Hydrogel precursors and their applications

Abstract

The objective is to provide a hydrogel precursor that forms a hydrogel upon absorbing moisture, and which exhibits improved properties in several respects. [Solution] The following components (A), (B), and (C): (A) Polymers having hydrogen donating functional groups, (B) Polymers having hydrogen-accepting functional groups, (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. A mixed dried product containing the above is prepared to obtain a hydrogel precursor that forms an adhesive hydrogel upon absorbing moisture.

Description

Technical Field

[0001] The present disclosure relates to hydrogel precursors and their applications. Specifically, it relates to hydrogel precursors, methods for manufacturing them, and applications to medical materials using such hydrogel precursors, such as films for adhesion to the skin or mucosa, hemostatic materials, and the like.

Background Art

[0002] Hydrogels that adhere to living tissues have been widely studied for applications such as adhesion prevention materials, hemostatic materials, wound covering materials, or drug release devices, and some have already been commercialized. Film-like medical treatment materials that adhere to wet tissues such as mucous membranes and serous membranes and absorb surrounding moisture to form an adhesive gel are useful, for example, as adhesion prevention materials and hemostatic materials after surgery.

[0003] Hydrogels derived from animal proteins are known. However, hydrogels derived from animal proteins have risks such as infection with viruses and bovine spongiform encephalopathy, and immune responses to foreign proteins. As a means of avoiding these risks, hydrogels crosslinked with natural polysaccharides have also been developed. However, hydrogels crosslinked with natural polysaccharides have poor flexibility in the dry state and cannot fit well to a site with a complex shape, and there is a problem that it is difficult to use them as adhesion prevention materials or hemostatic materials for highly curved internal organs or fingertips. Furthermore, chemically crosslinked gels also have the problem of low biodegradability. In recent years, reports using hydrogels made of synthetic polymers have also increased. However, although synthetic polymers have a low risk of infection, they have problems such as low biocompatibility and generally complicated preparation.

[0004] As a polymeric composite formed from water-soluble synthetic polymers, a polymeric composite formed by hydrogen bonding between polyacrylic acid (PAA) and polyvinylpyrrolidone (PVP) is known (Non-Patent Literature 1). Since this polymeric composite uses safe synthetic polymers as raw materials and is easy to prepare, its potential as a hydrogel that avoids the above-mentioned problems can be imagined. However, although the polymeric composite of polyacrylic acid and polyvinylpyrrolidone is rapidly formed by mixing aqueous solutions of both, it has the property of immediately forming hydrophobic bonds and precipitating as fibrous aggregates. Therefore, simply mixing their aqueous solutions does not produce a stable hydrated hydrogel. Furthermore, when these aggregates are isolated and dried, a hard solid mass is obtained, but even if water is supplied to this solid mass, it does not absorb the water and maintains its solid state, and a hydrated, flexible hydrogel is not formed.

[0005] The inventors in this disclosure have succeeded in developing a polymeric hydrogel that swells in water and adheres strongly to living organisms by mixing polyacrylic acid (PAA) and polyvinylpyrrolidone (PVP) under special conditions (Patent Document 1).

[0006] Polyvinyl alcohol (PVA) is a biocompatible polymer material. Generally speaking, PVA is said to impart good flexibility and toughness when added to polymer films. It has been reported that attempts have been made to improve the flexibility of a PAA-PVP composite by adding PVA (Non-Patent Literature 2). [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Patent No. 6183831 [Non-patent literature]

[0008] [Non-Patent Document 1] Eur. Polym. J., 15, 223, 1979; Eur. Polym. J., 19, 923, 1983 [Non-Patent Document 2] J Biomed Mater Res. 2020;108B:503-512, Ito et. al., "Bioadhesive and biodissolvable hydrogels consisting of water-swellable poly(acrylic acid) / poly(vinylpyrrolidone) complexes" [Overview of the project] [Problems that the invention aims to solve]

[0009] Conventional PAA and PVP composites, in their dry state, lack flexibility and easily crumble or break before deformation occurs when force is applied, thus limiting their applications.

[0010] Furthermore, even when PVA was added to the PAA and PVP composite, while some morphologies showed improvement in strength, the flexibility was not entirely satisfactory. A more detailed examination of flexibility revealed that, for example, properties such as elongation, stretchability (with minimal force), softness, and crack resistance (when formed into thin forms such as films) did not show the expected improvement. Similarly, in terms of strength, no improvement was observed in some morphologies (for example, in the case of porous materials).

[0011] In light of the above circumstances, one of the challenges we aim to solve is to provide a hydrogel precursor that forms a hydrogel upon absorbing moisture, and which exhibits improved properties in several aspects. Examples of properties to be improved include, in a dry state, tensile strength, elongation at break (maximum elongation), ductility, softness, and resistance to cracking. Other properties include water resistance when in contact with moisture. Our goal is to improve at least one of these properties, and more preferably two or more.

[0012] Another challenge we aim to address is to provide a method for producing hydrogel precursors with improved properties as described above. Furthermore, one of the challenges we aim to solve is to provide various bioadhesive materials or medical devices that utilize hydrogel precursors with the improved properties described above, such as adhesive films or porous polymers for skin or mucous membranes, hemostatic agents, fluid absorbents, adhesion prevention materials, wound dressings, or protective materials. [Means for solving the problem]

[0013] The inventors have diligently pursued further research on multi-component polymer materials (hydrogel precursors) that form hydrogels exhibiting bioadhesive properties upon absorbing moisture, and have also researched additives other than PVA. As a result, they have discovered that by preparing these materials in the presence of certain low-molecular-weight polyhydric alcohols, it is possible to obtain hydrogel precursors with improved properties in one or more of the following areas: dry tensile strength, elongation at break (maximum elongation), stretchability, resistance to cracking, or water resistance after swelling.

[0014] The invention presented in this disclosure can be understood in multiple aspects and forms, and may include, for example, the following embodiments as means for solving the problem. In this disclosure, the invention presented in this disclosure is also referred to simply as "the present invention," either conceptually or according to each individual form.

