JP2005287790A - Bioabsorbable adhesion preventive material, and method of manufacturing and using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an bioabsorbable adhesion preventive material capable of sufficiently following the movement of an applied tissue and exhibiting the excellent adhesion preventive effects. <P>SOLUTION: The bioabsorbable adhesion preventive material includes a poly-ion complex of acidic polysaccharide and basic polysaccharide. The acidic polysaccharide in the bioabsorbable adhesion preventive material is synthetic polyuronic acid. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a bioabsorbable anti-adhesive material comprising a polyion complex of an acidic polysaccharide and a basic polysaccharide, and in particular, the acidic polysaccharide is a synthetic polyuronic acid, and a method for producing the same and for preventing undesired adhesion of living tissue Regarding usage.

  In a surgical operation, when a living tissue is invaded by a surgical operation, adhesion occurs due to inflammation in the tissue healing process of the site, and the normal operation of the tissue or organ is prevented by the adhesion, thereby causing postoperative complications. As a problem. For example, in the abdominal cavity region, intestinal obstruction caused by adhesion between the intestinal tracts and between the intestinal tract and the peritoneum after surgery is a serious complication. For the purpose of preventing such postoperative adhesion, a bioabsorbable adhesion preventing material is sometimes used in view of a barrier effect between tissues and organs.

As such an adhesion preventing material, Patent Document 1 discloses a polyion complex formed from a polyanionic substance composed of an acidic polysaccharide such as alginic acid or hyaluronic acid and a polypolycationic substance composed of a basic polysaccharide. Patent Document 2 discloses microbially produced fibrous cellulose. Patent Document 3 discloses a polysaccharide dextrin, and Patent Document 4 discloses an interpolymer complex of a carboxyl-containing polysaccharide and a polyether.
JP 2000-116765 A Japanese Patent No. 2853165 Special table 2003-520243 gazette Japanese translation of PCT publication No. 2002-511897

  However, it has been found that the anti-adhesion materials disclosed in Patent Documents 1 to 4 are poor in plasticity, and therefore cannot follow the movement of the applied tissue and often deviate from the applied location. This makes it difficult to sufficiently prevent adhesions.

  Accordingly, an object of the present invention is to provide a bioabsorbable anti-adhesive material that is excellent in plasticity, and therefore can sufficiently follow the movement of an applied tissue, and can exhibit an excellent anti-adhesion effect, and a method for producing the same. And

  According to a first aspect of the present invention, there is provided a bioabsorbable anti-adhesion material comprising a polyion complex of an acidic polysaccharide and a basic polysaccharide, wherein the acidic polysaccharide is a synthetic polyuronic acid. An anti-adhesion material is provided.

  According to the second aspect of the present invention, the method includes a step of preparing an aqueous solution of the acidic polysaccharide and the basic polysaccharide constituting the polyion complex of the present invention, a step of forming the polyion complex, and optionally, a shape imparting step. A method for producing a bioabsorbable anti-adhesion material is provided.

  Furthermore, according to the third aspect of the present invention, there is provided a method of using a bioabsorbable antiadhesive material characterized by applying the bioabsorbable antiadhesive material of the present invention to the surface of a living tissue.

  Since the bioabsorbable antiadhesive material of the present invention contains a polyion complex of acidic polysaccharide and basic polysaccharide, synthetic polyuronic acid having high safety to the living body, good bioabsorbability, and a clear structure as acidic polysaccharide is used. Since it is used, it has characteristic physical properties in which plasticity when wet, elasticity, binding properties, strength, and further, the decomposition rate are controlled.

  In the bioabsorbable anti-adhesion material of the present invention, as the acidic polysaccharide, (a) a synthetic polyuronic acid comprising β-1,4-glucopyranose and β-1,4-glucuronic acid as a constituent monosaccharide, (b) Synthetic polyuronic acid comprising α-1,4-glucopyranose and α-1,4-glucuronic acid as constituent monosaccharides, and (c) β-1,4-glucosamine and β-1,4-N-acetylglucosamine And at least one synthetic polyuronic acid selected from the group consisting of synthetic polyuronic acids having β-1,4-glucosaminouronic acid and β-1,4-N-acetylglucosamineuronic acid as constituent monosaccharides, etc. Is preferably used.

  The synthetic polyuronic acid can be obtained, for example, by regioselectively oxidizing natural polysaccharides such as cellulose, starch and chitin and introducing a carboxyl group or a salt thereof at the 6-position of the pyranose ring. As this selective oxidation method, the degree of oxidation can be controlled, and almost all the 6-positions of the pyranose ring can be oxidized to carboxyl groups without oxidizing the 2nd and 3rd positions of the pyranose ring. A method of oxidizing using an oxidizing agent in the presence of an N-oxyl compound catalyst is preferably used.

  As the N-oxyl compound, 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (hereinafter referred to as TEMPO) and the like are preferably used. Examples of the oxidizing agent 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. Furthermore, it is more preferable to carry out the oxidation 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. It is particularly preferable to perform the above oxidation using TEMPO as the N-oxyl compound and using sodium hypochlorite as the oxidizing agent in the presence of sodium bromide.

  Here, the amount of the N-oxyl compound used may be an amount as a catalyst. For example, 10 ppm to 5% is sufficient relative to the total number of moles of the constituent monosaccharides of the polysaccharide, but 0.05% to 3% is preferred. 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 total mole number of the constituent monosaccharide of a polysaccharide, More preferably, it is 1-50%.

  In addition, the reaction temperature is desirably room temperature or lower, more preferably 5 ° C. or lower for the purpose of increasing the selectivity of oxidation of the constituent monosaccharides to primary hydroxyl groups and suppressing side reactions. Furthermore, it is preferable to keep the system alkaline during the reaction. At that time, it is desirable to maintain the pH at 9 to 12, more preferably at pH 10 to 11.

