Water-swellable polymer gel and process for preparing the same

ES 2 260 098 T3

DESCRIPTION

Water-swellable polymer gel and its preparation procedure.

Fundamentals of the invention

Scope of the invention

The present invention relates to a water-swellable polymer gel and a process for the preparation of the water-swellable polymer gel. More particularly, the present invention relates to a water-swellable polymer gel which is excellent in human body safety, water absorbability, transparency and mechanical properties, and a process for its preparation.

Discussion of Related Art

A water-swellable hydrogel, obtained by chemical crosslinking of a polysaccharide, has been widely used in fields such as industry, agriculture, food, and medicine. Applications of the water-swellable gel in the medical field include, for example, wound dressings, materials to prevent adhesion, dialysis membranes, hemostatic materials, adhesive materials, sealants, contact lenses, materials for tissue regeneration, materials for microcapsules, drug delivery systems (DDS), and the like.

Chemical crosslinking of the polysaccharide can be carried out by a chemical reaction, e.g. eg, gelation with a polyfunctional reagent, cross-linking using a coordinate bond, eg. eg, gelation by alginic acid ions; crosslinking using a hydrophobic bond, e.g. eg, gelation by heating methyl cellulose or hydroxypropyl cellulose; crosslinking using intermolecular association, e.g. eg, cooling agar or carrageenan to cause gelation, or the like. Among them, crosslinking by a chemical reaction has an advantageous merit since the water adsorbability and the strength of the resulting polysaccharide gel can easily be controlled depending on its purposes.

Crosslinking of the polysaccharide by a chemical reaction can be carried out by treating a solution of the polysaccharide with crosslinking agent having at least two functional groups. However, there are some defects in crosslinking such that crosslinking may not progress efficiently in water, since many of the polysaccharides are substantially only dissolved in water.

As a process for crosslinking a polysaccharide by a chemical reaction, a process has been disclosed which comprises crosslinking a polysaccharide with a bifunctional low molecular weight reagent in an aqueous solvent (hereinafter simply referred to as "process of low molecular weight crosslinking agent ”). Among them, as a process for crosslinking a water-soluble polysaccharide by a chemical reaction, a process comprising crosslinking a polysaccharide with an epoxy compound in an acidic or basic aqueous solution has been disclosed (Patent Publication Japanese Examined No. Hei 6-69490 and Japanese Unexamined Patent Publication No. Hei 11-509256); a process comprising crosslinking a polysaccharide with divinyl sulfone in a basic aqueous solution (Japanese Patent Laid-Open No. Hei 2-138346), and the like.

However, there are some shortcomings in the low molecular weight crosslinking process such that the resulting gel is extremely brittle, at the same time that the gel tends to show relatively high water absorption, and that a complicated procedure is required. for the intense washing of the polymer gel after its preparation in order to eliminate a crosslinking agent and a catalyst remaining in large quantities inside the gel.

Accordingly, the low molecular weight crosslinking agent process cannot necessarily be considered a useful process from the viewpoints of physical properties and productivity of the hydrogel.

Recently, a process has been developed which comprises crosslinking a polysaccharide with a polyfunctional high molecular weight crosslinking agent (hereinafter simply referred to as "high molecular weight crosslinking agent process").

As the high molecular weight crosslinking agent process, a process comprising crosslinking an ester of a polysaccharide containing carboxyl groups, for example, propylene glycol alginate (hereinafter simply referred to as "PGA" has been disclosed. ), with a water soluble polymer having amino groups such as gelatin to cause insolubilization, as described in British Patent No. 962483; Japanese Unexamined Patent Publication No. Hei 8-508933; SB Mohamed and G. Stainsby, Food Chemistry, vol. 13, p. 241, (1984), JE McKay, G. Stainsby, EL Wilson, Carbohyd. Polym., Vol. 5, p. 223, (1985), and the like.

According to the above-mentioned procedure, gelation is thought to be caused by aminolysis (amidation) of the ε-amino group derived from the lysine residue of a polyamino acid (protein) with an ester residue of PGA in water.

ES 2 260 098 T3

However, there are some defects in the gel made from PGA and a protein such as gelatin, such as that the absorbability of the gel is low, since a protein solution having a high concentration is required for the preparation of the gel, such that a large amount of protein is inevitably contained in the gel. Furthermore, there is also a defect in this gel, such that the gel cannot be formed in a neutral aqueous solution, which is suitable for materials for medical use.

Likewise, it has been proposed that a synthetic high molecular weight compound having amino groups as repeating units, such as a polyethyleneimine, be used as a crosslinking agent for PGA as described in British Patent No. 962483. Sin However, this procedure requires a treatment with a basic substance for the formation of a gel. Accordingly, there are some shortcomings in this process that it is capable of generating small holes in the resulting gel, as well as some practical problems such as that the water absorbability and gel strength are remarkably low.

JP-A-09-278803 refers to medical wound treatment materials which are based on alginic acid gel. The gel comprises the reaction products of alginic acid and / or a water-soluble alginate with a diamine and / or a polyamine. Alternatively, the alginic acid gel may comprise a product obtained by converting at least part of the hydroxyl groups and / or the carboxyl groups of the alginic acid to hydrophobic groups. The gel described in JP-A-63056501 comprises spherical cellulose particles to which ε-polylysine has been attached via a functional group.

US Patent 3,873,749 is related to food products that contain protein in the form of a thermoset gel, which can be manufactured by a process that comprises, among others, the step of mixing an edible protein ingredient and a propylene glycol ester of alginic acid.

An object of the present invention is to provide a water-swellable polymer gel having high water absorbability and gel strength, the essential component of which comprises a natural ingredient, and a foam of a water-swellable polymer gel.

Another object of the present invention is to provide a process for the easy preparation of a water-swellable polymer gel in an aqueous solvent with high productivity and safety for human bodies.

These and other objects of the present invention will become apparent from the following description.

Summary of the invention

According to the present invention, there is provided a water-swellable polymer gel prepared by reacting an ester of a polysaccharide containing carboxyl groups, which is alginic acid or hyaluronic acid, with a compound having at least two α- groups. amino, which is derived from a natural amino acid and which is ε-poly (lysine), and a foam made from it.

Furthermore, the present invention provides a process for the preparation of a water-swellable polymer gel, comprising the reaction of an ester of a polysaccharide containing carboxyl groups, which is alginic acid or hyaluronic acid, with a compound having at least two α-amino groups, which is derived from a natural amino acid and which is ε-poly (lysine).

Detailed description of the invention

The ester of a polysaccharide containing carboxyl groups, that is, the ester of alginic acid or hyaluronic acid (hereinafter simply referred to as "esterified polysaccharide"), means a compound formed by the bonding of at least one of the carboxyl groups of the polysaccharide containing carboxyl groups, preferably at least two of the carboxyl groups of the polysaccharide containing carboxyl groups, with hydroxyl groups of an alcohol, to form ester linkages. Among the esterified polysaccharides, the substantially water-soluble ones are preferable.

