Bioabsorbable Medical Materials

Abstract

To provide a bioabsorbable medical material having adhesiveness to a biological tissue and improved degradability.SOLUTION: A bioabsorbable medical material contains a crosslinked polymer material and biodegradable polyester held in the crosslinked polymer material. The crosslinked polymer material has an anionic substituent, the content of the biodegradable polyester is 3 wt.% or more based on the dry weight of the bioabsorbable medical material, and the biodegradable polyester has a number average molecular weight of 1,000 Da or more and less than 30,000 Da.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to bioabsorbable materials for medical applications. [Background technology]

[0002] Polyanionic polysaccharides, such as hyaluronic acid, carboxymethylcellulose or alginic acid, have excellent water solubility, moderate viscosity, adhesion, moisture retention and biocompatibility.Therefore, polyanionic polysaccharides are widely used as food additives, medical materials, cosmetics, additives and thickeners for daily necessities.Among polyanionic polysaccharides, hyaluronic acid is a compound that is widely used in general.

[0003] Hyaluronic acid is a water-soluble polymer, and has good dispersibility and water retention, and therefore is used in various fields such as food, cosmetics, and medicine. Hyaluronic acid is also a natural mucopolysaccharide found in tissues such as vitreous humor, blood vessel walls, and umbilical cord, and is highly safe. For this reason, hyaluronic acid is also widely used in the medical field. In the medical field, hyaluronic acid is used as a raw material for joint function improving agents or adhesion prevention materials. However, due to its water solubility, it is difficult to keep hyaluronic acid in any place inside or on the surface of the body for a certain period of time. Therefore, depending on the application such as wound covering or adhesion prevention, some kind of insolubilization treatment is required for hyaluronic acid.

[0004] As for the insolubilization treatment of hyaluronic acid, a method of insolubilization by crosslinking reaction using carboxyl group present in hyaluronic acid molecule has been reported.RVSparer et al. describe the modification of hyaluronic acid, in which cysteine ​​residue is bonded to hyaluronic acid via amide bond, and disulfide bond is formed between the cysteine ​​residues bonded to cysteine-modified hyaluronic acid to crosslink hyaluronic acid (Non-Patent Document 1).

[0005] In addition, various methods have been reported as methods for insolubilization or structural reinforcement. (1) Patent Document 1 describes a method for producing water-insoluble derivatives of polyanionic polysaccharides such as hyaluronic acid and carboxymethylcellulose by a crosslinking reaction using a carbodiimide. (2) Patent Document 2 describes an adhesion prevention material in which a carboxyl group-containing polysaccharide such as hyaluronic acid is made water-insoluble by forming an ionic bond between the polysaccharide and the carboxyl group-containing polysaccharide using a polyvalent cation. (3) Patent Document 3 describes a method for crosslinking polysaccharides such as hyaluronic acid, proteins, or water-soluble polymers with divinyl sulfone. (4) In addition, methods such as those in Patent Documents 4, 6 and 7 have been reported in which structures are reinforced by complexing with biodegradable and bioabsorbable synthetic polymers, regardless of whether polysaccharides are crosslinked or not. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2003-518167 [Patent Document 2] Japanese Patent Application Publication No. 5-124968 [Patent Document 3] Japanese Patent Application Publication No. 2-138346 [Patent Document 4] International Publication No. 2016 / 136884 [Patent Document 5] JP 2004-51531 A [Patent Document 6] Japanese Patent Application Publication No. 8-208706 [Patent Document 7] China Patent Publication No. 105194739 [Non-patent literature]

[0007] [Non-Patent Document 1] RVSparer, N. Ekwuribe, AG Walton. Controlled release from glycosaminoglycan drug complexes. In: Controlled Release Delivery Systems. Dekker New York (1983) p. 107-119. Summary of the Invention [Problem to be solved by the invention]

[0008] However, in the method described in Patent Document 1, the carboxyl group in the polyanionic polysaccharide is amidated with an amino acid methyl ester. Therefore, the water insolubility of the resulting derivative is increased, and it is considered that the derivative may remain for a long time when placed in the body. In addition, Patent Documents 2 and 3 do not describe the degree of water insolubility of the obtained film, etc. Furthermore, Patent Document 4 does not fully consider the biodegradability control of the biodegradable polymer used to reinforce the structure, so it is considered that the biodegradable polymer may remain in the body for a long time.

[0009] Water-insolubilized polyanionic polysaccharides have been reported to be effective in the medical field as wound-covering medical materials, adhesion inhibitors, prosthetic materials, or raw materials thereof, and are used in the medical field. In fact, after covering the wound surface and its surroundings with an adhesion inhibitor in a living body, it takes about one week for the wound to heal, and it is desirable for the adhesion inhibitor to maintain a barrier layer such as a film without dissolving during that time.

[0010] It has been reported in Patent Document 5 that if the dissolution half-life of water-insolubilized carboxymethylcellulose is short, sufficient adhesion prevention ability is not exhibited even when applied to the wound surface and its surroundings in vivo. On the other hand, although the decomposition period of bioabsorbable materials in the body varies depending on the materials that compose them, many documents have pointed out that the long-term retention of bioabsorbable materials in the body causes foreign body reactions and induces inflammation, etc.

