Powder, wound covering material, anti-adhesion material, hemostatic material, and method for producing powder

Abstract

To provide a powder having excellent adhesion strength to biological tissues when applied to a wound covering material or the like. Also, to provide a wound covering material and an anti-adhesion material. A powder comprising particles containing a crosslinked gelatin derivative, wherein the gelatin derivative has a structure represented by formula (1): GltnNH-L-CHR 1 R 2 (in the formula, Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms), the average value of the sphericity of the particles is 1.45 or less, and the standard deviation of the sphericity of the particles is 0.25 or less.

Description

TECHNICAL FIELD

[0001] The present application relates to a powder suitable for a wound covering material, an anti-adhesion material, a hemostatic material, and the like, and a production method thereof. BACKGROUND

[0002] Gelatin is used in various medical uses because of its excellent biological adaptability and biodegradability. As such a material, "a crosslinked gelatin which is a gelatin crosslinked without using an external crosslinking agent, with an endotoxin content reduced to less than 1 EU / mL per 1.0% of protein, and a molecular weight of 30,000 to 300,000, wherein the crosslinking rate is 240 hours or less in a solubility time in physiological saline" is described in Patent Literature 1.

[0003] PRIOR ART DOCUMENTS

[0004] PATENT LITERATURE

[0005] Patent Literature 1: Japanese Patent Application Laid-Open No. 2010-83788 SUMMARY

[0006] An object of the present application is to provide a powder which has excellent adhesion to a biological tissue when applied to a wound covering material or the like. Another object of the present application is to provide a powder which, when applied to a wound covering material or the like, can reduce adhesion to other tissues after adhesion to a biological tissue. In addition, the present application also aims to provide a production method of such a powder. Furthermore, the present application also aims to provide a wound covering material, an anti-adhesion material, and a hemostatic material.

[0007] The present inventors have intensively studied in order to achieve the above object, and as a result, have found that the above object can be achieved by the following configuration.

[0008] [1] A powder comprising a particle containing a crosslinked gelatin derivative, wherein the gelatin derivative has a structure represented by the following formula (1):

[0009] GltnNH-L-CHR 1 R 2 ... (1)

[0010] [In formula (1), Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms],

[0011] The average value of the sphericity of the particle is 1.45 or less, and the standard deviation of the sphericity of the particle is 0.25 or less.

[0012] [2] The powder according to [1], wherein the gelatin derivative has a structure represented by the following formula (2):

[0013] GltnNH-CHR 1 R 2 …(2)

[0014] [In the formula, Gltn represents a residue of gelatin, R 1 is an alkyl group having 1 to 17 carbon atoms, and R 2 is a hydrogen atom or an alkyl group having 1 to 17 carbon atoms].

[0015] [3] The powder according to [1] or [2], wherein a water contact angle after 5 seconds of dripping water is less than 70°, or an adhesion strength to a tissue of a pig's inner wall of a stomach measured according to ASTM F-2258-05 before and after immersion in physiological saline for 5 minutes is reduced to 1 / 2 or less.

[0016] [4] The powder according to any one of [1] to [3], wherein the gelatin is an alkali-treated gelatin.

[0017] [5] The powder according to any one of [1] to [4], wherein the gelatin is a low-endotoxin-treated gelatin.

[0018] [6] The powder according to any one of [1] to [5], wherein the gelatin is derived from a cold-water fish.

[0019] [7] The powder according to any one of [1] to [6], wherein a cross-sectional area of a gel layer is 0.010 mm 2 or more:

[0020] Gel layer cross-sectional area measurement test: for every 2.5 cm x 2.5 cm of a surface of an esophageal submucosal tissue, 100 mg of a powder as a measurement object is sprayed, a gel is formed on the surface of the tissue by keeping at 37°C for 48 hours, the gel is fixed by neutral buffered formalin to obtain a fixed gel, the fixed gel is observed with a phase contrast microscope, from which a cross-sectional area of the gel is calculated in square millimeters, and the above test is performed three times, and an arithmetic mean value thereof is taken as the cross-sectional area of the gel layer.

[0021] [8] The powder according to any one of [2] to [7], wherein a storage modulus (G') measured 2 minutes and 30 seconds after mixing with pig's blood to which an anticoagulant is added is 200 or more.

[0022] [9] A wound covering material containing the powder according to any one of [1] to [8].

[0023]

[10] An anti-adhesion material comprising the powder described in any one of [1] to [8].

[0024]

[11] A topical hemostatic material comprising the powder described in [8].

[0025]

[12] A method for producing a powder, comprising the steps of:

[0026] a step of dissolving a gelatin derivative in a good solvent to obtain a gelatin solution containing the gelatin derivative and the good solvent, the gelatin derivative having a structure represented by the following formula (1):

[0027] GltnNH-L-CHR 1 R 2 (1)

[0028] [In formula (1), Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms];

[0029] a step of adding a poor solvent to the gelatin solution to precipitate an intermediate particle containing the gelatin derivative in the gelatin solution;

[0030] a step of freeze-drying the gelatin solution after the precipitation to obtain an intermediate powder containing the intermediate particle;

[0031] a step of cross-linking the gelatin derivative of the intermediate particle to obtain a powder containing a particle containing the cross-linked gelatin derivative.

[0032]

[13] The method described in

[12] , wherein the gelatin derivative has a structure represented by the following formula (2):

[0033] GltnNH-CHR 1 R 2 (2)

[0034] [In formula (2), Gltn represents a residue of gelatin, R 1 is an alkyl group having 1 to 17 carbon atoms, and R 2 is a hydrogen atom or an alkyl group having 1 to 17 carbon atoms].

[0035]

[14] The production method described in

[12] or

[13] , wherein the intermediate powder is heated to cross-link the gelatin derivative.

[0036]

[15] The production method according to

[14] , wherein the intermediate powder 2 is heated at 100 to 2000C for 2.5 to 5 hours to crosslink the gelatin derivative.

[0037]

[16] The production method according to any one of

[12] to

[15] , wherein, for a powder containing particles containing the crosslinked gelatin derivative, ultraviolet rays are irradiated to hydrophilize the surface of the particles.

[0038]

[17] The production method according to

[16] , wherein the powder is irradiated with ultraviolet rays for 3 hours to 6 hours.

[0039] According to one embodiment of the present application, a powder having excellent adhesion strength to a biological tissue when applied to a wound covering material or the like can be provided. Further, according to another embodiment of the present application, a powder which, when applied to a wound covering material or the like, can reduce adhesion to other tissues after adhering to a biological tissue can be provided. Further, according to still another embodiment of the present application, a wound covering material and an anti-adhesion material having such characteristics can also be provided. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 is a scanning electron microscope image of a powder modulated from 76.8C6 ApGltn (Mw: 31,000) by Method A-1.

[0041] Figure 2 is a scanning electron microscope image of a powder modulated from 76.8C6 ApGltn (Mw: 31,000) by Method B.

[0042] Figure 3 is a scanning electron microscope image of a powder modulated from Org ApGltn (Mw: 31,000) by Method A-1.

[0043] Figure 4 is a scanning electron microscope image of a powder modulated from 75C8 pig gelatin by Method C.

[0044] Figure 5 is an example of a phase contrast microscope image used in measurement of the cross-sectional area of a gel layer.

[0045] Figure 6Results of measurement of contact angle of water droplet with powder obtained by surface treatment by UV irradiation for different times (30 minutes, 1 hour, 2 hours, and 4 hours) or without the surface treatment, with powder modulated by Method A-4 with 36.4C10 ApGltn and Org ApGltn. Left is a graph showing the relationship between UV irradiation time and contact angle, and right is a graph showing the state of water droplet observed in each test.

[0046] Figure 7 Results of measurement of adhesion strength of powder obtained by surface treatment by UV irradiation for different times (30 minutes, 1 hour, 2 hours, and 4 hours) or without the surface treatment, with powder modulated by Method A-4 with 36.4C10 ApGltn and Org ApGltn, to the inner wall tissue of pig stomach.

[0047] Figure 8 Scanning electron microscope images of powder obtained by surface treatment by UV irradiation before or after cross-linking by heating, or further surface treatment by UV irradiation after the process of adjusting powder by Method A-4 with 36.4C10 ApGltn and Org ApGltn.

[0048] Figure 9 Scanning electron microscope images of powder obtained by surface treatment by UV irradiation or without the surface treatment, after adding the powder to physiological saline and leaving for different times (immediately after stirring, 30 minutes, 1 hour, 2 hours) with powder modulated by Method A-4 with 36.4C10 ApGltn and Org ApGltn.

[0049] Figure 10 Scanning electron microscope images of microporous starch spheres (trade name: Bard Arista AH, Medicon Co., Ltd.) after adding the spheres to physiological saline and leaving for different times (immediately after stirring, 30 minutes, 1 hour, 2 hours, 4 hours, 24 hours).

[0050] Figure 11 Results of measurement of adhesion strength of powder obtained by surface treatment by UV irradiation or without the surface treatment, after adding the powder to physiological saline and leaving for 5 minutes, to the inner wall tissue of pig stomach with powder modulated by Method A-4 with 36.4C10 ApGltn and Org ApGltn. As a control, also shown is the adhesion strength when no powder is used.

