JP2019019185A - Gelling composition and gel structure - Google Patents

Abstract

To provide a gelling composition that causes a phase transition from a state with flowability to a state without flowability by an unconventional mechanism and has excellent handleability, and provide a gel structure from the gelling composition.SOLUTION: The present invention provides a gelling composition that causes a phase transition from a state with flowability to a state without flowability, wherein the composition contains a polymer A having a boronic acid group, a polymer B having a diol structure, and a compound C having a diol structure.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a gelled composition and a gel structure.

  In the medical field, a technique is known in which various base materials are disposed in the vicinity of a tissue in a living body to treat various diseases related to the tissue. Examples of such a base material include a sheet for preventing adhesion of a wound generated in a living body, and a hydrogel for treating myocardial infarction.

  Individual tissues in a living body have a complicated structure. Furthermore, various tissues exist in the living body, and the tissue to be treated often exists in a state where it is buried in another tissue. Therefore, the above-mentioned base material (i) can take a complicated shape that can be in close contact with a tissue having a complicated structure, and (ii) can be easily administered to a tissue to be treated. Is required.

  In response to such demands, materials that cause a phase transition from a fluid state to a gel or the like in response to specific stimuli or environmental changes have been attracting attention. That is, it is a fluid (eg, a sol or a gel having fluidity because of its extremely low crosslink density) outside the living body, and a gel that loses fluidity in response to a stimulus in vivo. Development of an injectable gel that can be changed to the above is underway. For example, a light-responsive injectable gel in which chemical cross-linking is induced between polymers by light irradiation and gelation, and a temperature-responsive injectable in which chemical cross-linking is induced between polymers by heating (for example, heating due to body temperature). Researches on gels and pH-responsive injectable gels in which chemical cross-linking is induced between polymers by changes in pH and the like have been actively pursued. (For example, see Non-Patent Documents 1 to 7)

Zhang Z et. Al., “Biodegradable and thermoreversible PCLA-PEG-PCLA hydrogel as a barrier for prevention of post-operative adhesion.”, Biomaterials., 2011 Apr; 32: 4725-36. Li L et. Al., “Biodegradable and injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for postoperative adhesion prevention.”, Biomaterials., 2014 Feb; 35: 3903-17. Zhang Z et. Al., “Encapsulation of cell-adhesive RGD peptides into a polymeric physical hydrogel to prevent postoperative tissue adhesion”, J Biomed Mater Res., 2012 Jun; 100B: 1599-609. Yu L et. Al., “Comparative studies of thermogels in preventing post-operative adhesions and corresponding mechanisms”, Biomater. Sci., 2014 Mar; 2: 1100-9. Wang X et. Al., “Injectable silk-polyethylene glycol hydrogels”, Acta Biomaterialia., 2015 Oct; 12: 51-61. Ito T et. Al., “Dextran-based in situ cross-linked injectable hydrogels to prevent peritoneal adhesions.”, 2007 Biomaterials .; 28: 3418-26. Garberm J C et. Al., “Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium.”, 2011 Biomaterials.; 32: 2407-16.

  Since conventional injectable gels are gelated by light irradiation, heating, pH change, or the like, it is necessary to include a compound that responds to these stimuli. Many of the compounds are not guaranteed in vivo safety and are difficult to apply. For example, in the case of performing light irradiation, a device for irradiating a specific area with light is required. Such a device is not only expensive, but also has a problem with light permeability in living tissue, and it is difficult to uniformly irradiate a specific region in the living body having a complicated structure. It's not easy.

  On the other hand, in the case of heating by body temperature, it is not easy to deliver in the living body while maintaining the temperature in the sol state, and the time required for gelation becomes long. In order to shorten the time required for gelation, an apparatus for heating a specific region is required. Such an apparatus is not only expensive, but it is not easy to uniformly heat a specific region in a living body having a complicated structure.

  Furthermore, in order to gel an injectable gel by a change in pH in the living body, it is necessary to set the pH of the injectable gel at the time of administration to the living body to be alkaline or acidic. If the pH of the injectable gel is set to other than the pH in the living body (alkaline or acidic), cytotoxicity becomes a problem.

  The present invention has been made in view of the above-mentioned conventional problems, and its purpose is handling properties that cause a phase transition from a fluid state to a non-fluid state by a mechanism different from the conventional one. An object of the present invention is to provide a gelling composition excellent in the above and a gel structure formed from the gelling composition.