The alcohol includes aliphatic alcohols, aromatic aliphatic alcohols, cyclic aliphatic alcohols, and heterocyclic alcohols. Among them, in consideration of the water solubility of the esterified polysaccharide, there may be mentioned, for example, aliphatic alcohols having 1 to 16 carbon atoms such as methanol, ethanol and propanol; and polyhydric alcohols having at least two hydroxyl groups and 2 to 16 carbon atoms such as ethylene glycol, propylene glycol, and glycerol. With respect to the polyhydric alcohol, only one of the hydroxyl groups of the polyhydric alcohol is required to form an ester bond together with the carboxyl group of the carboxyl group-containing polysaccharide.

The carboxyl group-containing polysaccharide includes alginic acid and hyaluronic acid. Alginic acid and hyaluronic acid are used from the point of view of safety for human bodies and decomposability in human bodies.

Procedures for the preparation of an esterified polysaccharide include, for example, a general procedure described in Jikken Kagaku Koza 22, Yuki Gosei IV San, Aminosan, Pepuchido (Experimental Chemistry Lectu3

ES 2 260 098 T3 re 22, Organic Synthesis IV - Acids, Amino Acids, Peptides), 4^to Edition, edited by Nippon Kagaku Kai, published by Maruzen Publishing Company, pp. 43-83, (1992); and a procedure described by M. Yalpani in Tetrahedron, vol. 41, p. 2957, (1985), and the like. Particularly preferable processes include, for example, a process of treating a carboxyl group-containing polysaccharide with a 1,2-epoxide such as ethylene oxide or propylene oxide or a 1,3-epoxide such as triethylene oxide, such as described in US Patent No. 2,494,912, by AB Steiner and WH McNeely in Ind. Eng. Chem., vol. 43, p. 2073, (1951), or Japanese Patent Laid-open No. Sho 52-36177. The types of esterified polysaccharide prepared by the aforementioned process are not limited to those specified, any type can be used as long as they fall within the scope of the above concept.

When the carboxyl group-containing polysaccharide is alginic acid, the esterified polysaccharide includes PGA, ethylene glycol alginate, trimethylene glycol alginate, butylene glycol alginate, pentylene glycol alginate, and the like.

When the carboxyl group-containing polysaccharide is hyaluronic acid, the esterified polysaccharide includes propylene glycol hyaluronate, ethylene glycol hyaluronate, trimethylene glycol hyaluronate, butylene glycol hyaluronate, pentylene glycol hyaluronate, and the like.

Among the esterified polysaccharides, PGA and propylene glycol hyaluronate are preferable, from the point of view of safety for human bodies and decomposability in human bodies.

The compound having at least two α-amino groups, which is derived from a natural amino acid used as another essential component of the water-swellable polymer gel of the present invention (hereinafter simply referred to as "polyamine"), is e-poly (lysine). This polyamine is used in the invention from the viewpoint of availability and safety for human bodies. E-poly (lysine) is a water-soluble polymer compound, represented by the formula:

H - [NH - CH₂CH₂CH₂CH₂ - CH (NH₂) - CO]_n - OH where n is an integer from 2 to 500, which is prepared by the condensation reaction of an amino group at the ε-position of lysine with a carboxyl group at the α-position of lysine to form an amide bond , and an α-amino group of lysine that exists on the polymer chain.

The water-swellable polymer gel of the present invention may contain at least one of other water-soluble polymers (hereinafter simply referred to as "another water-soluble polymer") as a third component other than the esterified polysaccharide and polyamine.

The types of the other water-soluble polymers are not limited to those specified. The other water soluble polymers include, for example, water soluble polysaccharides such as agarose, sodium alginate, agar, carrageenan, xanthan gum, gellan gum, dextran, hyaluronic acid, pullulan and heparin, and their physiologically acceptable artificial derivatives; derivatives of chitin or chitosan, such as partially deacetylated chitin, chitosan, partially meleylated chitosan, partially succinylated chitosan, and carboxymethyl chitosan; cellulose derivatives such as carboxymethyl cellulose; polyamino acids (proteins) such as collagen, atelocollagen, gelatin and casein, and their physiologically acceptable artificial derivatives, and the like.

Between the molecules of at least two other water-soluble polymers, there may be crosslinking other than the crosslinking bond formed between the esterified polysaccharide and the polyamine. The procedure for the formation of the crosslinking includes, for example, a procedure described in the Gel Handbook (NTS, 1997), edited by Nagata and Kajiwara, or the like, that is, crosslinking the functional groups of the water-soluble polymer, using an aldehyde compound, an epoxy compound, an isocyanate compound, or the like; photo-crosslinking using a photodiimerizable group or polymerizable group; crosslinking by coordination bonding with polyvalent metal ions, and the like, without intending to limit the present invention to those exemplified.

The water-swellable polymer gel of the present invention may further contain salts such as inorganic salts and organic salts, from the viewpoints of improving the gel strength of the water-swellable polymer gel, and the dispersion stability of a mixed solution. containing the esterified polysaccharide and the polyamine. Examples of the salts include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, and sodium sulfate; and organic salts such as sodium acetate, sodium citrate, and sodium succinate.

The water-soluble polymer gel of the present invention can be obtained by reacting the esterified polysaccharide with the polyamine. This reaction is an aminolysis reaction of the ester moiety of the polysaccharide esterified with the α-amino group of the polyamine, fundamentally an amidation crosslinking reaction, such as in the gel formed from the PGA and gelatin previously described.

The mixing ratio for the esterified polysaccharide and the polyamine in the reaction can be arbitrarily determined depending on the gelation time, mechanical strength and absorbability of the polymer gel. In order to make the water-swellable polymer gel of the present invention substantially insoluble in water and to have its high

ES 2 260 098 T3 absorbability in water, it is desirable that the molar ratio of an ester group to the α-amino group [ester group (mol) / α-amino group (mol)] is 1 to 100. The higher the molar ratio , the greater the water absorbability of the water-swellable polymer gel becomes.

Processes for reacting the esterified polysaccharide with polyamine to produce gelation include a process comprising reacting the esterified polysaccharide with polyamine in solution states to produce gelation; a process comprising immersing or impregnating an esterified polysaccharide in the polyamine solution and reacting with one another to produce gelation; a process comprising immersing or impregnating a polyamine in the esterified polysaccharide solution and reacting with one another to produce gelation; and the like. The temperature during the reaction is not limited to a specified one, and can be freely controlled.

As a solvent for dissolving the esterified polysaccharide and polyamine, water is preferable. However, an aqueous solvent prepared by adding an organic solvent to water can be used in order to control the gelation rate or the like. Examples of the organic solvent include, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol, and propylene glycol; ether solvents such as tetrahydrofuran and dioxane; amide solvents such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; ketone solvents such as acetone and methyl ethyl ketone; dimethyl sulfoxide, and the like. The mixing ratio of the organic solvent to water is not limited to a specified one, and can be arbitrarily determined.