[0051] Figure 12Indicates the results of measuring the contact angle of the powder with a water droplet for the powder obtained by modulating 36.4C10 ApGltn and Org ApGltn by Method A-4, followed by surface treatment by UV irradiation or without the surface treatment, after leaving the obtained powder for a certain period of time (24 hours, 48 hours). The left is a graph indicating the contact angle under each condition, and the right is a graph indicating the state of the water droplet observed in each test.

[0052] Figure 13 Indicates the results of measuring the adhesive strength of the powder to the inner wall tissue of a pig stomach for the powder obtained by modulating 44.2C10 ApGltn by Method A-2 (crosslinking time 1 hour), Method A-3 (crosslinking time 2 hours), or Method A-4 (crosslinking time 3 hours), followed by surface treatment by UV irradiation or without the surface treatment.

[0053] Figure 14 Indicates the results of measuring the contact angle of the powder with a water droplet for the powder obtained by modulating 44.2C10 ApGltn by Method A-2, Method A-3, or Method A-4, followed by surface treatment by UV irradiation or without the surface treatment. The left is a graph indicating the contact angle under each condition, and the right is a graph indicating the state of the water droplet observed in each test.

[0054] Figure 15 Indicates the results of measuring the storage modulus (G') when mixed with pig blood to which an anticoagulant has been added for the powder obtained by modulating 44.2C10 ApGltn by Method A-2, Method A-3, or Method A-4, followed by surface treatment by UV irradiation or without the surface treatment. DETAILED DESCRIPTION

[0055] Hereinafter, the present application will be described in detail.

[0056] The following description is based on representative embodiments of the present application, and the present application is not limited to such embodiments.

[0057] Also, in the present specification, a numerical range indicated by "~" means a range including the numerical values described before and after the "~" as lower limit values and upper limit values.

[0058] 〔Powder〕

[0059] The powder of one embodiment of the present application is a powder containing particles containing a crosslinked gelatin derivative, wherein the gelatin derivative has a structure represented by the following formula (1):

[0060] GltnNH-L-CHR 1 R2 …(1)

[0061] [In formula (1), Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms],

[0062] The average value of the sphericity of the particles is 1.45 or less, and the standard deviation of the sphericity of the particles is 0.25 or less.

[0063] Although not bound by theory, the inventors have speculated on the mechanism by which such a powder exerts excellent adhesive strength on biological tissue as follows. Note that the following mechanism is speculative, and the effects of the present application can be obtained by mechanisms other than the following mechanism, and are included in the scope of the present application. Also, in the present specification, the term "powder" means an aggregate of a plurality of particles (including agglomerates).

[0064] The powder of the present embodiment, as shown in the above formula (1), contains particles that contain a crosslinked gelatin derivative into which a hydrophobic group (described later in detail) has been introduced. Therefore, if the powder in a dry state is sprayed, the introduced hydrophobic group increases the permeability of the powder into the target tissue, and as a result, it can be speculated that excellent adhesion to biological tissue can be achieved. This characteristic is also demonstrated in the examples described later, because the powder of Example 1, which contains particles of a crosslinked gelatin derivative into which a hydrophobic group has been introduced, was compared with the powder of Example 3, which contains particles of a crosslinked gelatin derivative into which a hydrophobic group has not been introduced, and the adhesive strength to biological tissue was increased by 2.4 times.

[0065] In addition, the powder of the present embodiment contains particles that have high sphericity and have little variation in shape. Therefore, when the present powder is applied to biological tissue, the present powder is hexagonally closest packed on the surface of the tissue, and as a result, it can be speculated that excellent adhesive strength to biological tissue can be achieved.

[0066] This characteristic is also demonstrated in the examples described later, because the powder of Example 1, which has high sphericity and has a small standard deviation of sphericity, was compared with the powder of Example 2, which has lower sphericity and has a large standard deviation of sphericity, and the adhesive strength to biological tissue was increased by 1.3 times or more.

[0067] It can be speculated that the powder of the present embodiment, by virtue of the synergistic effects of the above two characteristics, can achieve excellent adhesive strength, and the present application first provides such a powder.

[0068] The powder of another embodiment of the present application is a powder containing particles containing a crosslinked gelatin derivative, wherein the gelatin derivative has a structure represented by the following formula (1):

[0069] GltnNH-L-CHR 1 R 2 ... (1)

[0070] [In formula (1), Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms],

[0071] the contact angle of a water droplet after 5 seconds of dripping is less than 70°, or the adhesion strength to the inner wall tissue of a pig stomach before and after immersion in physiological saline for 5 minutes is reduced to 1 / 2 or less, as measured according to the standard of the American Society for Testing Materials (ASTM F-2258-05).

[0072] It is presumed that the powder of the present embodiment also has excellent adhesion to biological tissues by containing particles containing a crosslinked gelatin derivative into which a hydrophobic group is introduced. The powder of the present embodiment, as described above, has the following characteristics: the contact angle of a water droplet after 5 seconds of dripping is less than 70°, or the adhesion strength to the inner wall tissue of a pig stomach before and after immersion in physiological saline for 5 minutes is reduced to 1 / 2 or less. These characteristics, as described in the examples described later, can be understood as follows: by ultraviolet irradiation, the surface of the particles is hydrophilized, and in the powder of the present embodiment, although the adhesion strength to tissues remains high, the adhesion strength of the exposed surface decreases rapidly after adhesion to tissues, and has the advantage of preventing adhesion to other tissues. In addition, the mechanism of action is not necessarily clear, but as demonstrated in the examples described later, in the preferred mode of the present embodiment, the blood coagulation ability is excellent, and application using this characteristic is expected.

[0073] Hereinafter, the components and the like of the powder of these representative embodiments of the present invention (hereinafter, collectively referred to as the present powder) will be described in detail.

[0074] <gelatin derivative>

[0075] The present powder contains particles containing a crosslinked gelatin derivative. The gelatin derivative has a structure represented by the following formula (1).

[0076] GltnNH-L-CHR 1 R 2 ... (1)

[0077] In formula (1), Gltn represents a residue of gelatin, L represents a single bond or a divalent linking group, R 1 represents a hydrocarbon group having 1 to 20 carbon atoms, and R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms.

[0078] The divalent linking group as L is not particularly limited, and examples include -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 2 to 10 carbon atoms), an alkenylene group (preferably an alkenylene group having 2 to 10 carbon atoms), a combination thereof, and the like. Of these, -C(O)- is preferred. Thus, L is preferably a single bond or -C(O)-.

[0079] * -L-CHR 1 R 2 ( * indicates a binding site), and is preferably bound to an ε-amino group of gelatin as a raw material, and more preferably to an ε-amino group of lysine (Lys) in gelatin. As a method of binding * -CH2R 1 R 2 to an amino group, preferably to an amino group of lysine, with or without a linking group (in other words, directly), for example, a method using a so-called reductive amination reaction (a method using an aldehyde or a ketone), a Schotten-Baumann reaction (a method using an acyl chloride), and the like can be mentioned.

[0080] Further, the -NH- structure of formula (1), for example, can be detected in an FT-IR (Fourier Transform Infrared Absorption) spectrum from a waveband of 3300 cm －1 or less.

[0081] The hydrocarbon group having 1 to 20 carbon atoms is not particularly limited, and examples include a chain hydrocarbon group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a combination thereof.

[0082] R 2 R 2 may be the same as or different from R 1 . In addition, R 1 and R 2 may be a straight chain or a branched chain.

[0083] The chain hydrocarbon group having 1 to 20 carbon atoms is not particularly limited, and examples include a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group (or an octanoyl group), a nonyl group (or a pelargornyl group), a decyl group, a dodecyl group (or a lauryl group), and a tetradecyl group (or a myristyl group). Of these, based on the fact that a powder having more excellent adhesiveness can be obtained, R 1R is an alkyl group having 1 to 13 carbon atoms, more preferably an alkyl group having 7 to 12 carbon atoms, further preferably an alkyl group having 8 to 11 carbon atoms, and particularly preferably an alkyl group having 9 to 11 carbon atoms. As R 2 There is no particular limitation, but hydrogen atoms are preferred.

[0084] As the alicyclic hydrocarbon group having 3 to 20 carbon atoms, for example, cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and the like can be mentioned.

[0085] As the aromatic hydrocarbon group having 6 to 14 carbon atoms, there is no particular limitation, but phenyl, tolyl, naphthyl, and the like can be mentioned.

[0086] As the group obtained by combining the above, there is no particular limitation, and for example, aralkyl groups having 6 to 12 carbon atoms such as benzyl, phenethyl, naphthylmethyl, and naphthylethyl can be mentioned.

[0087] As the gelatin derivative represented by formula (1), at least one gelatin derivative selected from the group consisting of formula (2) and formula (3) is preferred, and a gelatin derivative represented by formula (2) is more preferred.

[0088] GltnNH-CHR 1 R 2 (2)

[0089] [Chemical Formula 1]

[0090]

[0091] In formula (2) and formula (3), the meanings of the symbols are the same as those of formula (1) described above, and the preferred modes are also the same.