  As a result of intensive studies, the present inventors have found that a compound that inhibits cross-linking between polymers constituting the gel structure and is easily diluted by free diffusion can be used to improve the fluidity from a fluid state. It has been found that a new injectable gel that causes a phase transition to a state that does not exist can be realized, and the present invention has been completed.

In order to solve the above problems, a gelled composition that causes a phase transition from a fluid state to a non-fluid state according to one embodiment of the present invention includes a polymer A having a boronic acid group,
A polymer B having a diol structure and a compound C having a diol structure are contained.

  In the gelled composition according to one aspect of the present invention, the diol structure is at least one structure selected from the group consisting of a 1,2-diol structure, a 1,3-diol structure, an oligool structure, and a polyol structure. Preferably there is.

  In the gelled composition according to one embodiment of the present invention, the polymer B and / or the compound C preferably contains a sugar or saccharide analogue having a diol structure as a constituent component.

  In the gelled composition according to one embodiment of the present invention, the sugar and saccharide analog are preferably a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, or a nucleotide sugar.

  In the gelled composition according to one aspect of the present invention, the sugar and saccharide analog are glucose, galactose, fructose, mannose, glucuronic acid, glucosamine, galactosamine, sorbitol, sucrose, lactose, maltose, trehalose, gentiobiose, raffinose, It is preferably maltotriose, melezitose, alkaboose, stachyose, galactooligosaccharide, fructooligosaccharide, mannan oligosaccharide, ribose, deoxyribose, pinacol, catechol or trishydroxymethylaminomethane.

  In the gelled composition according to one embodiment of the present invention, the compound C preferably has a weight average molecular weight of 50 to 1,000.

  In the gelled composition according to one embodiment of the present invention, the concentration of the compound C in the gelled composition is preferably higher than the concentration of the compound C in vivo.

  In order to solve the above problems, the gel structure according to one embodiment of the present invention is obtained by bonding a polymer A having a boronic acid group and a polymer B having a diol structure.

  According to the present invention, since a phase transition occurs from a state having fluidity to a state having no fluidity, a gelled composition having excellent handling properties, and a gel structure formed from the gelled composition May provide a body.

It is the schematic of the mechanism which produces a phase transition from the state which has a fluidity | liquidity to the state which does not have a fluidity | liquidity, according to embodiment of this invention. The concentration of glucose in the gelled composition, the concentration of boronic acid group-containing polyacrylamide in the gelled composition, the concentration of β-glucan in the gelled composition, and the fluidity state according to the examples of the present invention It is a figure which shows correlation with the phase transition to the state which does not have fluidity | liquidity. 1 is a cross-sectional view of an apparatus used to measure storage modulus (G ′) and loss modulus (G ″) of a gelled composition that has undergone dialysis according to an embodiment of the present invention. It is a graph which shows the correlation with the glucose concentration in external liquid, the dialysis time, a storage elastic modulus (G '), and a loss elastic modulus (G ") based on the Example of this invention.

  An embodiment of the present invention will be described below, but the present invention is not limited to this. The present invention is not limited to each configuration described below, and various modifications can be made within the scope shown in the claims, and technical means disclosed in different embodiments and examples respectively. Embodiments and examples obtained by appropriately combining them are also included in the technical scope of the present invention. Moreover, all the academic literatures and patent literatures described in this specification are used as references in this specification. Unless otherwise specified in this specification, “A to B” representing a numerical range is intended to be “A or more and B or less”.

[1. Basic principle of the present invention]
First, the basic principle of the present invention will be described with reference to FIG.

  The polymer A can be bonded to the polymer B. In addition, the polymer A can also bind to the compound C. When the three of the polymer A, the polymer B, and the compound C coexist, the compound C has a competitive inhibition ability with respect to the binding between the polymer A and the polymer B. When Compound C is in a state of being bonded to Polymer A and Polymer B is in a state of being unable to bind to Polymer A, the gelled composition including the three components has a fluid state (for example, sol or The gel has fluidity due to its extremely low crosslink density.