Furthermore, the pH of the solution of the esterified polysaccharide and the polyamine can be appropriately adjusted, so that gelation can be carried out under mild conditions or rapidly. When adjusting the pH, for example an acidic substance such as hydrochloric acid or acetic acid can be used; a basic substance such as sodium hydroxide; or a buffer such as phosphate buffer or borate buffer as a pH regulator.

By reacting the esterified polysaccharide with the polyamine as described above, the water-swellable polymer gel can be obtained.

The water-swellable polymer gel of the present invention can be appropriately formed into a shape depending on its purposes. Examples of the shape include, for example, filamentous, membranous, tubular (hollow fibers, tubes), granular (microcapsule type), fibrillar nonwoven, pasty, honeycomb type, or foamed article type (fluffy), and the like. It is preferable that the water-swellable polymer gel of the present invention is in the form of a foam when used for applications requiring flexibility, packability against defects, high water absorbability, and the like. This foam can be molded into filamentous, membranous, tubular, granular, fibrillar non-woven, pasty, honeycomb, or the like. Alternatively, the foam can be used by application to, coating on, impregnation on, depositing on or embedded in other substrates and sites.

Furthermore, the water-swellable polymer gel of the present invention can be used by applying to, coating on, impregnating on, depositing on, or embedded in other substrates or sites. Other substrates and sites include, for example, gauze, woven fabrics, nonwovens, cotton materials, filamentary materials, films, mesh, porous sponges, rubbers, plastics, metals, artificial organs, and surfaces, surfaces of cuts and wounds. of living tissues, and the like. The size, thickness, length, diameter, and the like of the other substrates or sites are not limited to specified ones.

The molded water-swellable polymer gel can be prepared, for example, by a process comprising extruding an esterified polysaccharide solution or a polyamine solution through a die or die, or pouring the solution into a mold, molding it, in this way, in the aforementioned manner, and then contacting the resulting molded article with a solution of polyamine or an esterified polysaccharide, respectively, to produce gelation; a process comprising the preparation of a mixed solution of an esterified polysaccharide and a polyamine, the extrusion of the resulting mixed solution through a die or die or the pouring of the mixed solution into a mold, to produce gelation thereto time the mixed solution is molded into the aforementioned manner; and the like.

The foam of the water-swellable polymer gel of the present invention can be prepared by a general process comprising lyophilizing a water-swollen gel, or a process comprising introducing bubbles into the interior of the gel.

Examples of the process for the preparation of a foam comprising the introduction of bubbles into the interior of the gel include the processes described in British Patent No. 574,382, Japanese Patent Laid-Open Nos. Hei 5-254029, 8- 208868 and 8-337674 and Japanese Unexamined Patent Publication No. Hei 6-510330, and the like. When the foam of the water-swellable gel of the present invention is prepared by the above process, a foam of a water-swellable polymer gel can be obtained which has higher water absorbability and higher stability compared to the foams described in said publications.

Specific examples for the process for the preparation of a foam comprising introducing bubbles into the interior of the gel include a process comprising introducing bubbles into

ES 2 260 098 T3 of an esterified polysaccharide solution or a polyamine solution for foaming, and then contacting the foamed solution with a polyamine solution or an esterified polysaccharide, respectively, to produce gelation; a process comprising introducing bubbles into a mixed solution of an esterified polysaccharide and a polyamine for foaming, and then terminating their gelation.

The process comprising the introduction of bubbles into the foaming solution includes a process comprising the addition of a foaming agent that generates a water insoluble gas with heating or reaction, for example, a decomposable blowing agent such as carbonate ammonium, azodicarbonamide, p-toluenesulfonyl hydrazide; a volatile swelling agent such as butane, hexane, an ether, or the like for foaming; a process comprising mechanical stirring of the solution, thereby diffusing a supplied gas into the aqueous solution for foaming; and the like.

The aforementioned solution may contain an ionic or non-ionic surfactant, which is a bubble-forming agent, as occasion demands, in order to stabilize the foam.

The ionic surfactant includes, for example, anionic surfactants such as sodium stearate, sodium dodecyl sulfate, α-olefin sulfonate, and sulfoalkylamides; cationic surfactants such as alkyldimethylbenzylammonium salts, alkyltrimethylammonium salts, and alkylpyridinium salts; and amphoteric surfactants such as imidazoline surfactants.

The nonionic surfactant includes, for example, polyethylene oxide alkyl ethers, polyethylene oxide alkylphenyl ethers, glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, and the like.

Among the surfactants, those having a low molecular weight would impart irritation and denaturing actions to a living tissue or a physiologically active substance (an enzyme or the like). Therefore, it is preferable to avoid the use of a surfactant when the foam of the water-swellable polymer gel of the present invention is used in the applications for medical materials.

The esterified polysaccharide itself shows amphipathic property, so that the esterified polysaccharide functions as a bubble-forming agent for stabilization of the gas-liquid interface. Accordingly, the surfactant may not necessarily be used, since the esterified polysaccharide has a property for stably introducing (foaming) bubbles. Since the esterified polysaccharide has reactivity in addition to the amphipathic property, the esterified polysaccharide can be referred to as "reactive surfactant polysaccharide".

Furthermore, as the surfactant, a protein such as albumen, gelatin or albumin, or lecithin can also be used.

When the above solution is foamed, the stability of the foam may not become high enough in some cases. For example, when the bubbles disappear before the crosslinking is complete, a higher alcohol such as dodecyl alcohol, tetradecanol or hexadecanol can be added to this solution as a bubble stabilizer; an amino alcohol such as ethanolamine; a water soluble polymer such as carboxymethyl cellulose; and the like.

Similarly, the foam can be stabilized by adding a polysaccharide, which dissolves in water when heated and gels when cooled, to the aqueous solution of the esterified polysaccharide to finally produce gelation of the entire solution. The polysaccharide includes natural polysaccharides such as agarose, agaropectin, amylose, amylopectin, arabinane, isoliquenan, rennet, agar, carrageenan, gellan gum, nigeran, and laminorane.

The water-swellable polymer gel of the present invention is molded into a foamed article as described above, but the molding process is not limited to those described.

The polymer gel contains unreacted ester groups derived from the esterified polysaccharide and unreacted α-amino groups derived from polyamine that do not participate in the amide bond. Accordingly, from the viewpoint of improvements in the function and water absorbability of the polymer gel, after the esterified polysaccharide and polyamine have reacted to form a water-swellable polymer gel, the water-swellable polymer gel is impregnate with a compound reactive with the ester group or an α-amino group to react the compound with the gel having unreacted ester groups or unreacted α-amino groups.

Since the α-amino group of the water-swellable polymer gel is highly reactive to various compounds, the water-swellable polymer gel can be subjected to, for example, acylation, alkylation, imine formation (Schiff's base), reductive alkylation, or Similar. The compound reactive with an α-amino group includes, for example, acid anhydrides such as acetic anhydride and succinic anhydride; aldehydes such as acetaldehyde and glyoxylic acid; alkylating agents such as alkyl halides and dimethyl sulfate; and the like, without intending to be limited to those exemplified.

