group consisting of the following formulas (2-a) and (2-b).

式（２−ｂ）中、Ｘは水素またはアルカリ金属を表す。

In formula (2-b), X represents hydrogen or an alkali metal.

式（３）中、Ｙは炭素数７０以下の置換されていてもよいアルキル基を表す。

In formula (3), Y represents an optionally substituted alkyl group having 70 or less carbon atoms.

式（４）中、Ｒ^６およびＲ^７は、それぞれ独立に、炭素数が２０以下の炭化水素基を表し、互いに結合して環構造を形成していてもよい。

In Formula (4), R ⁶ and R ⁷ each independently represent a hydrocarbon group having 20 or less carbon atoms, and may be bonded to each other to form a ring structure.

  The polysaccharide derivative hydrogel of the present invention retains high viscoelasticity even after high-pressure steam sterilization.

  Moreover, according to the production method of the present invention, the β-alanine derivative is introduced into the main chain of the polysaccharide simultaneously with other substituents. In other words, the conventional method had to go through two or more steps of synthesis, whereas the production method of the present invention can be carried out in one step, and the introduction rate of substituents is also different when other catalysts are used. Higher than

  The present invention is a polysaccharide derivative composed of a repeating unit represented by the following formula (1) and a hydrogel thereof.

The molecular weight of such a polysaccharide derivative is not particularly limited as long as it exhibits the intended effect.
In the above formula (1), R ¹ , R ² , and R ³ each independently comprises the following formulas (1-a), (1-b), (1-c), and (1-d). Represents a group selected from the group;

In the above formulas (1-b) and (1-d), X represents hydrogen or an alkali metal, and in the formula (1-c), Y represents an alkyl group having 70 or less carbon atoms which may be substituted.
As the alkali metal of X, lithium, sodium and potassium are preferable, and sodium is particularly preferable.
The optionally substituted alkyl group having 70 or less carbon atoms of Y includes a branched one and a ring structure. Examples of the substituent of the alkyl group of Y include a) a hydroxyl group, b) a carboxyl group, c) an amino group, d) a thiol group, e) a phosphoric acid group, and f) an aromatic group. Among these, a hydroxyl group, a carboxyl group, and a phosphate group are preferable, and a phosphate group is particularly preferable. When the substituent of the alkyl group of Y is ionic, the salt is also included in the definition of Y.
Such Y is preferably a group represented by the following formula (1-e).

In the formula (1-e), X represents hydrogen or an alkali metal, ^{R 4} and ^{R 5} each independently represent an alkyl group or alkenyl group having 10 to 28 carbon atoms.
As the alkali metal of X, lithium, sodium and potassium are preferable, and sodium is particularly preferable.
Further, as R ⁴ and R ⁵ , an alkyl group, an alkenyl group, and an alkynyl group are preferable, and in particular, R ⁴ and R ⁵ are —CH ₂ (CH ₂ ) ₆ CH═CH (CH ₂ ) ₇ CH _3. preferable.

  Further, the group represented by the above formula (1-d) is preferably 1.0 to 20.0 [mol% / sugar residue], and the group represented by the above formula (1-c). Is preferably 0.5 to 5.0 [mol% / sugar residue].

  Further, the present invention provides a carboxymethyl cellulose composed of a repeating unit represented by the following formula (2) and an amine represented by the following formula (3), a condensing agent represented by the following formula (4), and N- The method for producing a polysaccharide derivative, wherein the reaction is performed in the presence of hydroxysuccinimide or a derivative thereof.

式（２）中、Ｒ^１１、Ｒ^２１、およびＲ^３１は、それぞれ独立に、下記式（２−ａ）および（２−ｂ）からなる群より選ばれる。

In the formula (2), R ¹¹ , R ²¹ and R ³¹ are each independently selected from the group consisting of the following formulas (2-a) and (2-b).

式（２−ｂ）中、Ｘは水素またはアルカリ金属を表す。

In formula (2-b), X represents hydrogen or an alkali metal.

式（３）中、Ｙは炭素数７０以下の置換されていてもよいアルキル基を表す。

In formula (3), Y represents an optionally substituted alkyl group having 70 or less carbon atoms.

式（４）中、Ｒ^６およびＲ^７は、それぞれ独立に、炭素数が２０以下の炭化水素基を表し、互いに結合して環構造を形成していてもよい。

In Formula (4), R ⁶ and R ⁷ each independently represent a hydrocarbon group having 20 or less carbon atoms, and may be bonded to each other to form a ring structure.