[0015] [1] The following components (A) and (B): (A) Polymers having hydrogen donating functional groups, (B) Polymers having hydrogen-accepting functional groups, A hydrogel precursor comprising a mixed dried product of which forms an adhesive hydrogel upon absorbing moisture, The aforementioned mixed dried product further contains the following component (C): (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. The hydrogel precursor comprising the above. [2] The hydrogel precursor according to [1], which forms a hydrogel that has adhesive properties to biological tissue when it absorbs water. [3] The hydrogel precursor according to [1] or [2] above, wherein component (A) is polyacrylic acid. [4] The hydrogel precursor according to any one of the above items [1] to [3], wherein the component (B) is polyvinylpyrrolidone. [5] The hydrogel precursor according to any one of the above items [1] to [4], wherein component (C) is one or more selected from the group consisting of glycerin, erythritol, glucitol, and xylitol. [6] The hydrogel precursor according to [1] to [5] above, wherein the weight ratio of component (C) in the hydrogel precursor is 0.05 to 2.5 when the weight ratio of component (A) is 1.0. [7] The above component (A) is polyacrylic acid, The aforementioned component (B) is polyvinylpyrrolidone, The aforementioned component (C) is one or more selected from the group consisting of glycerin, erythritol, glucitol, and xylitol. A hydrogel precursor as described in any one of the above items [1], [2], or [6]. [8] A hydrogel precursor according to any one of the above items [1] to [7], having a film-like form. 〔9〕 The hydrogel precursor according to any one of the above 〔1〕 to 〔7〕, which is a porous body. 〔10〕 The hydrogel precursor according to any one of the above 〔1〕 to 〔9〕, which is a medical treatment material. 〔11〕 The hydrogel precursor according to 〔10〕 above, which is a hemostatic material, a body fluid absorbent material, a wound covering or protecting material, or an anti-adhesion material. 〔12〕 The hydrogel precursor according to any one of the above 〔1〕 to 〔11〕, which is for adhesion to the skin or mucosa. 〔13〕 The hydrogel precursor according to any one of the above 〔1〕 to 〔11〕, which is for intraoral adhesion. 〔14〕 A method for producing a hydrogel precursor that forms an adhesive hydrogel when absorbing moisture, comprising: preparing a solid-phase substrate in a dry state from a solution of one of the following components (A) and (B): (A) A polymer having a hydrogen-donating functional group, (B) A polymer having a hydrogen-accepting functional group, contacting a solution of the other component with the solid-phase substrate and then drying to prepare a mixed dry product of the components (A) and (B) to obtain a hydrogel precursor, and adding the following component (C) to both or either one of the solutions of the components (A) and (B): (C) One or more selected from the group consisting of glycerin, sugar alcohols of tetroses, sugar alcohols of pentoses, and sugar alcohols of hexoses, wherein the above production method is provided. 〔15〕 A method for producing a porous hydrogel precursor that forms an adhesive hydrogel when absorbing moisture, comprising: preparing a solid-phase substrate in a dry state from a solution of one of the following components (A) and (B): ​​​​​​​​​ The process includes freeze-drying the frozen material to prepare a porous material from a mixed dried product of components (A) and (B), thereby obtaining a porous hydrogel precursor. To both or either of the solutions of components (A) and (B) above, add component (C): (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. The manufacturing method comprising the formulation of the above. [Effects of the Invention]

[0016] In one or more embodiments of the inventions presented herein, a hydrogel precursor with improved properties of one or more of the above-described properties can be provided. Furthermore, according to one or more aspects of the invention presented herein, a method for producing a hydrogel precursor with improved properties of one or more of the above-mentioned characteristics can be provided. Furthermore, according to one or more aspects of the invention presented in this disclosure, various bioadhesive materials or medical devices utilizing hydrogel precursors with the above-described properties can be provided, such as adhesive films or porous polymers for skin or mucous membranes, hemostatic materials, fluid absorbents, adhesion prevention materials, wound coverings or protective materials (wound coverings or wound protective materials). [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 is a schematic diagram showing the measuring instruments used to evaluate fracture strength and elongation. [Figure 2] Figure 2 shows an example of the measurement results of stress change until a test film piece breaks. (Vertical axis: stress, Horizontal axis: distance traveled by the indentation rod) [Figure 3(a)] Figure 3(a) shows the stress at the fracture point of the test film sample. [Figure 3(b)] Figure 3(b) shows the distance the pushing rod traveled at the break point of the test film piece. [Figure 3(c)]Figure 3(c) shows the stress when the pressing rod is lowered by a further 0.8 mm from the position where it was in contact with the test film piece. [Figure 4] Figure 4 shows an example of the measurement results of stress change until a test sponge piece fractures. (Vertical axis: stress, Horizontal axis: distance traveled by the indentation rod) [Figure 5(a)] Figure 5(a) shows the stress (breaking strength) at the fracture point of the test sponge piece. [Figure 5(b)] Figure 5(b) shows the insertion distance of the push rod at the fracture point of the test sponge piece, expressed as elongation. [Figure 6] Figure 6 shows the ratio of the weight of the swollen hydrated gel to the initial weight of the film after a film was formed in a petri dish, PBS (phosphate-buffered saline) was added, and the mixture was shaken. (Vertical axis: Weight ratio of swollen gel to film, Horizontal axis: Time after PBS addition) [Figure 7] Figure 7 shows the calculated ratio of stress to elongation of the test film sample. [Figure 8(a)] Figure 8(a) is a schematic diagram showing the test equipment used to evaluate the water pressure resistance of the film and some of its operation. [Figure 8(b)] Figure 8(b) is a schematic diagram showing the test equipment used to evaluate the water pressure resistance of the film and some of its operation. [Figure 9] Figure 9 shows the measurement results of the water pressure resistance evaluation test of the film. (Vertical axis: Time until PBS starts to flow out) [Modes for carrying out the invention]

[0018] The embodiments of the present invention will be described below. In this disclosure, the term "an embodiment" in relation to the present invention refers to any one embodiment used to describe the present invention in detail, unless otherwise specified, and does not negate or limit the existence of other or more embodiments. As shown below, the present invention may have multiple embodiments that fall within its scope. These multiple embodiments may also be provided as modified forms, for example, by various combinations of the components (or technical features) shown in this disclosure. Furthermore, in this disclosure, when the term "embodiment" is used, it includes one or more embodiments unless otherwise specified.

[0019] In this disclosure, unless otherwise specified, the notation "AA~BB" in relation to a numerical range means "AA or greater and BB or less" (where "AA" and "BB" represent any numerical value). Furthermore, unless otherwise specified, the units for both the lower and upper limits are the same as the unit immediately following the latter (i.e., "BB" in this case). In this disclosure, the combination of the lower and upper limits of a numerical range can be any combination of numerical values ​​selected from the set of lower or upper limits provided as examples of preferred values. Also, the expression "X and / or Y" means both X and Y, or either one of them.

[0020] The compounds and materials described herein, unless otherwise specified, may take on several forms, such as salts or ionized states, under the specific circumstances in which they exist.

[0021] In this disclosure, the term "(meth)acrylic" means acrylic and / or methacrylic. Similarly, the term "(meth)acrylo" means acrylo and / or methacrylo, and the term "(meth)acrylate" means acrylate and / or methacrylate.

[0022] In this disclosure, polyacrylic acid may be abbreviated as "PAA," polyvinylpyrrolidone as "PVP," and polyvinyl alcohol as "PVA." Furthermore, conventionally, a mixture of PAA and PVP as a hydrogel precursor has been referred to as a "PAA / PVP complex," and while this may be considered one expression from one perspective, in this disclosure, the hydrogel precursor composed of "PAA" and "PVP" will be referred to as a "hybrid (or hybrid product)" rather than a "complex."

