Bone filler and kit

Abstract

To provide a bone filler having excellent underwater stability and simultaneously exhibiting excellent injectability.SOLUTION: A bone filler comprises a first agent containing a solvent and a gelatin derivative having a structure represented by the following formula (1), and a second agent containing calcium phosphate, wherein the concentration of the gelatin derivative in the first agent is higher than 10 w / v%. In the formula (1), Gltn represents a gelatin residue, L represents a single bond or a divalent linking group, and n is 1 to 5.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a bone substitute material and a kit. [Background technology]

[0002] Bone fillers are materials used for the purpose of reconstruction and regeneration of bone defects. Chemically synthesized artificial bones such as carbonate apatite and octacalcium phosphate, complexes of these with biopolymers, and autologous / allogeneic bones are used.

[0003] Meanwhile, in Non-Patent Document 1, the inventors of the present application have synthesized catechol-introduced gelatin by introducing catechol groups into Alaska pollock-derived gelatin, which has high biocompatibility and low-temperature fluidity, and have clarified that an adhesive using this has high tissue adhesiveness. The technology reported in Non-Patent Document 1 was inspired by the fact that mussels exhibit high adhesive strength by interacting with various substrates such as inorganic materials in water, and that the key molecule in this is the catechol group. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Colloids Surf B, 2022, 220, 112946. Summary of the Invention [Problem to be solved by the invention]

[0005] Conventional bone filling materials have often been used in the form of granules or porous bodies in clinical practice. For this reason, it has been difficult to fix them to the affected area and mold them into the shape of the bone defect in an environment (aqueous environment) where there is a large amount of body fluid such as blood. In addition, if the bone filling material does not harden sufficiently in water, for example, there is a risk that the hardened material will diffuse into the blood and travel with the bloodstream, causing blockage of blood vessels. For this reason, there has been a demand for a bone paste that hardens without diffusing in an aqueous environment such as blood.

[0006] The present invention is to solve the above problems, and provides a bone filling material which has excellent aqueous stability that allows it to be used in the aqueous environment in a living body, and at the same time, exhibits excellent injectability. [Means for solving the problem]

[0007] As a result of extensive investigations aimed at achieving the above object, the present inventors have found that the above object can be achieved by the following configuration.

[0008] [1] A bone substitute material comprising: A first agent containing a solvent and a gelatin derivative having a structure represented by formula (1) described below; A second agent containing calcium phosphate, A bone filler, wherein the concentration of the gelatin derivative in the first agent is higher than 10 w / v %. [2] The bone filler described in [1], wherein the concentration of the gelatin derivative in the first agent is 50 w / v% or less. [3] The bone filler according to [1], wherein the concentration of the gelatin derivative in the first agent is 15 w / v% to 40 w / v%. [4] The bone filler according to [1], wherein the concentration of the gelatin derivative in the first agent is 20 w / v% to 30 w / v%. [5] A bone filler according to any of [1] to [4], wherein the ratio (M2 / M1) of the mass of the second agent (M2) to the mass of the first agent (M1) is 1 / 1 to 4 / 1. [6] The bone filler according to any one of [1] to [5], wherein in formula (1), the divalent linking group is at least one selected from the group consisting of -C(O)-, an alkylene group having 1 to 10 carbon atoms, and a polyethylene oxide having 1 to 10 repeating numbers. [7] The bone filler according to any one of [1] to [6], wherein in formula (1), n ​​is 1 to 3. [8] The bone filler according to [7], wherein in formula (1), the hydroxyl group in the benzene ring is at the meta position and / or para position relative to the bonding position of L. [9] The bone filler according to any one of [1] to [5], wherein the structure represented by formula (1) is a structure represented by formula (3) described below.

[10] The bone filler according to any one of [1] to [9], wherein the gelatin derivative is a derivative of gelatin derived from cold-water fish.

[11] The bone filler according to any one of [1] to

[10] , wherein the calcium phosphate is α-tricalcium phosphate (α-TCP).

