JP2018033559A - Method for producing water-insoluble molded body, water-insoluble molded body, and adhesion preventing material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a water-insoluble molded body in which the inherent property of polyanionic polysaccharide as raw material is retained, as well as, since it is not necessary to use a chemical crosslinking agent, it is highly safe and has moderate flexibility (resiliency), stretchability, and sticking property, and to provide a water-insoluble molded body produced by the production method.SOLUTION: Provided is a method for producing water-insoluble molded body including a step in which a raw material molded body comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or an alcohol (excluding glycerin) is treated with a treatment liquid containing an acid anhydride to make the raw material molded body water insoluble.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a water-insoluble molded article, a water-insoluble molded article, and an adhesion preventing material.

  Polyanionic polysaccharides such as hyaluronic acid and alginic acid are known to exhibit moderate viscosity, adhesiveness, moisture retention, and biocompatibility. For this reason, these polyanionic polysaccharides and salts thereof are widely used as raw materials for medical materials, food materials, cosmetic materials and the like.

  Of these, hyaluronic acid is used for various applications such as foods, cosmetics, and pharmaceuticals because of its excellent physical properties such as water retention and high safety and biocompatibility. For example, in the medical field, hyaluronic acid is used as a raw material for joint lubricants and anti-adhesion materials. However, since sodium hyaluronate as a raw material has high water solubility, it is necessary to perform some insolubilization treatment depending on the application. Various additives may be added to improve the physical properties of the product.

  Until now, various methods for insolubilizing sodium hyaluronate by a crosslinking reaction utilizing a carboxy group have been studied. For example, Patent Document 1 describes a method for producing a water-insoluble derivative of a polyanionic polysaccharide such as hyaluronic acid or carboxymethylcellulose by a crosslinking reaction using carbodiimide.

  Patent Documents 2 and 3 describe a method for water-insolubilizing polyanionic polysaccharides such as hyaluronic acid and carboxyalkyl cellulose by ionic bonding using a polyvalent cation. Furthermore, Patent Document 4 describes a method for obtaining a water-insolubilized film by ion-exchanging carboxymethyl cellulose using a metal salt.

  Patent Document 5 describes a method in which an aqueous sodium hyaluronate solution is cooled to −20 ° C. under acidic conditions to form intramolecular crosslinks and thereby insolubilize in water. Patent Document 6 describes a gel containing hyaluronic acid, a polyhydric alcohol, an acid, and a water-soluble organic solvent. Furthermore, Patent Document 7 describes a cosmetic gel sheet containing carboxy group-containing water-soluble polymer, polyhydric alcohol, and acid as essential components, and Patent Document 8 discloses a raw material molded body made of sodium hyaluronate. Is described in which water is insolubilized by treatment with acetic anhydride.

Special table 2003-518167 gazette JP-A-5-124968 JP 2008-13510 A JP-A-6-128395 JP 2003-252905 A JP-A-8-53501 JP-A-5-58881 International Publication No. 2015/029892

  However, since the method described in Patent Document 1 uses a cross-linking agent, it is often difficult to apply when considering the safety of uses such as pharmaceuticals that are imparted to the human body. Patent Documents 2 to 4 do not describe any degree of water insolubility of the obtained film or the like.

  Furthermore, in the method described in Patent Document 5, it is necessary to adjust the pH of the sodium hyaluronate aqueous solution to about 1.2, and the viscosity is remarkably increased, so that handling such as molding is difficult. In addition, since freeze-drying over a long period of time, there is also a problem in terms of power cost required for cooling. Furthermore, when the sodium hyaluronate aqueous solution is placed under acidic conditions, the viscosity increases rapidly, so that molding becomes difficult and uses may be limited. In Patent Document 5, the intramolecular cross-linked structure is confirmed, but the degree of insolubilization is not mentioned.

  Moreover, although the acid, alcohol, etc. are added to the gel sheet etc. which were described in patent documents 6 and 7, the gel itself is not water-insoluble. For this reason, it was difficult to maintain the gel shape in a saturated state.

  According to the method described in Patent Document 8, it is not possible to produce a water-insoluble molded article useful as a medical material such as an anti-adhesion material, in which characteristics such as hyaluronic acid as a raw material are maintained. It was. However, the physical properties such as flexibility and stretchability of the water-insoluble molded product to be produced may still be insufficient depending on the application, and there is room for improvement.