[0023] 1. Hydrogel precursor One embodiment of the present invention provides a hydrogel precursor. The hydrogel precursor, according to one embodiment of the present invention, forms an adhesive hydrogel when it absorbs water. In this disclosure, the term "hydrogel precursor" means the state before hydrogel formation, that is, the state before it absorbs water and swells. Therefore, in this disclosure, when the term "hydrogel precursor" is used, unless otherwise specified, it can be understood to mean a dry state that has not swollen.

[0024] One embodiment of the present invention, a hydrogel precursor, is composed of at least two polymer components and is thought to have a special molecular mixture state in which, in a dry state, the polymer molecules are partially entangled with each other, one polymer component is partially hydrogen-bonded to another polymer component, or some polymer molecules exist without bonding to other polymer molecules. One embodiment of the present invention, a hydrogel precursor, is thought to exhibit the ability to swell and form a hydrogel when it absorbs moisture due to having such a special mixture state. In this disclosure, the terms "hybrid" or "hybrid body" are used as appropriate terms to describe a material having such a molecular mixture state of hydrogel precursor in a dry state. ("Hybrid" or "hybrid body" can be translated into English simply as "Hybrid," "Hybrid Matter," or "Hybrid Body." In this disclosure, the term "Hybrid Dry Matter" refers to a hybrid in a dry state.)

[0025] One embodiment of the present invention, a hydrogel precursor, comprises, as its basic structure, a dried mixture of the following components (A) and (B). Component (A): Polymer having hydrogen-donating functional groups Component (B) Polymer having hydrogen-accepting functional groups The polymer of component (A) and the polymer of component (B) are a combination of polymers capable of forming hydrogen bonds via hydrogen-donating and hydrogen-accepting functional groups.

[0026] In the hydrogel precursor according to one embodiment of the present invention, the polymer molecules of components (A) and (B) are thought to have a special molecular mixture state as described above, and it is believed that by possessing such a special mixture state, they exhibit the property of being able to absorb water, swell, and form a hydrogel. Even if a mixed material contains components (A) and (B), if it cannot absorb water and form a hydrogel (i.e., does not have hydrogel-forming ability), it cannot be said to be a hydrogel precursor in the first place. For example, aggregates formed by simply mixing solutions of components (A) and (B) do not usually have hydrogel-forming ability even when dried, and therefore cannot be said to be a hydrogel precursor. Furthermore, multilayer structures in which single layers of component (A) and single layers of component (B) are stacked so that they can be clearly distinguished, or multilayer structures in which solid single layers are bonded together, usually do not readily form a hydrogel as a whole. Since component (A) is a polymer having hydrogen-donating functional groups and component (B) is a polymer having hydrogen-accepting functional groups, components (A) and (B) are often water-soluble, and simple single-layer structures tend to dissolve in water before hydrogel formation occurs. Furthermore, multilayer structures tend to form water-insoluble complexes when water is added.

[0027] Components (A) and (B) are components that provide the basic framework of a hydrogel, which, when a hydrogel precursor absorbs water to form a hydrogel, forms a fine three-dimensional network structure via hydrogen bonding, hydrophobic interactions, etc., thereby maintaining a flexible solid or highly viscous form while retaining water. In other words, the term "hydrogel" in this disclosure is not limited to a completely solid state in appearance or form, but may also include highly viscous bodies that deform slowly under gravity.

[0028] The mixed dried product, mainly composed of components (A) and (B), forms the core of the hydrogel precursor. The special mixed state of components (A) and (B) in the mixed dried product can be most characteristically identified as a structure capable of forming a hydrogel when it absorbs water, but from other perspectives, it can also be described as having the following form, for example.

[0029] [Example of the form of a mixed dried product (1)] A hybrid dried product that is not a multilayer laminate of a single layer of component (A) and a single layer of component (B), but rather includes a hybrid state in which both component (A) and component (B) are mixed and coexist at the molecular level, at least in part.

[0030] [Examples of the form of mixed dried products (2)] A hybrid dried product having a hybrid state formed by contacting (or impregnating) a dry solid-phase substrate of either component (A) or component (B) with a solution containing the other component, and then drying it.

[0031] A polymer having a hydrogen-donating functional group is used as component (A). A polymer having a hydrogen-donating functional group is a polymer that contains a functional group having hydrogen atoms capable of forming hydrogen bonds within its molecule. A group of atoms containing positively polarized hydrogen atoms can be a hydrogen-donating functional group. A polymer having a hydrogen-donating functional group may be linear or branched, may or may not have substituents, may or may not have crosslinks, and may or may not have a cyclic structure. One type of polymer may be used alone as component (A), or two or more types may be used in combination.

[0032] Examples of polymers having hydrogen-donating functional groups include polyacrylic acid, polyvinyl alcohol, polymethacrylic acid, and carboxymethylcellulose. Among these, polyacrylic acid may be preferred from the viewpoint of high hydrogen-donating capacity, water solubility, and biocompatibility.

[0033] The weight-average molecular weight (Mw) of the polymer of component (A) is preferably 10,000 or more, more preferably 50,000 or more, and even more preferably 100,000 or more, from the viewpoint of ensuring ease of preparation of the hydrogel precursor, sufficient strength and stability of the hydrogel formed by water absorption, and adhesion to biological tissues. There is no particular upper limit to the weight-average molecular weight (Mw) of the polymer of component (A). A polymer with a large weight-average molecular weight (Mw) having a cross-linked structure may be used for component (A). Here, the weight-average molecular weight (Mw) of the polymer of component (A) is a polystyrene equivalent value measured by gel permeation chromatography (GPC).

[0034] As component (B), a polymer having a hydrogen-accepting functional group is used. A polymer having a hydrogen-accepting functional group is a polymer that has a functional group (atom or group of atoms) in its molecule that can form a hydrogen bond by pairing with a positively polarized hydrogen atom in a hydrogen donor. A negatively polarized atom or group of atoms, or an atom or group of atoms with a lone pair of electrons, can be a hydrogen-accepting functional group. A polymer having a hydrogen-accepting functional group may be linear or branched, may or may not have substituents, may or may not have crosslinks, and may or may not have a cyclic structure. One type of polymer may be used alone as component (B), or two or more types may be used in combination.

[0035] Examples of polymers having hydrogen-accepting functional groups include polyvinylpyrrolidone, polyurethane, and polycarbonate. Among these, polyvinylpyrrolidone may be preferred from the viewpoint of high hydrogen-accepting capacity, water solubility, and biocompatibility.

[0036] The weight-average molecular weight (Mw) of the polymer of component (B) is preferably 10,000 or more, more preferably 50,000 or more, and even more preferably 100,000 or more, from the viewpoint of ensuring ease of preparation of the hydrogel precursor, sufficient strength and stability of the hydrogel formed by water absorption, and adhesion to biological tissues. There are no particular restrictions on the weight-average molecular weight (Ms) of the polymer of component (B). The polymer of component (B) may be one with a large weight-average molecular weight (Mw) having a cross-linked structure. Here, the weight-average molecular weight (Mw) of the polymer of component (B) is a polystyrene equivalent value measured by gel permeation chromatography (GPC).