[0092] In the present specification, the "derivatization rate" is defined by the molar ratio of the content of the imino group (*-NH-L-CHR 1 R 2 ) in which an alkyl group is combined, in the gelatin derivative, with respect to the content of the amino group in the raw material gelatin.

[0093] The derivatization rate of the above gelatin derivative is not particularly limited, and is generally preferably 20 to 80 mol%, and more preferably 30 to 70 mol%. In other words, the imino group / amino group (molar ratio) in the obtained gelatin derivative is preferably 20 / 80 to 80 / 20, and more preferably 30 / 70 to 70 / 30.

[0094] Further, in the present specification, the derivatization rate is calculated from the following formula by quantifying the number of amino groups of the raw material gelatin and the number of amino groups of the gelatin derivative by the 2,4,6-trinitrobenzenesulfonic acid method (TNBS method).

[0095] Derivatization rate (mole %) = [amino group number of raw gelatin - amino group number of gelatin derivative] / [amino group number of raw gelatin] x 100

[0096] The gelatin as a raw material of the gelatin derivative (hereinafter also referred to as "raw gelatin") can be of natural origin, or can be synthetic (including fermentation and gene recombination, etc.), or can be one which has been subjected to some treatment on natural origin or synthetic gelatin.

[0097] More specifically, for example, there can be mentioned gelatin of natural origin obtained from the skin, bone and tendon of mammals, birds and fish, etc., and treated gelatin in which natural origin gelatin has been treated with an acid or a base (extracted with heating as necessary), etc.

[0098] Among these, the gelatin treated with a base is preferred based on the point that a powder having more excellent effects of the present application can be obtained.

[0099] In addition, when the above powder is used in vivo, for example, when used as a wound covering material, etc., it is preferred to use a gelatin treated for low endotoxin which has a reduced endotoxin content. As such a gelatin treated for low endotoxin, there is no particular limitation, and a publicly known one can be used, for example, there can be mentioned the one described in Japanese Patent Application Laid-Open No. 2007-231225, the content of which is incorporated into the present specification by reference.

[0100] As the gelatin derived from mammals, there can be mentioned gelatin derived from pigs and cattle. As the gelatin derived from fish, there is no particular limitation, and among these, gelatin derived from cold water fish (cold water fish) such as salmon, trout, cod, sea bream, tilapia and tuna (hereinafter also referred to as "cold water fish-derived gelatin") is preferred.

[0101] The cold water fish-derived gelatin is a polymer in which two or more amino acids are linearly linked, and has 190 or less imino acids per 1000 constituent amino acids, and more specifically, has 80 or less hydroxyproline and 110 or less proline. The room temperature fluidity of the cold water fish-derived gelatin is considered to depend on the number of hydroxyproline being 80 or less or the number of proline being 110 or less. If either of these conditions is satisfied, the denaturation temperature is substantially room temperature or less, and it is considered that room temperature fluidity is produced.

[0102] The number of hydroxyproline of the snapper gelatin is 73, the number of proline is 108, and the denaturation temperature is 302.5 K. The number of hydroxyproline of the tilapia gelatin is 82, the number of proline is 110, and the denaturation temperature is 309 K. In contrast, the number of hydroxyproline of the pig gelatin is 95, the number of proline is 121, and the denaturation temperature is 316 K.

[0103] Further, the cold water fish-derived gelatin, like the animal-derived gelatin, has an amino acid arrangement that is easily decomposed by enzymes and has high biocompatibility.

[0104] The molecular weight of the raw gelatin is not particularly limited, but the weight average molecular weight (Mw) is preferably 5,000 to 100,000, more preferably 10,000 to 50,000, and further preferably 20,000 to 40,000. In the present specification, the weight average molecular weight means the weight average molecular weight obtained by gel permeation chromatography (GPC).

[0105] In the embodiment of the present application, the powder contains particles containing the above-described gelatin derivative crosslinked.

[0106] In the present specification, the "crosslinking" does not include a reversible physical crosslinking structure, but means a crosslinking structure obtained by an irreversible crosslinking reaction. Therefore, the "crosslinked gelatin derivative" is a gelatin derivative having an irreversible crosslinking structure obtained by a crosslinking reaction caused by applying energy such as heat, light, and energy rays to the gelatin derivative and / or using a crosslinking agent. Typically, it is caused by a reaction between functional groups (-NH2, -OH, -SH, -COOH, etc.) of the side chains of the gelatin. As shown in the examples described later, the particles containing the crosslinked gelatin derivative are more suitable for a wound covering material or the like because the adhesion strength is enhanced.

[0107] In the preferred embodiment of the present application, the particles containing the crosslinked gelatin derivative are surface-hydrophilized. More specifically, the contact angle of a water droplet after 5 seconds is less than 70°, and is preferably 50° or less.

[0108] In the present application specification, the so-called "contact angle of water droplet" or "water contact angle" means the angle of the water droplet with the particle surface when the water droplet is dropped on the particle surface, calculated by the tangent method. Specifically, 20 mg of each powder is spread flat on a 1.5 cm x 1 cm double-sided tape, 1 μl of ion exchange water is dropped, and from the time 1 second after the dropping, a photograph is taken every 0.5 seconds from the side of the water droplet, and the contact angle is calculated by the tangent method from the shape of the water droplet at the time point when the shape of the water droplet becomes stable.

[0109] The particle of the present embodiment has a property of easily swelling in the presence of moisture, and the adhesion strength to the inner wall tissue of the stomach of a pig, measured according to ASTM F-2258-05 (details of the test procedure are described in the Examples described later) before and after immersion in physiological saline for 5 minutes, is reduced to 1 / 2 or less, preferably 1 / 3 or less. Such a property is typically achieved by UV irradiation, as described in the Examples described later. In addition, such a property can prevent adhesion to other tissues, because the exposed surface of the particle rapidly decreases in adhesion strength due to the presence of moisture after the particle is adhered to the biological tissue.

[0110] In a preferred embodiment of the present application, the powder has an excellent blood coagulation ability. More specifically, the powder is mixed with pig blood to which an anticoagulant (for example, sodium citrate) is added, using a vortex, at a concentration of 10 mass%, and the storage modulus (G') of the mixture is measured 2 minutes later, and the storage modulus (G') is 30 Pa or more, preferably 200 Pa or more, more preferably 300 Pa or more, and further preferably 400 Pa or more. A powder having such a high storage modulus (G') can be considered for use as a hemostatic material or the like.

[0111] Here, the "storage modulus (G')" in the present application specification means the value of the above-mentioned mixed solution measured using a rheometer (trade name: MCR30, manufactured by ANTON PAAR GMBH) under the conditions of 5 minutes, 1 Hz, and 1% strain in the stage of preheating to 37 degrees.

[0112] <Particle>

[0113] In the present embodiment of the present application, the particle contains the crosslinked gelatin derivative alone, and can contain other components within the range where the effects of the present application are exerted. The content of the crosslinked gelatin derivative in the particle is not particularly limited, but based on the fact that a powder having more excellent effects of the present application is easily obtained, it is preferable that the crosslinked gelatin derivative be contained in an amount of 90 mass% or more, and more preferably 99 mass% or more, relative to the total mass of the particle.

[0114] The other components that can be contained as the particles are not particularly limited, and examples thereof include non-crosslinked gelatin derivatives, solvents, buffers, coloring agents, preservatives, excipients, and pharmaceutical agents (antithrombotics, antibacterial agents, and growth factors, etc.).

[0115] The sphericity of the particles is preferably 1.29 or less, more preferably 1.20 or less, and further preferably 1.15 or less, based on the fact that a more excellent adhesion strength to a biological tissue can be obtained. In the present specification, the sphericity means a value obtained by the following test method.

[0116] Test method

[0117] The powder to be measured is scattered on a scanning electron microscope stage to which a carbon tape is attached, and then the powder not adhered to the carbon tape is removed by spraying with an air spray gun. The resulting sample is observed with a scanning electron microscope, and the length of the horizontal axis and the length of the vertical axis are measured for 20 particles randomly selected from one field of view using "ImageJ (vl.51)". Next, "horizontal axis / vertical axis" is calculated for each particle, and the arithmetic mean thereof is calculated. The third decimal place of the obtained value is rounded off to the second decimal place, and the value is used as the sphericity. In the above measurement and calculation, (vertical axis) is defined to be ≤ (horizontal axis). That is, the largest particle diameter among the particle diameters of one particle measured is defined as the horizontal axis. In addition, the vertical axis is the diameter of a position rotated 90 degrees from the horizontal axis.

[0118] In addition, the standard deviation (SD) of the sphericity of the above particles in the powder is preferably 0.20 or less, and more preferably 0.15 or less, based on the fact that a more excellent adhesion strength to a biological tissue can be obtained.

[0119] In addition, the standard deviation of the sphericity of the particles in the powder is calculated from the sphericities of the above 20 particles, and the third decimal place of the obtained calculated value is rounded off to the second decimal place as the standard deviation.

[0120] The average particle diameter of the particles is usually 0.5 to 50 μm, preferably 1 to 30 μm, and more preferably 1 to 10 μm. The "average particle diameter" in the present specification is a value obtained by averaging the particle diameters (major axes) of 100 particles randomly measured by an electron microscope.