[0011] The present invention has been made in consideration of the problems associated with the conventional technology, and its object is to provide a medical material which retains its shape on the surface of an injured area where wound healing or adhesion needs to be prevented for the period required for wound healing, is effective in wound healing or prevention of adhesion, and is rapidly absorbed in its entirety after wound healing, with very little risk of foreign body reaction, inflammation or infection due to long-term residue. [Means for solving the problem]

[0012] As a result of examining the above-mentioned problems, the present inventors have discovered the constitution of a medical material which, when placed in a living body, has better shape retention than untreated or physically crosslinked polysaccharides or proteins, is less susceptible to foreign body reactions due to long-term retention, and is highly degradable than polysaccharides or proteins that are crosslinked by covalent bonds or are complexed with polymers for reinforcement. The gist of the present invention is as follows.

[0013] (1) A crosslinked polymeric material that forms a specific shape and a decay retardant material that is held by the crosslinked polymeric material; the crosslinked polymeric material has a decomposition property in water that is inhibited in the presence of an acid; The decay-retarding material is a bioabsorbable medical material that releases 0.5 mol % or more of acid per day by the 7th day upon contact with water at 37°C.

[0014] (2) The crosslinked polymer material covers at least a portion of the decay-retarding material, The decay retardant comprises a material that releases acid upon contact with water; the acid releasing material has an acid releasing capacity of 0.3 mol% / day or more for 7 days after immersion in water at 37°C; The bioabsorbable medical material according to (1), wherein the crosslinked polymer material includes a polyanionic polymer having a plurality of anionic substituents in the molecule.

[0015] (3) The bioabsorbable medical material according to (2), wherein the acid-releasing material is a biodegradable polyester.

[0016] (4) The bioabsorbable medical material according to (3), wherein the number average molecular weight of the biodegradable polyester is 1,000 Da or more and less than 30,000 Da.

[0017] (5) A bioabsorbable medical material according to (3) or (4), in which the content of the biodegradable polyester is 3 wt % or more based on the dry weight of the bioabsorbable medical material.

[0018] (6) The bioabsorbable medical material according to any one of (3) to (5), wherein the biodegradable polyester is polyglycolic acid or a copolymer containing structural units derived from glycolic acid.

[0019] (7) The bioabsorbable medical material according to any one of (1) to (6), wherein the crosslinked polymer material is a crosslinked polyanionic polysaccharide.

[0020] (8) The bioabsorbable medical material according to any one of (1) to (7), wherein the crosslinked polymer material contains hyaluronic acid and carboxymethyl cellulose.

[0021] (9) The bioabsorbable medical material according to any one of (1) to (8), which is a wound dressing material, a tissue regeneration material, a drug sustained-release substrate, a gap retainer, or an adhesion barrier. Effect of the Invention

[0022] When the bioabsorbable medical material of the present invention is applied to a target site in a living body, it rapidly absorbs water derived from the living body, swells, and adheres closely to the tissue. The breakdown of the structure of the medical material is suppressed by the acid generated by contact of the decay-retarding material with water. This provides a bioabsorbable medical material that can maintain a desired function in a living body for a predetermined period of time. Thus, according to the present invention, it is possible to provide a medical material that maintains its shape on the surface of a wounded area where wound healing or adhesion is desired to be prevented for a period of time required for wound healing, is effective in wound healing or adhesion prevention, is quickly absorbed in its entirety after wound healing, and has very little risk of foreign body reaction, inflammation, or infection due to long-term residue. [Brief description of the drawings]

[0023] [Figure 1] FIG. 2 is a photograph showing a typical appearance of an example of the present invention, which received a grade of 2 in the appearance evaluation. [Diagram 2] FIG. 2 is a photograph showing a typical appearance of an example of the present invention, which received a rating of 1 in appearance evaluation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments.

[0025] The bioabsorbable medical material of the present invention includes a crosslinked polymeric material that forms a specific shape and a decay-retardant material held by the crosslinked polymeric material. For example, the bioabsorbable medical material of the present invention (hereinafter also referred to as "bioabsorbable material") includes a decay-retardant material that releases acid and a crosslinked polymeric material that covers at least a part of the decay-retardant material. The crosslinked polymeric material includes, for example, a polyanionic polymer having a plurality of anionic substituents in the molecule.

[0026] 1.Crosslinked polymer materials The crosslinked polymer material contained in the bioabsorbable material of the present invention has degradability in water. The degradability is suppressed in the presence of acid. The crosslinked polymer material may be a polymer compound that can be crosslinked, may be a polymer compound that has already been crosslinked, or may contain both. The crosslinked polymer material can be appropriately selected from polymer compounds having these properties. The crosslinked polymer material may be one or more types.

[0027] The crosslinked polymer material contained in the bioabsorbable material of the present invention may contain a polyanionic polymer. The polyanionic polymer has a plurality of anionic substituents such as carboxyl groups and hydroxyl groups in the molecule. The polyanionic polymer can be obtained by chemically modifying a polymer compound with anionic substituents as necessary. By introducing a cationic substituent into the polyanionic polymer, a physical crosslink can be formed. Depending on the state of the physical crosslink formed, it is possible to adjust various physical properties of the polyanionic polymer, such as water solubility and mechanical properties.

[0028] Although physically crosslinked polyanionic polymers are less likely to be hydrated than non-physically crosslinked polyanionic polymers, they do not have enough water insolubility to maintain their structure until the damaged site in the body is healed. However, the present inventors have found that the presence of an acid contributes to the maintenance of the crosslinked structure. When a physically crosslinked polyanionic polymer is implanted in the body, the crosslinked structure collapses due to neutralization or hydration by cationic ions or water molecules, and the water solubility increases. However, in the presence of an acid, the anionic substituents that are the starting points of crosslinking, such as carboxyl groups, are less likely to be neutralized or hydrated, and therefore the crosslinked structure is maintained.