  In the oxidation method, the degree of oxidation can be controlled by the amount of oxidizing agent and the amount of alkali added to keep the pH 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 the oxidation reaction, water-soluble polysaccharides such as starch, pullulan, and hyaluronic acid, and water-insoluble cellulose and chitin 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 to the viscous liquid of this chitin to neutralize it, flaky chitin is precipitated, but the chitin is almost amorphous, and after washing it thoroughly with water, the above oxidation is performed without drying. By subjecting to the reaction, molecular weight reduction can be 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 that is 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 with chitin. Can return to chemical structure. Through this operation, what has been washed thoroughly with water is subjected to the above oxidation reaction without drying or after lyophilization, so that only the primary hydroxyl group at the 6-position is oxidized with high selectivity as in the case of alkali-regenerated chitin. The In this case, the degree of N-acetylation of the oxidation raw material can be controlled by the amount of acetic anhydride added.

By controlling the conditions as described above and oxidizing chitin / chitosan, a synthetic polyuronic acid having a structure represented by the following general formula (I) (hereinafter referred to as chitouronic acid) is obtained. This chitouronic acid is particularly preferred as the acidic polysaccharide of the bioabsorbable anti-adhesion material of the present invention.

(Wherein, X and Y each independently represent hydrogen or an alkali metal, and a, b, c and d represent the number of moles of each unit).

  Here, (a + c) / (a + b + c + d) represents the degree of N-acetylation of chitouronic acid. When the degree of N-acetylation is low, that is, when the amount of amino groups in the molecule is large, the stability during oxidation reaction Is not preferable because it lowers the molecular weight and lowers the water solubility of chitouronic acid. In the present invention, the N-acetylation degree is preferably 80% or more. Further, (a + b) / (a + b + c + d) represents the degree of carboxylation (degree of oxidation) of chitouronic acid. A low degree of oxidation is not preferable because it does not become water-soluble and the uniformity in forming a polyion complex with a basic polysaccharide is reduced. In the present invention, the degree of oxidation is desirably 70% or more. Therefore, the ratio (molar ratio) of (a + c) :( b + d) is in the range of 8: 2 to 10: 0, and the ratio (molar ratio) of (a + b) :( c + d) is in the range of 7: 3 to 10: 0. It is desirable to use some chitouronic acid. A polyion complex with a basic polysaccharide obtained using such chitouronic acid is a particularly excellent bioabsorbable anti-adhesion material. For example, such a polyion complex has plasticity when wet and can be deformed into various shapes, or once wetted with a dry powder, forms a film with good binding properties and physical strength. It has characteristics.

  Synthesis of β-1,4-glucopyranose and β-1,4-glucuronic acid, which is obtained by oxidizing regenerated cellulose by the above-described oxidation method and introducing a carboxyl group at the 6-position of D-glucose, as constituent monosaccharides Synthetic polyuron having α-1,4-glucopyranose and α-1,4-glucuronic acid as constituent monosaccharides, in which polyuronic acid is celouronic acid and starch is oxidized to introduce a carboxyl group at the 6-position of D-glucose The acid will be called amylouronic acid.

  The 6-position carboxyl group of the synthetic polyuronic acid used in the present invention is more stable when it exists in the form of a salt such as a sodium salt, and these synthetic polyuronic acid salts are particularly highly water-soluble. Further, desalted COOH-type synthetic polyuronic acid can be obtained by adding an acid such as hydrochloric acid to the aqueous solution of synthetic polyuronic acid or treating it 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.

  In the bioabsorbable anti-adhesion material of the present invention, the synthetic polyuronic acid can be used alone as an acidic polysaccharide, but a plurality of types of synthetic polyuronic acids may be mixed and used. For example, a bioabsorbable anti-adhesive material in which a polyion complex is formed by using chitouronic acid alone as an acidic polysaccharide and chitosan described later as a basic polysaccharide is easily decomposed by the action of lysozyme. When a polyion complex is formed by mixing acid or celouronic acid, resistance to lysozyme is improved, the degradation rate in vivo is slowed, and the remaining period of the bioabsorbable antiadhesive material in vivo can be controlled. Is possible.

  As described above, the acidic polysaccharide used in the bioabsorbable anti-adhesion material of the present invention is a synthetic polyuronic acid having a clear structure and a uniform structure, unlike natural polyuronic acids such as alginic acid, pectin, and hyaluronic acid, In particular, since it is water-soluble in a wide pH range of pH 1 to 14, it has a feature that it is easy to form a more uniform polyion complex.

  Next, the basic polysaccharide used in the bioabsorbable anti-adhesion material of the present invention is preferably a polysaccharide having glucosamine and N-acetylglucosamine as constituent monosaccharides, and particularly preferably chitosan.

  Chitin, which is present as a main component of the skeleton of shrimp and shrimp and also in cell membranes of fungi and the like, is a polysaccharide in which N-acetyl-D-glucosamine is mainly linked by β-1,4 glycosides. This deacetylated product of chitin is chitosan. Chitosan is a polysaccharide having N-acetyl-D-glucosamine and D-glucosamine as constituent monosaccharides, and has a cationic amino group. Chitin is insoluble in water, but chitosan dissolves in dilute acid solutions such as acetic acid and hydrochloric acid.

