JP2019037608A - Method of manufacturing flexible molded body, and flexible molded body - Google Patents

Abstract

To provide a method of manufacturing a flexible molded body, with which the flexible molded body excellent in flexibility and smoothness can be easily manufactured, and a flexible molded body manufactured by using the method.SOLUTION: There is provided a method of manufacturing a flexible molded body including a step in which a first raw material molded body comprising a raw material containing a water-soluble salt of polyanionic polysaccharide and a monosaccharide is water-insolubilized. There is also provided a method of manufacturing flexible molded body including: a step in which a second raw material molded body comprising a raw material containing a water-soluble salt of polyanionic polysaccharide is water-insolubilized; and a step in which a solution containing monosaccharide is impregnated into the water-insolubilized second raw material molded body.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a flexible molded body and a flexible molded body.

  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 water insolubilization treatment depending on the application.

  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 that acetylation is performed by reacting powdered hyaluronic acid and acetic anhydride in the presence of concentrated sulfuric acid. Furthermore, Patent Document 7 describes a method for producing a hyaluronic acid gel using an acidic liquid containing alcohol. Patent Document 8 describes a method in which a raw material molded body containing a water-soluble salt of hyaluronic acid and glycerin is treated with an acid anhydride to make it water-insoluble.

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 Japanese Patent Laid-Open No. 2006-163695

  However, all of the molded articles produced by the methods described in Patent Documents 1 to 7 have low flexibility and have not necessarily been excellent in flexibility. 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.

  Patent Document 6 does not describe any degree of water insolubility of the obtained acetylated product of hyaluronic acid. Furthermore, since the hyaluronic acid gel obtained by the method described in Patent Document 7 contains a large amount of moisture, it is difficult to lift. For this reason, it is difficult to insolubilize while maintaining the shape of the molded body. In addition, according to the method described in Patent Document 8, it was possible to insolubilize water while maintaining the shape of the raw material molded body containing the water-soluble salt of hyaluronic acid. However, since glycerin is contained in the water-insolubilized molded article, for example, when used as a medical material, glycerin may function as a radical scavenger, and the sterilization effect may be reduced. there were. For this reason, in order to fully sterilize, it was necessary to increase the radiation dose. In addition, when attempting to sterilize with ethylene oxide gas, epichlorohydrin may be generated due to the reaction between glycerin and ethylene oxide. For this reason, the process for removing epichlorohydrin may be needed, and the manufacturing process may become complicated.

  The present invention has been made in view of such problems of the prior art, and the object is to provide a flexible molded article having good transparency and excellent flexibility and smoothness. It is in providing the manufacturing method of the flexible molded object which can manufacture easily. Another object of the present invention is to provide a flexible molded article excellent in flexibility and smoothness.

  According to the present invention, a method for producing a flexible molded body having a step of water-insolubilizing a first raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and a monosaccharide (hereinafter referred to as “first Also referred to as "manufacturing method").

  Furthermore, according to the present invention, a step of water-insolubilizing the second raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide, and monosaccharides are added to the water-insoluble second raw material molded body. And a step of impregnating the contained solution with a flexible molded body (hereinafter also referred to as “second manufacturing method”).

  Moreover, according to this invention, the flexible molded object manufactured by said manufacturing method is provided.

  ADVANTAGE OF THE INVENTION According to this invention, while being excellent in flexibility and smoothness, the manufacturing method of the flexible molded object which can manufacture easily the flexible molded object with favorable transparency can be provided. Moreover, according to this invention, while being excellent in flexibility and smoothness, the flexible molded object with favorable transparency can be provided.

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

<Flexible molded body and manufacturing method thereof>
The method for producing a flexible molded body of the present invention (first production method) is a step of water-insolubilizing a first raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and a monosaccharide (first). Water insolubilization step). Moreover, the manufacturing method (2nd manufacturing method) of the flexible molded object of this invention is the process (2nd manufacturing method) which water-solubilizes the 2nd raw material molded object which consists of a raw material containing the water-soluble salt of polyanionic polysaccharide. A water insolubilization step) and a step of impregnating the water-insolubilized second raw material molded body with a solution containing a monosaccharide (impregnation step). And the flexible molded object of this invention is manufactured by these manufacturing methods. Hereinafter, the details of the flexible molded article and the method for producing the same according to the present invention will be described.