[12] A kit comprising the bone filler according to any one of [1] to

[11] and a syringe for applying the bone filler to an affected area. Effect of the Invention

[0009] The bone substitute of the present invention has excellent stability in water and at the same time exhibits excellent injectability. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is a diagram illustrating a method for synthesizing a gelatin derivative (Cat-ApGltn) in an example. [Diagram 2] Photographs showing test results of each bone filling material prepared in the examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention will be described in detail below. The following description of the components may be based on a representative embodiment of the present invention, but the present invention is not limited to such an embodiment. In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0012] In the description of groups (atomic groups) in this specification, the description that does not indicate whether substituted or unsubstituted includes both unsubstituted and substituted groups, as long as it does not impair the effects of the present invention. For example, "alkyl group" includes not only alkyl groups that do not have a substituent (unsubstituted alkyl groups), but also alkyl groups that have a substituent (substituted alkyl groups). This also applies to each compound.

[0013] [Bone replacement material] The bone filler of this embodiment includes a first agent containing a gelatin derivative containing a structure represented by formula (1) described below, and a second agent containing calcium phosphate. The first agent and the second agent are packaged separately and supplied, and are mixed at the time of use. By mixing, the gelatin derivative and calcium phosphate interact with each other to form the skeleton of a hardened material (hardened bone filler material). The hardening reaction typically occurs by the -O group derived from a hydroxyl group (e.g., a catechol group) on a benzene ring of the gelatin derivative. - and Ca from calcium phosphate 2+ The gelatin derivative functions as a binder for calcium phosphate, an active ingredient in bone filling materials, which has osteoconductivity (the property of attracting bone to the surrounding area).

[0014] 1. First agent The first agent of the present embodiment contains a gelatin derivative having a structure represented by the following formula (1) and a solvent.

[0015] <Gelatin derivatives> The gelatin derivative having the structure represented by formula (1) has a benzene ring having at least one hydroxyl group (hereinafter, appropriately referred to as a "specific phenol group") bonded to the raw material gelatin (raw material gelatin) via -NH-L-.

[0016] [ka] In formula (1), Gltn represents a gelatin residue, L represents a single bond or a divalent linking group, and n is 1 to 5.

[0017] The hardened bone filler of this embodiment (i.e., the hardened gelatin derivative) has, in addition to interparticle crosslinking by amorphous hydroxyapatite formed by partial dissolution of calcium phosphate, physical crosslinking (e.g., π-π stacking) between specific phenol groups (typically, catechol groups, etc.) and electrostatic interaction between the specific phenol groups and calcium phosphate, which results in excellent water stability. Here, "water stability" means that the mixture of the first agent and the second agent quickly hardens in water, and the obtained hardened product exists stably without diffusing in water. As a result, the bone filler of this embodiment can adhere to the affected area and promote reconstruction and regeneration of bone defects even in an environment (aqueous environment) where a large amount of body fluid such as blood is present. In addition, the diffusion of the hardened product into the blood, which may cause vascular blockage, can also be suppressed.

[0018] In addition, since the gelatin derivative of the present embodiment has a specific phenol group, it is more easily dissolved in an aqueous solvent than, for example, a gelatin derivative having a linear alkyl group introduced therein. Therefore, when preparing the first agent using an aqueous solvent, the preparation time can be significantly shortened and excellent injectability can be easily achieved.

[0019] In addition, the bone filler of the present embodiment has high biocompatibility because it uses a derivative of gelatin, which is a biocompatible polymer. In addition, complex intermolecular interactions such as hydrogen bonds, π-π stacking, and cation-π interactions act between the specific phenol group and the protein contained in the biological tissue, so the hardened bone filler of the present embodiment exhibits strong adhesive strength to biological tissue and inorganic materials including calcium phosphate in the bone filler. Furthermore, the gelatin derivative of the present embodiment into which the specific phenol group has been introduced has a lower swelling property in physiological saline than, for example, a gelatin derivative into which a linear alkyl group has been introduced. Therefore, the hardened bone filler of the present embodiment also has the advantage of being less likely to peel off from biological tissue.

[0020] In the specific phenol group of formula (1), n ​​is 1 to 5, preferably 1 to 3, and more preferably n = 2. The position of the hydroxyl group is not particularly limited, but when n = 1 to 3, the hydroxyl group in the benzene ring is preferably at the meta position and / or para position relative to the bonding position of L.