[0121] Cross-sectional area of gel layer

[0122] The cross-sectional area of the gel layer of the present powder, which is preferably measured by the specific gel layer cross-sectional area measurement test, is 0.010 mm 2The above. If the cross-sectional area of the gel layer is 0.010 mm 2 The above, and when the powder is applied to a biological tissue, a more excellent adhesive strength can be obtained.

[0123] The cross-sectional area of the gel layer is not particularly limited, but is more preferably 0.020 mm 2 The above, and further preferably 0.030 mm 2 The above, and more further preferably 0.050 mm 2 The above, and particularly preferably 0.100 mm 2 The above, and most preferably 0.120 mm 2 The above.

[0124] The upper limit of the area of the gel layer is not particularly limited, and is generally preferably 0.500 mm 2 The above.

[0125] The "gel layer cross-sectional area measurement test" in the present application specification can be performed in the following manner: 100 mg of the powder to be measured is sprayed for every 2.5 cm x 2.5 cm of the surface of the submucosal tissue of the esophagus, and a gel is formed on the tissue surface by keeping it at 37°C for 48 hours. The formed gel is fixed with neutral buffered formalin, and the fixed gel is observed with a phase contrast microscope. Generally, the width and thickness of the gel are measured from the phase contrast microscope image, and the cross-sectional area of the gel is calculated in square millimeters. This test is performed three times, and the arithmetic mean thereof is used as the area of the gel layer. For the observation of the gel layer, it is convenient to perform hematoxylin-eosin staining to obtain a stained gel. The cross-sectional area of the gel can also be calculated from the phase contrast microscope image by observing the stained gel obtained.

[0126] Further, Figure 5 The phase contrast microscope image shown is a cross-sectional image of the stained gel, and the area of the gel layer is calculated from the proportion of the stained gel in the cross-sectional image of the known area. Specifically, this is calculated by binarizing the phase contrast microscope image with "ImageJ (v1.51)".

[0127] [Method for producing the powder]

[0128] The method for producing the powder described above is not particularly limited, but is preferably produced by a method including the following steps.

[0129] • Step 1: a step of dissolving a gelatin derivative in a good solvent to obtain a gelatin solution containing the gelatin derivative and the good solvent

[0130] • Step 2: a step of adding a poor solvent to the gelatin solution to precipitate intermediate particles containing the gelatin derivative in the gelatin solution

[0131] • Step 3: a step of freeze-drying the precipitated gelatin solution to obtain an intermediate powder containing intermediate particles

[0132] • Step 4: a step of cross-linking the gelatin derivative of the intermediate particles to obtain a powder containing particles containing cross-linked gelatin derivative

[0133] • Step 5: a step of, optionally, further irradiating the powder containing particles containing cross-linked gelatin derivative with ultraviolet rays to hydrophilize the surface of the particles

[0134] Hereinafter, each of the above steps will be described in detail.

[0135] • Step 1 (dissolution step)

[0136] Step 1 is a step of dissolving the above-mentioned gelatin derivative in a good solvent to obtain a gelatin solution. In the present specification, the good solvent means a solvent in which the gelatin derivative is easily dissolved, and is not particularly limited, and examples include water, glycerol, acetic acid, and a mixture thereof, among which water is preferred. In addition, the above-mentioned good solvent can be warmed. The temperature at the time of warming is not particularly limited, but is preferably 50 to 70°C.

[0137] The method of dissolving the gelatin derivative in the good solvent is not particularly limited, and a publicly known method can be used. For example, the following methods can be used: a method of adding the good solvent at a low temperature (e.g., room temperature) to the gelatin derivative to swell the gelatin derivative, heating the obtained swollen body, and obtaining a gelatin solution (swelling dissolution method); and a method of adding the gelatin derivative to the above-mentioned good solvent which has been previously heated, and obtaining a gelatin solution (direct dissolution method).

[0138] The content of the gelatin derivative in the gelatin solution is not particularly limited, but the content (final concentration) of the gelatin derivative with respect to the total volume of the gelatin solution is preferably 0.01 to 30 mass / volume%, more preferably 1 to 25 mass / volume%, further preferably 5 to 20 mass / volume%, and particularly preferably 5 to 15 mass / volume%.

[0139] If the content of the gelatin in the gelatin solution is within the above-mentioned range, the standard deviation of the sphericity of the particles in the obtained powder is easily smaller.

[0140] • Step 2 (precipitation step)

[0141] Step 2 is a step of adding a poor solvent to the gelatin solution to precipitate intermediate particles containing the gelatin derivative in the gelatin solution.

[0142] In the present specification, the so-called poor solvent means a solvent in which the gelatin derivative is more difficult to dissolve than the good solvent used in the process 1. That is, in the present specification, the so-called good solvent and poor solvent are not defined by the absolute amount of the solubility of the gelatin derivative, but are defined relatively in the relationship between the poor solvent and good solvent.

[0143] The poor solvent is not particularly limited, and for example, an organic solvent can be exemplified, in which a water-soluble organic solvent is preferred, and an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like is more preferred.

[0144] If the poor solvent is added to the gelatin solution, the intermediate particles are precipitated in the gelatin solution. The intermediate particles are particulate matters containing the above-mentioned gelatin derivative. In the present process, the particle diameter of the precipitated intermediate particles is not particularly limited, but is preferably 0.1 to 100 μm, more preferably 1 to 50 μm, and further preferably 1 to 10 μm.

[0145] If the particle diameter is within the above-mentioned range, the intermediate particles precipitated in the gelatin solution are more difficult to settle, and when the gelatin solution containing the above-mentioned intermediate particles is frozen and further freeze-dried in the process 3 described later, the aggregation between the intermediate particles is more easily suppressed. As a result, the sphericity and the like of the particles obtained in the process 4 are easily within the intended range.

[0146] The temperature at the time of adding the poor solvent is not particularly limited, but is generally 10 to 30°C, and more preferably 15 to 25°C. In the process 1, when the gelatin derivative is dissolved by heating the solvent, it is preferable to have a process of cooling the gelatin solution between the process 1 and the process 2.

[0147] When the poor solvent is dropped, the gelatin solution is preferably stirred. The method of stirring is not particularly limited, and a publicly known method can be used. By stirring the gelatin solution while adding the poor solvent, the precipitated particles are more difficult to aggregate, and are more difficult to settle. As a result, the powder containing the particles having the desired properties can be more easily and simply obtained.

[0148] • Process 3 (drying process)

[0149] The process 3 is a process of freeze-drying the dispersion solution of the precipitated uncrosslinked gelatin particles by the above-mentioned aggregation, to obtain an intermediate powder containing the particles containing the uncrosslinked gelatin derivative.

[0150] The method of freezing the gelatin solution is not particularly limited, but from the viewpoint that the aggregation of the particles containing the uncrosslinked gelatin derivative is more difficult to occur at the time of freezing, it is preferable to freeze more rapidly. At this time, the temperature of the atmosphere at the time of freezing is not particularly limited, but is preferably -20°C or lower, and more preferably -30°C or lower.

[0151] Further, the method of freeze-drying is not particularly limited, and a known method can be used.

[0152] The intermediate powder is a powder containing intermediate particles. The intermediate powder can also contain components other than the intermediate particles. As such components, for example, the above-mentioned good solvent and poor solvent, etc. can be listed.

[0153] • Step 4 (cross-linking step)

[0154] Step 4 is a step of cross-linking the gelatin derivative of the intermediate particles to obtain a powder containing the cross-linked gelatin derivative. Through this step, the gelatin derivative of the particles irreversibly cross-links intermolecularly and / or intramolecularly. As a result, a powder containing particles containing the cross-linked gelatin derivative can be obtained.

[0155] The method of cross-linking is not particularly limited, and for example, a method of providing thermal energy to the gelatin derivative, or irradiating active light or radiation (e.g., electron rays, etc.), etc. can be listed.

[0156] Among them, from the viewpoint of more easily obtaining the cross-linked product of the gelatin derivative, and eliminating the safety aspect of impurities caused by the cross-linking agent, a method of providing thermal energy (in other words, heating) is preferred (thermal cross-linking). In this method, for example, the amino group in the gelatin derivative reacts with other reactive groups (e.g., carboxyl group and sulfhydryl group, etc.) to form a cross-linked structure.

[0157] The method of thermal cross-linking is not particularly limited, and a known method can be used. As the method of thermal cross-linking, for example, a method of placing a container containing the powder precursor in a heated atmosphere (e.g., an oven) together with the container, and maintaining it for a prescribed time can be listed.

[0158] The heating temperature at the time of thermal cross-linking is not particularly limited, and generally 80 to 200°C is preferred, and 100 to 200°C is more preferred.

[0159] The heating time at the time of thermal cross-linking is not particularly limited, and generally 0.1 to 20 hours is preferred, 0.5 to 10 hours is more preferred, 1 to 6 hours is further preferred, 2 to 5 hours is more further preferred, and 2.5 to 4 hours is particularly preferred.

[0160] If the heating time is within the above numerical range, the obtained powder easily obtains more excellent adhesiveness.