[0029] Currently, there are many examples of such polyanionic polymers, as various chemical modification methods have been developed. From the viewpoint of high biocompatibility and bioabsorbability, the polyanionic polymer is preferably a polyanionic polysaccharide, protein, or polyamino acid.

[0030] (Cross-linked polyanionic polysaccharides) In one embodiment of the present invention, the physically crosslinked polyanionic polymer is preferably a crosslinked polyanionic polysaccharide. KishiPolyanionic polysaccharides refer to polysaccharides having a plurality of anionic functional groups in the molecule, each of which has a negative charge, such as an anionic functional group. Polyanionic polysaccharides also include salts thereof, for example, alkali metal salts such as sodium salts or potassium salts, or alkaline earth metal salts such as calcium salts or magnesium salts. Examples of natural polyanionic polysaccharides include pullulan, alginic acid, hyaluronic acid, chondroitin sulfate, dextran sulfate, and pectin. Examples of polyanionic polysaccharides synthesized by artificially introducing anionic groups include carboxymethyl amylose, carboxymethyl cellulose, carboxymethyl dextran, carboxymethyl starch, sulfated cellulose, and sulfated dextran. From the viewpoint of safety to the living body or ease of handling, the polyanionic polysaccharide is preferably alginic acid, hyaluronic acid, carboxymethyl cellulose, or carboxymethyl amylose. These polyanionic polysaccharides can be used alone or in combination of two or more.

[0031] The crosslinked polyanionic polysaccharide is a crosslinked polyanionic polysaccharide having a structure obtained by subjecting the above-mentioned polyanionic polysaccharide to a crosslinking treatment. Examples of the method for crosslinking the polyanionic polysaccharide include ultraviolet treatment, heat treatment, and crosslinking agent treatment, and crosslinking agent treatment is preferred. The crosslinking agent used in the crosslinking agent treatment is preferably a compound having a cationic substituent from the viewpoint of physically crosslinking the polyanionic polymer. Examples of such crosslinking agents include carbodiimide, triazine, and imidazole. Specific examples of carbodiimide include ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonic acid, and EDC that can be used in an aqueous solvent is more preferred.

[0032] As an example of a method of crosslinking agent treatment, first, polyanionic polysaccharide is dissolved in water or an aqueous solution, and a crosslinking agent is added and stirred. When EDC is used as a crosslinking agent, the reaction is carried out at a low pH in order to convert the carboxyl group of the polyanionic polysaccharide into an acid form because EDC has high stability. This allows the reaction to be completed efficiently. The pH should preferably be 4.0 to 5.5. Since the pH increases during the reaction, it is preferable to adjust the pH using an acid such as 0.01M hydrochloric acid.

[0033] EDC, a preferred crosslinking agent, reacts with anionic substituents such as carboxylic acids on polyanionic polysaccharide molecules. This reaction produces a mixture of relatively stable N-acylurea and O-acylisourea, which are unstable in water. This reaction introduces cationic substituents into the polyanionic polysaccharide molecules, which strengthens the intermolecular interactions of the polyanionic polysaccharides and results in a physically crosslinked gel-like polyanionic polysaccharide (crosslinked polyanionic polysaccharide).

[0034] (Protein or polyamino acid) In another embodiment of the present invention, the crosslinkable polymer material is preferably a protein or a polyamino acid. Examples of proteins include gelatin, collagen, albumin, fibrin, and chemically modified compounds thereof. Examples of polyamino acids include polyglutamic acid and polyaspartic acid having an anionic substituent. Among these proteins or polyamino acids, acid-treated gelatin is preferred. Acid-treated gelatin has a carboxyl group obtained by hydrolysis of an acid amide during the manufacturing process, and therefore has many anionic substituents in the molecule. As with polyanionic polysaccharides, physically crosslinked gelatin can be obtained by chemically modifying the anionic substituent and introducing a cationic substituent into the anionic substituent.

[0035] 2. Collapse retardant material The decay-retarding material contained in the bioabsorbable material of the present invention releases a specific amount of acid per unit time for a specific period of time upon contact with water. The acid release period and release capacity of the decay-retarding material can be appropriately determined according to the application to the living body, and from the viewpoint of such application, the acid release period is 7 days and the acid release capacity is 0.5 mol% / day or more upon contact with water at 37°C. It is sufficient that the release capacity is achieved for at least one day of the acid release period (7 days), and it is preferable that the release capacity is achieved over the entire period.

[0036] The start and end of the acid release period are not limited. The start of the acid release period may be at the time of contact with water at 37°C, or may be after a certain period of time has elapsed since the contact. The lower limit of the acid release capacity may be appropriately determined from a range that satisfies 0.5 mol% / day or more depending on the application of the bioabsorbable material of the present invention in the living body. For example, in the case of application to prevent wound adhesion in the living body, the decay retardant releases 0.5 mol% / day or more of acid by the 7th day upon contact with water at 37°C. The amount of acid released by the 7th day may be 2.0 mol% / day or more, or may be 3.5 mol% / day or more.

[0037] The upper limit of the acid release capacity is not limited from the viewpoint of suppressing the breakdown of the crosslinked polymer material. The upper limit of the acid release capacity can be appropriately determined depending on the application of the bioabsorbable material of the present invention in the living body, and from the viewpoint of suppressing the occurrence of an inflammatory reaction in the living body, for example, it is preferably 40 mol% / day or less after one day, more preferably 20 mol% / day or less.

[0038] The acid release capacity can be measured by titrating the aqueous dispersion of the decay retardant with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), as described in the examples below. The acid release capacity can be adjusted to some extent depending on the type or molecular weight of the decay retardant, and the smaller the molecular weight, the higher the acid release capacity tends to be.