  As the chitosan used as the basic polysaccharide of the bioabsorbable antiadhesive material of the present invention, the above-mentioned general chitosan can be used, and the raw material, purification method, degree of polymerization, etc. are not particularly limited. . Further, the ratio (molar ratio) of glucosamine and N-acetylglucosamine in the constituent monosaccharide is not particularly limited, but is in the range of 40:60 to 100: 0 from the viewpoint of solubility in water or acid. It is preferable. Glucosamine has one cationic amino group, and this ratio is one of the important factors for controlling the physical properties of the bioabsorbable antiadhesive material of the present invention.

  The ratio of glucosamine and N-acetylglucosamine, that is, the ratio of amino group and N-acetyl group is determined by deacetylation by hydrolysis with acid or alkali, or conversely by N-acetylation using acetic anhydride or the like. Control is possible. In the deacetylation reaction, the amino group ratio can be controlled by the hydrolysis reaction time, and in the N-acetylation reaction, the amount of reagent added.

  The ratio of glucosamine and N-acetylglucosamine in this chitosan is generally expressed as the degree of deacetylation or the degree of N-acetylation (degree of N-acetylation (%) = 100%-(degree of deacetylation (%))). However, 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.

  As described above, chitosan generally dissolves in a dilute acid solution by forming a salt, but is neutral or alkaline and insoluble in water. However, it is known that the ratio (molar ratio) of glucosamine to N-acetylglucosamine is soluble in water in a wide pH range in the range of 40:60 to 60:40.

  When preparing this water-soluble chitosan, it is important to make the distribution of glucosamine and N-acetylglucosamine more uniform between molecules and within the molecule by N-acetylation or deacetylation in a homogeneous system. is there.

  Since this water-soluble chitosan is soluble in water in a wide pH range of pH 1 to 14, formation of water insolubility caused by mixing in water with a water-soluble acidic polysaccharide in the wide pH range such as chitouronic acid and amylouronic acid described above. The product is a highly uniform polyion complex that does not include a single component insolubilized. Therefore, chitosan having a ratio of glucosamine to N-acetylglucosamine in the range of 40:60 to 60:40 is particularly preferably used as the basic polysaccharide of the bioabsorbable anti-adhesion material of the present invention.

  Here, the compounding ratio of the acidic polysaccharide and the basic polysaccharide is not particularly limited, and can be arbitrarily set within a range satisfying the physical properties required as a bioabsorbable adhesion preventing material. For example, acidic polysaccharide and basic polysaccharide can be used in a molar ratio of 1:10 to 10: 1.

  The range of the weight average molecular weight of acidic polysaccharides and basic polysaccharides may be 10,000 to 500,000 for acidic polysaccharides and 10,000 to 1,000,000 for basic polysaccharides.

  The shape of the bioabsorbable adhesion preventing material of the present invention is preferably a sheet or powder from the viewpoint of ease of use as a bioabsorbable adhesion preventing material. The bioabsorbable adhesion-preventing material sheet of the present invention absorbs moisture when deformed on the surface of a living tissue and deforms into a shape along the surface of the living tissue, thereby preventing adhesion between organs. In addition, the bioabsorbable anti-adhesion material powder of the present invention absorbs moisture on the surface of the living tissue by spraying or coating on the surface of the living tissue, and forms a polyion complex gel film by binding to prevent adhesion between organs. To do. The thickness of the bioabsorbable adhesion preventing material sheet of the present invention is preferably 50 to 500 μm.

  The bioabsorbable anti-adhesion material of the present invention has a plastic property when wet, and can be formed into various shapes other than the above-described sheet shape and powder shape. Furthermore, even if the dried gel once dried is moistened, almost the same physical properties as a wet gel are reproduced. Furthermore, even if the powder-like polyion complex is wetted in water, it can exhibit adhesiveness and binding properties and return to the block or sheet shape again. Therefore, when the bioabsorbable anti-adhesion material powder of the present invention is deposited on the surface of a living tissue, it can form a gel film having physical strength there, and has very characteristic properties that reproduce physical properties as a wet gel. It is what has.

  Next, the manufacturing method of the bioabsorbable adhesion preventing material of the present invention will be described.

  The method for producing a bioabsorbable anti-adhesion material of the present invention includes the above-described characteristic acidic polysaccharide (synthetic polyuronic acid) and basic polysaccharide aqueous solution preparation step, polyion complex formation step, and optionally shape imparting step. .

  First, the preparation process of the aqueous solution of acidic polysaccharide and basic polysaccharide is demonstrated.

  The synthetic polyuronic acid described above as an acidic polysaccharide is particularly highly water-soluble and can be easily dissolved in water at room temperature even at a high concentration of 5 to 10% to easily prepare an aqueous solution. In particular, an aqueous solution of chitouronic acid or amylouronic acid is water-soluble in a wide range of pH 1 to 14 even if the pH is changed by adding acid or alkali.

  On the other hand, when preparing an aqueous solution of chitosan as a basic polysaccharide, by dissolving chitosan in an aqueous solution of dilute acetic acid or dilute hydrochloric acid, or by dispersing chitosan in water and adding acetic acid or hydrochloric acid to dissolve, An aqueous chitosan solution can be prepared.

  Here, as the basic polysaccharide, when water-soluble chitosan having a ratio of glucosamine to N-acetylglucosamine of 40:60 to 60:40 is used, an alkaline is added to the acidic chitosan aqueous solution prepared as described above to adjust the pH. The chitosan aqueous solution is soluble in a wide pH range of pH 1 to 14 even if it is changed. Alternatively, this water-soluble chitosan can be directly dispersed in water and repeated freezing and thawing to prepare an aqueous solution having no counter ion at a concentration of about 1 to 2%.

  Next, in the polyion complex formation step, the acidic polysaccharide aqueous solution and the basic polysaccharide aqueous solution prepared as described above are mixed and the pH is adjusted to 3 to 9, whereby the polyion complex is precipitated.