[0161] Further, the cross-linked product of the gelatin derivative can also be obtained by reacting the gelatin derivative and a cross-linking agent. The cross-linking agent is not particularly limited, and for example, genipin, polybasic acids activated by N-hydroxy succinimide, N-hydroxy thiosuccinimide, aldehyde compounds, acid anhydrides, dithio carbonates, and diisothiocyanates, etc. can be listed.

[0162] As the crosslinking agent, for example, the compound described in paragraphs 0021 to 0024 of International Publication No. 2018 / 079538 can also be used, the contents of which are incorporated herein.

[0163] • Step 5 (hydrophilization of the surface of the particles)

[0164] Step 5 is a step of further irradiating the particles containing the crosslinked gelatin derivative with ultraviolet rays to hydrophilize the surface of the particles. By the surface treatment by the irradiation with ultraviolet rays, the contact angle of the particles with water droplets becomes small, and the particles are more easily swollen in the presence of water. On the other hand, if the particles are brought into contact with tissue in a dry state, the particles after the irradiation with ultraviolet rays still have excellent adhesiveness.

[0165] The conditions for the irradiation with ultraviolet rays are not particularly limited, and the irradiation is usually performed for 1 to 10 hours, more preferably for 2 to 8 hours, and further preferably for 3 to 6 hours. The ultraviolet ray intensity is preferably 0.05 to 50 mW / cm 2 , more preferably 0.5 to 10 mW / cm 2 . In addition, the cumulative light quantity of the ultraviolet rays is preferably 1 to 100 J / cm 2 , more preferably 5 to 100 J / cm 2 .

[0166] The ultraviolet irradiation device is not particularly limited, and a commercially available ultraviolet irradiation device can also be used.

[0167] Further, during the irradiation, it is preferable to mix the particles at regular time intervals (for example, every 30 minutes) so that the particles can be uniformly irradiated with ultraviolet rays. In addition, after the irradiation with ultraviolet rays, since the surface of the particles is hydrophilic, it is preferable to store the particles in a dry atmosphere with a desiccant or the like.

[0168] <Use of the powder>

[0169] The powder of the embodiment of the present application can be used as a wound covering material. The wound covering material is not particularly limited, and can be applied to incisions in surgical operations in respiratory surgery (particularly, the wound part after lung cancer surgery), digestive surgery, cardiovascular surgery, oral surgery, and digestive internal medicine, and the like, and skin wounds, and the like.

[0170] In the case of ESD (Endoscopic Submucosal Dissection), the powder can be applied in a dry state with the aid of a hemostatic clamp, a stent, an air bag, an endoscope, and the like. The amount of application can be appropriately adjusted depending on the application site and the wound.

[0171] In addition, the powder of the embodiment of the present application has the advantage that it is rapidly decomposed and absorbed after exerting the wound dressing effect as the wound heals.

[0172] In addition, the powder can also be used as an anti-adhesion material. The so-called (postoperative) adhesion is a phenomenon that occurs in the process of repairing a biological tissue damaged by surgery or the like. The anti-adhesion material containing the powder adheres to the surface of the tissue at the application site to form a gelatinous coating film, which becomes a physical barrier, thereby exerting an anti-adhesion effect, by spraying it on the affected part. In addition, the gelatinous coating film is rapidly decomposed and absorbed after exerting the anti-adhesion effect.

[0173] In addition, the powder of the embodiment of the present application can also be used to form a member having both the wound dressing and anti-adhesion functions. For example, if it is applied to a damaged part after surgery, a film having both the wound dressing and anti-adhesion effects can be formed.

[0174] Compared with the conventional case where a wound covering material and an anti-adhesion material are separately applied, both can be achieved more simply.

[0175] In addition, the powder of the embodiment of the present application has excellent blood coagulation ability and can be used as a hemostatic material. In addition to the functions of wound dressing and anti-adhesion, it can also be used to form a member having blood coagulation ability.

[0176] Example

[0177] The present application will be described in more detail based on examples. The materials, amounts used, proportions, processing contents, processing steps, and the like shown in the following examples can be appropriately changed without departing from the gist of the present application. Therefore, the scope of the present application should not be interpreted limitatively by the examples shown below.

[0178] [Preparation of gelatin derivative (1)]

[0179] A gelatin derivative "76.8C6 ApGltn" was prepared according to the following procedure.

[0180] An alkali-treated gelatin (Mw = 31000, "beMatrix fish gelatin TA (trade name)", manufactured by Shintoku Gelatin Co., Ltd., amount of amino groups measured by the method described below: 324 μmol / g, hereinafter also referred to as "OrgApGltn") 10 g derived from mackerel was added to a mixture of ultrapure water-ethanol 50 mL in a tomato flask immersed in an oil bath at 50°C, and dissolved while stirring for about 2 hours to prepare a 20 mass% aqueous solution.

[0181] Next, 1.5 equivalents of methylpyridine borane (manufactured by Pure Chemical Industries Co., Ltd.) of hexanal was added to the obtained aqueous solution, and 2 equivalents of hexanal (manufactured by Tokyo Chemical Industry Co., Ltd.) with respect to the amino group of the gelatin (1 mole of hexanal per 1 mole of the amino group of the gelatin) was added thereto.

[0182] Next, a loop cooler was attached to the flask, and the reaction was performed at 50°C for 17 hours while stirring.

[0183] Next, the reaction solution was dropped into 1 L of ethanol and reprecipitated. After stirring for 1 hour, the mixture was left to stand in a freezer for 1 hour, and then filtered with a glass filter. The residue was reprecipitated in 1 L of ethanol in a beaker, stirred for 1 hour, and left to stand in a freezer for 1 hour. After being filtered again with a glass filter, the residue was dried with a reduced-pressure drier for one night or more, and a gelatin derivative into which a hexyl group was introduced was obtained at a yield of 91%.

[0184] The introduction rate of the hexyl group in the obtained gelatin derivative was determined by the following method.

[0185] First, 0.1 mass / volume% of the raw gelatin and the gelatin derivative were dissolved in a water-DMSO (dimethyl sulfoxide) mixed solvent (volume ratio 1:1, hereinafter the same), and 100 μL of each solution was dispensed into a 48-well plate.

[0186] To this, 100 μL of 0.1 volume / volume% of triethylamine (TEA, manufactured by Nacalai Tesque) dissolved in the water-DMSO mixed solvent was added, and stirred for 1 minute at 400 rpm with a microplate shaker. Then, 100 μL of 0.1 mass / volume% of trinitrobenzenesulfonic acid (TNBS, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in the water-DMSO mixed solvent was added, and stirred for 1 minute at 400 rpm with a microplate shaker. After being left to stand in a thermostat at 37°C for 2 hours in the dark with an aluminum foil, the mixture was taken out of the thermostat, and the reaction was stopped by adding 50 μL of 6N HCl, and stirred for 1 minute at 400 rpm with a microplate shaker.

[0187] Next, after being left to stand in the dark for 10 minutes, the absorbance (Abs) at 340 nm was measured with an absorbance meter (manufactured by TECAN, Spark 10M-NMST). From the measured absorbance, the absorbance of a blank sample which was different only in that it did not contain gelatin was subtracted, and the introduction rate of the hexyl group of the gelatin derivative was determined to be 76.8 mole% according to the following formula.

[0188] Introduction rate (mole%) = [Abs (raw gelatin) - Abs (gelatin derivative)] / [Abs (raw gelatin)] x 100

[0189] The gelatin derivative obtained by the above method is "76.8C6". Hereinafter, in the same manner as described above, using hexanal, or using octanal, heptanal, decanal and dodecanal instead of hexanal, the charge ratio was adjusted in a manner that the introduction rate of each gelatin derivative was adjusted, and each gelatin derivative was obtained. Also, in the following examples, each gelatin derivative was named by "(introduction rate of hydrophobic group) (number of carbon atoms of aldehyde used for derivatization)". For example, as "10.6C6", it means that the introduction rate of hexyl group was 10.6 mol% using hexanal.

[0190] [Preparation of powder (1)]

[0191] In a graduated vial (50 mL), 0.5 g of each gelatin derivative obtained by the above method was measured, and 7.5 mL of MilliQ (registered trademark) water was added.

[0192] Next, after dissolving in a water bath at 50°C, it was diluted to 10 mL with MilliQ water.

[0193] At this time, the content of the gelatin derivative in the gelatin solution (final concentration) was 5 mass / volume%, and the type of gelatin was appropriately changed depending on the experimental conditions.

[0194] Next, while stirring with a stirrer at room temperature, ethanol (EtOH) was added dropwise until the gelatin solution became white, and a gelatin solution containing intermediate particles was obtained.

[0195] Next, the gelatin solution was left to stand in a freezer (-30°C) for 2 hours or more. Next, the mouth of the vial taken out of the freezer was covered with Kimwipes (registered trademark), and freeze-drying was performed to obtain an intermediate powder containing intermediate particles. The obtained intermediate powder was heated at 150°C for 6 hours to crosslink it, and each powder was obtained. Hereinafter, the powder preparation method described in this paragraph will be referred to simply as "Method A-1".

