JP5024262B2 - Material and biocompatible material coated or impregnated with oxidized polysaccharide material - Google Patents

Description

  The present invention relates to a material coated or impregnated with an oxidized polysaccharide material having excellent characteristics such as biocompatibility, and particularly relates to a material coated with or impregnated with an oxidized polysaccharide material having good processability and a controlled molecular structure.

  Cellulose is a polysaccharide present in the largest amount in nature as the main component of plants. Its chemical structure is a β-1,4 glycosidic bond of D-glucose and has 3 hydroxyl groups (C2-position, C3-position, C6-position of D-glucose) per glucose unit. Cellulose is insoluble in water because it has a high-order structure in which hydrogen bonds are strongly bonded between molecules while having many hydrophilic hydroxyl groups in the molecule.

  In addition, the biostructural polysaccharide of crustaceans and insects such as shrimp and crab is chitin, and N-acetylglucosamine with an acetamide group instead of the hydroxyl group at the C2 position of D-glucose is β1,4 like cellulose. It is a combination. Chitin that exists in nature is known to contain a part of a glucosamine unit with an amino group at the C2 position and bind to biological substances such as proteins via an amino group, and N-acetylglucosamine 100 It is not necessarily composed of%. On the other hand, chitosan is a substance obtained by deacetylating chitin with an alkali or the like. These chitin and chitosan cannot be clearly distinguished by the degree of acetylation. Chitosan dissolves in a dilute acid with an amino group forming a salt, but chitin is insoluble in water like cellulose.

  Furthermore, starch is mentioned as a polysaccharide which exists in large quantities in nature. Starch is D-glucose with α1,4 or 1,6 bonds. Starch is soluble in hot water but not in cold water.

  A representative water-solubilization method for these water-insoluble polysaccharides is etherification using the hydroxyl group. Carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), etc. are water-soluble cellulose derivatives, thickeners, dispersion stabilizers, food / cosmetic additives, medical materials It is also widely used.

  However, these etherification reactions react randomly with the three hydroxyl groups per glucose unit described above, have low selectivity, and have a non-uniform substituent distribution. Further, the aqueous solution of CMC, MC, HEC, and HPC is a 2% aqueous solution with a high viscosity of about 20 to 2000 mPa · s depending on the degree of polymerization, and the upper limit of the solution concentration is about 3 to 10%. Therefore, impregnation processing and coating processing with a high concentration solution are difficult. In addition, when used as a medical material, there is a problem that the metabolism of CMC, MC, HEC, and HPC is not clear.

  As a water-solubilization technique using an oxidation reaction, a method is known in which water-soluble polyglucuronic acid is obtained by oxidizing a primary hydroxyl group at the C6 position to a carboxyl group with chloroform in nitrogen dioxide. Glucuronic acid is said to be completely metabolized in vivo. However, the oxidation reaction with nitrogen dioxide is a side reaction, and cleavage of the main chain and oxidation to ketones at the C2 position and C3 position occur, and it cannot be said that the reaction selectivity is high. There is also a problem with the toxicity of the reagent.

  On the other hand, in the medical field, biocompatible materials such as wound dressings, bioabsorbable materials for hemostasis, and medical materials that suppress the healing of body organs, such as oxidized cellulose, chitin, chitosan, collagen, hyaluronic acid, etc. The usefulness of the material has been reported (Patent Documents 1 to 3).

  However, although bio-derived materials such as collagen and hyaluronic acid have characteristics of excellent biocompatibility, they are expensive and difficult to obtain, have antigenicity, and have problems such as deterioration due to bacterial infection.

  With regard to chitin and chitosan, superiority such as a wound healing promoting effect and antibacterial properties have been reported, but a process such as wet spinning by dissolving in an amide solvent is required.

  As the oxidized cellulose, there are reports of a method of oxidizing regenerated cellulose gauze with nitrogen dioxide or oxidizing gauze coated with CMC or MC (Patent Document 1). There are problems with coating properties and the toxicity of nitrogen dioxide.