[0039] The decay retardant contained in the bioabsorbable material of the present invention includes a material that releases acid when it comes into contact with water. The material that releases acid is a material that continuously releases acid, specifically, a material that has an acid release capacity of 0.3 mol% / day or more after immersion in water at 37°C for 7 days. The lower limit of the release capacity after immersion in water at 37°C for 7 days may be appropriately determined according to the use of the bioabsorbable material of the present invention in a living body from a range that satisfies 0.3 mol% / day or more. For example, in the case of use for preventing wound adhesion in a living body, the acid release capacity of the decay retardant after immersion in water at 37°C for 7 days may be 1.0 mol% / day or more, or may be 1.3 mol% / day or more.

[0040] The acid releasing capacity is expressed as a percentage of the amount of substance of acid released in water at 37° C. relative to the amount of substance of acid contained in the acid-releasing material. When an acid is contained in the acid-releasing material as an acid precursor that generates an acid by hydrolysis, the acid releasing capacity is expressed as a percentage of the amount of substance of acid released in water at 37° C. relative to the theoretical amount of acid generated when all of the acid precursor is hydrolyzed, divided by the number of days that have passed.

[0041] The acid releasing capacity over 7 days can be calculated by dividing the acid releasing capacity value converted from the measured acid concentration value over 7 days in contact with water at 37° C. by the number of days between measurements. When the acid concentration is measured multiple times within 7 days, the acid releasing capacity value can be calculated as the acid releasing capacity value from the previous measurement to the current measurement, and in this case, the acid releasing capacity over 7 days can be calculated as the releasing capacity value for any period in the measured values ​​up to the 7th day.

[0042] The acid-releasing material contained in the decay-retarding material has the above-mentioned characteristics, and the bioabsorbable material is placed at a predetermined position in the living body, and the decay-retarding material comes into contact with the water in the living body, so that the decay-retarding material can continuously release acid. This maintains the crosslinked structure of the crosslinked polymer material, suppresses its collapse, and allows the desired function to be maintained for a predetermined period of time. For example, when the bioabsorbable material is an adhesion inhibitor, it can be placed between organs to suppress adhesion between organs in the living body. The acid-releasing material is preferably a sustained-release material or a biodegradable polyester, which will be described later.

[0043] (Sustained release material) In one embodiment of the present invention, the material that releases an acid may be a sustained-release material that contains a carrier and an acid and has a function of gradually releasing an acid when in contact with water. Examples of the acid include acetic acid, propionic acid, malic acid, succinic acid, phthalic acid, and maleic acid. When the content of the acid is a specific amount or more relative to the dry weight of the bioabsorbable material, a high effect is expected in maintaining the structure of the crosslinkable polymer material.

[0044] Examples of sustained-release materials include compositions in which acid powder is coated with a carrier (coatings), and solid dispersions in which the acid is dispersed in the carrier in the form of fine particles or molecules.

[0045] The acid powder to be coated is not limited to a powder consisting of only acid. The acid powder to be coated may be a powder obtained by layering an acid powder around carrier particles such as sucrose, lactose, D-mannitol, corn starch, or crystalline cellulose as a core. Alternatively, the acid powder to be coated may be a powder obtained by impregnating the carrier particles with a liquid acid or an acid solution and optionally volatilizing the solvent. A composition in which such an acid powder is coated with a carrier may be used as a sustained release material.

[0046] The carrier may contain one or both of a water-soluble material and a water-insoluble material. A water-soluble coating agent can be used as the carrier used for coating (hereinafter also referred to as "coating agent"). The water-soluble coating agent dissolves when it comes into contact with water. When the coating by the carrier is removed, the encapsulated acid is released.

[0047] In addition, a non-water-soluble coating agent can also be used as the carrier used for the coating. The non-water-soluble coating agent is preferably a material that has water permeability when used as a coating material. When the coating material has water permeability, water penetrates the coating formed from the non-water-soluble coating agent and enters the sustained-release material. The acid encapsulated in the sustained-release material dissolves in the invaded water. The aqueous acid solution resulting from the dissolution penetrates the coating and is released from the sustained-release material to the outside. Examples of non-water-soluble coating agents that can form a water-permeable coating include polymers having a mesh structure larger than the molecules of the encapsulated acid, porous inorganic materials, and porous polymeric materials.

[0048] In addition, even if a water-permeable coating cannot be obtained by using a non-water-soluble coating agent alone, a water-permeable coating can be obtained by using the non-water-soluble coating agent in combination with the water-soluble coating agent. That is, when a coating formed by mixing a non-water-soluble coating agent and a water-soluble coating agent comes into contact with water, only the water-soluble coating agent is removed. This makes it possible to obtain a water-permeable coating formed from the non-water-soluble coating agent and having a plurality of voids that communicate with the acid encapsulated from the surface of the sustained-release material. The compatibility of the water-soluble coating agent and the non-water-soluble coating agent can be appropriately adjusted by the mixing ratio of the water-soluble coating agent and the non-water-soluble coating agent, or by selecting the water-soluble coating agent and the non-water-soluble coating agent. This makes it possible to adjust the size or shape of the voids in the coating formed by contact with water, and as a result, to control the release of the acid.

[0049] Alternatively, the sustained release material may be composed of a carrier having open cell voids. In the sustained release material, the acid is contained in the voids of the carrier. The carrier may be a material having a porous structure due to the voids, and can be appropriately selected from a range that does not substantially interact with the living body. In such a sustained release material, the release of the acid can be controlled, for example, by adjusting the size or shape of the voids as described above.