[0037] One embodiment of the hydrogel precursor further contains component (C) in addition to components (A) and (B) above. Component (C) is an additive that is incorporated into the mixed dry product and plays an additive role in adding a predetermined function or role to the hydrogel precursor.

[0038] Examples of component (C) include glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. These components may be used individually or in combination of two or more. The sugar alcohol may be either the D-isomer or the L-isomer. By incorporating these components, the overall elongation at break (or maximum elongation) of the hydrogel precursor can be improved.

[0039] Each individual component of component (C) can be further endowed with a distinctive function. For example, the addition of glycerin can significantly improve the elongation at break (maximum elongation) and stretchability (ability to stretch with small forces) of hydrogel precursors. Furthermore, in the case of hydrogel precursors formed into films, the addition of glycerin significantly improves the breaking strength compared to the case without glycerin, although it does not reach the level of PVA addition. In contrast, in the case of hydrogel precursors formed into porous bodies, the addition of glycerin significantly improves the breaking strength compared to both the case with and without PVA addition.

[0040] The addition of tetrasaccharide, pentose, and hexose sugar alcohols can improve tensile strength, elongation at break, softness, and crack resistance, although the degree of improvement varies depending on the individual component. Furthermore, these sugar alcohols show improvements whether the hydrogel precursor is formed into a film or into a porous material.

[0041] Furthermore, the following effects can be observed regarding the properties after the material absorbs moisture, swells, and forms a hydrogel. The addition of glycerin, erythritol, or xylitol can slow down the dissolution and disappearance of the hydrogel under physiological conditions. In other words, the addition of glycerin, erythritol, and xylitol can extend the retention time when used under physiological conditions.

[0042] While the addition of sugar alcohols does not provide the same level of water pressure resistance as the addition of PVA, it can impart higher water pressure resistance compared to other additives (such as xylose and glucose) and to the case without any additives.

[0043] More specifically, component (C) preferably includes one or more selected from the group consisting of glycerin, erythritol, xylitol, and glucitol. Depending on the required performance for the application, component (C) may more preferably include glycerin, erythritol, and xylitol, and even more preferably include erythritol and xylitol. Furthermore, considering a good balance of breaking strength, elongation at break, and flexibility, a combination of (c1): glycerin and (c2): sugar alcohol, for example, a combination of (c1): glycerin and (c2): either or both of erythritol and xylitol as the sugar alcohol, may also be a preferred embodiment.

[0044] A preferred embodiment of the hydrogel precursor is one that exhibits adhesive properties to biological tissues when a hydrogel is formed. Because it exhibits adhesive properties to biological tissues, it can be suitably used as a medical treatment material for various purposes.

[0045] As described above, the candidate components (C) have different properties depending on the type, but considering their use in medical treatment materials, glycerin and / or xylitol are generally particularly preferred additives. Xylitol is also preferable because it can modify the taste to be more palatable when the hydrogel precursor is intended to be used orally.

[0046] The mixing ratios of components (A), (B), and (C) may be set as appropriate depending on the type of component and the desired performance. As an example of a guideline for implementation, it may be preferable to adjust the amounts of components (A) and (B) so that the ratio of hydrogen-donating functional groups contained in component (A) to hydrogen-accepting functional groups contained in component (B) is, for example, from 1.0:0.3 to 1.0:3.0 or 1.0:2.0.

[0047] Regarding component (C), although it depends on the type of component, generally speaking, the higher the amount added, the easier it is to obtain the effects caused by that component. Since component (C) plays an additive or auxiliary role to the hydrogel body, as an example to guideline for implementation, when the weight ratio of component (A) is 1.0, the weight ratio of component (C) may preferably be around 0.05 to 2.5. More specifically, when the weight ratio of component (A) is 1.0, the lower limit of the weight ratio of component (C) may preferably be 0.05 or more, more preferably 0.1 or more, and even more preferably 0.15 or 0.2 or more. When the weight ratio of component (A) is 1.0, the upper limit of the weight ratio of component (C) may preferably be 2.5 or less, more preferably 2.0 or less. When the weight ratio of component (A) is set to 1.0, the weight ratio of component (C) may be further set to, for example, 1.8, 1.5, 1.3, 1.2, 1.1, or 1.0 or less, depending on the type and desired properties.

[0048] As a preferred embodiment of the hydrogel precursor, considering various properties such as strength (durability), flexibility (elongation, stretchability, softness, resistance to cracking), biocompatibility, and adhesion to biological tissues, the following combination of components can be exemplified for its practical balance. Component (A) is polyacrylic acid Component (B) is polyvinylpyrrolidone Component (C) is one or more selected from the group consisting of glycerin, erythritol, glucitol, and xylitol.

[0049] Furthermore, regarding ingredient (C), when used in the oral cavity, xylitol, glucitol, erythritol, etc., which are safe for use in the oral cavity, may be preferred.

[0050] In embodiments of the present invention, the hydrogel precursor may contain other optional components in addition to the above components (A), (B), and (C). These optional components may have hydrogen-receiving or hydrogen-donating functional groups. Examples of optional components include polyvinyl alcohol, hyaluronic acid, hydroxypropyl cellulose, polyalginic acid, and other water-soluble polymers, as well as chitosan powder or hydroxyapatite.

[0051] For example, by adding polyvinyl alcohol (PVA), depending on the form of the hydrogel precursor, it may be possible to adjust or improve properties such as strength or flexibility in the dry state, or water resistance after water absorption. When preparing a film-like hydrogel precursor, for example, it may be preferable to use PVA in a repeating unit molar ratio of approximately 1:1 for PAA and PVP, with PVA used in a repeating unit molar ratio of about 0.5 to 1.5 relative to PAA.

[0052] Furthermore, adding hyaluronic acid can increase the strength of the polymer porous material, potentially allowing for the preparation of a more robust polymer porous material.

[0053] Depending on the application, the hydrogel precursor may contain one or more drugs such as antibacterial agents, anti-inflammatory agents, blood coagulants, anticoagulants, local anesthetics, vasoconstrictors, or vasodilators. For example, when the hydrogel precursor is used as a material to prevent visceral adhesions in abdominal surgery, one or more drugs such as antibacterial agents, anticoagulants, or anti-inflammatory agents may be added. When the hydrogel precursor is used as a topical hemostatic agent, for example, local anesthetics may be added in addition to antibacterial agents as needed. More specifically, for hemostatic purposes, polysaccharides such as chitin and chitosan may be added.

[0054] There are no particular restrictions on the shape of the hydrogel precursor, and it can be prepared as appropriate depending on the application. Examples of hydrogel precursor shapes include film-like, porous, cube-like, spherical, or disc-like tablets. In this disclosure, "film-like" simply refers to a thin, membrane-like material. Generally, the thickness of what is considered a "film" varies depending on the application and technical field, but in this disclosure, "film-like" can refer to a material with a thickness of 1 mm or less, and in some cases, a more specific example may be a material with a thickness of around 200 μm. In this disclosure, "porous material" refers to a material having a large number of pores or voids, and may include, for example, sponge-like or nonwoven fabric-like materials. The hydrogel precursors in this disclosure are formed using polymer materials, and those that are porous can also be called polymeric porous materials. For medical treatment materials to be applied to the skin or mucous membranes, film-like or porous forms may be preferred.