  On the other hand, when the gelling composition is administered in an environment containing compound C at a concentration lower than that of compound C in the gelling composition, compound C in the gelling composition diffuses into the environment. The concentration of compound C in the gelled composition is reduced. As the concentration of compound C, which is a substance that inhibits the binding between polymer A and polymer B, decreases, polymer A and polymer B bind to each other, and the gelled composition gels (in other words, gel structure Body is formed). Since Compound C diffuses into the living body and is diluted to a low concentration, the gelled composition has low toxicity. Therefore, the gelled composition can be administered to any site in the living body.

[2. Gelling composition]
The gelled composition that causes a phase transition from the fluid state of the present embodiment to the non-fluid state has a polymer A having a boronic acid group, a polymer B having a diol structure, and a diol structure. And having compound C.

  In addition, examples of the state having fluidity include sol or gel having fluidity due to low crosslinking density, and examples of the state having no fluidity include crosslinking density. A gel that does not have fluidity due to its high viscosity can be mentioned.

  Each configuration will be described below.

[2-1. Polymer A]
In the gelled composition of the present embodiment, the polymer A has a boronic acid group.

  The boronic acid group may form a cyclic ester with the polymer B and the compound C having a diol structure accompanied by acid dissociation. More specifically, the boronic acid includes polymer B and compound C (for example, polymer B and compound C having a 1,2-diol or 1,3-diol structure), a 5-membered ring ester or a 6-membered ring. Esters may be formed.

  Examples of the boronic acid group include a phenylboronic acid group, a naphthalene boronic acid group, a quinoline boronic acid group, a pyridine boronic acid group, a thiophene boronic acid group, a furan boronic acid group, an indole boronic acid group, and a cyclohexyl boronic acid group. It is done.

  The boronic acid group may be contained in the side chain of the polymer A or may be contained in the main chain.

  The boronic acid group can be contained in the monomer constituting the polymer A. Examples of the monomer having a boronic acid group include 4- (acryloylamino) phenylboronic acid, 3- (acryloylamino) phenylboronic acid, 3- (methacryloylamino) phenylboronic acid, 4-vinylphenylboronic acid, 4- (Vinylcarbamoyl) phenylboronic acid, 2-methoxypyridine-5-boronic acid, 5-carboxythiophene-2-boronic acid, a compound in which the aromatic hydrogen atom is substituted with one or more fluorine atoms, and their Examples include compounds in which the aminophenylboronic acid structure is substituted with N-alkylaminomethylphenylboronic acid. The polymer A may be composed of one or more monomers selected from these.

  The polymer A may be composed only of a monomer having a boronic acid group, or may be composed of a combination of a monomer having a boronic acid group and a monomer having no boronic acid group. The content of the monomer having a boronic acid group in the polymer A is preferably 1% by mass or more and 10% by mass or less, and more preferably 3% by mass or more and 5% by mass or less. If it is the said structure, the density | concentration of the compound C which has an antagonistic inhibitory ability with respect to the coupling | bonding of the polymer A and the polymer B is more than the density | concentration of the compound C in the living body in a gelatinization composition, and is practical. The concentration of the polymer A and the polymer B can be inhibited in a range of concentrations. And when the density | concentration of the compound C falls in the living body, there exists an advantage that the coupling | bonding of the polymer A and the polymer B can be accelerated | stimulated.