  The present invention has been made in view of such problems of the prior art, and the problem is that the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and a chemical crosslinking agent is used. An object of the present invention is to provide a method for producing a water-insoluble molded article having high safety because it does not need to be used and having moderate flexibility (flexibility), stretchability, and sticking property. Moreover, the place made into the subject of this invention is providing the water-insoluble molded object and adhesion prevention material which are manufactured by said method.

That is, according to the present invention, the following method for producing a water-insoluble molded article is provided.
[1] A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or an alcohol (excluding glycerin) is treated with a treatment liquid containing an acid anhydride, and the raw material molded body A method for producing a water-insoluble molded article having a step of making water insoluble (hereinafter also referred to as “first production method”).
[2] The method for producing a water-insoluble molded article according to [1], wherein the acid component is at least one of citric acid and hydrochloric acid.
[3] The method for producing a water-insoluble molded article according to [1], wherein the alcohol is at least one of ethanol and methanol.
[4] A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride and at least one acid component of a polycarboxylic acid and a hydroxy acid, A method for producing a water-insoluble molded article comprising a step of water-insolubilizing the raw material molded article (hereinafter also referred to as “second production method”).
[5] The method for producing a water-insoluble molded article according to [4], wherein the polycarboxylic acid is at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid.
[6] The method for producing a water-insoluble molded article according to [4] or [5], wherein the hydroxy acid is citric acid.
[7] The method for producing a water-insoluble molded article according to any one of [1] to [6], wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid. .
[8] The method for producing a water-insoluble molded article according to any one of [1] to [7], wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.

Moreover, according to this invention, the water-insoluble molded object shown below is provided.
[9] A water-insoluble molded product produced by the production method according to any one of [1] to [8].

Furthermore, according to this invention, the adhesion prevention material shown below is provided.
[10] An adhesion-preventing material obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the water-insoluble molded article according to [9].

  According to the present invention, the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and since there is no need to use a chemical cross-linking agent, the safety is high, and appropriate flexibility (flexibility), expansion and contraction are achieved. The manufacturing method of the water-insoluble molded object which has adhesiveness and sticking property can be provided. Moreover, according to this invention, the water-insoluble molded object manufactured by said manufacturing method and the adhesion preventing material using the same can be provided.

  Embodiments of the present invention will be described below, but the present invention is not limited to the following embodiments.

(Water-insoluble molded product and method for producing the same)
The method for producing a water-insoluble molded product (first production method) of the present invention comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or alcohol (excluding glycerin). And a process (water insolubilization process) of treating with a treatment liquid containing an acid anhydride to insolubilize the raw material molded body. Further, the method for producing a water-insoluble molded product of the present invention (second production method) comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide, an acid anhydride, a polycarboxylic acid and a hydroxy It has the process (water insolubilization process) of processing with the process liquid containing at least any acid component of an acid, and making a raw material molded object water-insolubilized. Hereinafter, the detail of the manufacturing method of the water-insoluble molded object of this invention is demonstrated.

  The raw material molded body used in the water insolubilization step is formed using a raw material containing a water-soluble salt of a polyanionic polysaccharide. Moreover, the raw material molded object used at the water insolubilization process of a 1st manufacturing method is formed using the raw material which further contains an acid component or alcohol (except glycerol) other than the water-soluble salt of polyanionic polysaccharide. The The reason is not clear, but by using a raw material containing an acid component or alcohol, the flexibility, stretchability, and stickiness are higher than when using a raw material not containing an acid component or alcohol. An improved water-insoluble molded product can be produced.

  The content of the acid component in the raw material is preferably 0.2% by mass or more, and more preferably 0.25 to 1.0% by mass. Further, the content of alcohol in the raw material is preferably 25% by mass or more, and more preferably 50% by mass or more. Further, the raw material may further contain a radiopaque agent such as a contrast agent such as barium sulfate.

  As the acid component, it is preferable to use at least one of citric acid and hydrochloric acid. Among these, when citric acid is used, the stretchability and flexibility of the obtained water-insoluble molded product can be further improved. Moreover, as alcohols, it is preferable to use at least one of ethanol and methanol.