[0055] 2. Method for producing hydrogel precursors The following describes embodiments relating to the method for producing the hydrogel precursor of this disclosure. In the following description, an embodiment using the solid / liquid interface contact method is shown as an example.

[0056] 2.1 Method for producing (film-like) hydrogel precursors As one embodiment of a method for producing a hydrogel precursor that forms an adhesive hydrogel when it absorbs moisture, the following form is shown (first embodiment of the manufacturing method). The first embodiment of the manufacturing method includes the following steps.

[0057] [Process 1] The following components (A) and (B): (A) Polymers having hydrogen donating functional groups, (B) Polymers having hydrogen-accepting functional groups, A step of preparing a dry solid-phase substrate from one of the solutions.

[0058] [Process 2] A step of bringing a solution of the other component into contact with the solid-phase substrate, drying it, and preparing a mixed dried product of components (A) and (B) to obtain a hydrogel precursor. Here, "the other component" refers to the component that was not used as the solid-phase substrate in step 1. In other words, if the solid-phase substrate is prepared using component (A), component (B) is used as "the other component," and conversely, if the solid-phase substrate is prepared using component (B), component (A) is used as "the other component."

[0059] [Process 3] A step of blending one or more components selected from the group consisting of the following components (C) into both or either of the solutions of components (A) and (B). Here, component (C) includes glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols.

[0060] The numbers assigned to the above steps are for convenience in classifying each step and are not intended to indicate that the order of steps in the overall manufacturing method is uniquely determined by these numbers. As is clear from the descriptions of each step, step 2 requires the solid-phase substrate formed in step 1, and therefore is usually performed after step 1 as part of the series of operations. However, since step 3 is the operation of preparing the "solution" used in step 1 or 2, whether it is performed before or as part of step 1, or before or as part of step 2, depends on which solution to which component (C) is added.

[0061] In steps 1 to 3 described above, the solvent for dissolving components (A) and (B) may be water, a mixture of aqueous organic solvents that mix with water in any proportion such as methanol, ethanol, acetone, or dimethyl sulfoxide, or an organic solvent. When selecting the solvent to which component (C) is added, its compatibility with component (C) should also be considered. From the standpoint of workability and efficient freeze-drying in the case of freeze-drying, which will be explained separately below, it is preferable to use water as the main component in step 2.

[0062] The concentrations of components (A) and (B) in the solution may be set as appropriate. The solution of the component that forms the solid-phase substrate may be, for example, 0.01 to 10% (W / V), preferably 0.1 to 5% (W / V), or 0.3 to 2.5% (W / V). The solution of the component that comes into contact with the solid-phase substrate ("other component" in "Step 2") may be, for example, 0.1 to 30% (W / V), preferably 0.5 to 20% (W / V), or 1 to 10% (W / V).

[0063] The concentration of component (C) in the solution to which component (C) is added may be appropriately set from a preferred weight ratio relative to the amount of component (A) or component (B).

[0064] In step 1, to obtain a dry solid-phase substrate, it is sufficient to remove the solvent from the solution and allow it to solidify. Drying can be carried out by general methods, and treatments such as heating, reduced pressure, and blowing air may be used. In step 2, drying is also performed by bringing the solution into contact with the solid-phase substrate and then removing the solvent until the entire substrate solidifies. Here again, treatments such as heating, reduced pressure, and blowing air may be used for drying.

[0065] In this disclosure, the term "drying" can be interpreted broadly to include not only a state in which all water and other solvents have been completely removed, but also a state in which some water and other solvents remain during the drying process. In step 1, drying is sufficient if the solid-phase substrate obtained after drying maintains its shape, and in step 2, drying is sufficient if the film-like hydrogel precursor obtained after drying has not swollen to form a hydrogel. If we were to express the water content of the hydrogel precursor numerically, it could be, for example, about 0.1 to 10% by weight. The thickness of the hydrogel precursor in the dried state can be set as appropriate, but in practice, it can be adjusted to, for example, about 0.1 μm to 1 mm.

[0066] 2.2 Method for producing porous hydrogel precursors The following is a second embodiment of a method for producing a hydrogel precursor that forms an adhesive hydrogel when it absorbs moisture. The second embodiment of this production method is a method for producing a porous hydrogel precursor. The second embodiment of this production method includes the following steps.

[0067] [Process 1] The following components (A) and (B): (A) Polymers having hydrogen donating functional groups, (B) Polymers having hydrogen-accepting functional groups, A step of preparing a dry solid-phase substrate from one of the solutions.

[0068] [Step 2-1] A step of preparing a frozen product by bringing a solution of the other component into contact with the solid-phase substrate and then freezing it. [Step 2-2] A step of freeze-drying the frozen material to prepare a porous body of the mixed dried material of components (A) and (B), thereby obtaining a porous hydrogel precursor.

[0069] [Process 3] A step of blending one or more components selected from the group consisting of the following components (C) into both or either of the solutions of components (A) and (B). (C) Glycerin, tetrasaccharide sugar alcohol, pentose sugar alcohol, and hexose sugar alcohol

[0070] In very brief terms, the second embodiment of the manufacturing method differs from the first embodiment in that freeze-drying is used as the drying method (the procedures in "Step 2-1" and "Step 2-2" above). Steps 1 and 3 of both can be carried out similarly. As with the first embodiment of the manufacturing method described above, Step 3 is an operation to prepare the "solution" used in Step 1 or Step 2-1, so whether it is carried out before or as part of Step 1, or before or as part of Step 2-1, depends on which solution to which component (C) is added.

[0071] Freeze-drying can be carried out according to general methods. Freezing can be performed by rapidly cooling and freezing at a temperature of, for example, -50°C to -20°C, depending on the types of components (A) and (B), or by first cooling to about -1°C to a supercooled state and then freezing at a temperature of about -50°C to -20°C. Drying of the frozen product can be done, for example, by placing it under reduced pressure using a vacuum pump to lower the boiling point and sublimate the water (generally called primary drying). After sublimating the water under reduced pressure, heat drying may be performed to further remove bound water (generally called secondary drying).

[0072] By drying by freeze-drying, a hydrogel precursor having a porous morphology such as a sponge-like structure can be obtained.

[0073] 2.3 Method for producing hydrogel precursors of PAA / PVP / xylitol Next, a more specific embodiment of the hydrogel precursor manufacturing method will be described as an example in which polyacrylic acid (PAA) is used as component (A), polyvinylpyrrolidone (PVP) as component (B), and xylitol as component (C).