  Examples of the monomer having no boronic acid group include acrylamide monomers, methacrylamide monomers, acrylic monomers, and methacrylic monomers. Further specific examples of such monomers include, for example, (meth) acrylamide, N-methyl (meth) acrylamide, N-ethyl (meth) acrylamide, N-isopropyl (meth) acrylamide, N, N-dimethyl (meth) ) Acrylamide, N, N-dimethylaminopropyl (meth) acrylamide, ethylenebis (meth) acrylamide, N- [3- (dimethylamino) propyl] (meth) acrylamide, Nt-butyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N- (butoxymethyl) (meth) acrylamide, N- (isobutoxymethyl) (meth) acrylamide, N-phenyl (meth) acrylamide, isobutoxymethyl (meth) acrylamide, N-vinyl Lactone, methyl vinyl ether (Meth) acryloylmorpholine, (meth) acrylic acid, various alkyl (meth) acrylates, 1,4-cyclohexanedimethanol mono (meth) acrylate, (3- (meth) acrylamidopropyl) trimethylammonium chloride, trimethyl-2- ( (Meth) acryloyloxyethylammonium chloride, 2-((meth) acryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl, 2- (2-ethoxyethoxy) ethyl (meth) acrylate, (meth) acrylic acid Glycidyl, di (ethylene glycol) divinyl ether, tri (ethylene glycol) divinyl ether, poly (ethylene glycol) divinyl ether, trimethylolpropane ethoxylate tri (meth) acrylate, trimethylolpropane Ropoxylate tri (meth) acrylate, N- [tris (3- (meth) acrylamidepropoxymethyl) methyl] (meth) acrylamide, vinyl acetate, vinyl carboxylate (C3-C10), N-vinylpyrrolidone, acrylonitrile, styrene , Polyethylene glycol di (meth) acrylate, 1,6-hexanediol di (meth) acrylate, neopentyl glycol di (meth) acrylate, tripropylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, 2,2 -Bis [4-((meth) acryloxydiethoxy) phenyl] propane, 2,2-bis [4-((meth) acryloxypolyethoxy) phenyl] propane, 2,2-bis [4-((meta ) Acryloxypolypropoxy) Nenyl] propane, ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, 1,3-butylene glycol di (meth) acrylate, 1,6-hexanediol di (meth) Acrylate, 2,2-bis [4-((meth) acryloxyethoxy) phenyl] propane, 2,2-bis [4-((meth) acryloxyethoxydiethoxy) phenyl] propane, 2,2-bis [ 4-((meth) acryloxyethoxypolyethoxy) phenyl] propane, trimethylolpropane tri (meth) acrylate, tetramethylolmethane tri (meth) acrylate, tetramethylolmethane tetra (meth) acrylate, dipentaerythritol hexa (meth) Ak , N, N′-methylenebis (meth) acrylamide, diethylene glycol diallyl ether, divinylbenzene, 4- (meth) acrylamide benzo-18-crown-6-ether, acryloylaminobenzocrown ether, (meth) acryloylaminobenzocrown ether , 4-vinylbenzocrown ether and the like. In the gelled composition of the present embodiment, one or more selected from these can be used in combination.

[2-2. Polymer B and Compound C]
In the gel composition of the present embodiment, both the polymer B and the compound C have a diol structure. At this time, the diol structure of the polymer B and the diol structure of the compound C may be the same diol structure or different diol structures.

  If the diol structure possessed by polymer B and the diol structure possessed by compound C are the same diol structure, the reactivity of polymer B to polymer A and the reactivity of compound C to polymer A should be substantially the same. Can do. If it is the said structure, the molar ratio (for example, polymer B: compound C) of the polymer B in a gelatinization composition required in order to inhibit the coupling | bonding formed between the polymer A and the polymer B is required. However, 1:10 to 1: 1000) can be easily determined.

  The diol structure is preferably at least one structure selected from the group consisting of a 1,2-diol structure, a 1,3-diol structure, an oligool structure, and a polyol structure. Among these diol structures, a diol structure contained in glucose (more specifically, glucose) from the viewpoint of high biocompatibility, high diffusion rate, and high affinity with boronic acid. Is more preferable.

  In the gelled composition of the present embodiment, it is preferable that the polymer B and / or the compound C contain a diol structure and a sugar or a sugar saccharide as a constituent component. Moreover, the said compound C may be the said saccharide | sugar or saccharide-related body itself. Sugars and sugar analogues are extremely safe substances for living bodies. Therefore, with this configuration, it is possible to realize a safer gelled composition for a living body.

  The sugar is preferably a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or nucleotide sugar. Examples of the monosaccharide include glucose, galactose, fructose, mannose, glucuronic acid, glucosamine, galactosamine, sorbitol and the like. Examples of the disaccharide include sucrose, lactose, maltose, trehalose, and gentiobiose. Examples of the trisaccharide include raffinose, maltotriose, melezitose and the like. Examples of the tetrasaccharide include alkaboose and stachyose. Examples of the oligosaccharide include galactooligosaccharide, fructooligosaccharide, and mannan oligosaccharide. Examples of the nucleotide sugar include ribose and deoxyribose.

  Examples of the sugar saccharide include pinacol, catechol, trishydroxymethylaminomethane, and the like.

  In the gelled composition of the present embodiment, the sugar is more preferably glucose, galactose, or fructose, and the sugar saccharide is more preferably pinacol, catechol, or trishydroxymethylaminomethane.

  The sugar and the saccharide analog may be included in various living organisms in nature. Examples of the organism include plants and fungi.