JP-A-10-66723 Japanese Patent Laid-Open No. 10-99422 JP-A-4-370258

  An object of the present invention is to provide a material which is coated or impregnated with a water-soluble or water-dispersible polysaccharide material having a uniform chemical structure with good processability, inexpensively and safely. Another object of the present invention is to provide a biocompatible material comprising a material coated or impregnated with a water-soluble or water-dispersible polysaccharide material having a uniform chemical structure.

The invention of claim 1, be oxidized in the presence of cellulose or polysaccharide material in water which is selected reproduced cellulose scan or al 2,2,6,6-tetramethyl-1-piperidine -N- oxyl Is obtained by selectively oxidizing only the reducing end of the molecule of the polysaccharide material or the 6th position of the pyranose ring to a carboxyl group, and the carboxyl group is based on the number of moles of monosaccharides constituting the polysaccharide material. 60% or more (oxidation degree 60% or more) water-soluble or water-dispersible oxidized polysaccharide material impregnated or coated on a material selected from natural cellulose fiber, regenerated cellulose fiber, or oxidized regenerated cellulose fiber It is a material coated or impregnated with an oxidized polysaccharide material.

The invention of claim 2 is obtained by oxidizing a polysaccharide material comprising finely divided cellulose in water in the presence of 2,2,6,6-tetramethyl-1-piperidine-N-oxyl , Only the reducing end of the molecule of the polysaccharide material or only the 6th position of the pyranose ring is selectively oxidized to a carboxyl group, and the carboxyl group is 10 to 60% or more with respect to the number of moles of monosaccharides constituting the polysaccharide material. A water-soluble or water-dispersible oxidized polysaccharide material having an oxidation degree of 10 to 60% is impregnated or applied to a material selected from natural cellulose fibers, regenerated cellulose fibers, or oxidized regenerated cellulose fibers. A material coated or impregnated with an oxidized polysaccharide material.

The invention of claim 3 is characterized in that the oxidation treatment is performed by oxidizing at least one of hypohalous acid, halous acid, perhalogenic acid and salts thereof in the presence of an alkali metal bromide or an alkali metal iodide in water. A material coated or impregnated with the oxidized polysaccharide material according to claim 1 or 2 , wherein an agent is used.

The invention according to claim 4 is characterized in that the oxidation treatment is performed by coating the oxidized polysaccharide material according to any one of claims 1 to 3 , wherein the oxidation treatment is performed while adding an alkali and maintaining the pH at 9 to 12. It is an impregnated material.

The invention of claim 5, wherein the shape of the material impregnating the oxidized polysaccharide materials, cloth, gauze, sponge, porous sheet, any one of claims 1 to 4, characterized in that it is selected from paper material A material coated or impregnated with the oxidized polysaccharide material described in 1.

The invention of claim 6 is a biocompatible material made of a material coated or impregnated with the oxidized polysaccharide material according to any one of claims 1 to 5 .

  The material coated or impregnated with the oxidized polysaccharide material of the present invention has a uniform chemical structure of the coated or impregnated oxidized polysaccharide and a completely metabolized uronic acid structure. high. Moreover, the oxidation reaction is carried out under mild conditions in an aqueous system, and can be said to be safer than the oxidation method using nitrogen dioxide.

  Furthermore, since the oxidized polysaccharide in the present invention has high solubility in water and low solution viscosity, it has good processability when impregnating and coating the material and is coated with a uniform and excellent oxidized polysaccharide material. Alternatively, an impregnated material is obtained. Furthermore, since the solution concentration can be set high, the processing cost can be reduced by reducing the amount of drying heat and improving the processing speed.

  Furthermore, the chemical structure of bio-derived materials such as hyaluronic acid and chondroitin, which are excellent in moisture retention and biocompatibility, is a copolymer structure of glucuronic acid and N-acetylglucosamine. The chemical structure of chitosan is a structure in which a carboxyl group is introduced at the C6 position of N-acetylglucosamine or glucosamine, the chemical structure is similar, and it can be expected to exhibit the same function. The material coated or impregnated with the oxidized polysaccharide material of the oxidized polysaccharide of the present invention, particularly the coated material of oxidized chitin and oxidized chitosan has great potential as a biocompatible material, and although it has not been confirmed, it has physiological activity etc. Expectation is also held.

  Details of the present invention will be described below.