  Here, when chitouronic acid or amylouronic acid is used as the acidic polysaccharide and water-soluble chitosan is used as the basic polysaccharide, both aqueous solutions are water-soluble in a wide pH range of pH 1 to 14, and thus insoluble precipitates at pH 3 to 9 The object is a uniform polyion complex. Furthermore, these mixed aqueous solutions become uniform aqueous solutions in the acidic region of pH 1 to 3, or in the alkaline region of pH 9 to 14. Therefore, in the step of forming the polyion complex, once the pH of the mixed aqueous solution is adjusted to pH 1 to 3 or pH 9 to 14, the polyion complex deposited by adjusting the pH to 3 to 9 with stirring is more uniform. High polyion complex.

  At this time, the presence of a salt between counter ions generated for pH adjustment affects physical properties such as elongation and elasticity of the generated polyion complex. However, since the bioabsorbable anti-adhesion material of the present invention is excellent in strength when wet, the salt between counter ions is removed from the polyion complex gel by washing with water after the polyion complex formation step or after the shape imparting step. It is also possible to exclude.

  Furthermore, a COOH-type synthetic polyuronic acid aqueous solution is used as the acidic polysaccharide aqueous solution, and an aqueous solution in which water-soluble chitosan is dissolved without counterion is used as the basic polysaccharide aqueous solution. When both solutions are mixed, the polyion complex immediately precipitates and counterions A polyion complex can also be formed without the presence of salts between each other.

  Next, the shape imparting step will be described.

  When the stirring is stopped, the polyion complex deposited in the water as described above is deposited on the bottom of the container to form a flake-like, lump-like or sheet-like polyion complex, which is taken out and pressed in a wet state. When dried, a sheet-like bioabsorbable anti-adhesion material is obtained. The polyion complex of the bioabsorbable adhesion-preventing material of the present invention has a plastic property in a wet state, and in this process, it can be molded into various shapes in addition to pressing. Also, when the dispersion of the polyion complex is cast immediately after the stirring is stopped, the polyion complex is uniformly deposited and bound, and a sheet-like bioabsorbable anti-adhesion material can be obtained even if this is dried. .

  Further, the dried polyion complex can be pulverized by a known method to obtain a powdery bioabsorbable adhesion preventing material. This polyion complex powder binds when wet in water and reproduces the physical properties of the wet gel again. Therefore, it is also possible to re-disperse in water after making it into a powder form as described above, and use this dispersion liquid again for the shape imparting step.

  The bioabsorbable anti-adhesion material of the present invention is preferably used after being sterilized by a method such as filtration sterilization or ethylene oxide gas sterilization during or after production. The filter sterilization may be performed, for example, by passing a synthetic polyuronic acid aqueous solution or a basic polysaccharide aqueous solution through a commercially available filter sterilization filter when the bioabsorbable adhesion preventing material is produced. The ethylene oxide gas sterilization may be performed, for example, by putting the obtained bioabsorbable anti-adhesion material in a sealed container and enclosing the ethylene oxide gas, and then leaving it for a predetermined time.

  However, in the sterilization process, physical properties of the bioabsorbable anti-adhesion material may be deteriorated. Therefore, the bioabsorbable anti-adhesion material of the present invention is a sterilization-resistant treatment that suppresses the physical property decrease in the sterilization process. It is preferable to have properties.

  In particular, in sterilization treatment using radiation such as γ-rays or electron beams, polysaccharides constituting so-called bioabsorbable adhesion preventing materials, so-called polymers, may be decomposed. This is believed to occur by the excision of the polymer and by the cleavage of polymer radicals generated during the stabilization process of the excitable molecules, or by reaction of the generated radicals with enzymes. By suppressing the generation of radicals related to such decomposition and oxidation reactions, it is possible to suppress a decrease in physical properties of the material. Examples of the compounding agent (radical trapping agent) that can inactivate radicals include an electron / ion scavenger, an energy transfer agent, a radical scavenger, an antioxidant, and the like, which can be appropriately selected and blended.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these Examples.

  Here, first, production examples of acidic polysaccharides and basic polysaccharides as raw materials used in Examples and Comparative Examples will be described, and then Examples and Comparative Examples of polyion complexes 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% by weight acetic acid, diluted with 1 L of methanol, and anhydrous with stirring. When 12.68 g (2 equivalents) of acetic acid 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, wash well 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))
The same treatment as in Production Example 1 was carried out except that the amount of acetic anhydride added in Production Example 1 was changed to 5.71 g (0.9 equivalent) to obtain 11.4 g of N-acetylated chitosan. The degree of N-acetylation by elemental analysis was 80%.

Production Example 3 (Preparation of N-acetylated chitosan (3))
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% by weight acetic acid, diluted with 1 L of methanol, and anhydrous with stirring. 3.17 g (0.5 equivalent) of acetic acid was added and stirred at room temperature for 15 hours. When 2N-NaOH aqueous solution was added to this to neutralize to pH 7, flaky chitosan precipitated, which was 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 its 1% by weight aqueous solution had a pH of 8.2. Furthermore, even when acid or alkali was added to this aqueous solution to change the pH, chitosan was dissolved. From the result of ¹ H-NMR analysis measured by dissolving this chitosan in deuterated chlorodeuterated aqueous solution, the degree of N-acetylation was 45%. The ¹ H-NMR spectrum of this chitosan is shown in FIG. In FIG. 1, N-acetylglucosamine origin is indicated by aH and glucosamine origin is indicated by bH.