  The polymer B may contain a diol structure in the side chain of the polymer B or in the main chain.

  The polymer B is not particularly limited as long as it has a diol structure, and examples thereof include β-glucan, polyvinyl alcohol, polyglycidol, and dextran. The β-glucan is a natural polysaccharide having a glucose structure in the side chain, and is an edible polysaccharide extracted from Aureobasidium pullulans. Of the β-glucans, schizophyllan is a safe material that is also used as an intramuscular injection aimed at enhancing the effects of radiation therapy in cervical cancer.

  In the gelled composition of the present embodiment, the compound C preferably has a weight average molecular weight of 50 to 1,000. The smaller the weight average molecular weight, the easier it is to diffuse. Therefore, if it is the said structure, the gelatinization composition which is easier to gelatinize is realizable. The weight average molecular weight can be measured according to a known method. For example, it is possible to perform measurement under the following conditions: (1) Equipment used: Tosoh HLC-8220GPC equivalent, (2) Column: Tosoh TSK gel Super AWM-H (6.0 mm ID × 15 cm) × 2, (3) Guard column: Tosoh TSK guard column super AW-H, (4) Eluent: 30 mM LiBr + 20 mM H3PO4 in DMF, (5) Flow rate: 0.6 mL / min, (6) Column temperature: 40 ° C. (7) Detection conditions: RI: Polarity (+), Response (0.5 sec), (8) Sample concentration: about 5 mg / mL, (9) Standard product: PEG (polyethylene glycol).

  In addition, when the compound C is a uniform substance, the molecular weight of the compound C calculated logically can be regarded as the weight average molecular weight.

  The compound C can antagonize the polymer B and inhibit the formation of a bond between the polymer A and the polymer B. Therefore, the binding force between the boronic acid group of polymer A and the diol structure of compound C is preferably stronger than the binding force between the boronic acid group of polymer A and the diol structure of polymer B.

  The gelling composition is preferably for administration into a living body. The compound C in the gelled composition diffuses in the living body, and in some cases, is metabolized by the living body, thereby reducing the concentration of the compound C in the gelled composition. This means that the concentration of the substance that inhibits the formation of a bond between polymer A and polymer B is reduced. As a result, the polymer A and the polymer B are bonded and gelled to form a gel structure.

  In the gelled composition of the present embodiment, the concentration of the compound C in the gelled composition is preferably higher than the concentration of the compound C in the living body. More specifically, the concentration of the compound C in the gelled composition is preferably 2 times or more, more preferably 5 times or more higher than the concentration of the compound C in vivo, more preferably 10 times or more. Higher is more preferable, and it is most preferable that it is 20 times higher. According to this configuration, when the gelled composition is administered into the living body, the compound C diffuses from the gelled composition toward the living body, and the concentration of the compound C in the gelled composition decreases. As a result, the gelled composition of the present embodiment can cause a phase transition from a state having fluidity to a state having no fluidity.

  That is, when the concentration of Compound C in vivo is 1 mg / ml, the concentration of Compound C in the gelled composition is preferably 2 mg / ml or more, more preferably 5 mg / ml or more, More preferably, it is 10 mg / ml or more, and most preferably 20 mg / ml or more.

  The concentration ratio of the polymer A, the polymer B, and the compound C in the gelation composition is not particularly limited as long as it is a concentration ratio that allows gelation when administered in vivo. For example, polymer A: polymer B: Compound C = 0.1-5: 5-10: 5-10, 0.1-20: 5-10: 10-20, 0.1-40: 5-10: 20-30, 0.1 ~ 200: 5 to 10:30 to 40, 0.1 to 0.5: 10 to 20: 5 to 10, 0.1 to 5:10 to 20:10 to 20, 0.1 to 1:10 to 20 : 20 to 30, or 0.1 to 1:10 to 20:30 to 40 is preferable. More preferably, it is polymer A: polymer B: compound C = 0.1-40: 5-10: 20-30. More preferably, it is polymer A: polymer B: compound C = 5-15: 5-10: 20-30.