  The present invention relates to a material obtained by coating or impregnating a polysaccharide material that has been oxidized in water in the presence of an N-oxyl compound (oxoammonium salt). The term “coated or impregnated” as used in the present invention means three modes: only coating, only impregnation, and partial impregnation and surface coating.

In the present invention, the oxidation of the oxidized polysaccharide selectively oxidizes the reducing end of the polysaccharide molecule or the primary hydroxyl group in the pyranose ring of the constituent monosaccharide. Moreover, according to the degree of oxidation, a carboxyl group can be uniformly and efficiently introduced into the polysaccharide material.
This oxidation method is characterized by oxidizing using a co-oxidant using an N-oxyl compound as a catalyst. Examples of the N-oxyl compound include 2,2,6,6-tetramethyl-1-piperidine N-oxyl (hereinafter referred to as TEMPO) which is a water-soluble stable radical. The N-oxyl compound may be a catalytic amount. For example, 10 ppm to 5% is sufficient with respect to the number of moles of the constituent monosaccharide of the polysaccharide, but 0.05% to 3% is preferable.

  Examples of the co-oxidant include halogens, hypohalous acids, halous acids, perhalogen acids or salts thereof, halogen oxides, nitrogen oxides, peroxides, and the like that can promote the target oxidation reaction. Any oxidizing agent can be used if present.

This oxidation reaction is advantageously performed in the presence of the N-oxyl compound and bromide or iodide. As the bromide or iodide, a compound that can be dissociated and ionized in water, such as an alkali metal bromide or an alkali metal iodide, can be used.
The amount of bromide and / or iodide used can be selected within a range where the oxidation reaction can be promoted.
In particular, TEMPO is preferably used for the N-oxyl compound, and sodium hypochlorite is preferably used as a co-oxidant in the presence of sodium bromide.

The oxidation reaction conditions and the like of the present invention are not particularly limited, and should be optimized depending on the materials and equipment used. Selection of oxidation to primary hydroxyl groups of constituent monosaccharides when the reaction temperature is not more than room temperature. This is desirable because it can increase the properties and suppress side reactions.
Moreover, it is desirable that the reaction system has a pH of 9 to 12 in terms of reaction efficiency. In addition, it is preferable to perform the oxidation reaction in the presence of bromide or iodide because the oxidation reaction can proceed smoothly even under mild conditions and the introduction efficiency of the carboxyl group can be greatly improved.

  In the above oxidation method, the degree of oxidation (primary hydroxyl group is converted and introduced by controlling the amount of co-oxidant, the amount of alkali added to keep the pH in the system constant, and the reaction time. The amount of carboxyl groups) can be controlled.

  The polysaccharide material used in the present invention is not particularly limited, and examples thereof include cellulose, regenerated cellulose, starch, chitin, chitosan, regenerated chitin, regenerated chitosan, and refined cellulose. Various things can be used.

  In the present invention, when a highly crystalline material such as cellulose or chitin is used as the polysaccharide material, it is swollen with alkali or subjected to dissolution-regeneration treatment, so that only the primary hydroxyl group is uniformly and highly selective. Oxidation can yield polyuronic acids.

  The refined cellulose in the present invention is a physically refined cellulose fiber. For example, microfibrillated cellulose or colloidal grade of crystalline cellulose is preferably used. Although these oxides do not become water-soluble, the cellulose molecules on the surface are oxidized with uron and a highly stable aqueous dispersion can be obtained.

  When the amount of carboxyl groups in the oxidized polysaccharide is oxidized to 60% or more (oxidation degree 60% or more) with respect to the number of moles of the constituent monosaccharide of the polysaccharide material, the solubility in water is improved. On the other hand, in the oxidation of crystalline fine cellulose, etc., it is necessary to make the reaction conditions strict in order to increase the degree of oxidation to 60% or more, which is not preferable because it causes an increase in side reactions and a decrease in molecular weight. In these materials, it is preferable to adjust the degree of oxidation to 10 to 60% even if water-insoluble.

  The oxidized polysaccharide obtained by the oxidation reaction is sufficiently washed with an alcohol or water-soluble organic solvent, and if necessary, a drying step is performed to prepare an aqueous solution or aqueous dispersion having a predetermined concentration.