In addition, the ester group of the water-swellable polymer gel is reacted with a compound having an amino group to form an amide bond. The compound having amino groups includes, for example, ethanolamine,

ES 2 260 098 T3 phosphoryl ethanolamine, taurine, amino acids, proteins and oligopeptides. It is preferable that the reaction of the water-swellable polymer gel with the compound having an amino group is carried out under basic conditions such as pH of not less than 7.

The water-swellable polymer gel of the present invention can be used as is. Alternatively, the gel can be used after the gel has been washed by immersing the gel in the aqueous solvent. Furthermore, the gel can be used after some or all of the aqueous solvent has been removed from the gel by heating drying, drying under reduced pressure or lyophilization.

Washing the water-swellable polymer gel is an effective means of removing toxic additives and by-products when these ingredients are incorporated into the gel.

The process for drying the water-swellable polymer gel of the present invention is not limited to specified ones, and may be appropriately selected depending on the applications of the water-swellable polymer gel. The water-swellable polymer gel can be dried after immersion of the water-swellable polymer gel in a water-miscible organic solvent, for example, an alcohol solvent such as methanol, ethanol or propanol, or an acetone solvent, thereby replacing, at least a part of the aqueous solvent contained in the water-swellable polymer gel by the water-miscible organic solvent. The temperature during drying of the water-swellable polymer gel is not limited to specified ones, and the temperature can be appropriately selected within a range, so that the object of the present invention is not hindered.

In order to improve the flexibility of the dry water-swellable polymer gel of the present invention, a plasticizing agent can be used. The plasticizing agent includes, for example, polyhydric alcohols such as glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol and polypropylene glycol, dimethyl sulfoxide, water, and the like. The plasticizing agent can be incorporated into the water-swellable polymer gel by adding the plasticizing agent to the solution before gelation, impregnating the plasticizing agent inside the water-swellable polymer gel after gelation, or adding the plasticizing agent to the polymer gel. swellable in water after drying of the gel.

In addition to the process using the above-mentioned plasticizing agent as a process for softening the foam of the water-swellable polymer gel, a process comprising compressing the foam of the water-swellable polymer gel into a relatively thin sheet can be mentioned. When the foam of the water-swellable polymer gel is compressed, since a three-dimensional structure supporting the polymer foam is partially destroyed, it is believed that flexibility can be imparted to the gel. Compression can be carried out with a pressing machine, a roller, or the like. Similarly, the foam thickness of the water-swellable polymer gel can be controlled by adjusting a spacer, an opening, or the like. The foam thickness of the water-swellable polymer gel after compression is not limited to a specified one, and the thickness can be appropriately adjusted in accordance with the applications of the water-swellable polymer gel of the present invention.

The water-swellable polymer gel of the present invention is a hydrogel material having high gel strength and high water absorbability. Accordingly, the water-swellable polymer gel of the present invention can be applied to a wide range of fields such as industry, agriculture, food, medicine, and the like. Among them, the water-swellable polymer gel of the present invention can be suitably applied especially to materials for medical use, from the viewpoints of water absorbability, safety and mechanical properties.

The material for medical use includes, for example, wound dressings, materials to prevent adhesion, dialysis membranes, hemostatic materials, adhesive materials, sealants, contact lenses, materials for tissue regeneration, materials for microcapsules, systems for the drug supply (DDS), and the like. The material for medical use can incorporate a physiologically active substance (for example, heparin, dermatan sulfate, heparan sulfate, cytokine, an anti-inflammatory agent, a growth factor, an enzyme or the like), an antibacterial agent, a living cell, or the like.

When the wound dressing is used for the treatment of an injury such as trauma, burn or ulcer, the injury can be treated by effectively maintaining the growth factor by applying the gel to the injured site. When the amount of exudates coming from the injured site is relatively large, it is preferable to use a water-swellable polymer gel foam in order to carry out the filling of wounds appeals, and the absorption, retention and drainage of excess exudates.

The water-swellable polymer gel of the present invention may contain, or may bind to, at least one member selected from the group consisting of disinfectants, antibiotics, antibacterial agents, growth factors [eg, fibroblast growth factor (FGF), epidermal growth factor (EGF), and the like], structural proteins (eg, fibrin, collagen, and the like), and various amino acids and vitamins in order to accelerate wound healing and prevent infection by bacteria.

When the foam of the water-swellable polymer gel of the present invention is used for the above applications, it is desirable that the gel is used in a state in which at least a part of the water is removed. When the dry foam is softened by the compression procedure, the foam can easily deform with the

ES 2 260 098 T3 wound, so that the foam is not necessarily required to contain a low molecular weight compound having eluting property, such as a plasticizer. Accordingly, the moist wound environment can be maintained down to a level of the original living body, so that there is little risk of inhibiting wound healing.

Furthermore, a water-swellable polymer gel or a dry membranous water-swellable polymer gel can be applied to a wound site in which exudates exist in a relatively small amount. Alternatively, the water-swellable polymer gel of the present invention or its foam can be formed at the wound site.

The adhesion preventing material is a material that prevents the adhesion of a surgical wound during surgery, thereby speeding up wound recovery. The water-swellable polymer gel of the present invention can also be used as the adhesion-preventing material. In this case, adhesion can also be prevented by forming a paste with the water-swellable polymer gel at the site where adhesion should be prevented, such as the abdominal wall or intraperitoneal organs, or the formation of the water-swellable polymer gel in situ, covering and protecting, in this way, the site with the gel. The water-swellable polymer gel can be used in any of forms such as films, coatings, and foams. When the water-swellable polymeric gel is formed in situ, its coating can be easily formed by supplying the water-swellable polymeric gel to the site in the form of a liquid. Accordingly, this procedure is particularly useful for surgeries under an endoscope or the like.

The water-swellable polymer gel of the present invention can also be used as a material for tissue regeneration, that is, as an extracellular matrix for the regeneration of skin, mucosa, bones, cartilage, blood vessels, valves, nerves, and cornea. In this case, the tissue regeneration material may contain or may be bound to a cell growth factor, such as FGF or BMP; a structural protein, such as fibrin or collagen; a cell adhesion molecule, such as RGD peptide; a living cell, such as a hepatocyte, fibroblast, osteoblast, or cartilage cell. When the water-swellable polymeric gel is used as a material for tissue regeneration, the water-swellable polymeric gel can be formed into a paste at the site for tissue regeneration, or the gel can be formed in situ. Furthermore, injured living tissue would be coated by self-therapy, if invasion of fibrous tissue to a defective site can be prevented. Accordingly, the water-swellable polymer gel of the present invention can be used as a barrier to prevent invasion of fibrous tissue.