  The polyanionic polysaccharide is a polysaccharide having one or more negatively charged anionic groups such as a carboxy group and a sulfonic acid group in its molecular structure. The water-soluble salt of the polyanionic polysaccharide is a salt in which at least a part of the anionic group in the polyanionic polysaccharide forms a salt. The anionic group in the polyanionic polysaccharide may be introduced into the polysaccharide molecule.

  Specific examples of the polyanionic polysaccharide include carboxyalkyl cellulose such as carboxymethyl cellulose and carboxyethyl cellulose, carboxymethyl starch, carboxymethyl amylose, chondroitin sulfate (including chondroitin-4-sulfate and chondroitin-6-sulfate), hyaluronic acid, Examples include heparin, heparin sulfate, heparan sulfate, alginic acid, pectin, carrageenan, dermatan sulfate, and dermatan-6-sulfate. These polyanionic polysaccharides can be used singly or in combination of two or more.

  Examples of water-soluble salts of polyanionic polysaccharides include inorganic salts, ammonium salts, and organic amine salts. Specific examples of the inorganic salt include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium salts; metal salts such as zinc and iron.

  The raw material molded body can be obtained, for example, by forming a raw material (aqueous solution) into a desired shape and then drying it. Examples of the shape of the raw material molded body include a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape. By insolubilizing the raw material molded body of these shapes, a water-insoluble molded body having a shape corresponding to the use such as a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape is obtained. Can do. If necessary, the obtained water-insoluble molded product may be further molded and processed into a desired shape.

  For example, an aqueous solution of a water-soluble salt of a polyanionic polysaccharide is poured into a suitable container, and then dried or freeze-dried to obtain a raw material molded body having a film shape (sheet shape) or a block shape (block shape, sponge shape). be able to. Moreover, a fibrous raw material molded body can be obtained by extruding an aqueous solution of a water-soluble salt of a polyanionic polysaccharide into a poor solvent from a nozzle. A rod-shaped raw material molded body can be obtained by filling an appropriate tube with an aqueous solution of a water-soluble salt of a polyanionic polysaccharide and then drying or freeze-drying. Moreover, a powdery or particulate raw material molded body can be obtained by pulverizing the dried polyanionic polysaccharide. Thus, according to the method for producing a water-insoluble molded article of the present invention, a water-insoluble molded article having a shape suitable for the use is obtained because the water-insoluble treatment is performed after the polyanionic polysaccharide is molded into a desired shape. Can do.

  The treatment liquid used for treating the raw material molded body contains an acid anhydride. Specific examples of the acid anhydride include acetic anhydride, propionic anhydride, succinic anhydride, butyric anhydride, phthalic anhydride, and maleic anhydride. Of these, acetic anhydride and propionic anhydride are preferable. These acid anhydrides can be used singly or in combination of two or more.

  Further, the treatment liquid used in the water insolubilization step of the second production method further contains at least one acid component of polycarboxylic acid and hydroxy acid in addition to the acid anhydride. The reason is not clear, but by treating the raw material molded body with a treatment liquid containing these acid components, it is more flexible than when the raw material molded body is treated with a treatment liquid not containing these acid components. In addition, a water-insoluble molded article having improved stretchability and sticking property can be produced. In addition, it is preferable that content of the acid component in a process liquid is 1 mass% or more, and it is more preferable that it is 1.5-5.0 mass%.

  Of the acid components blended in the treatment liquid, it is preferable to use at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid as the polycarboxylic acid. Especially, when malonic acid is used, the stretchability, stickability, and flexibility of the resulting water-insoluble molded product can be further improved. Moreover, it is preferable to use a citric acid as a hydroxy acid among the acid components mix | blended with a process liquid. By using citric acid, the stretchability, sticking property, and flexibility of the obtained water-insoluble molded product can be further improved.

  The treatment liquid preferably further contains at least one medium of water and a water-soluble organic solvent, and the acid anhydride is preferably dissolved or dispersed in this medium. By using a treatment liquid in which an acid anhydride is dissolved or dispersed in such a medium, it is possible to sufficiently and quickly insolubilize the raw material molded body.

  Specific examples of the water-soluble organic solvent include methanol, ethanol, propanol, dimethyl sulfoxide (DMSO), acetonitrile, and tetrahydrofuran. Of these, methanol, ethanol, and dimethyl sulfoxide are preferable. These water-soluble organic solvents can be used alone or in combination of two or more.