  The concentration of polymer A is preferably 0.1 mg / ml to 5 mg / ml, the concentration of polymer B is preferably 5 mg / ml to 15 mg / ml, and the concentration of compound C is preferably 5 mg / ml to 10 mg / ml. Is preferably 0.1 mg / ml to 20 mg / ml, the concentration of polymer B is 5 mg / ml to 10 mg / ml, the concentration of compound C is preferably 10 mg / ml to 20 mg / ml, and the concentration of polymer A is 0.1 mg / Ml to 40 mg / ml, the concentration of polymer B is preferably 5 mg / ml to 10 mg / ml, the concentration of compound C is preferably 20 mg / ml to 30 mg / ml, and the concentration of polymer A is 0.1 mg / ml to 200 mg The concentration of polymer B is preferably 5 mg / ml to 10 mg / ml, and the concentration of compound C is preferably 30 mg / ml to 40 mg / ml. The concentration of polymer A is preferably 0.1 mg / ml to 0.5 mg / ml, the concentration of polymer B is preferably 10 mg / ml to 20 mg / ml, and the concentration of compound C is preferably 5 mg / ml to 10 mg / ml. The concentration of A is preferably 0.1 mg / ml to 5 mg / ml, the concentration of polymer B is preferably 10 mg / ml to 20 mg / ml, the concentration of compound C is preferably 10 mg / ml to 20 mg / ml, and the concentration of polymer A is 0.1 mg / ml to 1 mg / ml, polymer B concentration from 10 mg / ml to 20 mg / ml, compound C concentration from 20 mg / ml to 30 mg / ml, or polymer A concentration from 0.1 mg / ml to 1 mg / Ml, the concentration of polymer B is preferably 10 mg / ml to 20 mg / ml, and the concentration of compound C is preferably 30 mg / ml to 40 mg / ml. More preferably, the concentration of polymer A is 0.1 mg / ml to 40 mg / ml, the concentration of polymer B is 5 mg / ml to 10 mg / ml, and the concentration of compound C is 20 mg / ml to 30 mg / ml. More preferably, the concentration of polymer A is 5 mg / ml to 10 mg / ml, the concentration of polymer B is 5 mg / ml to 10 mg / ml, and the concentration of compound C is 20 mg / ml to 30 mg / ml.

  The gelled composition gels and forms a gel structure when the concentration of the compound C in the gelled composition decreases. That is, when the gelled composition is administered in an environment (for example, in a solution or in a living body) containing the compound C at a concentration lower than the concentration of the compound C in the gelled composition, Polymer A and polymer B combine to form a gel structure. This is because the compound C that binds to the polymer A and inhibits the binding between the polymer A and the polymer B is diffused into the environment, and the concentration of the compound C in the gelled composition is decreased.

  The gelled composition may be used as a biological transplant material.

  The biological transplant material may be used for tissue adhesion prevention (tissue adhesion prevention material) or myocardial infarction treatment (myocardial infarction treatment material).

  When using the gel composition for preventing tissue adhesion, the gel structure is administered to the tissue surface by administering the gel composition to the tissue surface in the living body or the gel structure generated from the gel composition. May be formed. By covering the tissue surface with the gel structure, tissue adhesion after surgery can be prevented.

  When the gelled composition is used for the treatment of myocardial infarction, the gelled composition may be injected into the ventricular wall thickness with respect to the heart in which the ventricular diameter is reduced due to thinning of the ventricular wall thickness. The gel structure generated from the gelled composition may be injected into the ventricle wall thickness. By injecting the gelled composition or gel structure, the ventricular wall can be thickened, the ventricular diameter can be reduced, and the strength of the ventricular wall can be maintained.

  Examples of the method for administering the gelled composition into a living body include spraying, injection, and application. Excellent adhesion to wounds, can be used in endoscopic surgery, easy to handle, and the gelled composition spreads over the tissue surface, making it easy to identify bleeding sites without specifying the location of the bleeding site Since it can be covered, the method for administering the gelled composition into the living body is preferably spraying or injection.

  The gelling composition may contain additives other than polymer A, polymer B, and compound C. For example, polymers other than polymer A and polymer B, buffers, pH adjusters, tonicity agents, antiseptics Agents, antioxidants, excipients, carriers, diluents, solvents, solubilizers, stabilizers, fillers, binders, surfactants, stabilizers and the like.

  Examples of the buffer include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ε-aminocaproic acid, trometamol Etc. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like. Examples of the borate include borax, sodium borate, and potassium borate. Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate. Examples of the tartrate salt include sodium tartrate and potassium tartrate.

  Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.