Production Example 4 (Preparation of sodium chitouronic acid salt (1))
10 g of N-acetylated chitosan prepared in Production Example 1 was suspended in 400 g of distilled water, a solution in which 0.15 g of TEMPO and 2.0 g of sodium bromide were dissolved in 100 g of distilled water was added and cooled to 5 ° C. or lower. 84 g of 11% strength by weight aqueous 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 of 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. Next, this reaction solution was poured into 2 L of ethanol to precipitate the product, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, dried under reduced pressure at 40 ° C., and white powder. 10.8 g of chitouronic acid sodium salt having a degree of oxidation of 100% was obtained. The ¹³ C-NMR spectrum of this chitouronic acid sodium salt is shown in FIG. The solubility of this chitouronic acid sodium salt in water was high, and its 5 wt% aqueous solution showed pH 6. Even when acid or alkali was added to this aqueous solution to change the pH, the sodium chitouronic acid was dissolved. The weight average molecular weight in terms of pullulan obtained by GPC method for chitouronic acid sodium salt was 32,000.

Production Example 5 (Preparation of chitouronic acid sodium salt (2))
10 g of N-acetylated chitosan prepared in Production Example 2 was suspended in 400 g of distilled water, and a solution in which 0.15 g of TEMPO and 2.0 g of sodium bromide were dissolved in 100 g of distilled water was added and cooled to 5 ° C. or lower. To this, 84 g of an 11% sodium hypochlorite aqueous solution was added dropwise to start the oxidation reaction. The reaction temperature was always kept below 5 ° C. During the reaction, the pH of 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. Next, this reaction solution was poured into 2 L of ethanol to precipitate the product, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, dried under reduced pressure at 40 ° C., and white powder. 10.6 g of sodium chitouronic acid salt having a degree of oxidation of 100% was obtained. FIG. 3 shows a ¹³ C-NMR spectrum of this chitouronic acid sodium salt. The solubility of this chitouronic acid sodium salt in water was high, and its 5 wt% aqueous solution showed pH 6.5. Even when acid or alkali was added to this aqueous solution to change the pH, the sodium chitouronic acid was dissolved. The weight average molecular weight in terms of pullulan obtained by GPC method for chitouronic acid sodium salt was 26,000.

Production Example 6 (Preparation of chitouronic acid sodium salt (3))
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. To this, 850 g of ice crushed with ice water or the like and crushed with stirring was added. Chitin was almost dissolved by this alkali treatment. After neutralizing with hydrochloric acid and thoroughly washing with water, it was used as an oxidation raw material without drying.

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 2.5% by weight suspension of regenerated chitin, and the mixture was cooled to 5 ° C. or lower. To this, 35 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 of 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 the mole number of 80% with respect to the total mole number of the primary hydroxyl group at the 6-position was reached, ethanol was added to stop the reaction. The reaction solution was poured into 1 L of ethanol to precipitate the product, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, and dried under reduced pressure at 40 ° C. 5.2 g of chitouronic acid sodium salt having an oxidation degree of 80% was obtained. FIG. 4 shows the ¹³ C-NMR spectrum of this chitouronic acid sodium salt. The solubility of this chitouronic acid sodium salt in water was high, and its 5 wt% aqueous solution showed pH 6. Even when acid or alkali was added to this aqueous solution to change the pH, the sodium chitouronic acid was dissolved. The weight average molecular weight in terms of pullulan obtained by GPC method for this chitouronic acid sodium salt was 35,000.

Production Example 7 (Preparation of sodium amylouronate)
10 g of corn 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% strength 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 of 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. Next, this reaction solution was poured into 2 L of ethanol to precipitate the product, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, dried under reduced pressure at 40 ° C., and white powder. 11.7 g of amylouronate sodium salt having a degree of oxidation of 100% was obtained. FIG. 5 shows the ¹³ C-NMR spectrum of this amylouronate sodium salt. The solubility of this amyloboronic acid sodium salt in water was high, and its 5 wt% aqueous solution showed pH 7. Even when acid or alkali was added to this aqueous solution to change the pH, amylouronate sodium salt was dissolved. The weight average molecular weight in terms of pullulan obtained by GPC method for this sodium amylouronate was 58,000.

Production Example 8 (Preparation of sodium cellulonic acid salt)
As the regenerated cellulose, Benise manufactured by Asahi Kasei Kogyo Co., Ltd. is used, 10 g of this regenerated cellulose is suspended in 400 g of distilled water, and a solution prepared by dissolving 0.18 g of TEMPO and 2.5 g of sodium bromide is added to 100 g of distilled water, up to 5 ° C. or less. Cooled down. To this, 104 g of an aqueous 11% sodium hypochlorite solution was added to initiate the oxidation reaction. The reaction temperature was always kept below 5 ° C. During the reaction, the pH of 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. Next, this reaction solution was poured into 2 L of ethanol to precipitate the product, washed thoroughly with a solution of water: acetone = 1: 7, dehydrated with acetone, dried under reduced pressure at 40 ° C., and white powder. 11.6 g of celolone acid sodium salt having a degree of oxidation of 100% was obtained. FIG. 6 shows the ¹³ C-NMR spectrum of this sodium cellulonate. The solubility of this sodium celouronic acid salt in water was high, and its 5 wt% aqueous solution showed pH 7. When an acid was added to this aqueous solution to adjust the pH to 3 or less, the solution became cloudy but was a uniform dispersion. The weight average molecular weight in terms of pullulan obtained by the GPC method for this sodium cellulonic acid salt was 52,000.