When the water-swellable polymer gel of the present invention is used for applications where a material for preventing adhesion, a hemostatic material, an adhesive material, a sealant, or a material for tissue regeneration is embedded in a living body, it is desirable that the water-swellable polymer gel display each of the functions and then be rapidly biodegraded and absorbed. Accordingly, it is preferable that the esterified polysaccharide used in the water-swellable polymer gel decomposes into low molecular compounds in the living body. The esterified polysaccharide that can be suitably used for this application includes, for example, esterified alginate, esterified hyaluronate, and the like.

It is preferable that the medical material made from the water-swellable polymer gel of the present invention is used after sterilization. The procedure for sterilization is not limited to a specified one, and any procedure can be used appropriately according to the types of materials for medical use. The sterilization procedure includes, for example, sterilization by autoclaving (eg, 121 ° C for 20 minutes), ethylene oxide gas sterilization, γ-ray sterilization, electron beam sterilization, or the like.

As discussed above, since the water-swellable polymer gel of the present invention is obtained by reacting the esterified polysaccharide with the polyamine, the gel can be efficiently formed even in an aqueous solvent close to neutral pH. Also, since an ingredient derived from nature in the gel is used as raw material, the gel is excellent in biodegradability and safety for human bodies, and furthermore, control of physical properties such as gelation time, water absorbability can be facilitated. and gel strength. The above advantages are believed to derive from the fact that the basicity of the α-amino group of polyamine is considerably less than that of the ε-amino group of lysine or an alkylamine used in the prior art. In other words, it follows that the above advantages derive from the fact that the concentration of free amino acid groups that can participate in crosslinking is higher in the case of the α-amino group even under low pH conditions, compared to the case of ε-amino group or alkylamine.

Examples

Hereinafter, the present invention, as defined in the appended claims, will be more specifically described by the following working examples.

In each of the Examples and Comparative Examples, the degree of swelling, viscosity, and gel strength were determined according to the following procedures.

ES 2 260 098 T3

A. Degree of swelling

The degree of swelling of a water-swellable polymer gel was determined by the equation:

[Degree of swelling] = [Wg1 (water swollen gel) - Wg2 (dry gel)] / Wg2 (dry gel) where Wg1 (water swollen gel) is a weight after immersion of a dry polymer gel or a polymer gel containing an aqueous solvent in ion exchanger treated water or physiological saline for not less than 4 hours, and Wg2 (dry weight) is a weight of the dry polymer gel.

B. Viscosity

Viscosity was determined using a Brookfield viscometer. The unit of viscosity is mPa-s. Viscosity is a value determined using a 1% by weight aqueous solution at 20 ° C.

Gel strength

Two sheets of mesh sheets with a size of 1 cm (width) x 2 cm (length) commercially available from ADVANTEC under the trade name of MESH SHEETS (76 mm), were placed at a distance of approximately 1 mm on a plate of fluorocarbon resin 1 cm x 1 cm in size. The 0.3 ml amount of a gel stock solution was widely spread over the entire plate, and the gel was formed according to the procedure described in each of the Examples and Comparative Examples. After removing the fluorocarbon resin plate, the mesh parts were clamped with an autograph template commercially available from Shimadzu Corporation under the trade name of EZ-test, and the maximum breaking strength, that is, the resistance to traction to breakage. This tensile strength to break was defined as gel strength.

Example 1

PGA-s-poly (isine) gel preparation

To 30 g of a 2% by weight aqueous solution of PGA commercially available from Wako Pure Chemicals Industries, Ltd (viscosity: 100 mPa-s), 2.4 ml of a 10% by weight aqueous solution of e- poly (lysine) commercially available from CHISSO CORPORATION, and the resulting mixed solution was vigorously stirred.

The mixed solution was allowed to stand at room temperature in a sample bottle, to cause gradual gelation of the mixed solution. The gelation time, which is defined as a period of time from the time when the aqueous solution of PGA and the aqueous solution of e-poly (lysine) were mixed to the time when the mixed solution did not flow from the sample vial when the vial was tilted, it was approximately 9 minutes,

The formed gel was then allowed to stand at room temperature for 16 hours and was then immersed in 300 ml of ion-exchanged water treated for 24 hours, yielding a clear polymer gel having a degree of swelling of 5, 2.

Examples 2 to 4

PGA-s-poly (lysine) gel preparation with controlled water absorbability

To 30 g of a 2% by weight aqueous solution of PGA commercially available from Wako Pure Chemicals Industries, Ltd (viscosity: 100 mPa-s), 4.8 ml, 0.8 ml or 0.4 ml of a 10% by weight aqueous solution of e-poly (lysine) commercially available from CHISSO CORPORATION, and the resulting mixed solution was vigorously stirred in the same manner as in Example 1.

The mixed solution was allowed to stand at room temperature in a sample bottle, to cause gradual gelation of the mixed solution. The gelation time was determined in the same way as in Example 1. The results are shown in Table 1.

The gel formed was then allowed to stand at room temperature for 16 hours and was then immersed in 300 ml of ion-exchanged water for 24 hours, yielding a water-swollen polymer gel. The gelation time and the degree of swelling of the resulting polymer are shown in Table 1.

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TABLE 1

<td>Example Do not.</td><td>Aqueous solution of PGA at 2% by weight (g)</td><td>Amount of 10% aqueous solution by weight of ε ^ Η ^^) (ml)</td><td>Gelation time (min)</td><td>Degree swelling</td>

<td> 1</td><td> 30</td><td> 2,4</td><td>approx. 9</td><td> 5,2</td>

<td> 2</td><td> 30</td><td> 4,8</td><td>approx. 5</td><td> 2,8</td>

<td> 3</td><td> 30</td><td> 0,8</td><td>approx. 30</td><td> 98,1</td>

<td> 4</td><td> 30</td><td> 0,4</td><td>approx. 60</td><td> 522,4</td>

From the results shown in Table 1, it is clear that the gelation time and the degree of swelling can be safely controlled by adjusting the amount of the aqueous ε-poly (lysine) solution.

Examples 5 to 8

PGA ^ -poly (lysine) gel preparation

A 10% by weight aqueous solution of ε-poly (lysine) was prepared by adjusting its pH to 7.5, 8.0, 8.5 or 9.0 with acetic acid.

Next, each of the previously prepared aqueous solutions of ε-poly (lysine) was added in an amount of 1 ml to 10 g of a 2% by weight aqueous solution of PGA commercially available from Funakoshi Co., Ltd. (viscosity: 100 to 150 mPa-s). and the resulting mixed solution was vigorously stirred.

The mixed solution was allowed to stand at room temperature in a sample bottle, to cause gradual gelation of the mixed solution. The gelation time was determined in the same way as in Example 1. The results are shown in Table 2.

The gel formed was then allowed to stand at room temperature for 5 hours, and then immersed in 300 ml of ion-exchanged treated water for 24 hours, yielding a water-swollen transparent polymeric gel. The degree of swelling of the resulting polymer is shown in Table 2.