[0021] More preferred embodiments of the specific phenol group include those represented by the following formula: In the following formula, * indicates the linking position with L in formula (1). Among them, the specific phenol group is preferably a catechol group having two hydroxyl groups, in that a bone filling material having a more excellent effect of the present embodiment can be obtained.

[0022] [ka]

[0023] The divalent linking group for L in formula (1) includes, for example, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -N(R)- (R represents a hydrogen atom or a monovalent organic group (preferably a hydrocarbon group having 1 to 20 carbon atoms)), an alkylene group (preferably an alkylene group having 1 to 10 carbon atoms), an alkenylene group (preferably an alkenylene group having 2 to 10 carbon atoms), a polyethylene oxide having a repeat number of 1 to 10 (-(CHCHO) n Among these, -C(O)-, an alkylene group having 1 to 10 carbon atoms, polyethylene oxide having a repeating number of 1 to 10, and combinations thereof are preferred.

[0024] For example, in formula (1), L may be an alkylene group having 1 to 10 carbon atoms, preferably an alkylene group having 1 to 3 carbon atoms, more preferably a methylene group. In this case, the gelatin derivative of this embodiment has a structure in which a specific phenol group is bonded to gelatin (raw material gelatin) via an imino group (-NH-) and an alkylene group. L may also be a polyethylene oxide having a repeat number of 1 to 10. In this case, the gelatin derivative of this embodiment has a structure in which a specific phenol group is bonded to gelatin (raw material gelatin) via an imino group (-NH-) and polyethylene oxide.

[0025] Also, for example, L in formula (1) may be a combination of -C(O)- and a divalent linking group L1. That is, the gelatin derivative of this embodiment may contain a structure represented by the following formula (2).

[0026] [ka]

[0027] In formula (2), Gltn represents a gelatin residue, L1 represents a divalent linking group, and n is 1 to 5. The gelatin derivative having the structure represented by formula (2) has a structure in which a specific phenol group is bonded to gelatin (raw gelatin) via an amide group (-NHC(O)-) and a divalent linking group L1. The divalent linking group L1 in formula (2) may have the same form as that described for the divalent linking group of L in formula (1), and the preferred forms are the same. In addition, the specific phenol group in formula (2) may have the same form as that described for formula (1), and the preferred forms are the same.

[0028] In formulas (1) and (2), the nitrogen atom (N) directly bonded to the gelatin residue Gltn is derived from the ε-amino group of mainly lysine (Lys) in gelatin. The NH structures of formulas (1) and (2) are, for example, shown to have a peak at 3300 cm -1 It can be detected by nearby bands.

[0029] The gelatin residue Gltn is a structure derived from the raw gelatin. Details of the raw gelatin will be explained in the method for producing gelatin derivatives described below.

[0030] Here, the molar ratio of the content of imino groups (-NH-) or amide groups (-NHC(O)-) to which a specific phenol group (e.g., catechol group) is bonded (introduced) in the gelatin derivative to the content of amino groups (primary amino groups, -NH2) in the raw material gelatin is defined as the "hydrophobic group introduction rate."

[0031] The hydrophobic group introduction rate is not particularly limited, but from the viewpoint of obtaining a bone filling material having a more excellent effect of the present embodiment, it is preferable that the hydrophobic group introduction rate is, for example, 30 mol% to 90 mol%, or 40 mol% to 80 mol%. In other words, the imino group (or amide group) / amino group (molar ratio) in the gelatin derivative is preferably 30 / 70 to 90 / 10, or 40 / 60 to 80 / 20.

[0032] In the embodiment, the hydrophobic group introduction rate is calculated from the values ​​obtained by quantifying the number of amino groups in the raw gelatin and the number of amino groups in the gelatin derivative by the 2,4,6-trinitrobenzenesulfonic acid method (TNBS method) using the following formula. Hydrophobic group introduction rate of gelatin derivative (mol%) = [Number of amino groups in raw gelatin - Number of amino groups in gelatin derivative] / [Number of amino groups in raw gelatin] x 100

[0033] The number of specific phenol groups (e.g., catechol groups) introduced into one molecule of gelatin derivative is not particularly limited, and may be appropriately adjusted so that the hydrophobic group introduction rate is a predetermined value based on the molecular weight of raw material gelatin. For example, the number of specific phenol groups in one molecule of gelatin derivative may be 5 to 10, 6 to 9, or 6 to 8.