  The concentration of the acid anhydride in the treatment liquid is usually 0.1 to 50% by mass, and preferably 5 to 30% by mass. When the concentration of the acid anhydride is less than 0.1% by mass, the degree of water insolubilization of the resulting water-insoluble molded article tends to be insufficient, or it takes a long time for water insolubilization. On the other hand, when the concentration of the acid anhydride exceeds 50% by mass, the effect tends to reach its peak.

  In addition, since a polyanionic polysaccharide has high hydrophilicity, it is preferable that a process liquid contains water as a medium from a viewpoint of water-insolubilizing a raw material molded object more fully and rapidly. The content of water in the treatment liquid is preferably set to such an extent that the raw material molded body does not dissolve or swell. Specifically, the content of water in the treatment liquid is preferably 0.01 to 50% by mass, and more preferably 5 to 20% by mass. If the content of water in the treatment liquid is less than 0.01% by mass, water insolubilization may be insufficient with a solvent other than methanol. Moreover, when the content of water in the treatment liquid is more than 50% by mass, it may be difficult to maintain the shape of the obtained water-insoluble molded article.

  In the water insolubilization step, the raw material molded body is treated with a treatment liquid containing an acid anhydride. By treating the raw material molded body with the treatment liquid, the raw material molded body is insolubilized while maintaining its shape, and a water-insoluble molded body is formed. The method of treating the raw material molded body with the treatment liquid is not particularly limited, but it is preferable to treat the raw material molded body so that the treatment liquid contacts the entire raw material molded body and penetrates into the raw material molded body. Specific examples of the treatment method include a method of immersing the raw material molded body in the treatment liquid and applying or spraying (spraying) the treatment liquid onto the raw material molded body.

  In the case where the powdery or particulate raw material molded body is treated to make it water-insoluble, first, the powdery or particulate raw material molded body is made of the water-soluble salt of the polyanionic polysaccharide constituting the raw material molded body. Disperse in a poor solvent. Next, the treatment liquid may be added, the powder or particulate raw material molded body dispersed in the poor solvent is brought into contact with the treatment liquid, and the raw material molded body may be treated with the treatment liquid. As the poor solvent, methanol, ethanol, propanol, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or the like can be used. These poor solvents can be used alone or in combination of two or more. In addition, this poor solvent may contain a trace amount of water to such an extent that the powdery or particulate raw material molded body does not dissolve.

  Moreover, the temperature at the time of a process should just be the temperature which does not exceed the boiling point of a process liquid, and is not specifically limited. From the viewpoint of suppressing degradation and modification of the polyanionic polysaccharide, and from the viewpoint of suppressing volatilization of the medium and by-products, the temperature during the treatment is preferably 0 to 80 ° C, and preferably 0 to 70 ° C. It is further more preferable, and it is especially preferable to set it as room temperature (25 degreeC)-60 degreeC. However, if the treatment liquid is not volatilized during the treatment, for example, heat treatment or a heat roller, a water-insoluble molded article can be obtained in a shorter time without causing decomposition and modification. For example, when processing by a heat press, a heat roller, etc., it is preferable that the temperature at the time of processing shall be 50-90 degreeC, and it is preferable that processing time shall be 30 minutes or less. After the water insolubilization step, the water-insoluble molded product of the present invention can be obtained by washing with water or a water-soluble organic solvent as necessary.

  The reaction assumed when the raw material molded object formed using the sodium salt of polyanionic polysaccharide is processed with the alcohol solution of acetic anhydride is shown below. In addition, although the assumed reaction can be one factor of water insolubilization, there is a possibility that water insolubilization is caused by a combination with other water insolubilization factors or completely different factors. That is, this invention is not limited at all by the following reaction assumed.

In reaction formula (1), R ₁ represents the main chain of the polyanionic polysaccharide, and R ₂ represents the main chain of the alcohol. When acetic anhydride is cleaved in the presence of alcohol, it deprives the polyanionic polysaccharide of sodium and the carboxy group changes from the sodium salt form to the acid form. This can be confirmed by measuring the Na content in the water-insoluble molded article or titrating the water-insoluble molded article with an alkaline solution.