[0196] [Preparation of powder (2)]

[0197] Each gelatin derivative obtained by the above method was dissolved in water heated in a water bath at 50°C so that the gelatin concentration was 5 mass / volume%, and a gelatin solution was obtained. Next, the gelatin solution was allowed to flow into a tetrafluoroethylene container, and was placed on a heater at 40°C to dry the solvent. Next, the obtained dried gelatin solution was pulverized with a pulverizer (Wonder Crusher). Also, the pulverization conditions were 1 cycle for 3 times (20 seconds at speed 5, 1 minute at speed 10).

[0198] The pulverized intermediate powder was crosslinked in the same manner as described above to obtain a powder. Hereinafter, the powder preparation method described in this paragraph will be referred to simply as "Method B".

[0199] [Preparation of powder (3)]

[0200] Each of the gelatin derivatives obtained by the above method was dissolved in ultrapure water at 50°C to obtain a gelatin solution with a gelatin concentration of 6 mass%. Next, the same volume of ethanol was added to the above aqueous solution to obtain a diluted solution with a gelatin concentration of 3 mass% by dilution. Next, the temperature of the above diluted solution was maintained at 50°C, and the solution was set in a spray drying device (mini spray dryer, B-290, manufactured by BUCHI), and adjusted at 180°C at a nitrogen flow rate of 440 L / h and a diluted solution flow rate of 410 mL / h to obtain an intermediate powder containing intermediate particles. The obtained intermediate powder was heat-crosslinked as above to obtain a powder. Hereinafter, the powder preparation method described in this paragraph will be referred to as "Method C".

[0201] Example 1 was a powder prepared by "Method A-1" using the gelatin derivative "76.8C6 ApGltn". In addition, Example 2 was a powder prepared by "Method B" using the gelatin derivative "76.8C6 ApGltn".

[0202] In addition, Example 3 was a powder prepared by "Method A-1" using "Org ApGltn". In addition, the crosslinking time was 6 hours.

[0203] As the raw gelatin, in addition to the alkali-treated gelatin (Mw = 100,000, beMatrix (trade name), manufactured by Shintomi Gelatin Co., Ltd.) derived from pigskin, the gelatin derivative "75C8 pig gelatin" prepared by the method described in "Preparation of gelatin derivative" was used, and a powder prepared by "Method C" was used as Example 4.

[0204] Each of the obtained powders was observed by a scanning electron microscope by the following method, and the sphericity and standard deviation were calculated from the obtained image. The scanning electron microscope image is shown in Figures 1 to 4 The calculation results of the sphericity and standard deviation are shown in Table 1. In addition, Figures 1 to 4 Examples 1 to 4, respectively.

[0205] [Observation by scanning electron microscope (1)]

[0206] Each of the powders of the examples was scattered on a scanning electron microscope stage to which a carbon tape was attached, and then the powder not adhered to the carbon tape was removed by spraying from an air gun, and the resulting sample was observed by a scanning electron microscope.

[0207] [Calculation method of sphericity and standard deviation (1)]

[0208] • Sphericity

[0209] For 20 particles randomly extracted from 1 visual field, the lengths of the horizontal axis and the vertical axis (where the vertical axis < the horizontal axis, the horizontal axis being the largest particle diameter, and the vertical axis being the diameter of a position rotated 90 degrees from the horizontal axis) were measured using "ImageJ (v1.51)".

[0210] Next, "horizontal axis / vertical axis" was calculated for each particle, and the arithmetic mean thereof was calculated. The value obtained was rounded off to the second decimal place.

[0211] • Standard deviation of sphericity

[0212] The standard deviation of the sphericity of the particles in the powder was calculated from the sphericity of the above 20 particles, and the calculated value obtained was rounded off to the second decimal place.

[0213] [Table 1]

[0214] Gelatin derivative Modulation method Sphericity Standard deviation of sphericity Example 1 76.8C6 ApGltn (Mw: 31,000) Method A-1 1.08 0.06 Example 2 76.8C6 ApGlto (Mw: 31,000) Method B 1.49 0.32 Example 3-1 Org ApGltn (Mw: 31,000) Method A-1 1.07 0.06 Example 4 75C8 pig gelatin Method C 1.30 0.28

[0215] As is clear from the results shown in Table 1, by adjusting the powder by Method A-1, a powder having a desired sphericity and standard deviation can be obtained.

[0216] [Measurement Test of Adhesion Strength to Porcine Gastric Mucosa (1)]

[0217] The adhesion strength of the powder to porcine gastric mucosa was measured by the following method. The test method was performed in accordance with the standard of the American Society for Testing Materials (ASTM F-2258-05). The porcine stomach was opened, and the mucous membrane layer was removed. At this time, physiological saline was injected into the submucosal tissue, and the raised portions were removed, so that only the mucous membrane layer was removed in a state in which the submucosal tissue remained to some extent. The resulting tissue was cut into pieces of 2.5 cm square, and was fixed to the upper and lower clamps of the test device using instant adhesive. The temperature of the porcine gastric mucosa during measurement was maintained at 37°C using a heating plate.

[0218] Next, in order to remove excess moisture from the surface of the above tissue, an industrial paper cloth (trade name "Kim Wipes") was pressed against the tissue to remove the moisture. Next, the above tissue was compressed at 50 N for 3 minutes, and the exuded moisture was again removed.

[0219] Next, 100 mg of the powder was applied to the tissue. After pressing the upper clamp at 80 kPa for 3 minutes, the adhesion strength (kPa) was measured by pulling upward.

[0220] Next, the adhesion strength of the powder of Example 3-1 was taken as 1.0, and the ratio of the adhesion strengths of the powders of Examples 1 and 2 was calculated. The results are shown in Table 2.

[0221] [Table 2]

[0222]

[0223] In Table 2, Examples 1 to 3-1 indicate the same powders as Examples 1 to 3-1 in Table 1, respectively. As described above, the powder of Example 1 has a more excellent adhesion strength to a tissue than the powders of Examples 2 and 3-1.

[0224] Further, the same test as described above was performed using porcine gelatin (Mw: about 40,000, Lot No. 180425, manufactured by Nitta Gelatin Co., Ltd., hereinafter referred to as "Org porcine gelatin").

[0225] • Example A: Org porcine gelatin, Method A-1

[0226] • Example B: 78.7C6 porcine gelatin, Method A-1

[0227] • Example C: 78.7C6 porcine gelatin, Method B

[0228] When the adhesion strength ratio was calculated as described above, it was found that, when Example A was taken as 1.0, Example C was 0.7 and Example B was 1.1. As described above, the same result was obtained regardless of the source of the raw material gelatin.

[0229] [Preparation of gelatin derivative (2)]

[0230] Octanal (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed in the gelatin solution in an amount corresponding to 2 equivalents relative to the amino group of the gelatin, and otherwise, the gelatin derivative was prepared in the same manner as described above in [Preparation of gelatin derivative (1)]. Further, in the same manner as described above in [Preparation of gelatin derivative (1)], the introduction rate of decyl group was measured, and it was confirmed that the introduction rate of octyl group was 57.7. Hereinafter, the obtained gelatin derivative will be referred to as gelatin derivative "57.7C8 ApGltn".

[0231] [Preparation of powder (4)]

[0232] The powder was prepared in the same manner as "Method A-1" using the gelatin derivative obtained in [Preparation of gelatin derivative (2)] described above. The powder obtained in this manner is Example 5.

[0233] [Preparation of gelatin derivative (3)]

[0234] Decanal (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed in a gelatin solution in an amount corresponding to 2 equivalents relative to the amino groups of the gelatin, and otherwise, the gelatin derivative was prepared in the same manner as in the above [Preparation of gelatin derivative (1)]. Also, in the same manner as in the above [Preparation of gelatin derivative (1)], the introduction rate of decyl group was measured, and it was confirmed that the introduction rate of decyl group was 46.1. Hereinafter, the obtained gelatin derivative will be referred to as "gelatin derivative 46.1C10 ApGltn".

[0235] [Preparation of powder (5)]

[0236] The gelatin derivative obtained in the above [Preparation of gelatin derivative (3)] was used, and the powder was prepared in the same manner as in "Method A-l", or heat crosslinking was performed for 1 hour or 3 hours, and otherwise, the powder was prepared in the same manner as in "Method A-l". These methods in which the heat crosslinking time was changed are referred to as "Method A-2" and "Method A-4", and the obtained powders are Example 6-1, Example 6-2 and Example 6-3, respectively.

[0237] [Preparation of gelatin derivative (4)]

[0238] Dodecanal (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed in a gelatin solution in an amount corresponding to 2 equivalents relative to the amino groups of the gelatin, and otherwise, the gelatin derivative was prepared in the same manner as in the above [Preparation of gelatin derivative (1)]. Also, in the same manner as in the above [Preparation of gelatin derivative (1)], the introduction rate of dodecyl group was measured, and it was confirmed that the introduction rate of dodecyl group was 48.6. Hereinafter, the obtained gelatin derivative will be referred to as "gelatin derivative 48.6C12 ApGltn".

[0239] [Preparation of powder (6)]

[0240] The gelatin derivative obtained in the above [Preparation of gelatin derivative (4)] was used, and the powder was prepared in the same manner as in "Method A-l". The powder obtained in this manner is Example 7.