[0034] The molecular weight of the gelatin derivative is not particularly limited, and is determined by the molecular weight of the raw gelatin and the type and amount (number) of the hydrophobic group (specific phenol group, etc.) introduced. Therefore, the range of the weight average molecular weight (Mw) of the gelatin derivative is almost the same as the range of the weight average molecular weight (Mw) of the raw gelatin described later.

[0035] The gelatin derivative may consist of only one type of gelatin derivative, or may be a mixture of two or more types of gelatin derivatives.

[0036] <Method of producing gelatin derivatives> The method for producing (synthesizing) the gelatin derivative is not particularly limited, and any known method can be used.

[0037] For example, a method of reacting an ε-amino group of gelatin with an aldehyde or ketone, binding a hydrophobic group (including a specific phenol group) via a Schiff base, and reducing the Schiff base to obtain a gelatin derivative (see FIG. 1). This method is described, for example, in paragraphs 0029 to 0031 of JP 2019-216755 A. According to this method, a gelatin derivative in which a hydrophobic group is bound to a gelatin residue via an imino group is obtained. This hydrophobic group is derived from the aldehyde or ketone used in the reaction.

[0038] Another method is to react an acid halide or a chloroformate compound with an ε-amino group of gelatin in the presence of a base such as triethylamine to obtain an amide. This method is described, for example, in paragraphs 0072 to 0080 of WO 2014 / 112208. According to this method, a gelatin derivative is obtained in which a hydrophobic group (including a specific phenol group) is bonded to a gelatin residue via an amide bond (including an imino group). This hydrophobic group is derived from the acid halide or chloroformate compound used in the reaction.

[0039] When a large excess of a poor solvent, for example cold ethanol, is added to the reaction solution obtained above, the gelatin derivative precipitates, which is then filtered off and dried to obtain a powdered gelatin derivative. The gelatin derivative may be washed with ethanol or the like before drying.

[0040] The raw material gelatin used in the production of gelatin derivatives (hereinafter also referred to as "Org gelatin") is typically gelatin that has no hydrophobic groups introduced therein (is not derivatized).

[0041] The molecular weight of Org gelatin is not particularly limited, and generally, the weight average molecular weight is preferably 10,000 to 300,000. In one embodiment, it is also preferable that the molecular weight is less than 50,000 from the viewpoint of easily suppressing allergic reactions to the living body. In this respect, the molecular weight of gelatin is preferably 45,000 or less, more preferably 40,000 or less. There is no particular lower limit, but it is preferably 10,000 or more from the viewpoint that the hardened material of the bone filler has superior mechanical strength.

[0042] Org gelatin can be used without any particular limitation, regardless of whether it is naturally derived, chemically synthesized, fermented, or obtained by genetic recombination. Naturally derived gelatin is preferred. Examples of naturally derived gelatin include gelatin derived from mammals such as cows and pigs, and gelatin derived from fish such as sea bream, sturgeon, salmon, and cod.

[0043] From the viewpoint of handling, it is preferable that the Org gelatin has excellent fluidity at the temperature of use (e.g., the temperature of a living body), and in this respect, the Org gelatin is preferably fish-derived gelatin, and in particular, gelatin derived from cold-water fish such as salmon and Alaska pollock is preferable.

[0044] Fish-derived gelatin, particularly cold-water fish gelatin, preferably has, per 1000 amino acids as constituent units, the number of units derived from hydroxyproline of 80 or less and / or the number of units derived from proline of 110 or less. Gelatin satisfying these conditions has superior fluidity at room temperature, and therefore, when used in the first agent, a bone filler having superior handling properties can be obtained.

[0045] The Org gelatin may be either acid-processed gelatin or alkali-processed gelatin. The first agent may contain two or more different types of gelatin as the Org gelatin. The two or more different types mean that one or more of the origin, molecular weight, processing method, etc. are different.

[0046] <Solvent> The solvent used in the first agent may be an aqueous solvent, and the aqueous solvent may be ultrapure water, physiological saline, various inorganic salt buffer solutions such as boric acid, phosphoric acid, and carbonate, or a mixture thereof.