  Examples of the isotonic agents include ionic tonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.). Can be mentioned.

  Examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.

  Examples of the antioxidant include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.

  The gelation composition of this Embodiment may contain the additive known to those skilled in the art besides having illustrated above.

  The amount of the additive is not particularly limited as long as the amounts of the polymer A, the polymer B, and the compound C satisfy the above-mentioned amounts.

[3. Gel structure
The gel structure of the present embodiment is obtained by bonding a polymer A having a boronic acid group and a polymer B having a diol structure.

  The polymer A, the polymer B, and the diol structure are described in [2. Since it was described in the column of [Gelating composition], the description thereof is omitted here.

  Since the polymer A having a boronic acid group has the ability to bind to sugar chains on cell membranes, mucous membranes and biological membranes, the formed gel structure has tissue adhesion and affinity.

  The gel structure may be used as a biological transplant material.

  The biological transplant material may be used for tissue adhesion prevention (tissue adhesion prevention material) or myocardial infarction treatment (myocardial infarction treatment material).

  When the gel structure is used for preventing tissue adhesion, the gel structure may be formed on the tissue surface by administering the gel structure to the tissue surface in the living body. By covering the tissue surface with the gel structure, tissue adhesion after surgery can be prevented.

  When the gel structure is used for preventing tissue adhesion, the gel structure is preferably degradable (more specifically, biodegradable). That is, the main chains of the polymer A and the polymer B are preferably degradable (more specifically, biodegradable) polymers.

  When using the gel structure for the treatment of myocardial infarction, a method of injecting the gel structure into the ventricle wall thickness to the heart in which the ventricular wall thickness is enlarged (remodeling) due to thinning of the ventricular wall thickness It may be. By injecting the gel structure, it is possible to thicken the ventricular wall, suppress further expansion of the ventricular diameter, and maintain the strength of the ventricular wall.

  When the gel structure is used for the treatment of myocardial infarction, the gel structure is preferably non-degradable (more specifically, non-biodegradable). That is, the main chains of the polymer A and the polymer B are preferably non-degradable (more specifically, non-biodegradable) polymers. Since the gel structure is non-degradable, the strength of the ventricular wall can be maintained for a long time.

  The storage elastic modulus of the gel structure is preferably 2.5E + 02 Pa or more, and more preferably 3.0E + 02 Pa or more.

  The gel structure of the present embodiment can also be configured as follows.

  In the gel structure according to the present embodiment, the diol structure may be at least one structure selected from the group consisting of a 1,2-diol structure, a 1,3-diol structure, an oligool structure, and a polyol structure. preferable.

  In the gel structure of the present embodiment, it is preferable that the polymer B contains a diol structure or a sugar or a sugar saccharide as a constituent component.

  In the gel structure of the present embodiment, the saccharide and saccharide analog are preferably monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, or nucleotide sugar.

  In the gel structure of the present embodiment, the sugar and saccharide analog are glucose, galactose, fructose, mannose, glucuronic acid, glucosamine, galactosamine, sorbitol, sucrose, lactose, maltose, trehalose, gentiobiose, raffinose, maltotriose. , Melezitose, alkaboose, stachyose, galactooligosaccharide, fructooligosaccharide, mannan oligosaccharide, ribose, deoxyribose, pinacol, catechol or trishydroxymethylaminomethane.

  The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.

<Example 1>
Each concentration of boronic acid group-containing polyacrylamide, β-glucan, and glucose (weight average molecular weight: approximately 180) was mixed in a test tube. The state in which the test tube was turned upside down and the mixture in it flowed down was judged to have fluidity and was marked “x”. Even if the test tube was turned upside down, the state in which the mixture inside solidified at the bottom and did not flow down was judged as a gel state, and “◯” was given.

  FIG. 2 shows the phase transition from a fluid state of a solution containing boronic acid group-containing polyacrylamide at each concentration and β-glucan at each concentration to a state without fluidity at each glucose concentration. The result of Example 1 is shown.

  As an example of the results, when the β-glucan concentration was 10 mg / ml, the boronic acid concentration was 0.1 mg / ml to 40 mg / ml, and the glucose concentration was 20 mg / ml, the solution was in a gel state. When the β-glucan concentration was 10 mg / ml, the boronic acid concentration was 0.1 mg / ml to 40 mg / ml, and the glucose concentration was 1 mg / ml, the solution was in a fluid state. From this result, when the concentration of β-glucan is 10 mg / ml and the concentration of boronic acid is 0.1 mg / ml to 40 mg / ml, it has fluidity when the glucose concentration is reduced from 20 mg / ml to 1 mg / ml. From the above, it was found that the fluidity was not obtained.