  The aqueous solution or aqueous dispersion of oxidized polysaccharide thus obtained has a lower viscosity than conventional aqueous solutions of water-soluble polysaccharides such as CMC and MC, and can be dissolved at a higher concentration. The solution viscosity of the oxidized polysaccharide material of the present invention depends on the polymerization degree of the polysaccharide raw material. For example, in a 5% aqueous solution of oxidized cellulose having a degree of oxidation of 100% obtained from regenerated cellulose having a degree of polymerization of 600, the viscosity is 25 ° C. Can be prepared to an aqueous solution of about 20%.

  The material coated or impregnated with the oxidized polysaccharide of the present invention comprises an aqueous solution or aqueous dispersion of the oxidized polysaccharide using a known impregnation or coating equipment, dipping coat, roll coat, spray coat, blade coat, comma The material can be coated by a known method such as coating or size pressing.

  The material for coating or impregnating the oxidized polysaccharide material of the present invention is not particularly limited, and can be appropriately selected depending on the application. For example, woven fabrics such as gauze, non-woven fabrics, sponges, sheets of paper, etc. can be mentioned. These may be made of natural cellulose, regenerated cellulose, oxidized regenerated cellulose fiber, or the like, or may be made of a material other than cellulose. In the case of impregnating the oxidized polysaccharide material, a porous or network material is preferable.

  Since the aqueous solution or aqueous dispersion of oxidized polysaccharide used in the present invention has a low viscosity and a high solution concentration, the processability and efficiency in the processing of impregnation and coating can be improved. That is, for example, when 3 kg of oxidized polysaccharide material is coated on a cellulose woven fabric substrate, a 3% aqueous solution requires 100 kg of liquid, but if it is 10%, the liquid may be 30 kg and dried. It is possible to greatly reduce the amount of heat required for the process and improve the processing speed. Moreover, since it has a low viscosity, it has a high permeability to the substrate, particularly in the impregnation process, the processing speed is increased, and a more uniform impregnation product is obtained.

  When the material coated or impregnated with the oxidized polysaccharide of the present invention is used as a biocompatible material for medical purposes, a material that can be used for medical purposes is used, and an appropriate sterilization treatment is performed after coating the oxidized polysaccharide. It is desirable to apply.

  Hereinafter, examples of the present invention will be described in detail, but the present invention is not limited thereto.

<Example 1>
0.192 g of TEMPO and 2.54 g of sodium bromide are dissolved in 200 ml of water and cooled. 10 g of a small piece of regenerated cellulose fiber Benize (manufactured by Asahi Kasei Kogyo Co., Ltd.) is dispersed in 200 ml of water, mixed with the TEMPO solution, the reaction system is cooled, and then an aqueous sodium hypochlorite solution (Cl = 5%) Add 100 ml and start the oxidation reaction. The reaction temperature was always maintained at 5 ° C. During the reaction, the pH in the system was lowered, but 0.5N-NaOH aqueous solution was sequentially added to adjust the pH to around 10.8. When the alkali addition amount corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction, and washing was sufficiently performed with water: alcohol = 2: 8. Then, it dehydrated with acetone and dried under reduced pressure at 40 ° C. to obtain a white powder of oxidized cellulose.

  A 10% aqueous solution was prepared from the obtained oxidized cellulose. The oxidized cellulose was completely dissolved, and the viscosity measured with a B-type viscometer at 25 ° C. was 10 to 15 mPa · s. 3 g of Japanese Pharmacopoeia gauze was immersed in this solution for 10 seconds, spread on a wire mesh and air-dried to obtain an oxidized cellulose-coated gauze of Example 1.

  The coated state of the oxidized cellulose was uniform, and about 1.5 g of oxidized cellulose was coated due to the increase in weight.