  When water is present in the reaction system, in addition to the reaction represented by the above reaction formula (1), the reaction represented by the following formula (2) proceeds simultaneously, and the carboxy group changes from the sodium salt type to the acid type. is expected.

  In the obtained water-insoluble molded product, all anionic groups in the molecule may not be in the acid form.

  Even if a raw material molded body formed using a water-soluble salt of a polyanionic polysaccharide is immersed in an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, it is extremely difficult to obtain a molded body sufficiently insoluble in water. Further, even if the acid anhydride in the treatment liquid is replaced with an acid corresponding to this acid anhydride, a water-insoluble molded product cannot be obtained. From this, it is expected that a water-insoluble molded product is obtained by adding factors other than the change of the anionic group of the polyanionic polysaccharide to the acid type.

  Since it is not necessary to use a chemical crosslinking agent in the method for producing a water-insoluble molded article of the present invention, a structure such as a functional group derived from the chemical crosslinking agent is incorporated in the molecule constituting the obtained water-insoluble molded article. There is nothing. For this reason, the water-insoluble molded product of the present invention produced by the above production method retains the original characteristics of the polyanionic polysaccharide as a raw material and has high safety. Therefore, the water-insoluble molded product of the present invention is suitable as a medical material such as an adhesion preventing material. In addition, when using the water-insoluble molded object of this invention as a constituent material of an adhesion preventing material, the thickness of a water-insoluble molded object is although it does not specifically limit, Preferably it is 20-200 micrometers, More preferably, it is 60-120 micrometers.

(Adhesion prevention material)
The anti-adhesion material of the present invention is obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the water-insoluble molded article. Specific examples of the polyhydric alcohol include ethylene glycol, diethylene glycol, polyethylene glycol, methylglycerol, polyoxyelene glycoside, maltitol, mannitol, xylitol, sorbitol, reduced starch syrup, dipropylene glycol, butylene glycol, valine, propylene glycol, Examples thereof include glycerin (glycerol), polyglycerin, and glycerin fatty acid ester. Of these, polyhydric alcohols used in the medical field and food field such as glycerin, xylitol, sorbitol, and low molecular weight polyethylene glycol are preferably used. These suitably used polyhydric alcohols can be obtained from the market and used as they are. As for glycerin, sorbitol, etc., it is desirable to use those suitable for the Japanese Pharmacopoeia. Glycerin is particularly preferable because it is a material that is safe enough to be used as an intravenous injection.

  Examples of the method for retaining the polyhydric alcohol or the polyhydric alcohol aqueous solution in the water-insoluble molded body include a method of immersing the water-insoluble molded body in the polyhydric alcohol or a polyhydric alcohol aqueous solution having a predetermined concentration. That is, by immersing a water-insoluble molded article having a predetermined shape in a polyhydric alcohol aqueous solution and replacing the interior of the water-insoluble molded article with the polyhydric alcohol aqueous solution, the polyhydric alcohol aqueous solution having a desired concentration is retained, The adhesion preventing material of the present invention can be obtained. In addition, the thickness of the adhesion preventing material of the present invention is not particularly limited, but is preferably 20 to 200 μm, and more preferably 60 to 120 μm.

(Injection material)
The injection material contains a water-insoluble molded body having a powder or particle shape among the water-insoluble molded bodies described above. The injection material may further contain a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that has not been insolubilized in water. As described above, the water-insoluble molded body constituting the injection material can be manufactured without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are maintained, it is safe to use. Are better. In addition, since the injection material contains a powdery or particulate water-insoluble molded product, it has high fluidity and can be easily injected into the affected area via an injection needle by appropriately adjusting the particle size of the powder or particles. can do. Therefore, the injection material is useful as, for example, an intra-articular injection for joint deformation treatment, a subcutaneous injection, or the like.

(Slow release formulation)
The sustained-release preparation contains the above-mentioned water-insoluble molded article and a pharmaceutically acceptable active ingredient. As described above, the water-insoluble molded article constituting the sustained-release preparation can be produced without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are retained, it is safe. Excellent in properties. Further, since the water-insoluble molded article is gradually decomposed and absorbed in the living body, the active ingredient can be gradually released. The type of active ingredient is not particularly limited as long as it is pharmaceutically acceptable.