Example 1
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 1 g of chitouronic acid sodium salt prepared in Production Example 4 was dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid concentration of 5% by weight and a pH of 6. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution while stirring, a uniform aqueous solution having a pH of 2 was obtained. When a 2N-NaOH aqueous solution was added to this aqueous solution, a gel was precipitated in the range of pH 3 to 9, but when the pH was further raised to pH 12.5, a uniform solution was obtained. Thereafter, the pH was adjusted to 7 with 1N hydrochloric acid to precipitate the gel. The mixture was stirred as it was for 1 minute, and then quickly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited and bound on the bottom of the container to form a wet gel sheet. The wet gel sheet was thoroughly washed with deionized water and then air-dried to obtain a bioabsorbable adhesion preventing material. This polyion complex sheet is a yellow-brown transparent sheet with a thickness of 100 to 200 μm when dried, and the sheet shape does not collapse even when washed with deionized water, and removes NaCl, which is a salt between counter ions. Was possible.

Example 2
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 1 g of chitouronic acid sodium salt prepared in Production Example 5 was dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid content concentration of 5% by weight and a pH of 6.5. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution with stirring, a uniform aqueous solution having a pH of 2 was obtained. A 1N-NaOH aqueous solution was added to this aqueous solution to adjust the pH to 7 to precipitate a gel. The mixture was stirred as it was for 1 minute, and then quickly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited and bound on the bottom of the container to form a wet gel sheet. The wet gel sheet was thoroughly washed with deionized water and then air-dried to obtain a bioabsorbable adhesion preventing material. This polyion complex sheet is a yellow-brown transparent sheet with a thickness of 100 to 200 μm when dried, and the sheet shape does not collapse even when washed with deionized water, and removes NaCl, which is a salt between counter ions. Was possible.

Example 3
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 1 g of chitouronic acid sodium salt prepared in Production Example 6 was dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid concentration of 5% by weight and a pH of 6. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution with stirring, a uniform aqueous solution having a pH of 2 was obtained. 1N-NaOH aqueous solution was added to this aqueous solution to adjust the pH to 7 to precipitate a gel. The mixture was stirred as it was for 1 minute, and then quickly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited and bound on the bottom of the container to form a wet gel sheet. The wet gel sheet was thoroughly washed with deionized water and then air-dried to obtain a bioabsorbable adhesion preventing material. This polyion complex sheet is a yellow-brown transparent sheet with a thickness of 100 to 200 μm when dried, and the sheet shape does not collapse even when washed with deionized water, and removes NaCl, which is a salt between counter ions. Was possible.

Comparative Example 1
0.1 g of sodium alginate (viscosity 500 to 600 cP) manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in 10 ml of distilled water to obtain an acidic polysaccharide aqueous solution. A basic polysaccharide aqueous solution was obtained by dissolving 0.1 g of chitosan 500 manufactured by Wako Pure Chemical Industries, Ltd. in 10 ml of 0.1N acetic acid. On the glass plate, the acidic polysaccharide aqueous solution was used as a lower layer, and the basic polysaccharide aqueous solution was used as an upper layer, followed by drying to obtain a film (bioabsorbable adhesion preventing material). When this film was put into distilled water, it disintegrated so as to melt out, and the film shape was not retained.

Comparative Example 2
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 1 g of sodium alginate (viscosity: 500 to 600 cP) manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid content of 1% by weight and a pH of 7. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution while stirring, a gel was precipitated. 2N-NaOH aqueous solution was added to this, pH was adjusted to 12.5, and it was set as the uniform solution. Thereafter, the pH was adjusted to 7 with 1N hydrochloric acid to precipitate the gel. After stirring this mixed liquid for 1 minute, it rapidly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The precipitated gel remained highly swollen and did not form a sheet, but the supernatant was discarded and air-dried to obtain a bioabsorbable anti-adhesion material. The thickness of this polyion complex sheet upon drying was 50 to 300 μm and had a lot of unevenness. Moreover, when this sheet | seat was thrown into water, it swelled and the sheet | seat shape was not stopped.

Comparative Example 3
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 1 g of carboxymethylcellulose sodium salt (Mw = 250,000; DS = 0.7) manufactured by ALDRICH was dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid content of 1% by weight and a pH of 7. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution while stirring, a gel was precipitated. 2N-NaOH aqueous solution was added to this, pH was adjusted to 12.5, and it was set as the uniform solution. Thereafter, the pH was adjusted to 7 with 1N hydrochloric acid to precipitate the gel. After stirring this mixed liquid for 1 minute, it rapidly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited on the bottom surface of the container, but the binding force was weak and it could not be handled in a wet state, and it was air-dried as it was to obtain a bioabsorbable adhesion preventing material. The thickness of this polyion complex sheet when dried was 100 to 200 μm. When this sheet was put into water, swelling was large and partial collapse was observed.

Example 4
The polyion complex sheet of Example 1 was freeze-pulverized to obtain a powder-like bioabsorbable adhesion-preventing material.

1 g of this powder was added to 100 g of distilled water with stirring. After stirring this for 3 minutes, it was quickly poured into a polystyrene container having a bottom area of 36.3 cm ² and allowed to stand overnight. The wet gel deposited on the bottom of the container was bound to form a wet gel sheet having tensile strength.

Example 5
The polyion complex sheet of Example 2 was freeze-pulverized to obtain a powder-like bioabsorbable adhesion-preventing material.

1 g of this powder was added to 100 g of distilled water with stirring. After stirring this for 3 minutes, it was quickly poured into a polystyrene container having a bottom area of 36.3 cm ² and allowed to stand overnight. The wet gel deposited on the bottom of the container was bound to form a wet gel sheet having tensile strength.