Preferable X in the above formula (2) is preferably the same as described above for X in the above formula (1).
As preferable Y in the said Formula (2), group represented by following formula (5) is preferable.

In formula (5), X represents hydrogen or an alkali metal, and R ⁴ and R ⁵ each independently represents an alkyl group or an alkenyl group having 10 to 28 carbon atoms.
Preferred X, R ⁴ , and R ⁵ in the formula (5) include the same as those described above for X, R ⁴ , and R ^{5 in the} formula (1-e).

The amine represented by the above formula (3) is preferably reacted at a ratio of 0.5 to 20 equivalents with respect to 100 equivalents of sugar residues of carboxymethyl cellulose.
Examples of the condensing agent represented by the above formula (4) include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and its salt, diisopropylcarbodiimide, di-t-butylcarbodiimide, dicyclohexylcarbodiimide, ditolylcarbodiimide, 1 -T-butyl-3-ethylcarbodiimide, 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide, and salts thereof. Among these, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is preferable from the viewpoint of water solubility, reactivity, and achievements in medical material synthesis.

  Examples of N-hydroxysuccinimide or a derivative thereof used in the production method of the present invention include N-hydroxysuccinimide and N-hydroxysulfosuccinimide. Among these, N-hydroxysuccinimide is preferable from the viewpoint of solubility and reactivity.

  The condensing agent represented by the above formula (4) is preferably used in an amount of 1 to 50 equivalents per 100 equivalents of sugar residues of carboxymethylcellulose. On the other hand, N-hydroxysuccinimide or a derivative thereof is preferably used in an amount of 1 to 50 equivalents with respect to 100 equivalents of sugar residues of carboxymethyl cellulose.

  The reaction between carboxymethyl cellulose and the amine represented by the above formula (3) can be carried out using a solvent system in which water and an organic solvent compatible with water are mixed, or water alone. Among them, a solvent system in which all of carboxymethylcellulose, the amine represented by the above formula (3), the condensing agent represented by the above formula (4), N-hydroxysuccinimide or a derivative thereof is desirable.

  The method for purifying the product of the above reaction is not particularly limited, but it can be efficiently purified by the following method to produce a highly pure polysaccharide derivative. That is, after the reaction between carboxymethyl cellulose and the amine represented by the above formula (3), the solvent is distilled off under reduced pressure, and the residue is added to an organic solvent in which the solubility of the polysaccharide is not large, thereby precipitating the polysaccharide derivative. . Specific examples of the organic solvent include monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and t-butanol, ethylene glycol, 1,2-propylene glycol, and 1,3-propylene. Examples thereof include polyhydric alcohols such as glycol and glycerin, ketones such as acetone, and aromatic alcohols such as phenol. Among these, ethanol is preferable from the viewpoint of safety in vivo.

<Hydrogel with polysaccharide derivative>
The polysaccharide derivative obtained by the above method can form a hydrogel (hereinafter, this hydrogel may be simply abbreviated as “hydrogel”). At this time, the hydrogel which has moderate viscoelasticity by containing 0.1-5.0 weight part of the polysaccharide derivative of this invention with respect to 100 weight part of water, Preferably 0.5-5.0 weight part Can be obtained.

  Usually, any hydrogel can obtain a desired gel strength by increasing the concentration of the polymer. However, the hydrogel of the present invention is sufficient even at a low polymer concentration of 5% by weight or less with respect to water. Gel viscoelasticity can be obtained. As a particularly preferred physical property of the hydrogel, it has viscoelasticity that does not flow down even if the container containing the hydrogel is tilted, and can be easily deformed when touched with a metal spatula such as a spatula, It is easy to apply to the affected area. Further, such a hydrogel can be injected with an instrument having a thin tube such as a syringe. Further, such hydrogel is colorless and transparent, and when foreign matters such as dust are mixed in the manufacturing process, it can be detected, and has an advantage in industrial production.

  As a preferable viscoelasticity of the hydrogel, an absolute viscosity when measured at an angular velocity of 10 rad / sec using a dynamic viscoelasticity measuring device called a rheometer under a temperature of 37 ° C. is 0.2 to 100 Pa · s. More preferably, it is 2 to 30 Pa · s, and this range is a range in which good handling properties as an injectable gel and retention in the body can be satisfied at the same time. it can.