  Examples of sustained-release preparations include, for example, a water-insoluble molded product formed into a sheet shape impregnated with an active ingredient or a solution thereof, a capsule made of a water-insoluble molded product, and a capsule enclosed in this capsule. And those composed of active ingredients. By appropriately setting the thickness, shape, etc. of the sheet or capsule, the sustained release in vivo can be controlled.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to these Examples. In the examples and comparative examples, “parts” and “%” are based on mass unless otherwise specified.

Details of the reagents used are shown below. As the water, water having an electrical conductivity of 18.0 MΩ · cm or more prepared using an ultrapure water production apparatus (manufactured by Sartorius Japan) was used.
Sodium hyaluronate: manufactured by Shiseido Co., Ltd., molecular weight 1.5 million Da
Citric acid: Wako Pure Chemical Industries, reagent special grade Glycerin: Sakamoto Yakuhin Kogyo Co., Japan Pharmacopoeia Hydrochloric acid: Wako Pure Chemical Industries, reagent special grade Ethanol: Junsei Chemical Co., reagent special grade Methanol: Wako Pure Chemical Industries, reagent Special grade Acetic anhydride: Wako Pure Chemical Industries, reagent special grade Malonic acid: Wako Pure Chemical Industries, reagent special grade Oxalic acid: Wako Pure Chemical Industries, reagent special grade Succinic acid: Wako Pure Chemical Industries, reagent special grade

<Production of water-insoluble molded product (hyaluronic acid film) (1)>
(Examples 1-6, Comparative Example 1)
Each component was mixed so that it might become the mixture ratio (unit:%) shown in the upper stage of Table 1, and sodium hyaluronate aqueous solution was prepared. 100 g of the prepared aqueous solution was poured into a stainless tray having a length of 12 cm and a width of 10 cm and dried in a constant temperature bath at 20 ° C. to obtain a sodium hyaluronate film. The obtained film was immersed in a treatment solution (acetic anhydride: 75% ethanol solution = 80: 20) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.

<Production of water-insoluble molded product (hyaluronic acid film) (2)>
(Examples 7 to 10)
Each component was mixed so that it might become the compounding quantity (unit: g) shown in the upper stage of Table 2, and sodium hyaluronate aqueous solution was prepared. The total amount of the prepared aqueous solution was poured into a stainless tray having a length of 12 cm and a width of 10 cm, and dried in a constant temperature bath at 20 ° C. to obtain a sodium hyaluronate film. The obtained film was immersed in a treatment solution (acetic anhydride: 75% ethanol solution = 80: 20) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.

<Production of water-insoluble molded product (hyaluronic acid film) (3)>
(Examples 11 to 16, Comparative Example 2)
100 parts of an aqueous solution containing 1 part of sodium hyaluronate powder was prepared. 100 g of the prepared aqueous solution was poured into a stainless tray having a length of 12 cm and a width of 10 cm and dried in a constant temperature bath at 20 ° C. to obtain a sodium hyaluronate film. On the other hand, each component was mixed so as to have a blending ratio (unit:%) shown in the upper part of Table 3 to prepare a treatment liquid. The obtained films were immersed in the prepared treatment solution and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.

<Evaluation>
(Elasticity)
The produced water-insoluble hyaluronic acid film was immersed in water and sufficiently swollen, and the stretchability was evaluated according to the following evaluation criteria. The results are shown in Tables 1-3.
A: There is an elongation of 10% or more of the total length before pulling and breaking.
B: There is an elongation of 5% or more and less than 10% of the total length before pulling and breaking.
C: There is an elongation of 1% or more and less than 5% of the total length until it is pulled and broken.
D: Elongation until pulling and breaking is less than 1% of the total length.

(Adhesiveness)
The produced water-insoluble hyaluronic acid film was immersed in water and sufficiently swollen, and the sticking property was evaluated according to the following evaluation criteria. The results are shown in Tables 1-3.
a: When affixed to a hand, it clings and is difficult to peel off.
b: When attached to a hand, it cannot be easily peeled off.
c: Affixed to the hand, but can be easily peeled off.
d: It does not stick to the hand and moves easily when the hand is moved.