Example 6
1 g of the polyion complex powder of Example 5 was added to 100 g of distilled water with stirring. After stirring this for 3 minutes, it was quickly poured into a polystyrene container having a bottom area of 36.3 cm ² and allowed to stand overnight. The wet gel sheet deposited on the bottom of the container was air-dried to obtain the bioabsorbable adhesion preventing material of Example 6. This polyion complex sheet was a yellow-brown transparent sheet having a dry film thickness of 100 to 200 μm, and exhibited the same physical properties as the polyion complex sheet of Example 2.

Comparative Examples 4-6
The polyion complex sheets of Comparative Examples 1 to 3 were freeze-pulverized to form powders, and bioabsorbable adhesion preventing materials of Comparative Examples 4 to 6 were obtained.

  1 g of each powder was added to 100 g of distilled water with stirring. After stirring this for 3 minutes, it was quickly poured into a polystyrene container having a bottom area of 36.3 cm 2 and allowed to stand overnight, but none of them bound and became a sheet.

Example 7
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. Dissolve 0.7 g of sodium chitouronic acid prepared in Production Example 5 and 0.3 g of sodium ceurouronic acid prepared in Production Example 8 in distilled water to obtain an acidic polysaccharide aqueous solution having a solid content of 5% by weight and a pH of 7. It was. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution while stirring, a thin white turbid solution having a pH of 2 was obtained. A 1N-NaOH aqueous solution was added to the white turbid solution to adjust the pH to 7 to precipitate a gel. The mixture was stirred as it was for 1 minute, and then quickly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited and bound on the bottom of the container to form a wet gel sheet. The wet gel sheet was thoroughly washed with deionized water and then air-dried to obtain a bioabsorbable adhesion preventing material. This polyion complex sheet is a yellow-brown transparent sheet with a thickness of 100 to 200 μm when dried, and the sheet shape does not collapse even when washed with deionized water, and removes NaCl, which is a salt between counter ions. Was possible.

Example 8
2 g of N-acetylated chitosan prepared in Production Example 3 was dissolved in a diluted hydrochloric acid solution to obtain a basic polysaccharide aqueous solution having a solid content concentration of 3% by weight and a pH of 1. 0.5 g of chitouronic acid sodium salt prepared in Production Example 5 and 0.5 g of sodium amyluronate prepared in Production Example 7 were dissolved in distilled water to obtain an acidic polysaccharide aqueous solution having a solid content concentration of 5% by weight and a pH of 7. It was. When the acidic polysaccharide aqueous solution was added to the basic polysaccharide aqueous solution with stirring, a uniform aqueous solution having a pH of 2 was obtained. 1N-NaOH aqueous solution was added to this aqueous solution to adjust the pH to 7 to precipitate a gel. The mixture was stirred as it was for 1 minute, and then quickly poured into a polystyrene container having a bottom area of 127.5 cm ² and allowed to stand overnight. The deposited gel was deposited and bound on the bottom of the container to form a wet gel sheet. The wet gel sheet was thoroughly washed with deionized water and then air-dried to obtain a bioabsorbable adhesion preventing material. This polyion complex sheet is a yellow-brown transparent sheet with a thickness of 100 to 200 μm when dried, and the sheet shape does not collapse even when washed with deionized water, and removes NaCl, which is a salt between counter ions. Was possible.

Test example 1
Each of the bioabsorbable anti-adhesion material sheets of Examples 1 to 3, Examples 6 to 8, and Comparative Examples 1 to 3 was used as a 1 cm square test piece, and each in 10 ml of phosphate buffered saline contained in a 20 ml glass bottle. Soaked in. After storage at 37 ° C. for 3 days, morphological changes were observed. Although all the test pieces of Examples 1 to 3 and Examples 6 to 8 maintained the sheet shape even when swollen, all the test pieces of Comparative Examples 1 to 3 did not collapse and retain the sheet shape. It was.

Test example 2
Each of the bioabsorbable anti-adhesion material sheets of Example 2, Example 7 and Example 8 was used as a 1 cm square test piece and immersed in 10 ml of phosphate buffered saline in a 20 ml glass bottle. To this, 10 μg of lysozyme (derived from egg white) manufactured by Wako Pure Chemical Industries, Ltd. was added and stored at 37 ° C. for 2 days, and morphological changes were observed. Thereafter, the remaining gel sheet was taken out, washed and dried, and weight loss (%) = (100−dry weight after test / dry weight before test × 100) was determined.

  In the test piece of Example 2, only fragments remained, and the weight loss was almost decomposed at 90% or more. On the other hand, in addition to chitouronic acid as an acidic polysaccharide, each of them contained ceurouronic acid and amylouronic acid. The test piece of Example 8 maintained the sheet shape, and the weight loss was 80% in Example 7 and 40% in Example 8.

Test example 3
The bioabsorbable anti-adhesion material sheets of Example 2, Example 7 and Example 8 were subjected to adhesion prevention evaluation in a rat cecal abrasion model.

  Sprague-Dawley (SD) rats were opened by incision under Nembutal anesthesia, and only the cecum was removed from the incision wound. Scraped until bleeding occurred.

  A bioabsorbable adhesion-preventing material sheet (2 × 2 cm) was coated on the entire rubbing site (1 × 1 cm). Thereafter, the cecum was stored in the abdominal cavity so that the incision was directly above the bioabsorbable antiadhesive material sheet, and the incision was sutured. One week after application of the coating, 2 weeks later, the abdomen was opened, the degree of adhesion on the surface of the cecum was observed with the naked eye, and a tissue specimen was prepared and examined histologically. In addition, the thing which produced the same damage site | part and did not apply | coat was used as control.

  As a result, in the samples coated with the bioabsorbable anti-adhesion sheet of Example 2, Example 7 and Example 8, the samples between the abdominal wall and the cecum and between the cecum and the other organs were used after 1 week and 2 weeks. Adhesion did not occur, and the remaining of the sheet was observed in the tissue after 1 week, and there was little infiltration of capillaries and cells. After 2 weeks, the surface of the cecum was healed and the sample disappeared unchanged from normal.