[0047] <Additives> The first agent may be composed of only the gelatin derivative, or may be composed of only the gelatin derivative and the solvent, or may contain other additives within the range in which the effect of the present embodiment is achieved. The total content of the gelatin derivative containing the structure represented by formula (1) and the solvent in the first agent may be 90% by mass or more, 98% by mass or more, or 100% by mass. Examples of additives include colorants, pH adjusters, and preservatives. For example, a colorant (e.g., brilliant blue) may be added to make it easier to see where the bone filling material is applied. The amount added may be, for example, 10 to 100 μg / mL.

[0048] The concentration of the gelatin derivative containing the structure represented by formula (1) in the first agent (grams of gelatin derivative dissolved in 100 mL of the first agent) is higher than 10 w / v%, and is preferably 15 w / v% or more, or 20 w / v% or more. When the concentration of the gelatin derivative is within the above range, high stability in water is easily obtained. In addition, the upper limit of the concentration of the gelatin derivative containing the structure represented by formula (1) in the first agent is not particularly limited, but is preferably 50 w / v% or less, 40 w / v% or less, or 30 w / v% or less, for example. When the concentration of the gelatin derivative is within the above range, high injectability is easily obtained.

[0049] The method for preparing the first agent is not particularly limited, and for example, it can be produced by mixing a gelatin derivative and a solvent, and, if necessary, additives, etc., by a known method.

[0050] 2. Second agent The second agent contains calcium phosphate. The calcium phosphate having osteoconductivity is an active ingredient of the bone filler of the present embodiment, and at the same time, it interacts with the gelatin derivative containing the structure represented by formula (1), and contributes to improving the stability of the hardened material of the bone filler in water. Therefore, the bone filler of the present embodiment does not need to contain a hardener for the gelatin derivative separately.

[0051] Examples of calcium phosphate include α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP), tetracalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, etc., and among these, α-tricalcium phosphate (α-TCP) is preferred. As calcium phosphate, only one type may be used, or multiple types may be mixed and used.

[0052] The second agent may be composed of calcium phosphate alone, or may contain other components within the range in which the effects of the present embodiment are achieved. Examples of other components include the solvents, additives, and inorganic components such as magnesium phosphate that can be contained in the first agent described above. The content of calcium phosphate in the second agent may be, for example, 90% by mass or more, 98% by mass or more, or 100% by mass.

[0053] The ratio (M2 / M1) of the mass (M2) of the second agent to the mass (M1) of the first agent (typically, the ratio (M2 / M1) of the mass (M2) of calcium phosphate to the mass (M1) of the gelatin derivative solution) is not particularly limited, but may be, for example, (M2 / M1) = 1 / 1 to 4 / 1 from the viewpoint of obtaining a bone filler having a superior effect of this embodiment.

[0054] [How to use bone substitute material] The bone filler of the present embodiment can be used as a bone filler for implants or a bone filler for bones. For example, just before use, the first agent and the second agent are mixed to prepare a paste, and the paste is applied to a living tissue (for example, an affected area such as a bone defect).

[0055] The temperature during the curing reaction is not particularly limited, but is generally preferably 15 to 45° C., more preferably 20 to 42° C. The curing time is not particularly limited, but sufficient stability in water can be obtained within 1 to 10 minutes.

[0056] The method of applying the bone filler to the biological tissue is not particularly limited, and for example, it may be applied (injected) using a syringe. The syringe is not particularly limited, and a general-purpose one can be used. The paste prepared by mixing the first and second agents of the bone filler of this embodiment has good injectability and can be easily discharged using a syringe and applied to the affected area. The bone filler of this embodiment may be included in a kit together with a syringe for applying (injecting) the bone filler to the affected area. EXAMPLES

[0057] The present invention will be described below with reference to examples, but the present invention is not limited to these.

[0058] <Synthesis of gelatin derivatives> A gelatin derivative with a catechol group introduced therein (hereinafter, referred to as "Cat-ApGltn") was synthesized using raw gelatin (gelatin derived from Alaska pollack, hereinafter, referred to as "Org-ApGltn" as appropriate). In this example, as shown in Figure 1, 3,4-dihydroxybenzaldehyde was reacted with the amino group of Org-ApGltn to form a Schiff base, and the resulting Schiff base was then reduced to a stable secondary amine with a reducing agent to obtain Cat-ApGltn.