[0050] The solid dispersion can be prepared by drying a solution in which the carrier and the acid are both dissolved by a method such as spray drying, heat drying, hot air drying, vacuum drying, freeze drying, etc. Alternatively, the solid dispersion can be prepared by dispersing the acid in a molten carrier and then cooling the resulting mixture.

[0051] The coating agent and the carrier for the solid dispersion can be the same. Examples of coating materials include sucrose, lactose, D-mannitol, corn starch, crystalline cellulose, talc, precipitated sodium carbonate, gelatin, gum arabic, pullulan, povidone, copolyvidone, hydroxypropyl cellulose, hypromellose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxyethyl cellulose, ethyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydrogenated oil, carnauba wax, aminoalkyl methacrylate copolymer RS, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and ethyl acrylate-methyl methacrylate-copolymer emulsion.

[0052] (Biodegradable polyester) In another embodiment of the present invention, the acid releasing material is preferably a biodegradable polyester, and the content of the biodegradable polyester is preferably 3 wt% or more based on the dry weight of the bioabsorbable material, since this is highly effective in maintaining the structure of the crosslinked polymer material.

[0053] From the viewpoint of the absorption rate of the crosslinked polymer material in the living body and the sustained release of the acid, the biodegradable polyester is preferably a composition containing a low molecular weight biodegradable polyester, specifically, a biodegradable polyester with a number average molecular weight of less than 30,000 Daltons (Da). By containing at least 3 wt% or more of a biodegradable polyester with a molecular weight of less than 30,000 Daltons relative to the dry weight of the bioabsorbable material, the collapse of the crosslinked structure of the crosslinked polymer material can be more appropriately suppressed. The low molecular weight biodegradable polyester has a higher hydrolysis rate than the high molecular weight biodegradable polyester, and can rapidly release a desired amount of acid. The released acid not only suppresses the collapse of the crosslinked structure of the crosslinked polymer material, but also acts as a catalyst for the decomposition reaction of the biodegradable polyester itself (autocatalysis). For this reason, the low molecular weight biodegradable polyester can more effectively promote the sustained release of acid.

[0054] The number average molecular weight of the biodegradable polyester is preferably 1,000 Da or more from the viewpoint of sufficiently extending the acid release period in the body. Thus, the number average molecular weight of the biodegradable polyester can be one means for adjusting the desired acid release period corresponding to the desired use of the bioabsorbable material.

[0055] The acid releasing material may contain a biodegradable polyester having a molecular weight of 50,000 Da or more for the purpose of reinforcing the bioabsorbable material, in addition to the biodegradable polyester having a low molecular weight. Even if a biodegradable polyester having a molecular weight of 50,000 Da or more is contained, the decomposition of the biodegradable polyester having a large molecular weight can be promoted by the above-mentioned autocatalytic action of the low molecular weight biodegradable polyester preferably contained in the bioabsorbable material of this embodiment. Therefore, even if a biodegradable polyester having a molecular weight of 50,000 Da or more is contained, the long-term persistence of the material constituting the bioabsorbable material in the living body is suppressed.

[0056] From the above viewpoint, it is preferable that the molecular weight distribution of the biodegradable polyester is bimodal, with peaks at number average molecular weights of 1,000 Da or more and less than 50,000 Da, and 50,000 Da or more and 500,000 Da or less, respectively. In this case, the proportion of biodegradable polyesters having molecular weights of 1,000 Da or more and less than 50,000 Da in the biodegradable polyester is preferably 3% by weight (3wt%) or more, more preferably 5wt% or more, even more preferably 10wt% or more, and most preferably 20wt% or more, from the viewpoint of suppressing long-term persistence in the body as described above.

[0057] The biodegradable polyester may be in any form, but is preferably in the form of a fiber, a pulverized form, or a mixture thereof. The fibrous form includes all fibrous materials such as short fiber, long fiber, monofilament, multifilament, nonwoven fabric, etc. The pulverized form is, for example, particles or powder.

[0058] Specifically, the biodegradable polyester is preferably polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, or copolymers thereof, which release acid upon hydrolysis. Among them, glycolic acid homopolymer (polyglycolic acid) or copolymers containing glycolic acid-derived structural units, which have a short bioabsorption period, is preferred, and glycolic acid homopolymer is most preferred.

[0059] 3. Manufacturing method of bioabsorbable materials The shape of the bioabsorbable material of the present invention can be appropriately determined within the range that allows application to a living body, and may be, for example, a sheet, a powder, or a gel or sol containing a protic solvent. The sheet-shaped bioabsorbable material can be obtained as a continuous membrane or a porous sheet-shaped material, for example, by pouring a mixture, solution, or dispersion of a crosslinkable polymer material and a decay retardant into an appropriate container, and then air-drying or freeze-drying the mixture.

[0060] The obtained sheet-like material may be heat-treated using a heat press device. A bioabsorbable material with improved water solubility can be obtained by heat treatment. This allows the structure of the bioabsorbable material to be maintained in the body for a longer period while maintaining its flexibility. From the viewpoint of appearance and handling, the heat treatment temperature is preferably 80°C to 150°C. In addition, regardless of heat treatment, the water solubility can be adjusted, for example, increased, by the form such as the content and thickness of the decay retardant, or the concentration of the crosslinking agent when the crosslinked polymer material is a crosslinked polyanionic polysaccharide.