  The first raw material molded body is formed using a raw material containing a water-soluble salt of a polyanionic polysaccharide and a monosaccharide. The second raw material molded body is formed using a raw material containing a water-soluble salt of a polyanionic polysaccharide. 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 used for forming the first raw material molded body contains a monosaccharide together with a water-soluble salt of a polyanionic polysaccharide. Moreover, although the raw material used in order to form a 2nd raw material molded object contains the water-soluble salt of polyanionic polysaccharide, it does not need to contain a monosaccharide. However, the raw material used for forming the second raw material molded body may further contain a monosaccharide. Examples of monosaccharides include glucose, galactose, fructose, mannose and the like. Of these, glucose is preferably used. Although the reason is not clear, by using a raw material containing monosaccharides such as glucose, a flexible molded article having excellent flexibility and improved flexibility and smoothness can be produced. That is, the monosaccharide is considered to function as a flexible component that imparts flexibility to a molded body made of a polyanionic polysaccharide. In addition, it is preferable to set it as 0.1-5 mass%, and, as for content of the monosaccharide in a raw material, it is more preferable to set it as 0.25-3 mass%.

  Examples of the flexible component that imparts flexibility to the molded body formed of the polymer compound include urea. However, when urea is used in place of the monosaccharide, urea crystals are likely to precipitate, and a white turbid and opaque molded product tends to be formed. Moreover, it is not possible to produce a flexible molded article having improved flexibility and smoothness by using disaccharides or polysaccharides such as sucrose instead of monosaccharides. When glycerin is used in place of the monosaccharide, it is possible to produce a flexible molded body, but the obtained flexible molded body contains glycerin. For this reason, as mentioned above, the subject that the sterilization process in the case of using as a medical material becomes complicated arises. On the other hand, by using a monosaccharide, it is excellent in flexibility and smoothness, does not become cloudy, can be easily sterilized thereafter, and can easily obtain a flexible molded article having good transparency. Can do.

  The first raw material molded body can be obtained, for example, by forming a raw material (aqueous solution) obtained by dissolving a water-soluble salt of a polyanionic polysaccharide and a monosaccharide in water into a desired shape, followed by drying or the like. it can. In addition, the second raw material molded body can be obtained, for example, by forming a raw material (aqueous solution) obtained by dissolving a water-soluble salt of a polyanionic polysaccharide in water into a desired shape, followed by drying. . Examples of the shape of the raw material molded body include a sheet shape, a film shape, a sponge shape, a string shape, a powder shape, and a particle 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 sheet shape, a film shape, a sponge shape, a string shape, a powder shape, and a particle shape can be obtained. If necessary, the obtained water-insoluble molded product may be further molded and processed into a desired shape.

  For example, by pouring an aqueous solution of a water-soluble salt (and monosaccharide) of a polyanionic polysaccharide into a suitable container, and then drying or freeze-drying, a sheet-shaped, film-shaped, or sponge-shaped raw material molded body is obtained. Can do. Moreover, a fibrous raw material molded body can be obtained by extruding an aqueous solution of a water-soluble salt (and monosaccharide) of a polyanionic polysaccharide into a poor solvent from a nozzle. A string-shaped raw material molded body can be obtained by filling a suitable tube with an aqueous solution of a water-soluble salt (and monosaccharide) of a polyanionic polysaccharide and then drying or freeze-drying. In addition, a powdered or particulate raw material molded body can be obtained by pulverizing the dried water-soluble salt (and monosaccharide) of the polyanionic polysaccharide. Thus, according to the manufacturing method of this invention, since the raw material molded object shape | molded in the desired shape is water-insolubilized, the flexible molded object of the shape according to a use can be obtained.

  The method for water insolubilizing the raw material molded body is not particularly limited, and a conventionally known method for water insolubilizing a raw material molded body made of a water-soluble salt of a polyanionic polysaccharide can be employed. Specific examples of the method of water insolubilizing the raw material molded body include a method of chemically cross-linking using a cross-linking agent to insolubilize water; a method of irradiating with an electron beam and cross-linking to insolubilize water; And a method of cross-linking by ionic bond to insolubilize the water; contacting with a treatment solution containing an acid anhydride to insolubilize in water; and the like. Among these, it is preferable to bring the raw material molded body into contact with a treatment liquid containing an acid anhydride because it is simple and can sufficiently and quickly insolubilize the raw material molded body. Regarding the reaction mechanism assumed when a raw material molded body formed using a water-soluble salt of polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride such as acetic anhydride, for example, International Publication No. It is disclosed in 2015/029892, JP-A-2016-163695, and the like.