[0074] First, a dry, film-like solid-phase substrate is prepared from a solution of either PAA or PVP. The concentration of the PAA or PVP solution is adjusted to, for example, about 0.01 to 10%, preferably about 1 to 5% (W / V).

[0075] The preparation of a dry, film-like solid substrate from either a PAA or PVP solution can be performed, for example, by placing the PAA or PVP solution in a flat-bottomed container, spreading the solution uniformly to a uniform thickness, and removing the solvent under forced air or heating. The thickness of the solution in the container before drying can be appropriately set from, for example, about 1 mm to 50 mm.

[0076] The thickness of the film-like solid substrate after drying can be set appropriately depending on the application, but generally, a thickness of about 0.1 μm to 2 mm is preferable. Drying can usually be carried out at a temperature of room temperature to about 100°C, but it may also be carried out at a lower temperature under forced air or reduced pressure. The moisture content of the film-like solid substrate after drying can be, for example, about 0.1% to 10%.

[0077] A film-like hydrogel precursor can be prepared by contacting a dried film-like solid substrate containing either PAA or PVP with the remaining solution of the other substance, and then drying it. The concentration of the PAA or PVP solution used for contact may be, for example, about 0.01 to 10%, preferably about 0.3 to 2.5%.

[0078] The xylitol in component (C) may be added to both the solution used to prepare the solid-phase substrate and the solution that comes into contact with the solid-phase substrate after its preparation, or it may be mixed into either one. Taking the case of adding xylitol to the latter solution as an example, when the weight ratio of PAA or PVP is 1.0, the weight ratio of xylitol should be added to the solution to be approximately 0.1 to 1.0.

[0079] The method for contacting a dried film-like solid substrate with a solution containing either PAA or PVP is not particularly limited, but examples include dropping, coating, or spraying the solution onto the surface of the film-like solid substrate. The amount of PAA or PVP solution to be contacted with the dried film-like solid substrate is also not particularly limited, but it is preferable to adjust the concentration and amount of the solution to be contacted so that the repeating unit molar ratio between the PAA or PVP contained in the dried film-like solid substrate and the PAA or PVP in the solution to be contacted is in the range of, for example, 0.1 to 10, preferably in the range of 0.5 to 2.

[0080] The drying of the film-like solid-phase substrate in contact with the above solution can be carried out under heating conditions of, for example, 50 to 100°C, but it may also be carried out at a lower temperature under forced air or reduced pressure. The film-like hydrogel precursor obtained after drying only needs to be such that it does not swell and form an adhesive hydrogel, for example, it can be about 0.1% to 10%. The thickness of the film-like hydrogel precursor can practically be, for example, about 0.1 μm to 1 mm.

[0081] A porous hydrogel precursor can be produced by freeze-drying, which involves contacting a solution with a dry solid-phase substrate and drying it. From the viewpoint of efficiently performing the freezing operation and freeze-drying, the solution is preferably an aqueous solution. Freezing is performed, for example, at a temperature of about -50°C, and then, for example, by placing it under reduced pressure using a vacuum pump to lower the boiling point and sublimate the water for primary drying. After sublimation of water under reduced pressure, heat treatment may be continued to perform secondary drying.

[0082] 3. Uses of hydrogel precursors, etc. One embodiment of the hydrogel precursor can be suitably used, for example, as a medical treatment material. One embodiment of the hydrogel precursor can form a hydrogel that exhibits bioadhesion and can also be made to have excellent flexibility, so, for example, adhesive films or porous bodies for skin or mucous membranes can be suitable embodiments. From other aspects, it can be suitably used, for example, as a hemostatic material, an absorbent material for bodily fluids such as lymph, an anti-adhesion material, a wound dressing, a protective material, and an adhesive film or porous body for oral use such as for stomatitis.

[0083] Adhesive films or porous materials for skin or mucous membranes can also be used, for example, as wound dressings for the purpose of protecting wounds or promoting healing. A wound is generally defined as an injury involving skin rupture, and may include, but is not limited to, cuts, lacerations, splits, abrasions, crush injuries, contusions, gunshot wounds, blast injuries, stab wounds, hammer wounds, bite wounds, burns, and pressure ulcers. For example, they may also be used for minor wounds that do not involve skin rupture. They may also be used as bodily fluid absorbents for lymphatic fluid leakage from wound sites.

[0084] Adhesion is a biological phenomenon in which tissues or organs that are normally separate become fused together, forming scar tissue between them. Adhesion can occur, for example, after surgical procedures in various fields such as gastroenterology, cardiology, orthopedics, gynecology, or ophthalmology, or it can occur in the form of adhesion between intestinal walls or adhesion between the intestinal wall and the abdominal wall when inflammatory bowel disease develops. Examples of visceral adhesions include adhesions that develop after surgery, as well as adhesive ileus (intestinal obstruction) caused by inflammatory bowel disease, irritable bowel syndrome, duodenal ulcer, acute enteritis, protein-losing enteropathy, colon cancer, appendicitis, hemorrhagic colitis, intestinal tuberculosis, intestinal Behcet's disease, or colonic diverticulosis, or intra-abdominal adhesions due to peritoneal dialysis or uterine adhesions due to Asherman's syndrome. [Examples]

[0085] The present invention will be described in more detail below with reference to examples, but the technical scope (or technical reach) of the invention presented herein is not limited to the following examples.

[0086] Some of the numerical values ​​and evaluations related to various shapes, physical properties, and other characteristics, as well as performance (or effectiveness) shown in this disclosure, can be determined by referring to the measurement and evaluation methods described below.

[0087] Figures 1 and 8 show the measuring instruments used in the evaluation methods described below. The various dimensions and shapes shown in the drawings, such as length and thickness, are schematic representations to facilitate understanding of the measuring instruments and their usage, and are not strictly limited to these representations. The measuring instruments used in the measurement or evaluation methods described below will be explained with reference to the drawings as appropriate.

[0088] <1. Preparation of PAA / PVP film and porous material (sponge)> [1.1 Experimental Materials] The following materials were used in the experiment. In the following experiments, unless otherwise specified, "%" or "mol%" indicating the component ratio in the solution refers to mass-to-volume ratio concentration: % (W / V) or volume molar concentration: mol% (mol / V). (a) Polyacrylic acid (PAA, Carbopol® 974, Lubrizol Advanced Materials Inc.) (b) Polyvinylpyrrolidone (PVP, Kollidon) (R) 90F, BASF) (c) Glycerin, erythritol, xylitol, glucitol, xylose, and glucose (Nacalai Tesque) (d) Polyvinyl alcohol (PVA) [Nippon Vinegar VIPA Co., Ltd. (saponification degree 88.5 mol%; 5.4 mPa·s [4% in water at 20℃])]

[0089] [1.2 Preparation of test film] A 1% PAA aqueous solution of 1.5 mL was placed in a mold and dried at room temperature to prepare a PAA film. After drying, 1.5 mL of a 1.54% PVP aqueous solution containing 0.3, 0.6, or 0.9 times the weight of each additive relative to the PAA was dropped onto the surface of the PAA film, and the film was dried at room temperature to obtain a polymer hybrid film. The thickness of each film was approximately 0.08 to 0.11 mm.