[0061] 4. Applications of bioabsorbable materials The bioabsorbable material of the present invention inhibits the collapse of the structure until the damaged site heals when placed in the living body, and there is little concern about inflammation due to long-term residual, and is useful as a medical material mainly used in the living body. The remaining period of the bioabsorbable material of the present invention in the living body can be appropriately adjusted by combining a crosslinked polymer material and a decay retardant. Although it cannot be said in general, the start of the degradation of the bioabsorbable material of the present invention in the living body can be adjusted between 7 days after application to the living tissue. The period of degradation of the bioabsorbable material of the present invention in the living body can be adjusted between 7 days and 14 days. The end of the degradation of the bioabsorbable material of the present invention in the living body can be adjusted between 14 days and 28 days after application to the living tissue. The above-mentioned "decomposition" means a state in which the state of the bioabsorbable material placed in the living body or an environment simulating it has changed to a degree that can be visually recognized. The "start of decomposition" is the first time when the above-mentioned change in state is confirmed, and the "end of decomposition" is the first time when the above-mentioned change in state is no longer confirmed.

[0062] The dried bioabsorbable medical material of the present invention can absorb water, swell, and adhere. Therefore, by using the bioabsorbable medical material of the present invention at a wound site in a living body caused by endoscopic submucosal dissection or the like, the accumulation of exudate is suppressed, maintaining a moist environment suitable for wound healing, while blocking external stimuli. Therefore, the bioabsorbable medical material of the present invention can be used as an internal covering material for preventing ulcer formation or perforation.

[0063] Furthermore, when the bioabsorbable medical material of the present invention is loaded with drugs such as growth factors and antibacterial agents and placed in a living body, the bioabsorbable medical material decomposes in the living body, and as its structure collapses, the drugs are gradually released near the placement position. Thus, the bioabsorbable medical material of the present invention can be used as a drug-releasing substrate.

[0064] In addition, the constituent raw materials of the bioabsorbable medical material of the present invention have high biocompatibility and bioabsorbability, and therefore the bioabsorbable medical material of the present invention can be used as a tissue regeneration material for the purpose of replacing autologous tissue by applying it to a site in the body where a part of biological tissue is missing.

[0065] Furthermore, the sheet-shaped bioabsorbable medical material of the present invention absorbs water and swells when implanted in the body, thereby functioning as a barrier layer that inhibits the movement of cells and body components relative to the coated surface, and therefore the bioabsorbable medical material of the present invention can also be used as an adhesion barrier.

[0066] Furthermore, the bioabsorbable medical material of the present invention can maintain its shape in a living body for a specific period of time, and therefore can be used as a gap retaining agent for maintaining gaps formed by biological tissues, for example, by applying it to the wall surface of a tubular structure that forms a gap in a living body. EXAMPLES

[0067] The present invention will be specifically described below based on examples, but the present invention is not limited to these examples.

[0068] 1. Measurement of acid release capacity As biodegradable polyester materials, the following polyglycolic acid (PGA) powder and fibers, DL-lactic acid / glycolic acid copolymer (PLGA) powder, and polylactic acid (PLA) powder were prepared. For the polyglycolic acid materials, polyglycolic acids with different molecular weights and commercially available polyglycolic acid sutures were prepared. PGA-P1: PGA powder (Mn: 11,000 Da, particle size: 38 μm or less) PGA-P2: PGA powder (Mn: 3,000 Da, particle size: 38 μm or less) PGA-P3: PGA powder (Mn: 31,000 Da, particle size: 38 μm or less) PGA-P4: PGA powder (Mn: 71,000 Da, particle size: 38 μm or less) PGA-P5: PGA powder (Mn: 200,000 Da, particle size: 38 μm or less) PGA-F1: Commercially available PGA suture ("SURGISORB" manufactured by Bear Medic Co., Ltd. ("SURGISORB" is a registered trademark of Nikcho Kogyo Co., Ltd.), size: 3-0) PLGA-P1: Commercially available PLGA powder (SIGMA's "RESOMER RG 752H" ("RESOMER" is a registered trademark of Evonik), unit ratio, lactic acid 75: glycolic acid 25, Mn: 4,000-15,000 Da) PLGA-P2: Commercially available PLGA powder (Sigma "RESOMER RG 502H", unit ratio, lactic acid 50: glycolic acid 50, Mn: 7,000-17,000 Da) PLA-P1: Commercially available PLA powder (SIGMA "RESOMER R202H", Mn: 10,000-18,000 Da)

[0069] Samples were prepared by dispersing 16.7 mg of each of the above biodegradable polyester materials in 16 mL of ultrapure water at 37°C, and the acid concentration was measured at a specific time after the preparation of the samples. The PGA-P1 sample was prepared by dispersing 13 mg of PGA-P1 in 12.4 mL of ultrapure water. The PGA-F1 sample was cut to a length of approximately 2 mm and used. The PLGA-P1 sample was prepared by dispersing 19.7 mg of PLGA-P1, 18.7 mg of PLGA-P2, and 20.7 mg of PLA-P1 in 16 mL of ultrapure water. The acid concentration was measured by titration with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The DBU concentration was previously confirmed by titration with 0.01 M HCl. As described above in the explanation of the acid release capacity, the acid release capacity was calculated by dividing the percentage of the amount of acid released in 37°C water relative to the theoretical amount of acid generated when each of the above biodegradable polyester materials is completely hydrolyzed after a specific time has elapsed by the number of days that have passed. The results are shown in Table 1.