  Specific examples of the acid anhydride used in the treatment liquid 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.

  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 flexible 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 resulting flexible molded body.

  In the water insolubilization process, it is preferable to bring the raw material molded body into water insolubility by bringing the raw material molded body into contact with a treatment liquid containing an acid anhydride. By bringing the raw material molded body into contact with the treatment liquid, the raw material molded body can be insolubilized while maintaining its shape, and a flexible molded body having a corresponding shape can be obtained. The method of bringing the raw material molded body into contact with the treatment liquid is not particularly limited, but it is preferable that the treatment liquid is in contact with the entire raw material molded body and the treatment liquid 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 is added, and the powder or particulate raw material molded body dispersed in the poor solvent may be brought into contact 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.

  The temperature during the treatment is not particularly limited as long as it does not exceed the boiling point of the treatment liquid. 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 is performed under conditions where the treatment liquid does not evaporate, for example, a heat press or a heat roller, the treatment can be carried out in a shorter time without causing degradation 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. In the first production method, the flexible molded body can be obtained by washing with water, a water-soluble organic solvent, or the like as necessary after the water insolubilization step.

  The second production method further includes a step (impregnation step) of impregnating the solution containing the monosaccharide into the second raw material molded body insolubilized in water. By impregnating the second raw material molded body with a solution containing a monosaccharide, the shape of the second raw material molded body can be substantially maintained, and a flexible molded body having a corresponding shape can be obtained. Examples of monosaccharides include glucose, galactose, fructose, mannose and the like. Of these, glucose is preferably used. The reason is not clear, but by impregnating the water-insolubilized second raw material molded body with a solution containing monosaccharides such as glucose, the flexibility is excellent, and the flexibility and smoothness are improved. A flexible molded body can be produced.

  The method for impregnating the water-insolubilized second raw material molded body with the monosaccharide-containing solution is not particularly limited, but the solution contacts the entire water-insoluble second raw material molded body and reaches the inside. It is preferable to process so that a solution may osmose | permeate. Specific examples of the method include immersing the water-insolubilized second raw material molded body in the solution, and applying or spraying (spraying) the solution onto the water-insoluble raw material molded body.

  From the viewpoint of quickly impregnating the water-insolubilized second raw material molded body with a solution containing monosaccharides, it is preferable to use an aqueous solution (monosaccharide aqueous solution) in which monosaccharides are dissolved in water. The monosaccharide content in the monosaccharide aqueous solution is preferably 1 to 30% by mass, and more preferably 5 to 20% by mass.

  When the raw material molded body is water-insolubilized by contacting with a treatment solution containing an acid anhydride, that is, when the raw material molded body is water-insolubilized without using a crosslinking agent, the resulting flexible molded body becomes a crosslinking agent. Structures such as derived functional groups are not incorporated. For this reason, the flexible molded body obtained by bringing the raw material molded body into water-insoluble by contacting with a treatment solution containing an acid anhydride retains the original characteristics of the polyanionic polysaccharide that is the raw material, and is more safe Therefore, it is suitable as an adhesion prevention material. In addition, when using the flexible molded object of this invention as a film-like adhesion prevention material, the thickness of a flexible molded object is although it does not specifically limit, Preferably it is 20-200 micrometers, More preferably, it is 60-120 micrometers.

  As used herein, “water-insoluble” means a property that does not easily dissolve in water. More specifically, in the flexible molded body of the present invention, the mass of the dried body obtained by repeating the drying operation after being swollen with water twice is 80% or more of the dry mass before this operation. .