[0059] 60 g of gelatin derived from Alaska pollock (Org-ApGltn) (Nitta Gelatin Co., Ltd., weight average molecular weight (Mw): 85 kDa, amino group content: 324 μmol / g) was dissolved in 700 mL of ultrapure water, and while stirring at 55 °C, 500 equivalents of 3,4-dihydroxybenzaldehyde (Tokyo Chemical Industry Co., Ltd.) was added to the solution together with ethanol (Junsei Kagaku Co., Ltd.) per 100 equivalents of the amino group amount (324 μmol / g) of Org-ApGltn to form an imine bond between 3,4-dihydroxybenzaldehyde and the amino group of Org-ApGltn. After stirring at the same temperature for 1 hour, 2-picoline borane (Junsei Kagaku Co., Ltd., 145.8 mmol) was added to the mixture together with ethanol to reduce the imine. The resulting mixed solution (Org-ApGltn concentration: 6 mass / volume%, water:ethanol = 105:45 mL) was stirred at 50 °C for 17 hours to allow the reaction to proceed. Then, the reaction solution (150 mL) was dropped into 8000 mL of cold ethanol (-7 to 4 °C) to purify Cat-ApGltn. The resulting reprecipitate was washed with 8000 mL of ethanol (1 hour x 2 times) to remove unreacted 3,4-dihydroxybenzaldehyde and 2-picoline borane. It was then vacuum dried for 3 days to obtain Cat-ApGltn in a yield of 96.7 mass%.

[0060] The obtained Cat-ApGltn was analyzed by Fourier transform infrared spectroscopy (FT-IR) at 3285 cm-1 The increase in the secondary amine peak was observed, and the proton nuclear magnetic resonance ( 1 H-NMR showed a peak of the aromatic ring derived from the catechol group at 6.8 to 7.0 ppm. From these qualitative analysis results, it was confirmed that a catechol group was introduced into Cat-ApGltn. In other words, Cat-ApGltn contains a structure represented by the following formula (3).

[0061] [ka] In formula (3), Gltn represents a gelatin residue.

[0062] The catechol group introduction rate (hydrophobic group introduction rate, hereinafter referred to as "DS") of Cat-ApGltn was calculated from the values ​​obtained by quantifying the number of amino groups in the raw gelatin and the number of amino groups in Cat-ApGltn using the 2,4,6-trinitrobenzenesulfonic acid method (TNBS method). The DS was 51 mol%.

[0063] Next, six types of bone filling materials each composed of a first agent (solution) and a second agent (powder) were prepared, as described below.

[0064] <Bone replacement material 05> As the first agent, the synthesized Cat-ApGltn was dissolved in physiological saline to prepare a solution with a Cat-ApGltn concentration of 5 w / v%. As the second agent (powder), α-tricalcium phosphate (α-TCP), a calcium phosphate, was prepared.

[0065] <Bone replacement material 10> Bone filler 10 was prepared in the same manner as bone filler 05, except that the Cat-ApGltn concentration was changed to 10 w / v %.

[0066] <Bone replacement material 15> Bone filler 15 was prepared in the same manner as bone filler 05, except that the Cat-ApGltn concentration was changed to 15 w / v %.

[0067] <Bone replacement material 20> Bone filler 20 was prepared in the same manner as bone filler 05, except that the Cat-ApGltn concentration was changed to 20 w / v %.

[0068] <Bone replacement material 25> Bone filler 25 was prepared in the same manner as bone filler 05, except that the Cat-ApGltn concentration was changed to 25 w / v%.

[0069] <Bone replacement material Org> Bone filler Org was prepared in the same manner as bone filler 05, except that raw gelatin (Org-ApGltn) was used instead of Cat-ApGltn and the Org-ApGltn concentration was set to 20 w / v %. [evaluation] (1) Injectability For each bone filler, 0.5 mL (approximately 500 mg, W1) of the first agent (saline solution of Cat-ApGltn) was added to 1000 mg (W2) of the second agent (α-TCP) (W2 / W1=2 / 1) and kneaded until homogenous to obtain a paste. The obtained paste was filled into a syringe (inner diameter of the nozzle: 1.6 mm) and extruded into saline at 37°C. For comparison, a similar test was performed using a commercially available bone filler (manufactured by HOYA Technosurgical Corporation, Biopex (registered trademark)-R). The commercially available product is a bone filler that can be injected using a syringe.