  The polysaccharide derivative of the present invention and the hydrogel thereof may be used for anti-adhesion materials, medical applications other than anti-adhesion materials (such as wound dressings, fillers, cell culture media, and drug transport system carriers), hair care products and skin. There are daily necessities such as moisturizers and cosmetics.

  The embodiments of the present invention will be described more specifically with reference to the following examples and comparative examples. However, the present invention is not limited to these examples.

(1) Materials used in Examples and Comparative Examples are as follows.
(I) CMCNa: carboxymethylcellulose sodium (Daiichi Kogyo Seiyaku Co., Ltd., PM250-L, degree of substitution of hydroxyl group with carboxymethyl group 0.7, viscosity average molecular weight 600000),
(Ii) CMCNa: sodium carboxymethyl cellulose (Daiichi Kogyo Seiyaku Co., Ltd., P-603A, degree of substitution of hydroxyl group with carboxymethyl group 0.7, viscosity average molecular weight 120,000),
(Iii) Tetrahydrofuran (manufactured by Wako Pure Chemical Industries, Ltd.)
(Iv) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC / HCl, manufactured by Osaka Organic Synthesis Co., Ltd.)
(V) N-hydroxysuccinimide (HOSu, Osaka Organic Synthesis Co., Ltd.),
(Vi) 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O, manufactured by Osaka Organic Synthesis Co., Ltd.),
(Vii) 1-hydroxy-7-azabenzotriazole (HOAt, manufactured by Wako Pure Chemical Industries, Ltd.),
(Viii) L-α-dioleoylphosphatidylethanolamine (DOPE, manufactured by NOF Corporation).

(2) Measurement of phosphatidylethanolamine content in polysaccharide derivatives The phosphatidylethanolamine content in polysaccharide derivatives can be determined by analyzing the total phosphorus content by vanadomolybdic acid spectrophotometry or by integrating the peaks of ¹ H-NMR spectrum. Asked.

(3) Measurement of β-alanine derivative content in polysaccharide derivative The proportion of β-alanine derivative in the polysaccharide derivative was determined from the integral ratio of the peaks of the ¹ H-NMR spectrum.

(4) Measurement of Viscoelasticity of Hydrogel The viscoelasticity of the hydrogel was measured at 37 ° C. and an angular velocity of 10 rad / sec using a Rheometer RFIII (TA Instrument) which is a dynamic viscoelasticity measuring device.

[Example 1]
3000 mg of CMCNa (PM250-L, degree of substitution 0.7, viscosity average molecular weight 600000) was dissolved in a mixed solvent of water and tetrahydrofuran. In this solution, 144 mg (0.194 mmol) of L-α-dioleoylphosphatidylethanolamine (DOPE), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl) 798 mg (4. 16 mmol) and 478 mg (4.16 mmol) of N-hydroxysuccinimide (HOSu) were added. After completion of the reaction, the polysaccharide derivative was precipitated by adding the reaction solution to ethanol and collected by filtration. The obtained solid was washed with ethanol and dried under reduced pressure. The degree of substitution of DOPE of the obtained polysaccharide derivative was 1.5 mol% / sugar residue, and the degree of substitution of the β-alanine derivative was 10.5 mol% / sugar residue.
20 mg of the obtained cellulose derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. The storage elastic modulus of the hydrogel after high-pressure steam sterilization (121 ° C., 20 minutes) was 106.2 Pa, the loss elastic modulus was 18.2 Pa, and the absolute viscosity was 10.8 Pa · s.

[Example 2]
DOPE 351 mg (0.472 mmol), WSC · HCl 399 mg (2.08 mmol) and HOSu 239 mg instead of DOPE 144 mg (0.194 mmol), WSC · HCl 798 mg (4.16 mmol) and HOSu 478 mg (4.16 mmol) A polysaccharide derivative was obtained in the same manner as in Example 1 except that (2.08 mmol) was used. The degree of substitution of DOPE of the obtained polysaccharide derivative was 2.8 mol% / sugar residue, and the degree of substitution of the β-alanine derivative was 2.7 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. The storage elastic modulus of this hydrogel after high-pressure steam sterilization (121 ° C., 20 minutes) was 213.0 Pa, the loss elastic modulus was 26.9 Pa, and the absolute viscosity was 21.5 Pa · s.