  The swelling ratio of the flexible molded article of the present invention is preferably 6,000% by mass or less, more preferably 900% by mass or less, particularly preferably 100 to 500% by mass, and 150 to 350%. Most preferably, it is mass%. Thus, among the flexible molded articles of the present invention, those having a sufficiently low swelling rate are suitable as food materials and cosmetic materials in addition to medical materials such as anti-adhesion materials. In the present specification, the “swelling ratio” is the ratio (mass%) of the “mass of the flexible molded body after moisture retention (after swelling)” to the “mass of the flexible molded body before moisture retention (before swelling)”. ). In addition, by increasing the amount of water in the treatment liquid used in the water insolubilization step within a range not exceeding 20% by mass, for example, flexible molding with a relatively high swelling rate (for example, 6,000% by mass or less) The body can be manufactured. Further, by increasing the amount of acid anhydride in the treatment liquid (for example, an upper limit of 20% by mass), a flexible molded body having a relatively low swelling rate (for example, 500% by mass or less) can be produced.

  When the raw material molded body is brought into contact with a treatment solution containing an acid anhydride to insolubilize the raw material molded body, the molecules of the polyanionic polysaccharide constituting the resulting flexible molded body are not substantially crosslinked. Furthermore, a new covalent bond is not substantially formed in the polyanionic polysaccharide. However, it is presumed that physical bonds such as hydrogen bonds, hydrophobic bonds, and van der Waals forces are formed between the molecules of the polyanionic polysaccharide. The fact that such a physical bond is formed between molecules of the polyanionic polysaccharide can be confirmed by measuring an infrared absorption spectrum.

  The flexible molded article of the present invention is stably water-insoluble in a wide pH range from acidic to alkaline. However, for example, when contacted or immersed in an aqueous medium having a pH of 12 or more, physical bonds between molecules can be dissociated and easily dissolved.

  When the flexible molded body of the present invention is used as an adhesion preventing material, it is preferable that a polyhydric alcohol or a polyhydric alcohol aqueous solution is held inside the flexible molded body. 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 holding the polyhydric alcohol or the polyhydric alcohol aqueous solution in the flexible molded body include a method of immersing the flexible molded body in the polyhydric alcohol or a polyhydric alcohol aqueous solution having a predetermined concentration. That is, a flexible molded body having a predetermined shape is immersed in an aqueous solution of polyhydric alcohol or the like, and the inside of the flexible molded body is replaced with an aqueous solution of polyhydric alcohol or the like. An aqueous alcohol solution can be retained. 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.

  The injection material contains a flexible molded body having a powder or particle shape. 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. The injection material has high fluidity because it contains a powdered or particulate flexible molded body, and can be easily injected into the affected area or the like via an injection needle by appropriately adjusting the particle size of the powder or particles. be able to. For this reason, the injection material is useful as, for example, an intra-articular injection for joint deformation treatment, a subcutaneous injection, or the like.

  The sustained-release preparation contains the above-described flexible molded article and a pharmaceutically acceptable active ingredient. Since the flexible molded body 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 sheet-shaped or film-shaped flexible molded body impregnated with an active ingredient or a solution thereof, a capsule made of a flexible molded body, and 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.

<Preparation of reagents, etc.>
The following reagents were prepared.
-Sodium hyaluronate: manufactured by Shiseido Co., Ltd., molecular weight 1.5 million Da
・ Ethanol: Pure Chemical Co., reagent grade ・ Acetic anhydride: Wako Pure Chemical Co., reagent grade ・ Glycerin: Sakamoto Pharmaceutical Co., Japan Pharmacopoeia ・ Glucose: Wako Pure Chemical Co., reagent grade ・ Sucrose: Wako Jun Made by Yakuhin Co., Ltd., reagent special grade ・ Trehalose: Wako Pure Chemical Industries, reagent special grade ・ Urea: Wako Pure Chemical Industries, reagent special grade ・ Water: Water prepared using ultrapure water production equipment (Sartorius Japan Co., Ltd.) Specific resistance ≧ 18.0MΩ · cm)

<Manufacture of flexible molded body (film) (1)>
Example 1
Sodium hyaluronate was dissolved in water to prepare a 1% aqueous sodium hyaluronate solution. 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 having a thickness of about 50 μm. The obtained membrane was immersed in 100 mL of a treatment solution (acetic anhydride: 75% aqueous ethanol solution = 20: 80) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble membrane. The obtained water-insoluble film was immersed and washed in the order of ethanol and water, and then immersed in 50 mL of a 10% glucose aqueous solution for 2 hours. Thereafter, it was air-dried under room temperature conditions to obtain a water-insoluble flexible membrane.