[0090] [1.3 Preparation of sponges for testing] Following the dropwise addition of the PVP aqueous solution containing each additive as described in [1.2 Preparation of Test Film] above, the sponge was obtained by leaving it at room temperature for 20 minutes, then freezing it at -20 to -50°C and freeze-drying it. The thickness of each sponge was approximately 3 to 5 mm.

[0091] [1.4 Mixing ratio of PAA and PVP] The mixing ratio of PAA to PVP in the film and sponge prepared as described above was as follows: PAA:PVP = 1:1.54 in weight (1:1 in repeated unit molar ratio)

[0092] Using the method described in "1.2 Preparation of Test Films" above, each film sample was prepared by changing the type of additive as follows, and each film sample was evaluated. Glycerin added (Example 1F) Erythritol added (Example 2F) Xylitol added (Example 3F) Glucitol added (Example 4F) Xylose added (Comparative Example 1F) Glucose addition (Comparative Example 2F) PVA addition (comparative example 3F) No additives (Comparative Example 4F)

[0093] <2. Evaluation of the flexibility of PAA / PVP film (sensory evaluation)> When each film sample from Examples 1F to 4F was bent and stretched by hand, it was confirmed that they were all soft and flexible. The film pieces of Comparative Examples 1F to 3F felt somewhat stiffer or were more prone to bending or cracking compared to Examples 1F to 4F. The film piece of Comparative Example 4F easily broke when we tried to bend it by hand.

[0094] <3. Evaluation of the breaking strength and elongation of PAA / PVP films> Referring to Figure 1, the evaluation method for the breaking strength and elongation of the PAA / PVP composite film will be described. An aluminum block 1 was prepared, having a through-hole 12 with a diameter of 12 mm. A test film piece 31 (PAA:PVP:additive = 1:1.54:0.6 in weight) measuring 1.7 cm × 1.7 cm or larger was placed so as to completely cover the upper opening 11 of the vertical hole 12 in the aluminum block 1, and it was fixed with double-sided tape (not shown). At that time, a hole of the same size as the hole in the block was made in the double-sided tape, and the double-sided tape was not made to cover the hole in the block.

[0095] A cylindrical iron rod (push rod 2) with a diameter of 5.8 mm and a flat end (bottom) was prepared so that it could be inserted into the vertical hole 12 of the aluminum block 1. The push rod 2 was lowered from above the test film piece 31 at a speed of 50 mm / min so as to be inserted from the part with the top opening 11, and the stress with respect to the distance the push rod 2 moved was measured.

[0096] Figure 2 shows a typical example of the measurement results of stress change until the test specimen (test film piece) breaks. The point where the stress suddenly drops is defined as the break point, and the strength and elongation of the film at that time (the distance the indentation rod 2 moves from the point where it contacts the surface of the test film piece (contact point), and the stress when the indentation rod 2 is lowered 0.8 mm from the point where it contacts the surface of the test film piece (contact point)) were determined. Figure 3(a) shows the stress at the break point as the break strength. A larger stress at the break point indicates that a larger force is required to break the film. Figure 3(b) shows the distance the indentation rod 2 is lowered (moved) at the break point as the break elongation. A larger break elongation indicates a higher degree of deformation without breaking. Figure 3(c) shows the stress when the indentation rod 2 is lowered 0.8 mm from the contact point. A smaller stress at the same lowering distance indicates that elongation is achieved with less force, and can therefore be an indicator of softness.

[0097] As shown in Figure 3, the film piece without additives (Comparative Example 4F) did not stretch much and tore with relatively little force.

[0098] Compared to the unadded film (Comparative Example 4F), the film pieces with glycerin or sugar alcohols (erythritol, xylitol, or glucitol) added (Examples 1F-4F) withstood greater force (Figure 3(a)) and did not tear until they were significantly deformed (Figure 3(b)). Furthermore, compared to the unadded film (Comparative Example 4F), the film pieces with glycerin, erythritol, or xylitol added (Examples 1F-3F) were shown to stretch well with less force (Figure 3(c)). The film piece with glycerin added (Example 1F) showed particularly high elongation at break (maximum elongation), and was easily stretched even with small forces, exhibiting overall high flexibility. On the other hand, the film pieces with sugar alcohols added (Examples 2F-4F) showed high stress at break, excellent breaking strength, and were strong films, and their overall stretchability was also improved.

[0099] Furthermore, the film sample with added PVA (Comparative Example 3F) showed relatively high breaking strength (Figure 3(a)). However, the PVA-added film sample required a high stress to lower by 0.8 mm (Figure 3(c)), and its elongation at break (maximum elongation) was low (Figure 3(b)). From these findings, it became clear that the PVA-added film sample was difficult to stretch and required a relatively large force to stretch.

[0100] <4. Evaluation of the flexibility, tensile strength, and elongation of PAA / PVP sponge> Using the method described in "1.3 Preparation of Test Sponges" above, sponge pieces were prepared with the following variations in additive type (PAA:PVP:additive = 1:1.54:0.6 in weight), and each sponge piece was subjected to the same tests as described in "2. Evaluation of the Flexibility of PAA / PVP Film (Sensory Test)" and "3. Evaluation of the Breaking Strength and Elongation of PAA / PVP Film" above. Glycerin added (Example 1S) Erythritol added (Example 2S) Xylitol added (Example 3S) Glucitol added (Example 4S) Xylose added (Comparative Example 1S) Glucose addition (Comparative Example 2S) PVA addition (comparative example 3S) No additives (Comparative Example 4S)

[0101] Each sponge piece was slightly thicker than the film piece, and when held between the fingers, it had a slightly fluffy softness and elasticity. When each of the sponge pieces from Examples 1S to 4S was bent and stretched by hand, it was confirmed that they were all soft and flexible. The sponge pieces of Comparative Examples 1S to 3S felt somewhat stiffer or were more prone to breaking or cracking compared to Examples 1S to 4S. The sponge piece of Comparative Example 4S was somewhat hard, brittle, easily cracked, and easily crumbled.

[0102] Figure 4 shows a typical example of the measurement results of stress changes until each test specimen (test sponge piece) fractures. The point where the stress suddenly drops (or the stress peak point) was defined as the fracture point, and the stress (fracture strength) and elongation of the sponge at that time were determined.

[0103] Figure 5(a) shows the stress (breaking strength) at the fracture point of the sponge piece. Figure 5(b) shows the distance traveled by the indentation rod 2 (breaking elongation) from the point where the indentation rod 2 contacts the surface of the test sponge piece (contact point) at the fracture point of the sponge piece.

[0104] Similar to the film sample, the sponge sample without additives (Comparative Example 4S) tore with relatively little force and without much stretching. Adding sugar (xylose or glucose) or PVA (Comparative Examples 1S-3S) did not improve the breaking strength compared to the unadded sample.