[Comparative Example 1]
750 mg of CMCNa (PM250-L, substitution degree 0.7, viscosity average molecular weight 600000) was dissolved in a mixed solvent of water and tetrahydrofuran. To this solution, 351 mg (0.472 mmol) of DOPE, 100 mg (0.52 mmol) of WSC · HCl and 80 mg (0.52 mmol) of 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O) were added. . After completion of the reaction, the polysaccharide derivative was precipitated by adding the reaction solution to ethanol and collected by filtration. The obtained solid was washed with ethanol and dried under reduced pressure. The degree of substitution of DOPE in the obtained polysaccharide derivative was 1.5 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. After hydrosterilization of this hydrogel (121 ° C., 20 minutes), the storage elastic modulus was 10.1 Pa, the loss elastic modulus was 3.6 Pa, and the absolute viscosity was 1.1 Pa · s.

[Example 3]
3000 mg of CMCNa (P-603A, degree of substitution 0.7, viscosity average molecular weight 120,000) was dissolved in a mixed solvent of water and tetrahydrofuran. To this solution, 349 mg (0.468 mmol) of DOPE, 395 mg (2.06 mmol) of WSC · HCl and 237 mg (2.06 mmol) of HOSu were added. After completion of the reaction, the polysaccharide derivative was precipitated by adding the reaction solution to ethanol and collected by filtration. The obtained solid was washed with ethanol and dried under reduced pressure. The degree of substitution of DOPE of the obtained polysaccharide derivative was 2.8 mol% / sugar residue, and the degree of substitution of the β-alanine derivative was 2.1 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. This hydrogel was subjected to high-pressure steam sterilization (121 ° C., 20 minutes), the storage elastic modulus was 22.6 Pa, the loss elastic modulus was 6.7 Pa, and the absolute viscosity was 2.4 Pa · s.

[Comparative Example 2]
The polysaccharide derivative was obtained by performing the same operation as in Example 3 except that DOPE was not added. The substitution degree of the β-alanine derivative of the obtained polysaccharide derivative was 4.6 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. After the hydrogel was autoclaved (121 ° C., 20 minutes), the storage elastic modulus was 1.0 Pa or less, the loss elastic modulus was 1.0 Pa or less, and the absolute viscosity was 0.1 Pa · s or less.

[Comparative Example 3]
A polysaccharide derivative was obtained in the same manner as in Example 3 except that HOBt · H ₂ O 315 mg (2.06 mmol) was used instead of HOSu237 mg (2.06 mmol). The degree of substitution of DOPE in the obtained polysaccharide derivative was 1.5 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. The storage modulus of the hydrogel after high-pressure steam sterilization (121 ° C., 20 minutes) was 1.0 Pa or less, the loss elastic modulus was 1.0 Pa or less, and the absolute viscosity was 0.1 Pa · s or less.

[Comparative Example 4]
A polysaccharide derivative was obtained in the same manner as in Example 3 except that 280 mg (2.06 mmol) of 1-hydroxy-7-azabenzotriazole (HOAt) was used instead of 237 mg (2.06 mmol) of HOSu. The degree of substitution of DOPE of the obtained polysaccharide derivative was 1.2 mol% / sugar residue.
20 mg of the obtained polysaccharide derivative was dissolved in 1980 mg of distilled water for injection to prepare a hydrogel having a concentration of 1% by weight. The storage modulus of the hydrogel after high-pressure steam sterilization (121 ° C., 20 minutes) was 1.0 Pa or less, the loss elastic modulus was 1.0 Pa or less, and the absolute viscosity was 0.1 Pa · s or less.

  Table 1 summarizes the amounts of reagents used in the reactions, the degree of substitution of the side chains of the products, and the viscoelasticity of the hydrogel after high-pressure steam sterilization in Examples 1 to 3 and Comparative Examples 1 to 4.

  According to a comparison between Example 1 and Comparative Example 1, a polysaccharide derivative in which the same amount of DOPE side chain was introduced into the same polysaccharide main chain but a β-alanine derivative was introduced had a better β-alanine derivative. It was found that the hydrogel after high-pressure steam sterilization had higher viscoelasticity than the one not introduced.