TABLE 2

<td rowspan="3">Example Do not.</td><td rowspan="3">Solution Aqueous from 2% PGA .in weigh (g)</td><td colspan="4">Aqueous solution to</td>

<td colspan="2">10% by weight of εe-poly (lysine)</td><td rowspan="2">Gelation time (min)</td><td rowspan="2">Degree fan- I lie</td>

<td>Quantity (ml)</td><td>PH</td>

<td> 1</td><td> 10</td><td> 1</td><td> 7,5</td><td>approx. 70</td><td> 119,4</td>

<td> 2</td><td> 10</td><td> 1</td><td> 8,0</td><td>approx. 22</td><td> 59,1</td>

<td> 3</td><td> 10</td><td> 1</td><td> 8,5</td><td>approx. fifteen</td><td> 33,7</td>

<td> 4</td><td> 10</td><td> 1</td><td> 9,0</td><td>approx. 9</td><td> 16,1</td>

From the results shown in Table 2, it is clear that the gelation time and the degree of swelling can be safely controlled by adjusting the pH of the aqueous solution of ε ^ Η ^ ί ^).

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Example 9

PGA-s-poly (lysine) gel preparation

To 50 g of a 2% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd (viscosity: about 200 mPa-s), 0.22 ml of a 24% by weight aqueous solution of ε-poly (lysine) of which the pH had been adjusted to 7.5 with acetic acid (amount of α-amino group: 0.5 mmol).

The resulting mixed solution was allowed to stand at room temperature for 5 hours, and then the gel strength was determined. As a result, the gel strength was determined to be 13.7 mM. Furthermore, the formed gel was immersed in 300 ml of ion-exchanged water for 24 hours, providing a hydrogel having a degree of swelling of 142.9, of which the shape had been retained.

Comparative Example 1

Alginic acid-butanediol diglycidyl ether gel preparation

2.5 g of alginic acid commercially available from Kimitsu Chemical Industries Co., Ltd. (viscosity: about 500 mPa-s) were dissolved in 19 ml of 0.5% by weight aqueous solution of NaOH, over a period 16 hours. To the resulting solution, 0.95 ml of 1,4-butanediol diglycidyl ether was added, and the mixed solution was allowed to harden at 50 ° C for 2 hours. Then, the resulting gel was washed in ion-exchanged water for 2 hours, and the strength of the gel was determined. As a result, the gel strength was found to be 0 mN. When the gel was immersed in ion-exchanged water, its shape could not be maintained in any way.

Comparative Example 2

PGA-gelatin gel preparation

A 6% by weight aqueous solution of gelatin derived from bovine bones, commercially available from Wako Pure Chemical Industries Co., Ltd., was prepared, the pH of which was adjusted to 7.5 with 0.1M phosphate buffer.

Next, 10 ml of the previously prepared aqueous gelatin solution was added to 10 g of a 3% aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd. (viscosity: about 80 mPa-s), and the resulting mixture was vigorously stirred. The mixed solution was allowed to harden for 5 hours. Next, the strength of the gel was determined. As a result, the gel strength was found to be 0 mN. When this gel was immersed in ion exchanger treated water, its shape could not be maintained in any way.

Comparative Example 3

PGA-polyethyleneimine gel preparation

An 18% by weight aqueous solution of polyethyleneimine, commercially available from Aldrich (molecular weight: about 75000), was prepared, the pH of which was adjusted to 7.5 with acetic acid.

Next, 0.1 ml of the previously prepared polyethyleneimine solution (amount of amino group: 0.5 mmol) was added to 50 g of a 2% aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd. (viscosity: about 200 mPa-s). As a result, the mixed solution became cloudy. The mixed solution was allowed to stand at room temperature for 5 hours, and the gel strength of the formed gel was determined. As a result, the gel strength was found to be 6.9 mN. When this gel was immersed in ion exchanger treated water, its shape could not be maintained in any way.

Results for evaluation of gel strength (gel strength after curing for 5 hours) and degree of swelling (degree of swelling obtained after curing for 5 hours and then immersion in ion-exchanged water treated at room temperature for 24 hours) of the gels obtained in Example 9 and Comparative Examples 1 to 3, are shown in Table 3.

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TABLE 3

<td>Example Do not.</td><td>Hydrogel</td><td>Tensile strength (mN)</td><td>Degree of swelling</td>

<td> 9</td><td>PGA ^ -poly (lysine) gel</td><td> 13,7</td><td> 142,9</td>

<td>Ex Comp. 1</td><td>PGA-BDDE * *¹</td><td> 0</td><td>indeterminable</td>

<td>Ex Comp. 2</td><td>PGA-gelatin</td><td> 0</td><td>(dissolved) indeterminable</td>

<td>Ex Comp. 3</td><td>PGA-polyethyleneimine</td><td> 6,9</td><td>(dissolved) indeterminable</td>

<td></td><td></td><td></td><td>(dissolved)</td>

(Note) * 1: 1,4-butanediol diglycidyl ether

From the results shown in Table 3, it is clear that the water-swellable polymer gel obtained in Example 9 shows higher gel strength compared to the gels of Comparative Examples 1 to 3, which are from the prior techniques, even under conditions containing water.

Example 10

PGA ^ -poly (lysine) gel film preparation

To 50 g of a 2% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd (viscosity: about 200 mPa-s), a 24% by weight aqueous solution of ε-poly (lysine ) commercially available from CHISSO CORPORATION of which the pH had been adjusted to 9.5 with acetic acid, and the resulting mixed solution was vigorously stirred. Thirty grams of the resulting mixed solution was spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm, and allowed to harden for 5 hours. The cured coating was then dried with a temperature controlled drier at 70 ° C for 4 hours, providing a film.

The resulting dry gel film was immersed in physiological saline commercially available from Otsuka Pharmaceutical Co., Ltd. for 4 hours. As a result, the degree of swelling was found to be 34.6 and the gel strength 186.3 mN.

Comparative Example 4

PGA-gelatin gel film preparation

A 6% by weight aqueous solution of gelatin derived from bovine bones, commercially available from Wako Pure Chemical Industries Co., Ltd., was prepared, the pH of which was adjusted to 9.5 with phosphate buffer.

Next, 2.5 ml of the previously prepared aqueous gelatin solution was added to 10 g of a 3% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd. (viscosity: about 80 mPa-s) , and the resulting mixture was vigorously stirred. The mixed solution was allowed to stand at room temperature, providing a clear, soft gel. Thirty grams of this solution was allowed to spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm, and the coating was dried with a temperature controlled drier at 70 ° C for 4 hours, providing a film. In 100 ml of a 5% by weight aqueous potassium hydroxide, 0.3 g of the resulting film was immersed for 15 seconds, and then washed with ion exchanger treated water, then the film was dried to 70 ° C for 2 hours, providing a PGA-gelatin gel film. The resulting dry gel film was immersed in physiological saline for 4 hours. As a result, the degree of swelling was found to be 6.0 and the gel strength 120.6 mN.