[0241] [Measurement test of adhesion strength to inner wall tissue of pig stomach (2)]

[0242] The adhesion strength of each of the powders of Examples 3-1 and 5 to 7 to the inner wall tissue of pig stomach was measured in accordance with the standard of American Society for Testing Materials (ASTM F-2258-05). Details of the test method are as described in [Measurement test of adhesion strength to inner wall tissue of pig stomach (1)].

[0243] [Measurement test of cross-sectional area of gel layer]

[0244] The cross-sectional area of the gel layer of the powder is measured by the following method. 100 mg of the powder to be measured is sprayed per 2.5 cm x 2.5 cm of the surface of the esophageal submucosal tissue, and a gel is formed on the surface of the tissue by keeping it at 37°C for 48 hours. The gel is fixed by neutral buffered formalin to obtain a fixed gel. The fixed gel is observed with a phase contrast microscope, and the width and thickness of the fixed gel are measured from the phase contrast microscope image to calculate the cross-sectional area in square millimeters. The test is performed three times, and the arithmetic mean is used as the cross-sectional area of the gel layer.

[0245] The results are shown in Table 3.

[0246] In the preferred embodiment, the cross-sectional area of the gel layer is measured in a state in which the gel is easily recognized using a pigment such as hematoxylin-eosin staining. As an example, the cross-sectional area of the gel layer can be measured by the following method. 100 mg of the powder to be measured is sprayed per 2.5 cm x 2.5 cm of the surface of the esophageal submucosal tissue, and a gel is formed on the surface of the tissue by keeping it at 37°C for 48 hours. The gel is fixed by neutral buffered formalin to obtain a fixed gel, and the fixed gel is subjected to hematoxylin-eosin staining to obtain a stained gel. The stained gel is observed with a phase contrast microscope (cross-sectional image), and the phase contrast microscope image is binarized by "ImageJ (v1.51)" to calculate the cross-sectional area of the gel layer in square millimeters. The test is performed three times, and the arithmetic mean is used as the cross-sectional area of the gel layer.

[0247] Also, examples of the phase contrast microscope image are shown in Figure 5 . Figure 5 The scale bar in is 1 mm in the upper panel and 100 μm in the lower panel, which represents each partial enlarged view.

[0248] In Figure 5 , 1 h, 3 h, and 6 h correspond to Example 6-2 (1 h), Example 6-3 (3 h), and Example 6-1 (6 h) in Table 3. The upper panel represents a cross-sectional image, and the lower panel represents a partial enlarged view. From the results in Figure 5 , it is found that Example 6-3 forms a more dense gel and has a larger cross-sectional area of the gel layer than Examples 6-2 and 6-1.

[0249] A larger cross-sectional area of the gel layer means that the gel layer formed from the powder is more likely to remain in a wet environment (in water) and, when the powder is applied to a wound, it is presumed that the gel layer (film) always covers the wound, thereby enabling a more sustained adhesive strength. Thus, it also has the more excellent effect of providing a foothold for the proliferation and transplantation of cells for wound healing.

[0250] From the results in Figure 5 , it is found that the area of the gel layer can be controlled by controlling the cross-linking conditions.

[0251] [Table 3]

[0252]

[0253] Further, the powders of Example 3-1, Example 1, Example 5, Example 6-1 to Example 6-3 and Example 7 were obtained by cross-linking the intermediate powders under the conditions of 150°C for 1 to 6 hours, and the sphericity of the powders obtained was 1.45 or less, and the standard deviation was 0.25 or less.

[0254] According to the results shown in Table 3, the powders of Example 1, Example 5, Example 6-1 to Example 6-3 and Example 7 all had excellent adhesion strength compared with the powder of Example 3-1.

[0255] wherein R 2 is a hydrogen atom, and the number of carbon atoms of the alkyl group of R 1 is 7 or more, the powder of Example 5 had more excellent adhesion strength compared with the powder of Example 1.

[0256] Further, where R 2 is a hydrogen atom, and the number of carbon atoms of the alkyl group of R 1 is 9 or more, the powder of Example 6-1 had more excellent adhesion strength compared with the powder of Example 5.

[0257] Further, where R 2 is a hydrogen atom, and the number of carbon atoms of the alkyl group of R 1 is 11 or less, the powder of Example 6-1 had more excellent adhesion strength compared with the powder of Example 7.

[0258] Further, where the area of the gel layer is 0.010 mm 2 or more, the powders of Example 5, Example 6-1 to Example 6-3 and Example 7 had more excellent adhesion strength compared with the powder of Example 1 in which the area of the gel layer is less than 0.010 mm 2 .

[0259] Further, according to the comparison of Example 6-1 to Example 6-3, it was found that the area of the gel layer can be controlled by the cross-linking time, and the area of the gel layer is preferably 0.030 mm 2 or more, more preferably 0.110 mm 2 or more, and particularly preferably 0.120 mm 2 or more.

[0260] [Preparation of gelatin derivatives (5)]

[0261] The decanal (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed in the gelatin solution in an amount equivalent to 2 equivalents relative to the amino groups of the gelatin, and otherwise, the gelatin derivative was prepared in the same manner as described above in [Preparation of gelatin derivative (1)]. Also, the introduction rate of decyl group was measured in the same manner as described above in [Preparation of gelatin derivative (1)], and the introduction rate of decyl group was confirmed to be 36.4. Hereinafter, the obtained gelatin derivative will be referred to as "gelatin derivative "36.4C10 ApGltn".

[0262] [Preparation of powder (7)]

[0263] The powder was prepared in the same manner as "Method A-4" (heat crosslinking for 3 hours) using the gelatin derivative obtained in the above [Preparation of gelatin derivative (5)]. The powder obtained in this manner was used as Example 8.

[0264] Also, the powder prepared by "Method A-4" using "Org ApGltn" was used as Example 3-2.

[0265] [Surface treatment by UV irradiation (1)]

[0266] The powders of Example 8 and 3-2 obtained in [Preparation of powder (7)] were placed in a glass dish, and left to stand in a UV irradiation chamber (manufactured by Material and Research Institute) while mixing the particles every 30 minutes, and the surface treatment of the particles was performed by irradiating ultraviolet rays (light source: UV lamp MIYATA ELEVAM Inc.) of 185 nm and 254 nm at different times of 1 hour, 2 hours, and 4 hours at room temperature. The obtained powders were used as Example 8(U1), Example 8(U2), Example 8(U4), Example 3-2(U1), Example 3-2(U2), and Example 3-2(U4), respectively. Also, as a control, the powders without UV irradiation were used as Example 8(U0) and Example 3-2(U0), respectively.

[0267] [Measurement of contact angle with water (1)]

[0268] The water contact angle of each of the powders of Example 8(U1), Example 8(U2), Example 8(U4), Example 3-2(U1), Example 3-2(U2), and Example 3-2(U4) was measured by the water drop method, and the effect of the surface treatment was evaluated.

[0269] Each of the powders 20 mg was placed on a double-sided tape of 1.5 cm x 1 cm in a manner so as to be flat, and 1 μl of ion-exchange water was dropped. From the time of 1 second after the dropping, 10 photographs of the shape of the water drop were taken every 0.5 seconds from the side of the water drop, and the contact angle was measured based on the shape of the water drop taken at the time of 5 seconds after the dropping at which the shape of the water drop reached a certain state, and the average value (n = 10) was obtained.

[0270] Figure 6is a graph showing the image and contact angle of a water droplet at 5 seconds after the droplet was dropped. As shown in Figure 6

[0271] [Measurement Test of Adhesion Strength to Porcine Gastric Inner Wall Tissue (3)]

[0272] The adhesion strength of each powder of Example 8 (U1), Example 8 (U2), Example 8 (U4), Example 3-2 (U1), Example 3-2 (U2), and Example 3-2 (U4) to porcine gastric inner wall tissue was measured in accordance with the standard of the American Society for Testing Materials (ASTM F-2258-05). Details of the test method are as described in [Measurement Test of Adhesion Strength to Porcine Gastric Inner Wall Tissue (1)]. Figure 7 The test results are shown in Table 2.

[0273] The powders of Example 8 (U1), Example 8 (U2), and Example 8 (U4), and the powders of Example 3-2 (U1), Example 3-2 (U2), and Example 3-2 (U4) were subjected to surface treatment by UV irradiation, and the adhesion strength was not affected. The powders of the crosslinked gelatin derivatives of Example 8 (U1), Example 8 (U2), and Example 8 (U4) showed about 4 times the adhesion strength as compared to the powders of the crosslinked gelatin of Example 3-2 (U1), Example 3-2 (U2), and Example 3-2 (U4).

[0274] [Observation by Scanning Electron Microscope (2)]

[0275] The powders of Example 8 (U0) and Example 8 (U4), and the powders of Example 3-2 (U0) and Example 3-2 (U4) were observed by scanning electron microscope. In addition, as a comparative object, the intermediate powders of 36.4C10 ApGltn and Org ApGltn before thermal crosslinking in the process of "Method A-4" were also observed by scanning electron microscope. The preparation of the sample for observation by microscope was as described in <Observation by Scanning Electron Microscope (1)>.

[0276] Figure 8 The microscope images of each powder are shown in Table 2. As understood from each image, thermal crosslinking and UV irradiation had some influence on the shape and size of the particles.