<Example 2>
0.192 g of TEMPO and 2.54 g of sodium bromide are dissolved in 200 ml of water and cooled. As a starch sample, 10 g of ACS (manufactured by ACROS) was dispersed in 200 ml of water, heated and dissolved at 60 ° C., cooled to 5 ° C., mixed with the TEMPO solution, and then sodium hypochlorite aqueous solution (Cl = 5%) Add 100 ml and start the oxidation reaction. The reaction temperature was always maintained at 5 ° C. During the reaction, the pH in the system was lowered, but 0.5N-NaOH aqueous solution was sequentially added to adjust the pH to around 10.8. When the alkali addition amount corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction, and washing was sufficiently performed with water: alcohol = 2: 8. Then, it dehydrated with acetone and dried under reduced pressure at 40 ° C. to obtain a white powdered oxidized starch.

  A 10% aqueous solution was prepared from the resulting oxidized starch. The oxidized starch was completely dissolved without heating, and the viscosity measured with a B-type viscometer at 25 ° C. was 7 to 12 mPa · s. 3 g of Japanese Pharmacopoeia gauze was immersed in this solution for 10 seconds, spread on a wire mesh and air-dried to obtain an oxidized starch-coated gauze of Example 2.

  The coated state of the oxidized starch was uniform, and about 1.5 g of oxidized starch was coated due to the increase in weight.

<Example 3>
10 g of chitin (manufactured by Wako Pure Chemical Industries, Ltd.) was immersed in 150 g of a 45% aqueous sodium hydroxide solution and stirred at room temperature or lower for 2 hours. To this, 850 g of crushed ice was added little by little, and the mixture was stirred while being cooled with ice water. This treatment almost dissolves chitin. Thereafter, hydrochloric acid was added to neutralize, and after thoroughly washing with water, the regenerated chitin was suspended in 200 ml of water without drying. An aqueous solution prepared by dissolving 0.192 g of TEMPO and 2.54 g of sodium bromide in 200 ml of water was added, the reaction system was cooled, and then 90 ml of an aqueous sodium hypochlorite solution (Cl = 5%) was added to start the oxidation reaction. To do. The reaction temperature was always maintained at 5 ° C. During the reaction, the pH in the system was lowered, but 0.5N-NaOH aqueous solution was sequentially added to adjust the pH to around 10.8. When the alkali addition amount corresponding to 100% of the total number of moles of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction, and washing was sufficiently performed with water: alcohol = 2: 8. Thereafter, it was dehydrated with acetone and dried under reduced pressure at 40 ° C. to obtain white powdered chitin oxide.

  A 10% aqueous solution was prepared from the obtained chitin oxide. The chitin oxide was completely dissolved, and the viscosity measured with a B-type viscometer at 25 ° C. was 50 to 70 mPa · s. 3 g of Japanese Pharmacopoeia gauze was immersed in this solution for 10 seconds, spread on a wire mesh and air-dried to obtain an oxidized chitin-coated gauze of Example 3.

  The coated state of chitin oxide was uniform, and about 1.6 g of chitin oxide was coated due to the increase in weight.

<Example 4>
TEMPO 0.125 g and sodium bromide 1.25 g were dissolved in 200 ml of water and cooled in an absolute dry weight of 10 g of commercially available paste-like microcrystalline cellulose Theo's cream FP-03 (manufactured by Asahi Kasei Kogyo Co., Ltd.). An aqueous solution is added, the reaction system is cooled, and then 100 ml of an aqueous sodium hypochlorite solution (Cl = 5%) is added to initiate the oxidation reaction. The reaction temperature was always maintained at 5 ° C. During the reaction, the pH in the system was lowered, but 0.5N-NaOH aqueous solution was sequentially added to adjust the pH to around 10.8. One day later, ethanol was added to stop the reaction, and the mixture was sufficiently washed with water or alcohol to finally prepare an aqueous dispersion of oxidized cellulose having a concentration of 10%. Here, the amount of alkali added during the oxidation reaction was 100% with respect to the total number of moles of the primary hydroxyl group at the 6-position of the glucose unit.

  In this solution, 3 g of Japanese Pharmacopoeia gauze was immersed for 10 seconds, spread on a wire mesh and air-dried to obtain an oxidized cellulose-coated gauze of Example 4.

  The coated state of the oxidized cellulose was uniform, and about 1.2 g of oxidized cellulose was coated due to the increase in weight.

  The degree of oxidation of the oxidized cellulose was determined by the following IR analysis method, and the degree of oxidation was about 50%.