[0070] All of the prepared bone substitutes 05 to 25 and Org could be injected using a syringe and had excellent injectability equivalent to that of commercially available products.

[0071] (2) Stability in water First, pastes obtained from bone fillers 05-25, Org, and a commercially available product (Biopex (registered trademark)-R) were extruded into saline using a syringe in the same manner as in the above-mentioned "(1) Injectability" test. The saline from which the pastes were extruded was then stirred at a rotation speed of 600 rpm for 30 seconds. Figure 2 shows photographs of each paste extruded into saline before stirring (After injection) and after stirring (After stirring).

[0072] As shown in the photograph of each paste before mixing (after injection) in FIG. 2, all of the prepared bone fillers 05 to 25 and Org hardened similarly to the commercially available products without diffusing into physiological saline.

[0073] However, as shown in the photographs of the pastes after stirring (After injection) in FIG. 2, in the bone filler Org and bone fillers 5 and 10, the pastes were dispersed and clouded by stirring, and the solid content could not be confirmed. The commercially available product (Biopex (registered trademark)-R) also became cloudy, and only a small amount of solid content was confirmed. On the other hand, in the bone filler 15, cloudiness occurred, but a large amount of solid content remained. Furthermore, in the bone fillers 20 and 25, cloudiness was hardly generated. From these results, it was confirmed that the higher the Cat-ApGltn concentration of the first agent, the better the underwater stability of the hardened material. It is considered that the underwater stability of the hardened material is due to the interaction between the α-TCP of the second agent and the calcium salt precipitated after dissolving α-TCP and the first agent (Cat-ApGltn). From the viewpoint of improving the underwater stability of the cured product, the Cat-ApGltn concentration in the first agent preferably exceeds 10 w / v %, more preferably 15 w / v % or more, and even more preferably 20 w / v % or more. [Industrial Applicability]

[0074] The bone filler of the present invention can be used as a bone filler for bone defects or as a dental implant bone filler.

Claims

1. A bone substitute material, A first agent containing a solvent and a gelatin derivative having a structure represented by the following formula (1); A second agent containing calcium phosphate, A bone filler, wherein the concentration of the gelatin derivative in the first agent is higher than 10 w / v %. 【Chemistry 1】 In formula (1), Gltn represents a gelatin residue, L represents a single bond or a divalent linking group, and n is an integer of 1 to 5.

2. 2. The bone filling material according to claim 1, wherein the concentration of the gelatin derivative in the first agent is 50 w / v % or less.

3. 2. The bone filler according to claim 1, wherein the concentration of the gelatin derivative in the first agent is 15 w / v % to 40 w / v %.

4. 2. The bone filler according to claim 1, wherein the concentration of the gelatin derivative in the first agent is 20 w / v % to 30 w / v %.

5. A bone filler according to any one of claims 1 to 4, wherein the ratio (M2 / M1) of the mass of the second agent (M2) to the mass of the first agent (M1) is 1 / 1 to 4 / 1.

6. The bone filler according to any one of claims 1 to 5, wherein in formula (1), the divalent linking group is at least one selected from the group consisting of -C(O)-, an alkylene group having 1 to 10 carbon atoms, and a polyethylene oxide having 1 to 10 repeating numbers.

7. The bone filler according to any one of claims 1 to 6, wherein in formula (1), n ​​is 1 to 3.

8. 8. The bone substitute according to claim 7, wherein in formula (1), the hydroxyl group in the benzene ring is located at the meta position and / or the para position relative to the bonding position of L.

9. The bone filling material according to any one of claims 1 to 5, wherein the structure represented by formula (1) is a structure represented by the following formula (3): 【Chemistry 2】 In formula (3), Gltn represents a gelatin residue.

10. The bone filling material according to any one of claims 1 to 9, wherein the gelatin derivative is a derivative of gelatin derived from cold-water fish.

11. The bone filler according to any one of claims 1 to 10, wherein the calcium phosphate is α-tricalcium phosphate (α-TCP).

12. A kit comprising the bone filler according to any one of claims 1 to 11 and a syringe for injecting the bone filler.

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