<Example 2>
When the gelled composition is dialyzed into a low-concentration C compound-containing solution using the apparatus shown in FIG. 3, the storage elastic modulus (G ′) and loss elastic modulus (G ″) with respect to the dialysis time of the gelled composition. Was measured.

  The apparatus includes a silicone foot, a polyethylene sponge, a dialysis membrane, and an injection needle. The injection needle is for venting air between the dialysis membrane and the polyethylene sponge. A porous sheet is provided on the silicon foot, a dialysis membrane is provided on the porous sheet, and a measurement sample is set on the dialysis membrane. The outside of the dialysis membrane is filled with an external solution (glucose solution).

  A sample mixed with 10 mg / ml boronic acid group-containing polyacrylamide, 10 mg / ml β-glucan, and 30 mg / ml glucose was mixed with a dialysis membrane (trade name: Slide-A-Lyzer MWCO3500 with a semipermeable membrane on the lower surface. ) Set on top. The sample set on the dialysis membrane was dialyzed for 1 hour against an external solution of 1 mg / ml (assuming glucose concentration in the living body) or 30 mg / ml glucose solution. Measure the storage elastic modulus (G ′) and loss elastic modulus (G ″) using a dynamic viscoelasticity measuring device, applying a dynamic viscoelastic probe from above the sample under the conditions of 1% strain and 0.5 Hz frequency. When a 1 mg / ml glucose solution was used as the external solution, the measurement was once stopped after 1 hour from the start of dialysis, and the same gel was measured again for 10 minutes immediately after that.

  FIG. 4 is a graph showing the correlation between dialysis time, storage elastic modulus (G ′), and loss elastic modulus (G ″) at each glucose concentration.

  When a 1 mg / ml glucose solution was used as the external liquid, the storage elastic modulus (G ′) increased with the dialysis time. This increase in storage modulus (G ′) indicates an improvement in the gel strength of the sample or a loss in the fluidity of the gel. The rate of increase in gel strength or the rate of disappearance of the fluidity of the gel was fast, and the storage elastic modulus (G ′) became constant in about 1 hour. The gelation rate value depends on the thickness of the sample or the biological environment.

  On the other hand, when the same 30 mg / ml glucose solution as the glucose concentration in the sample was used as the external liquid, no increase in storage elastic modulus (G ′) was observed. It was shown that it has a state.

  INDUSTRIAL APPLICABILITY The present invention can be used as a gel for preventing tissue adhesion after surgery or treating myocardial infarction.

Claims (8)

A gelled composition that causes a phase transition from a fluid state to a non-fluid state,
Polymer A having boronic acid groups;
A polymer B having a diol structure;
A gelling composition containing Compound C having a diol structure.   The gelled composition according to claim 1, wherein the diol structure is at least one structure selected from the group consisting of a 1,2-diol structure, a 1,3-diol structure, an oligool structure, and a polyol structure.   The gelling composition according to claim 1 or 2, wherein the polymer B and / or the compound C contains a sugar or a sugar saccharide having a diol structure as a constituent component.   The gelled composition according to claim 3, wherein the sugar and saccharide-related substance are monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or nucleotide sugar.   The sugars and saccharide analogues are glucose, galactose, fructose, mannose, glucuronic acid, glucosamine, galactosamine, sorbitol, sucrose, lactose, maltose, trehalose, gentiobiose, raffinose, maltotriose, melezitose, alkose, stachyose, galactooligosaccharide, The gelled composition according to claim 3, which is fructooligosaccharide, mannan oligosaccharide, ribose, deoxyribose, pinacol, catechol or trishydroxymethylaminomethane.   The gelled composition according to any one of claims 1 to 5, wherein the compound C has a weight average molecular weight of 50 to 1,000.   The gelled composition according to any one of claims 1 to 6, wherein the concentration of the compound C in the gelled composition is higher than the concentration of the compound C in vivo.   A gel structure formed by bonding a polymer A having a boronic acid group and a polymer B having a diol structure.

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