IR analysis was performed by the KBr method using a sufficiently dried sample. The degree of oxidation was determined from the absorbance near 3350 cm ⁻¹ derived from the hydroxyl group in the sample and the absorbance ratio near 1620 cm ⁻¹ derived from the carboxyl anion. At this time, the unoxidized dry cellulose sample and the dry oxidized cellulose sample having a degree of oxidation of 100% prepared in Example 1 were mixed at a predetermined mixing ratio and similarly subjected to IR analysis. The content of 100% oxidized cellulose and the above A calibration curve was prepared from the absorbance ratio. The 100% oxidized cellulose content was defined as the degree of oxidation of the oxidized cellulose.

<Comparative Example 1>
5 g of CMC Serogen PR (Daiichi Kogyo Seiyaku Co., Ltd.) having a substitution degree of 0.6 to 0.7 was suspended in 95 g of water. It did not dissolve completely and became a viscous liquid. This was dipped in 3 g of Japanese Pharmacopoeia gauze for 10 seconds, spread on a wire mesh and air-dried to obtain CMC-coated gauze of Comparative Example 1, but the CMC coating state was uneven and non-uniform. It was.

<Comparative example 2>
2 g of CMC Serogen PR (Daiichi Kogyo Seiyaku Co., Ltd.) having a substitution degree of 0.6 to 0.7 was dissolved in 98 g of water to obtain a 2% aqueous solution. It was 100-110 mPa * s when the viscosity of the solution was measured with the B-type viscosity meter at 25 degreeC. 3 g of Japanese Pharmacopoeia gauze was immersed in this for 10 seconds, spread on a wire mesh and air-dried to obtain a CMC-coated gauze of Comparative Example 2.

  The coated state of CMC was almost uniform, but the amount of coated CMC calculated from the weight increase was as small as about 0.1 g.

Claims (6)

Obtained by oxidation treatment in the presence of cellulose or polysaccharide material in water which is selected reproduced cellulose scan or al 2,2,6,6-tetramethyl-1-piperidine -N- oxyl, said polysaccharide Only the reducing end of the molecule of the material or only the 6th position of the pyranose ring is selectively oxidized to a carboxyl group, and the carboxyl group is 60% or more with respect to the number of moles of monosaccharides constituting the polysaccharide material (degree of oxidation 60 %) Water-soluble or water-dispersible oxidized polysaccharide material
A material coated or impregnated with an oxidized polysaccharide material characterized by impregnating or applying a material selected from natural cellulose fiber, regenerated cellulose fiber, or oxidized regenerated cellulose fiber . Reduction of the polysaccharide material molecules obtained by oxidizing a polysaccharide material comprising finely divided cellulose in water in the presence of 2,2,6,6-tetramethyl-1-piperidine-N-oxyl. Only the terminal or the 6th position of the pyranose ring is selectively oxidized to form a carboxyl group, and the carboxyl group is 10 to 60% or more with respect to the number of moles of the constituent monosaccharide of the polysaccharide material (the degree of oxidation is 10 to 60%). Water-soluble or water-dispersible oxidized polysaccharide material
A material coated or impregnated with an oxidized polysaccharide material characterized by impregnating or applying a material selected from natural cellulose fiber, regenerated cellulose fiber, or oxidized regenerated cellulose fiber . The oxidation treatment uses at least one oxidizing agent selected from hypohalous acid, halous acid, perhalogenic acid and salts thereof in the presence of alkali metal bromide or metal iodide in water. A material coated or impregnated with the oxidized polysaccharide material according to claim 1 or 2 . Material wherein the oxidation treatment, in which it is coated or impregnated with oxidized polysaccharide material according to any one of claims 1 to 3, characterized in that oxidation treatment while keeping the pH9~12 by adding an alkali. The oxidized polysaccharide material according to any one of claims 1 to 4 , wherein the shape of the material impregnated with the oxidized polysaccharide material is selected from cloth, gauze, sponge, porous sheet, and paper material. A material coated or impregnated with. A biocompatible material comprising a material coated or impregnated with the oxidized polysaccharide material according to any one of claims 1 to 5 .