Further, according to the comparison between Example 3 and Comparative Example 2, even when only the β-alanine derivative is bonded to the polysaccharide, the hydrogel after high-pressure steam sterilization has low viscoelasticity, and the hydrogel after high-pressure steam sterilization has low viscoelasticity. It has been found that in order to increase the ratio, it is necessary to introduce both —CH ₂ CONHY (Y is an optionally substituted alkyl group having 70 or less carbon atoms) and a β-alanine derivative into the polysaccharide main chain.

Further, according to comparison between Example 3 and Comparative Examples 3 and 4, when the same amount of CMCNa and DOPE were used as raw materials in the reaction, HOSu was used as a catalyst rather than HOBt / H ₂ O or HOAt. It was found that more DOPE can be introduced into the polysaccharide main chain, and the β-alanine derivative is also introduced into the polysaccharide main chain at the same time, so that the viscoelasticity of the hydrogel after high-pressure steam sterilization is increased.

  The polysaccharide derivative and hydrogel thereof of the present invention can be used, for example, in anti-adhesion materials, wound dressings, fillers, cell culture media, drug transport system carriers, hair care products, skin moisturizers, cosmetics and the like.

Claims (13)

The polysaccharide derivative which consists of a repeating unit represented by following formula (1).

In formula (1), R ¹ , R ² , and R ³ are each independently a group consisting of the following formulas (1-a), (1-b), (1-c), and (1-d) Represents a group selected from However, in the polysaccharide derivative, both a group represented by the formula (1-c) and a group represented by the formula (1-d) are present.

In the formulas (1-b) and (1-d), X represents hydrogen or an alkali metal, and in the formula (1-c), Y represents an optionally substituted alkyl group having 70 or less carbon atoms. The polysaccharide derivative according to claim 1, wherein Y is a group represented by the following formula (1-e).

In formula (1-e), X represents hydrogen or an alkali metal, and R ⁴ and R ⁵ each independently represents an alkyl group or an alkenyl group having 10 to 28 carbon atoms. Polysaccharide derivative according to claim 2 R ⁴ and ^{R 5} are _{-CH 2 (CH 2) 6 CH} = CH (CH 2) 7 CH 3.   The polysaccharide derivative according to any one of claims 1 to 3, wherein the equivalent of the group represented by the formula (1-d) is 1.0 to 20.0 [mol% / sugar residue].   The polysaccharide derivative according to any one of claims 1 to 4, wherein the equivalent of the group represented by the formula (1-c) is 0.5 to 5.0 [mol% / sugar residue]. A carboxymethyl cellulose composed of a repeating unit represented by the following formula (2) and an amine represented by the following formula (3), a condensing agent represented by the following formula (4), and N-hydroxysuccinimide or a derivative thereof: The method for producing a polysaccharide derivative according to any one of claims 1 to 5, wherein the reaction is carried out in the presence.

In formula (2), R ¹¹ , R ²¹ and R ³¹ are each independently selected from the group consisting of the following formulas (2-a) and (2-b).

In formula (2-b), X represents hydrogen or an alkali metal.

In formula (3), Y represents an optionally substituted alkyl group having 70 or less carbon atoms.

In Formula (4), R ⁶ and R ⁷ each independently represent a hydrocarbon group having 20 or less carbon atoms, and may be bonded to each other to form a ring structure. The production method according to claim 6, wherein Y is a group represented by the following formula (5).

In formula (5), X represents hydrogen or an alkali metal, and R ⁴ and R ⁵ each independently represents an alkyl group or an alkenyl group having 10 to 28 carbon atoms. The production method according to claim 7, wherein R ⁴ and R ⁵ are —CH ₂ (CH ₂ ) ₆ CH═CH (CH ₂ ) ₇ CH ₃ .   N-hydroxysuccinimide or its derivative (s) is N-hydroxysuccinimide, The manufacturing method in any one of Claims 6-8.   The condensing agent represented by the formula (4) is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and a salt thereof, diisopropylcarbodiimide, di-t-butylcarbodiimide, dicyclohexylcarbodiimide, ditolylcarbodiimide, 1-t. The production method according to any one of claims 6 to 9, which is any one of -butyl-3-ethylcarbodiimide, 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide and a salt thereof.   The production method according to any one of claims 6 to 9, wherein the condensing agent represented by the formula (4) is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a salt thereof.   A hydrogel comprising the polysaccharide derivative according to any one of claims 1 to 5 and water.   The hydrogel according to claim 12, wherein the weight ratio of the polysaccharide derivative is 0.5 to 5.0 wt%.