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Comparative Example 5

PGA-polyethyleneimine gel film preparation

A 19% by weight aqueous solution of polyethyleneimine commercially available from Aldrich (approximate molecular weight 75000) was prepared, the pH of which was adjusted to 7.5 with acetic acid.

To 50 g of a 2% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd (viscosity: approximately 200 mPa-s) was added 0.09 ml of the previously prepared polyethyleneimine solution (amount of group amino: 0.5 mmol). As a result, the solution became cloudy. Thirty grams of this solution was spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm, and the coating was dried with a temperature controlled drier at 70 ° C for 4 hours, providing a film. In 100 ml of a 5% by weight aqueous potassium hydroxide, 0.3 g of the resulting film was immersed for 15 seconds and then washed with ion exchanger treated water, then the film was dried to 70 ° C for 2 hours, providing a PGA-polyethyleneimine gel film. The resulting dry gel film was immersed in physiological saline for 4 hours. As a result, it was found that the degree of swelling was 5.7 and the gel strength was 36.3 mN.

The results for the evaluation of the gel strength (gel strength after immersion in saline solution at 37 ° C for 4 hours) and the degree of swelling (degree of swelling obtained after immersion in physiological saline solution at 37 ° C during 4 hours) of the gels obtained in Example 10 and Comparative Examples 4 and 5, are shown in Table 4.

TABLE 4

<td>Example Do not.</td><td>Movie</td><td>Degree of swelling</td><td>Tear strength at break (mN)</td>

<td> 10</td><td>PGA-e-poly (lysine)</td><td> 34,6</td><td> 186,3</td>

<td>Ex Comp. 4</td><td>PGA-Gelatin</td><td> 6</td><td> 120,6</td>

<td>Ex Comp. 5</td><td>PGA-polyethyleneimine</td><td> 5,7</td><td> 36,3</td>

From the results shown in Table 4, it is clear that the water-swellable polymer gel film obtained in Example 10 has higher gel strength, while at the same time having a remarkably higher degree of swelling, compared to films of gels obtained in Comparative Examples 4 and 5.

Example 11

Preparation of PGA-s-poly (lysine) gel film containing κ-carrageenan

In 98 g of ion exchanger treatment, 2 g of κ-carrageenan commercially available from Wako Pure Chemical Industries, Ltd. was dissolved at 60 ° C, yielding a 2% by weight aqueous solution of κ-carrageenan.

Next, the previously prepared aqueous solution of κ-carrageenan was mixed with 20 g of a 2% by weight aqueous solution of PGA commercially available from Funakoshi Co., Ltd. (viscosity: 100 to 150 mPa-s). Next, 0.1 ml of a 26.9% by weight aqueous solution of e-poly (lysine) commercially available from CHISSO CORPORATION was added to the mixed solution, and 25 g of the resulting mixed solution was spread on a tray. of fluorocarbon resin having a size of 10 cm x 10 cm, and allowed to harden at room temperature for 2 hours. The gel was then dried with a temperature controlled drier at 70 ° C for 2 hours, providing a dry gel film. When the dry gel film was immersed in physiological saline for 24 hours, the gel film absorbed water, the swelling degree was found to be 21.3.

Example 12

PGA-s-poly (lysine) gel film preparation

To 30 g of a 2% by weight aqueous solution of PGA commercially available from Funakoshi Co., Ltd. (viscosity: 100 to 150 mPa-s), 0.3 ml of a 26.9% aqueous solution in weight of e-poly (lysine) commercially available from CHISSO CORPORATION. Twenty-five grams of the resulting mixed solution was spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm, and allowed to harden at room temperature for 2 hours. The resulting gel was immersed for 2 hours in 50 ml of an aqueous ethanol solution at

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50% by volume containing 1.5 ml of acetic anhydride commercially available from Kanto Kagaku KK The gel was washed thoroughly with ion exchanger treated water, and dried with a temperature controlled drier at 70 ° C for 2 hours, providing a dry gel film. When the dry gel film was immersed in physiological saline for 24 hours, the gel film absorbed water, the swelling degree was found to be 16.3.

Example 13

Foam preparation made of PGA-s-poly (lysine) gel

One hundred grams of a 1.5% by weight aqueous solution of PGA commercially available from Wako Pure Chemical Industries Ltd. (viscosity: 80 to 120 mPa-s), was stirred with introduction of air into the aqueous solution with a mixer ( kitchen aid mixer) for about 10 minutes for foaming. To the resulting foamed solution, 1 ml of a 26.9% by weight aqueous solution of e-poly (lysine) commercially available from CHISSO CORPORATION was added, and the stirred mixture was stirred with the mixer for an additional 5 minutes. At this point, the density of the solution was 0.29 g / cm³.

Then, 30 g of the foamed solution was spread on a fluorocarbon resin coated tray having a size of 10 cm x 10 cm, and allowed to stand at room temperature for 2 hours. The foamed gel absorbed in water was dried at 70 ° C for 3 hours, providing a flexible, fluffy foam of 10 cm x 10 cm x 0.7 cm.

In order to evaluate the water absorbability, the resulting dry foam was placed on a polyurethane sponge containing sufficient physiological saline solution and allowed to stand at 37 ° C to absorb water. As a result, the degree of swelling after 24 hours was approximately 38. In addition, the water absorbability of the sterilized dry foam was evaluated by γ-ray irradiation at 25 kGy. As a result, the degree of swelling after 24 hours was about 25. The γ-irradiated foam sufficiently retained its shape, even after water absorption, with no disintegration or dissolution of the foam being observed.

Example 14

Foam preparation made of PGA-s-poly (lysine) gel

One hundred grams of a 2% by weight aqueous solution of PGA commercially available from Wako Pure Chemical Industries Ltd. (viscosity: 80 to 120 mPa-s), was stirred with introduction of air into the aqueous solution with a mixer for about 10 minutes to foaming. To the resulting foamed solution was added 0.5 ml of a 26.9% by weight aqueous solution of e-poly (lysine) commercially available from CHISSO CORPORATION, and the stirred mixture was stirred with the mixer for an additional time of 5 minutes. At this point, the density of the foamed solution was 0.31 g / cm³.

Then, 30 g of the foamed solution was spread on a fluorocarbon resin coated tray having a size of 10 cm x 10 cm, and allowed to stand at room temperature for 2 hours. The resulting water-containing foamed gel was dried at 70 ° C for 3 hours, providing a flexible, fluffy foam of 10 cm x 10 cm x 0.7 cm.

In order to evaluate the water absorbability, the foam was allowed to absorb physiological saline at 37 ° C in the same way as in Example 13. As a result, the degree of swelling after 24 hours was about 45 In addition, the water absorbability of the sterilized dry foam was evaluated by γ-ray irradiation at 25 kGy. As a result, the degree of swelling after 24 hours was 38. The fluffy foam sufficiently retained its shape, even after water absorption, so that no disintegration or dissolution of the fluffy foam was observed.