(Flexibility)
Using the produced water-insoluble hyaluronic acid film immersed in water and sufficiently swollen, the flexibility was evaluated according to the following evaluation criteria. The results are shown in Tables 1-3.
1: It is not broken even if it is made into two folds and the crease is strongly crushed.
2: Even if it is made into two folds and the crease is pushed strongly, it does not break.
3: Can be folded into two folds, but breaks when pressed strongly.
4: Cracked when folded in two.

  From the results shown in Table 1, it can be seen that by adding an acid component to the raw material forming the sodium hyaluronate film, the stretchability and flexibility of the resulting water-insoluble hyaluronic acid film are improved. Especially, it turns out that the improvement effect by a citric acid is large.

  From the results shown in Table 2, it can be seen that the elasticity and flexibility of the water-insoluble hyaluronic acid film obtained can be improved by adding alcohols to the raw material for forming the sodium hyaluronate film. The improvement effect by ethanol and the improvement effect by methanol were almost the same.

  From the results shown in Table 3, it can be seen that the addition of polycarboxylic acid or hydroxy acid to the treatment liquid improves the stretchability, stickiness, and flexibility of the resulting water-insoluble hyaluronic acid film. Especially, it turns out that the improvement effect by malonic acid or a citric acid is large.

(Solubility test)
The produced water-insoluble hyaluronic acid film was cut into 2 cm square, placed in a container having a diameter of 3.5 cm and a depth of 1.5 cm, and 5 mL of PBS buffer (pH 6.8) was added. This container was put into a shaker adjusted to 37 ° C., shaken at 10 to 20 rpm, and the state change with time was visually observed. As a result, it was found that the original form of the film was retained and water insolubilized for each film even after 72 hours. Further, the degree of swelling (swelled film / dry film (mass ratio)) was in the range of 1.8 to 2.5 for all films.

(Animal experimentation)
The membranes produced in Examples 1, 7, and 11 were each immersed in a 10% by volume glycerin aqueous solution, then air-dried and sealed in a sterilization bag. The anti-adhesion membrane was obtained by sterilizing the entire sterilization bag with irradiation of 25 kGy. An adult dog (beagle dog, female, 1.5 years old, weight about 10 kg) was opened after general anesthesia treatment, and the epidermis epidermis was peeled into 3 cm square. The abdomen was closed by placing an adhesion-preventing membrane so as to cover the peeled portion. Two weeks later, the dog was laparotomized after general anesthesia, and no adhesion occurred in any of the membranes. In addition, the anti-adhesion membrane placed (implanted) in the dog's body disappeared two weeks after implantation. This is presumed that the carboxy group of hyaluronic acid constituting the anti-adhesion membrane was gradually neutralized by sodium ions etc. in the living body, and changed into soluble hyaluronate, dissolved and absorbed into the living body. The On the other hand, it was observed that adhesion occurred in the peeled portion and the intestine in dogs that were closed without placing an anti-adhesion membrane.

  The water-insoluble molded product of the present invention can be suitably used, for example, as a constituent material of an adhesion preventing material.

Claims (10)

  A raw material formed from a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or an alcohol (excluding glycerin) is treated with a treatment solution containing an acid anhydride, and the raw material formed is water-insolubilized. The manufacturing method of the water-insoluble molded object which has a process to make.   The method for producing a water-insoluble molded article according to claim 1, wherein the acid component is at least one of citric acid and hydrochloric acid.   The method for producing a water-insoluble molded product according to claim 1, wherein the alcohol is at least one of ethanol and methanol.   A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride and at least one acid component of a polycarboxylic acid and a hydroxy acid, and the raw material molding is performed. A method for producing a water-insoluble molded article comprising a step of water-insolubilizing a body.   The method for producing a water-insoluble molded article according to claim 4, wherein the polycarboxylic acid is at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid.   The method for producing a water-insoluble molded article according to claim 4 or 5, wherein the hydroxy acid is citric acid.   The method for producing a water-insoluble molded product according to any one of claims 1 to 6, wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid.   The method for producing a water-insoluble molded product according to any one of claims 1 to 7, wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.   The water-insoluble molded object manufactured by the manufacturing method as described in any one of Claims 1-8.   An adhesion preventive material comprising a water-insoluble molded product according to claim 9 and a polyhydric alcohol or a polyhydric alcohol aqueous solution held therein.