[0070] In the table below, "PEs material" refers to the biodegradable polyester material, "Ca" refers to the acid concentration (mmol / L), and "Ar" refers to the acid release capacity (mol% / day). In addition, the difference in acid concentration between consecutive measurement days (for example, from t0 to t1) was calculated, converted to acid release capacity, and divided by the measurement days to calculate ΔAr. More specifically, ΔAr is calculated by calculating the difference Ca1 between the acid concentration on day t1 and the acid concentration on day t0, converting Ca1 to acid release capacity Ar1, and dividing Ar1 by the difference Δt between t1 and t0. In Table 1, "*" indicates that it was not performed, and "**" indicates that it could not be calculated because the molecular weight of the suture was unknown. In Table 1, ΔAr for 24 hours is not listed, but this is the same as Ar in the table.

[0071] [Table 1]

[0072] From Table 1, it can be seen that PGA-P1 generates 2.71 mmol / L of acid for 7 days from the start of the test. It can be seen that PGA-P2 generates 4.71 mmol / L of acid for 7 days from the start of the test. It can be seen that PGA-P3 generates 0.81 mmol / L of acid for 7 days from the start of the test. It can be seen that PGA-P4 generates 0.13 mmol / L of acid from 7 days after the start of the test. It can be seen that PGA-P5 generates 0.10 mmol / L of acid for 7 days from the start of the test. It can be seen that PGA-F1 generates 0.01 mmol / L of acid for 7 days from the start of the test. It can be seen that PLGA-P1 generates 0.50 mmol / L of acid for 7 days from the start of the test. It can be seen that PLGA-P2 generates 0.91 mmol / L of acid for 7 days from the start of the test. It can be seen that PLA-P1 generates 0.09 mmol / L of acid from the start of the test up to 7 days. It was found that low molecular weight polyglycolic acid released more than 0.3 mol% / day of acid for 168 hours after immersion. In addition, polyglycolic acid with a relatively high molecular weight, commercial polyglycolic acid, commercial PLGA powder, and commercial PLA powder never released more than 0.3 mol% / day of acid.

[0073] 2. Preparation of Bioabsorbable Materials [Example 1] 4.4 g of sodium hyaluronate (HA, molecular weight 2,200,000 Da) was added and dissolved in 800 mL of ultrapure water, and 2.0 g of sodium carboxymethylcellulose (CMC, molecular weight 1,500,000 Da) was added to obtain a mixture. While maintaining the pH of the mixture at 4.5-5.2 with 0.1 M HCl, 8.5 g of ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was dissolved in 20 mL of ultrapure water, and the entire solution was added dropwise. After the addition of the EDC aqueous solution, stirring and pH adjustment with 0.1 M HCl were performed for 1.5-2.0 hours until the pH fluctuation of the solution subsided. The obtained reaction solution was dialyzed using a regenerated cellulose dialysis tube (molecular weight fraction 12,000-14,000), and low molecular weight components such as unreacted substances and by-products were removed from the reaction solution while exchanging the dialysis solution. The dialysis solution was exchanged three times within 36 hours from the start of dialysis. In this way, a crosslinked HA / CMC solution containing a crosslinked product of HA and / or CMC with EDC was obtained.

[0074] 252 mg of PGA-P1 (4 molar equivalents relative to the number of moles of HA's structural units) was added to 90 g of the resulting crosslinked HA / CMC solution to disperse PGA-P1. The crosslinked HA / CMC solution containing PGA-P1 was poured into a mold 11 cm long x 11 cm wide made of glass and silicone rubber and air-dried at room temperature. The film obtained by air-drying was heat-treated at 90°C for 15 minutes and then at 120°C for 10 minutes using a heat press device to obtain a film-like PGA / HA / CMC-1 (bioresorbable material 1).

[0075] [Comparative Example 1] A film-like sample (bioresorbable material 2) was obtained in the same manner as in Example 1, except that PGA-P1 was not used.

[0076] [Comparative Example 2] A commercially available adhesion barrier material ("Seprafilm" manufactured by Sanofi, "Seprafilm" is a registered trademark of Baxter) was prepared. This was designated "bioabsorbable material 3."

[0077] 3. Evaluation (1) Shape change after immersion in phosphate buffer solution Add 1 cm of each of bioabsorbable materials 1 to 3 to 8 mL of phosphate buffer (pH 7.3). 2 A sample (dimensions: 1 cm x 1 cm) was immersed in the solution and stored at 37°C. After 72 hours, 120 hours, and 168 hours of immersion, the shape of each sample was visually observed and evaluated. A rating of 2 or more on the following scale was considered to indicate that the film-like shape was maintained.

[0078] The results of the appearance observation were expressed as the average score determined by multiple skilled technicians (5 people) who judged the appearance images of Bioabsorbable Materials 1 to 3 using the following scores set based on the images. 4 points: The appearance is almost identical to the planar shape of the sample before immersion 3 points: The appearance of the sample is bulging overall from the flat shape before immersion, but the presence of the sample can be seen 2 points: The sample is bulging from its flat surface and contains some collapsed areas, but the sample is visible. 1 point: The appearance is irregular due to droplets. 0 points: Dissolved and appearance cannot be confirmed

[0079] The results are shown in Table 2. FIG. 1 shows a photograph showing a typical appearance of the above-mentioned grade 2, and FIG. 2 shows a photograph showing a typical appearance of the above-mentioned grade 1.

[0080] [Table 2]

[0081] From the results in Table 2, Bioabsorbable Material 1 maintained its flat shape even after 120 hours of immersion, and the shape was not observed after 168 hours. On the other hand, for Bioabsorbable Materials 2 and 3, which did not contain any PGA, the shape was not observed after 120 hours of immersion.