  On the other hand, in the control, adhesion occurs between the abdominal wall and the cecum and between the cecum and other organs in both the samples after 1 week and 2 weeks. In addition, the formation of capillaries and the like was also observed. Two weeks later, although the capillaries and the like were decreased, the amount of fibrous substances was increased, the fiber density was increased, and strong adhesion formation was observed.

  From the above, the bioabsorbable anti-adhesion material sheets of Example 2, Example 7 and Example 8 are excellent in plasticity and can sufficiently follow the movement of the applied tissue, so that the sheets deviate from the place of application. It was confirmed that adhesion could be prevented without any problems.

¹ H-NMR spectrum measured by dissolving N-acetylated chitosan of Production Example 3 in a deuterated aqueous solution of deuterated hydrochloric acid. ¹³ C-NMR spectrum measured by dissolving sodium chitouronic acid salt of Production Example 4 in heavy water. ¹³ C-NMR spectrum measured by dissolving the sodium chitouronic acid salt of Production Example 5 in heavy water. ¹³ C-NMR spectrum measured by dissolving sodium chitouronic acid salt of Production Example 6 in heavy water. ¹³ C-NMR spectrum measured by dissolving sodium amyluronate of Production Example 7 in heavy water. The spectrum of ¹³ C-NMR measured by dissolving the celluloronic acid sodium salt of Production Example 8 in heavy water.

Claims (17)

  A bioabsorbable anti-adhesive material comprising a polyion complex of an acidic polysaccharide and a basic polysaccharide, wherein the acidic polysaccharide is a synthetic polyuronic acid.   The acidic polysaccharide is (a) a synthetic polyuronic acid having β-1,4-glucopyranose and β-1,4-glucuronic acid as constituent monosaccharides, and (b) α-1,4-glucopyranose and α-. Synthetic polyuronic acid having 1,4-glucuronic acid as a constituent monosaccharide, and (c) β-1,4-glucosamine, β-1,4-N-acetylglucosamine, β-1,4-glucosamineuronic acid and β The at least one synthetic polyuronic acid selected from the group consisting of synthetic polyuronic acids having -1,4-N-acetylglucosaminuronic acid as a constituent monosaccharide. Bioabsorbable anti-adhesion material. The bioabsorbable antiadhesive material according to claim 1 or 2, wherein the acidic polysaccharide is a synthetic polyuronic acid represented by the structural formula (I).

(In the formula, X and Y each independently represent hydrogen or an alkali metal, and a, b, c and d represent the number of moles of each unit.)   The molar ratio (a + c) :( b + d) in the structural formula (I) is 8: 2 to 10: 0, and the molar ratio (a + b) :( c + d) is 7: 3 to 10: 0. The bioabsorbable adhesion preventing material according to claim 3.   The bioabsorbable adhesion preventing material according to any one of claims 1 to 4, wherein the basic polysaccharide is chitosan.   The basic polysaccharide is a polysaccharide having glucosamine and N-acetylglucosamine as constituent monosaccharides, and the molar ratio of glucosamine: N-acetylglucosamine is 40: 60-60: 40. The bioabsorbable adhesion preventing material according to any one of 5.   The bioabsorbable adhesion prevention according to any one of claims 1 to 6, wherein each of the acidic polysaccharide and the basic polysaccharide is a water-soluble polysaccharide at a pH of 1.0 to 14.0. Wood.   It is in the form of a sheet, The bioabsorbable adhesion preventing material according to any one of claims 1 to 7.   The bioabsorbable adhesion-preventing material according to any one of claims 1 to 7, which is in the form of powder.   A step of preparing an aqueous solution of the acidic polysaccharide and the basic polysaccharide according to any one of claims 1 to 7, a step of forming a polyion complex, and optionally, a step of imparting a shape. The method for producing a bioabsorbable adhesion preventing material according to any one of claims 9 to 10.   The polyion complex forming step includes adjusting a mixed aqueous solution of the acidic polysaccharide aqueous solution and the basic polysaccharide aqueous solution to pH 3 to 9 to form a polyion complex. A method for producing a bioabsorbable anti-adhesion material.   The step of forming the polyion complex includes adjusting the pH of the mixed aqueous solution of the acidic polysaccharide aqueous solution and the basic polysaccharide aqueous solution to pH 1 to 3, and then adjusting the pH to 3 to 9 to form a polyion complex. The method for producing a bioabsorbable antiadhesive material according to claim 11.   The step of forming the polyion complex includes adjusting the pH of the mixed aqueous solution of the acidic polysaccharide aqueous solution and the basic polysaccharide aqueous solution to pH 9 to 14, and then adjusting the pH to 3 to 9 to form the polyion complex. The method for producing a bioabsorbable antiadhesive material according to claim 11.   The shape imparting step of the polyion complex includes casting the dispersion of the polyion complex and drying to form a sheet, or pressing the polyion complex and drying to form a sheet. Item 14. A method for producing a bioabsorbable antiadhesive material according to any one of Items 10 to 13.   The bioabsorbable antiadhesive material according to any one of claims 10 to 13, wherein the step of imparting a shape of the polyion complex includes drying the polyion complex and crushing it into a powder. Production method.   A method for using a bioabsorbable anti-adhesion material, comprising sticking the polyion complex sheet according to claim 8 to a surface of a biological tissue.   A method for using a bioabsorbable antiadhesive material, characterized by spraying or applying the polyion complex powder according to claim 9 onto the surface of a living tissue.

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