Comparative Example 6

Production of foam made of PGA-polyethyleneimine gel

A 19% by weight aqueous solution of polyethyleneimine commercially available from Aldrich (approximate molecular weight 75000) was prepared, the pH of which was adjusted to 7.5 with acetic acid.

On the other hand, 500 g of a 2% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd (viscosity: about 200 mPa-s) was stirred with introduction of air into the aqueous solution with a mixer for about 10 minutes for foaming. When 0.9 ml of the previously prepared aqueous polyethyleneimine solution was added to the resulting foamed solution, the foamed solution contracted sharply, so that the density of the solution became 0.67 g / cm³. Thirty grams of this foamed solution was spread onto a fluorocarbon resin tray having a size of 10 cm x 10 cm. The resulting foamed gel was dried with a temperature controlled drier at 70 ° C for 2 hours.

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In 100 ml of a 5% by weight aqueous potassium hydroxide solution, 0.5 g of the dry gel was immersed for 15 seconds and then washed with ion exchanger treated water, This gel was dried at 70 ° C for 2 hours. However, it did not become bulky and turned into a 10 cm x 10 cm x 0.3 cm hard film. When the resulting dry gel film was allowed to absorb physiological saline solution at 37 ° C in the same manner as in Example 13, it was found that the degree of swelling was 4.3 and that the gel did not substantially absorb solution. saline.

Comparative Example 7

Foam preparation made of calcium alginate gel

To 100 g of a 2% by weight aqueous solution of sodium alginate commercially available from Wako Pure Chemical Industries Ltd. (viscosity: 500 to 600 mPa-s), 0.1 ml of a commercially available surfactant from Nacalaitesque was added under the trade name of Triton X-100, and the mixture was stirred with a mixer for foaming. The density after shaking was 0.29 g / cm³.

Next, 30 g of the foamed solution was spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm. The resulting foamed gel was immersed in 100 ml of a 5% by weight aqueous calcium chloride solution for 12 hours, and allowed to harden. The resulting fluffy gel was dried with a temperature controlled drier at 70 ° C for 2 hours. As a result, the foam gel contracted to a size of approximately 6 cm x 6 cm x 0.5 cm, forming a hard sponge. When this sponge was allowed to absorb physiological saline at 37 ° C in the same manner as in Example 13, the swelling after 24 hours was found to be 0.7. Furthermore, the water absorbability of the sterilized dry foam was evaluated by γ-ray irradiation at 25 kGy. As a result, the swelling degree after 24 hours was found to be 1.5.

Comparative Example 8

Foam preparation made of calcium alginate gel

In 84 g of ion-exchanged water, 3.8 g of sodium alginate commercially available from Wako Pure Chemical Industries Ltd. (viscosity: 100 to 150 mPa-s) were completely dissolved and 1.9 g of sodium carbonate were added, 0.5 g of calcium carbonate was added to the mixed solution, and it was stirred sufficiently.

On the other hand, a solution was prepared by completely dissolving 3.8 g of sodium alginate commercially available from Wako Pure Chemical Industries Ltd. (viscosity: 100 to 150 mPa-s) in 80 g of ion-exchanged treated water and, then adding 3.6 g of acetic acid thereto.

Twenty grams of each of the two aqueous sodium alginate solutions prepared as described above were mixed, resulting in sharp foaming. This foamed solution was then spread on a fluorocarbon resin tray having a size of 10 cm x 10 cm, and allowed to harden at room temperature for 0.5 hours. The resulting foamed gel was then dried with a temperature controlled drier at 70 ° C. As a result, the gel did not become bulky, transforming into a hard film of approximately 10 cm x 10 cm x 0.2 cm, When the resulting film was allowed to absorb physiological saline at 37 ° C in the same way as in Example 13, the film dissolved after 3 hours, so its shape could not be retained.

Example 15

Foam preparation made of PGA-s-poly (lysine) gel

To 500 g of a 2.5% by weight aqueous solution of PGA commercially available from Kibun Food Chemifa Co., Ltd. (viscosity: about 200 mPa-s), 2.5 g of sodium chloride was added, and dissolved sodium chloride. The resulting solution was then heated to 40 ° C. The solution was stirred, with introduction of air with a mixer for about 5 minutes for foaming.

To the foamed solution was added 1.95 ml of a 25% by weight aqueous solution of e-poly (lysine) commercially available from CHISSO CORPORATION, and the mixture was stirred with the mixer for about 1 minute. At this point, the density of the foamed solution was 0.35 g / cm³. Then, 30 g of this foamed solution was spread on a fluorocarbon resin coated tray having a size of 10 cm x 10 cm, and allowed to stand at room temperature for 1 hour. The resulting water-containing foamed gel was dried at 70 ° C for 4 hours to provide a fluffy foam, 10 cm x 10 cm x 0.8 cm. This fluffy foam was compressed with a pressure machine interposed with a 0.5mm spacer, providing a flexible compressed foamed sheet.

In order to evaluate the water absorbability of the resulting compressed foamed sheet, this compressed foamed sheet was allowed to absorb physiological saline at 37 ° C in the same way as in Example 13. As a result, the degree of swelling after 24 hours it was approximately 38. In addition, the

ES 2 260 098 T3 water absorbability of gaseous ethylene oxide sterilized dry foam. As a result, the degree of swelling after 24 hours was 35. The foam sufficiently retained its shape, even when the foam absorbed water, no disintegration or dissolution was observed in the foam.

Test Example 1

Appellate wounds with a diameter of 6 mm were made to a Japanese white rabbit (approximately 3.5 kg), in each of both ears. At that time, the wounds were made deep into the exposed cartilage. The foam obtained in Example 14 or the foam obtained in Comparative Example 7 was applied to each of the wounds as a control, each having about 2 cm on a side. Both applied foams were completely covered with a polyurethane film commercially available from Johnson &amp; Johnson under the trademark Bioclusive, and the film was fixed by suture. The Japanese white rabbits were fed a sufficient amount of water and food at a constant temperature, and then the rabbits were sacrificed on the 7th day of application, and the wounds were collected.

Wound tissues were fixed and stained and then viewed under a microscope. As a result, the area where the foam obtained in Example 14 was applied, the epithelial spacing was 1.8 mm, while the epithelial spacing for the foam obtained in Comparative Example 7 was about 3 mm.

To the wounds to which the foam obtained in Example 14 was applied, the residual dressing residues or the foreign body reaction was not significant inside the wound.

According to the process for the preparation of a water-swellable polymer gel of the present invention, an inexpensive and effective polymer gel can be prepared.

The water-swellable polymer gel of the present invention can be efficiently formed even in an aqueous solvent close to neutral pH, and its essential component comprises a natural component. Accordingly, the gel is excellent in terms of safety for human bodies. Furthermore, since the water-swellable polymer gel is excellent in physical properties such as water absorbability and mechanical strength, it can be suitably applied in the fields of industry, agriculture, food, medicine, and the like.