[0082] Thus, the degradation was inhibited in the bioabsorbable material 1. The acid release capacity of the degradation-retarding material of the bioabsorbable material 1 over a period of 7 days is at least 0.3 mol % / day or more in order to obtain a sufficient degradation-inhibiting effect.

[0083] 4. Examination of biodegradable polyester content Bioabsorbable materials 1-1 to 1-3 were prepared in the same manner as in Example 1, except that the amount of PGA-P1 added was changed to 0.5, 1, and 2 molar equivalents relative to the number of moles of the structural units of the contained HA. Then, the same evaluation as in "Shape change after immersion in phosphate buffer solution" described above was carried out. The results are shown in Table 3. In the table, "PEs content" represents the content of biodegradable polyester, and is the ratio of the number of moles of biodegradable polyester to the number of moles of the structural units of HA in the bioabsorbable material.

[0084] [Table 3]

[0085] As shown in Table 3, the period during which the membrane shape is maintained increases as the amount of PGA-P1 added to the bioabsorbable material increases. Although it depends on the application of the bioabsorbable material, from the viewpoint of preventing adhesion to other tissues in the wound, it is sufficient for the amount of PGA-P1 added to the bioabsorbable material to be 1 molar equivalent or more relative to HA, or 3 wt% or more in terms of the dry weight of the bioabsorbable material.

[0086] 5. Verification of adhesion prevention effect Next, in order to confirm whether this material shows postoperative adhesion prevention effect, the adhesion prevention effect of each material was evaluated using a rat partial liver resection model. First, bioabsorbable material 1-4 was prepared in the same manner as in Example 1, except that the crosslinked HA / CMC solution was replaced with 100g, and the amount of PGA-P1 added was replaced with 3.4 molar equivalents relative to the molar number of the constituent unit of the contained HA. In addition, bioabsorbable material 2-1 was prepared in the same manner as in Comparative Example 1, except that the crosslinked HA / CMC solution was replaced with 100g.

[0087] Each group consisted of seven rats, and a portion of the left lateral liver lobe was resected, and the resected surface of the liver was covered with bioabsorbable material 2-1 or bioabsorbable material 1-4 in close contact. Seven days after surgery, the rats were dissected, and adhesions between the resected surface of the liver and other tissues were scored as adhesion severity (0: no adhesion, 1: adhesion that can be separated by its own weight, 2: adhesion that can be separated by blunt dissection, 3: adhesion that requires sharp dissection). The results are shown in Table 4. In Table 4, the "score" value for bioabsorbable material 2-1 or bioabsorbable material 1-4 in "severity of adhesion" represents the number of rats that correspond to the above score. The "average" value is the sum of the products of the scores for bioabsorbable material 2-1 or bioabsorbable material 1-4 and the number of rats divided by the number of rats.

[0088] [Table 4]

[0089] As a result, as shown in Table 4, it was confirmed that bioabsorbable materials 1-4 containing PGA-P1 had a high adhesion prevention effect.

[0090] 6. Study of cross-linked polymer materials A crosslinked HA / Pul solution was prepared in the same manner as the preparation of the crosslinked HA / CMC solution using pullulan (Pul) instead of sodium hyaluronate and sodium carboxymethylcellulose, and ethyl-3-(3-dimethylaminopropyl)carbodiimide. 1.6 g of sodium hyaluronate was added and dissolved in 283 mL of ultrapure water, and 0.5 g of pullulan was added to obtain a mixed solution. While maintaining the pH of the mixed solution at 4.5-5.2 with 0.1 M HCl, 3 g of ethyl-3-(3-dimethylaminopropyl)carbodiimide was dissolved in 7 mL of ultrapure water, and the entire amount of the solution was dropped. Otherwise, the bioabsorbable material 4 was obtained in the same manner as in Example 1. The bioabsorbable material 4 is also expected to have the same disintegration suppression effect due to the release of acid as the bioabsorbable material 1. [Industrial Applicability]

[0091] The bioabsorbable medical material of the present invention is useful as an adhesion barrier. In addition, since the material that constitutes the material retains its shape for a certain period of time and does not remain for a long period of time, it can be used in medical applications as a wound dressing, tissue regeneration material, drug sustained release matrix, and gap retainer.

Claims

1. a crosslinked polymeric material; and a biodegradable polyester held by the crosslinked polymeric material; the crosslinked polymer material is a polyanionic polysaccharide, a polyanionic protein, or a polyanionic polyamino acid, and has decomposition in water that is inhibited in the presence of an acid; The content of the biodegradable polyester is 3 wt % or more based on the dry weight of the bioabsorbable medical material; The number average molecular weight of the biodegradable polyester is 1,000 Da or more and less than 30,000 Da; The biodegradable polyester is a homopolymer of glycolic acid or a copolymer containing 50 mol % or more of a structural unit derived from glycolic acid. Bioabsorbable medical materials.

2. The bioabsorbable medical material according to claim 1 , wherein the biodegradable polyester is hydrolyzed upon contact with water at 37° C. to release an acid.

3. 3. The bioabsorbable medical material according to claim 1, wherein the biodegradable polyester is polyglycolic acid or a copolymer containing structural units derived from glycolic acid.

4. The bioabsorbable medical material according to any one of claims 1 to 3, wherein the crosslinked polymer material is a crosslinked polyanionic polysaccharide.

5. The bioabsorbable medical material according to any one of claims 1 to 4, wherein the crosslinked polymer material contains hyaluronic acid and carboxymethyl cellulose.

6. 6. The bioabsorbable medical material according to claim 1, which is a wound dressing, a tissue regeneration material, a drug sustained release substrate, a gap retaining agent, or an adhesion preventing material.

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