[0105] On the other hand, sponge pieces to which glycerin or sugar alcohols (erythritol, xylitol, or glucitol) were added (Examples 1S to 4S) showed relatively higher values ​​for both tensile strength and elongation at break compared to Comparative Examples 1S to 4S, demonstrating their ability to withstand greater forces and stretch significantly.

[0106] <5. Swelling and dissolution behavior of the film> Each film piece was prepared in a 1.5 cm diameter petri dish in the same manner as described in "1.2 Preparation of Test Films" above. However, the formulations of PAA, PVP, and additives were set as follows. PAA: 3mg PAA:PVP:Additives = 1:1.54:0.6 in weight

[0107] One mL of PBS (phosphate-buffered saline) was added to each petri dish containing the prepared film, and the mixture was shaken continuously at 155 times / min. The supernatant was removed and the weight of the gel was measured every 5 minutes for the first 60 minutes, and then every 10 minutes thereafter. One mL of fresh PBS was added to each gel. Figure 6 shows the ratio of the gel weight to the weight of the initial film.

[0108] All films swelled rapidly in PBS and then gradually dissolved and disappeared. However, the films to which glycerin, erythritol, or xylitol was added (Examples 1F to 3F) dissolved and disappeared much more slowly after swelling compared to the other films, indicating that glycerin, erythritol, and xylitol have the effect of extending the retention time when used under physiological conditions. The retention time in PBS can be considered one of the indicators of water resistance.

[0109] <6. Tensile Test of Film> Each film piece was prepared in the same manner as described in "1. Preparation of PAA / PVP composite film and sponge" above. Each prepared film piece was cut to a width of 7 mm, fixed at the top and bottom with clamps at 1 cm intervals, and pulled at a speed of 50 mm / min. The stress with respect to the distance moved was measured. The results of calculating the ratio of stress to elongation of the film piece (referred to here as the "modulus of elasticity" (unit: N / mm)) are shown in Figure 7.

[0110] Films to which glycerin (Example 1F), sugar alcohols (Examples 2F-4F), or sugars (Comparative Examples 1F, 2F) were added were found to be more flexible than films without additives (Comparative Example 4F). In particular, films to which glycerin or sugar alcohols were added (Examples 1F-4F) showed a significant decrease in elastic modulus, indicating that the films were more flexible.

[0111] <7. Evaluation of the film's water pressure resistance> As one of the evaluation indicators for water resistance, water resistance under water pressure (water pressure resistance) was evaluated. The method for evaluating the water pressure resistance of the PAA / PVP film will be explained with reference to Figures 8(a) and (b). A tube 5 with an inner diameter of 15 mm was prepared. A removable cap (stopper) 51 was attached to the opening of the tube 5. An air vent hole (air hole 53) was made in the bottom of the tube 5. On the other hand, a hole 52 with a diameter of 8 mm was made in the cap 51. A test film piece 32 measuring 1 cm x 1 cm or larger was attached to the cap 5 so as to completely seal the hole 52 and secured with double-sided tape (not shown). Note that a hole with a diameter of 8 mm was made in the double-sided tape corresponding to the hole 52 so that the double-sided tape does not cover the hole 52 of the tube 5. The tube 5 was placed on its side and 3 mL of PBS (solution 6) was poured in through the air hole (Figure 8(a)). Tube 5 was fixed upside down with the cap 51 facing downwards (Figure 8(b)), and the time until the test film piece 32 ruptured and the solution 6 flowed out was measured. Figure 9 shows the measurement results.

[0112] Film pieces with added sugar alcohol (Examples 2F-4F) showed high water pressure resistance compared to other additives (Comparative Examples 1F and 2F) and no additives (Comparative Example 4S), although not as high as those with PVA added (Comparative Example 3F).

Claims

1. The following components (A) and (B): (A) Polymers having hydrogen-donating functional groups, (B) Polymers having hydrogen-accepting functional groups, A hydrogel precursor comprising a mixed dried product of which forms an adhesive hydrogel upon absorbing moisture, The aforementioned mixed dried product further contains the following component (C): (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. The hydrogel precursor comprising the above.

2. The hydrogel precursor according to claim 1, which forms a hydrogel having adhesive properties to biological tissues when it absorbs moisture.

3. The hydrogel precursor according to claim 1, wherein the component (A) is polyacrylic acid.

4. The hydrogel precursor according to claim 1, wherein the component (B) is polyvinylpyrrolidone.

5. The hydrogel precursor according to claim 1, wherein the component (C) is one or more selected from the group consisting of glycerin, erythritol, glucitol, and xylitol.

6. The hydrogel precursor according to claim 1, wherein the weight ratio of component (C) in the hydrogel precursor is 0.05 to 2.5 when the weight ratio of component (A) is 1.

0.

7. The aforementioned component (A) is polyacrylic acid, The aforementioned component (B) is polyvinylpyrrolidone, The aforementioned component (C) is one or more selected from the group consisting of glycerin, erythritol, glucitol, and xylitol. The hydrogel precursor according to claim 1.

8. A hydrogel precursor according to claim 1, having a film-like form.

9. A porous hydrogel precursor according to claim 1.

10. A hydrogel precursor according to any one of claims 1 to 9, which is a medical treatment material.

11. A hydrogel precursor according to claim 10, which is a hemostatic agent, a body fluid absorbent, a wound dressing or protective agent, or an adhesion prevention agent.

12. A hydrogel precursor according to any one of claims 1 to 9, which is for application to the skin or mucous membrane.

13. A hydrogel precursor according to any one of claims 1 to 9, for use as an intraoral adhesive patch.

14. A method for producing a hydrogel precursor that forms an adhesive hydrogel upon absorbing moisture, The following components (A) and (B): (A) Polymers having hydrogen-donating functional groups, (B) Polymers having hydrogen-accepting functional groups, To prepare a dry solid-phase substrate from one of the solutions, The process involves contacting a solution of the other component with the solid-phase substrate, then drying it to prepare a mixed dried product of components (A) and (B), thereby obtaining a hydrogel precursor. To both or either of the solutions of components (A) and (B) above, component (C) is added: (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. The manufacturing method comprising the formulation of the above.

15. A method for producing a porous hydrogel precursor that forms an adhesive hydrogel upon absorbing moisture, The following components (A) and (B): (A) Polymers having hydrogen-donating functional groups, (B) Polymers having hydrogen-accepting functional groups, To prepare a dry solid-phase substrate from one of the solutions, The other component's solution is brought into contact with the solid-phase substrate and then frozen to prepare a frozen product. The process includes freeze-drying the frozen material to prepare a porous body of the mixed dried material of components (A) and (B), thereby obtaining a porous hydrogel precursor. To both or either of the solutions of components (A) and (B) above, component (C) is added: (C) One or more selected from the group consisting of glycerin, tetrasaccharide sugar alcohols, pentose sugar alcohols, and hexose sugar alcohols. The manufacturing method comprising the formulation of the above.

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