(Comparative Examples 1-3, Reference Example 1)
A water-insoluble flexible membrane was obtained in the same manner as in Example 1 except that a 10% aqueous solution prepared using the additive components shown in Table 1 was used instead of the 10% glucose aqueous solution.

<Production of flexible molded body (film) (2)>
(Example 2)
Sodium hyaluronate was dissolved in water to prepare a 1% aqueous sodium hyaluronate solution. Glucose was added to the prepared aqueous solution so that it might become 0.25%. 100 g of the obtained 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 having a thickness of about 50 μm. The obtained membrane was immersed in 100 mL of a treatment solution (acetic anhydride: 75% aqueous ethanol solution = 20: 80) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble membrane. The obtained water-insoluble film was immersed and washed in the order of ethanol and water, and then air-dried at room temperature to obtain a water-insoluble flexible film.

(Comparative Examples 4-6, Reference Example 2)
A water-insoluble flexible membrane was obtained in the same manner as in Example 2 except that the additive components shown in Table 1 were added to the 1% aqueous sodium hyaluronate solution instead of glucose.

<Evaluation>
(Surface condition)
The manufactured flexible film in a dry state was observed, and the surface state was evaluated according to the evaluation criteria shown below. The results are shown in Tables 1 and 2.
A: Transparent.
B: Cloudy and slightly opaque.
C: Crystals are precipitated and there are opaque portions.
D: The crystal is entirely precipitated and is opaque.

(Flexibility)
The produced flexible film was immersed in water and sufficiently swollen to obtain a swollen film. Using the obtained swelling film, flexibility was evaluated according to the evaluation criteria shown below. The results are shown in Tables 1 and 2.
a: Even if the swelling film is folded in half and the crease is strongly creased, it does not break.
b: Even if a swelling film is folded in half and a crease is pushed, it does not break.
c: The swollen film can be folded in half, but it will break when the crease is pushed.
d: It breaks when the swelling film is folded in half.

(Smoothness)
The manufactured flexible film in a dry state was observed, and the smoothness was evaluated according to the evaluation criteria shown below. The results are shown in Tables 1 and 2.
1: Overall smooth.
2: Slightly rippled.
3: It is greatly undulating.

(Animal experimentation)
The flexible membrane manufactured in Examples 1 and 2 was sealed in a sterilization bag, irradiated with 25 kGy of radiation, and sterilized with the sterilization bag to obtain a film-like adhesion prevention material. 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. An anti-adhesive material was placed so as to cover the peeled portion, and the abdomen was closed. Two weeks later, the dog was laparotomized after general anesthesia treatment, and no adhesion occurred in any of the anti-adhesion materials. Further, the anti-adhesion material placed (implanted) in the dog's body disappeared two weeks after the implantation. This is presumed that the carboxy group of hyaluronic acid that constitutes the anti-adhesion material is gradually neutralized by sodium ions etc. in the living body, 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 of the dog that closed without placing an adhesion preventing material.

  The flexible molded body of the present invention is useful as an adhesion preventing material.

Claims (10)

  A method for producing a flexible molded body comprising a step of water-insolubilizing a first raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and a monosaccharide.   The method for producing a flexible molded body according to claim 1, wherein the first raw material molded body is water-insolubilized by contacting with a treatment liquid containing an acid anhydride. A step of water-insolubilizing a second raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide;
Impregnating the water-insoluble second raw material molded body with a solution containing monosaccharides;
The manufacturing method of the flexible molded object which has this.   The method for producing a flexible molded body according to claim 3, wherein the second raw material molded body is water-insolubilized by contacting with a treatment solution containing an acid anhydride.   The said monosaccharide is glucose, The manufacturing method of the flexible molded object as described in any one of Claims 1-4.   The method for producing a flexible molded body according to any one of claims 1 to 5, 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 flexible molded body according to any one of claims 1 to 6, wherein the shape of the flexible molded body is a sheet shape, a film shape, a sponge shape, or a string shape.   The flexible molded object manufactured by the manufacturing method as described in any one of Claims 1-7.   The flexible molded body according to claim 8, which is used as an adhesion preventing material.   The flexible molded article according to claim 8 or 9, wherein a polyhydric alcohol or a polyhydric alcohol aqueous solution is held therein.