[0277] [Agglomeration of Particles in Physiological Saline]

[0278] ​The powders from Examples 8(U0) and 8(U4), and 10 mg each of the powders from Examples 3-2(U0) and 3-2(U4) were added to 2 ml test tubes, along with 200 μl of physiological saline at 30°C. After vortex stirring, each test tube was placed in a constant temperature bath at 37°C. The powders in the physiological saline were removed from the samples immediately after stirring, 30 minutes after stirring, 1 hour after stirring, and 2 hours after stirring, and observed using a scanning electron microscope. Figure 9 The images show microscopic images of each powder at various times. As can be seen from the images, the 36.4C10 ApGltn particles fuse to form a film in an aqueous environment, regardless of whether they are exposed to UV radiation.

[0279] As a reference, the same test was performed on a local hemostatic material composed of microporous starch spheres (trade name: Bard Arista AH, Medicon Co., Ltd.). The powder in the saline was taken out from the sample immediately after stirring, 30 minutes after stirring, 1 hour, 2 hours, 4 hours and 24 hours after stirring, and observed with a scanning electron microscope. Figure 10 The images show microscopic images of the powder at various times. As can be seen from the images, Arista AH remains spherical even in an aqueous environment, with particles that do not fuse together and do not form a film.

[0280] [Measurement of adhesion strength with the lining of the pig stomach (4)]

[0281] The adhesion strength between the powders treated with physiological saline and the lining of the pig stomach was measured in accordance with the American Society for Testing and Materials (ASTM F-2258-05) standard.

[0282] The test method involved applying 100 mg of powder to the tissue, immersing it in 50 ml of physiological saline for 5 minutes, and then fixing it to the upper and lower clamps of the test device with adhesive. The upper clamp was then pressed with 50 N for 3 minutes, and the adhesion strength was measured by pulling it upwards. Other aspects were as described in [Test on the Measurement of Adhesion Strength to the Inner Wall of Pig Stomach Tissue (1)]. The test results showed... Figure 11 middle.

[0283] like Figure 11 As shown, the adhesive strength of the powder in Example 8 (U4), which was a cross-linked gelatin derivative powder that underwent further UV irradiation, and the powder in Example 3-2 (U4), which was a cross-linked gelatin powder (without hydrophobic groups introduced), both decreased after immersion in physiological saline. In particular, the adhesive strength of the powder in Example 8 (U4) decreased to 1 / 4 of its original value compared to the powder without immersion in physiological saline, reaching the same level as the powder in Example 3-2 (U4). This characteristic suggests that when the powder is bonded to biological tissues, the adhesion of the exposed surface of the powder to other tissues will be reduced.

[0284] [Measurement of contact angle with water (2)]

[0285] The change in the contact angle with water over time was measured for the particles of Example 8 (UO) and Example 8 (U4), and for each of the powders of Example 3-2 (UO) and Example 3-2 (U4).

[0286] Each of the powders was stored in a desiccator, and the contact angle with water was measured at each of the times immediately after UV irradiation, 24 hours later, and 48 hours later. The test method was as described in [Measurement of contact angle with water (1)].

[0287] Figure 12 The image of the water droplet and the contact angle 5 seconds after the droplet was dropped are shown in FIG. 8. As shown in FIG. 8, the surface treatment by UV irradiation reduced the contact angle for both the powder of Example 8 and the powder of Example 3-2, and the contact angle was greatly reduced for the powder of Example 8. On the other hand, the contact angle was not affected by the time of standing after UV irradiation. Figure 12

[0288] [Preparation of gelatin derivative (6)]

[0289] Capraldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed with the gelatin solution in an amount corresponding to 2 equivalents relative to the amino groups of the gelatin, and otherwise the gelatin derivative was prepared in the same manner as described in [Preparation of gelatin derivative (1)] above, to obtain the gelatin derivative at a yield of 90%. Also, the introduction rate of the capryl group was measured in the same manner as described in [Preparation of gelatin derivative (1)] above, and the introduction rate of the capryl group was confirmed to be 44.2 mol%. Hereinafter, the obtained gelatin derivative will be referred to as "gelatin derivative 44.2C10ApGltn".

[0290] [Preparation of powder (8)]

[0291] The gelatin derivative obtained in [Preparation of gelatin derivative (6)] above was subjected to heat crosslinking for 1 hour, 2 hours, or 3 hours, and otherwise the powder was prepared in the same manner as "Method A-l". This method is referred to as "Method A-2", "Method A-3", and "Method A-4", and the powders obtained by this method are Example 9, Example 10, and Example 11.

[0292] [Surface treatment by UV irradiation (2)]

[0293] ​Each of the powders of Example 9, Example 10 and Example 11 obtained by [Modulation of powder (8)] was put in a glass dish, left in a UV irradiation box (manufactured by the National Institute for Materials Science), the particles were mixed every 30 minutes, and irradiation of ultraviolet rays of 185 nm and 254 nm (line source: UV lamp, manufactured by MIYATA ELEVAM Inc.) was performed for 4 hours at ordinary temperature to perform surface treatment of the particles. Each of the powders subjected to UV irradiation was referred to as Example 9(UV4), Example 10(UV4) and Example 11(UV4), and each of the powders not subjected to UV irradiation was referred to as Example 9(UV0), Example 10(UV0) and Example 11(UV0).

[0294] [Measurement test of adhesion strength to inner wall tissue of pig stomach (5)]

[0295] The adhesion strength of each of the powders of Example 9(UV4), Example 10(UV4) and Example 11(UV4), and Example 9(UV0), Example 10(UV0) and Example 11(UV0) to the inner wall tissue of pig stomach was measured in accordance with the standard of American Society for Testing Materials (ASTM F-2258-05). Details of the test method are as described in [Measurement test of adhesion strength to inner wall tissue of pig stomach (1)]. Figure 13 The test results are shown in Table 2.

[0296] Regardless of whether the powder of the crosslinked gelatin derivative subjected to UV irradiation or the powder of the crosslinked gelatin not subjected to UV irradiation, a tendency that the adhesion strength becomes greater as the heat crosslinking time becomes longer was confirmed. This tendency was more remarkable in the powder of the crosslinked gelatin derivative not subjected to the surface treatment of UV irradiation.

[0297] [Measurement of contact angle with water (3)]

[0298] The contact angle with water was measured in the water drop method for each of the powders of Example 9(UV4), Example 10(UV4) and Example 11(UV4), and Example 9(UV0), Example 10(UV0) and Example 11(UV0). The test method is as described in [Measurement of contact angle with water (1)]. Figure 14 The image of the water drop 5 seconds after the drop of each of the powders and the water contact angle are shown. As shown in Table 3, the powders of Example 9(UV4), Example 10(UV4) and Example 11(UV4) subjected to the surface treatment of UV irradiation had a smaller water contact angle and a greater wettability of the particle surface than the powders of Example 9(UV0), Example 10(UV0) and Example 11(UV0) not subjected to the same treatment. Figure 14

[0299] [Evaluation of blood coagulation ability]

[0300] ​For each powder of Example 9 (UV4), Example 10 (UV4), and Example 11 (UV4), and Example 9 (UV0), Example 10 (UV0), and Example 11 (UV0), the blood coagulation ability was evaluated.

[0301] 500 μl of pig blood to which Na citrate was added was dropped onto a stage of a rheometer (trade name: MCR30, manufactured by ANTON PAAR GMBH) preheated to 37 degrees, and 50 mg of each powder (particle concentration 10 w / v%) was added to the blood to be mixed with a doctor blade. After 2 minutes and 30 seconds, measurement of the rheometer was started under conditions of 5 minutes, 1 hertz, and 1% strain to obtain the storage modulus (G').

[0302] The test results are shown in Table 1. Figure 15 The storage modulus (G') of the crosslinked gelatin derivative subjected to the surface treatment by UV irradiation or the crosslinked gelatin derivative not subjected to the surface treatment increased as the heat crosslinking time became longer. In particular, the storage modulus (G') of the crosslinked gelatin derivative subjected to the surface treatment by UV irradiation significantly increased when the heat crosslinking time was 3 hours.

Claims

1. A method for producing a powder, wherein, comprising the following steps: a step of dissolving a gelatin derivative having a structure represented by the following formula (1) in a good solvent at 50°C to 70°C to obtain a gelatin solution containing the gelatin derivative and the good solvent, wherein the content of the gelatin derivative is 0.01 to 30 mass / volume% with respect to the total volume of the gelatin solution: GltnNH-L-CHR 1 R 2 … (1) In formula (1), Gltn represents a residue of gelatin, L represents -C(O)-, R 1 represents a hydrocarbon group having 6 to 12 carbon atoms, R 2 represents a hydrogen atom; a step of adding a poor solvent to the gelatin solution at 10°C to 30°C to cause an intermediate particle containing the gelatin derivative to precipitate in the gelatin solution; a step of freeze-drying the gelatin solution after the precipitation to obtain an intermediate powder containing the intermediate particle; a step of heating the intermediate powder at 100°C to 200°C for 2.5 to 5 hours to crosslink the gelatin derivative of the intermediate particle, thereby obtaining a powder containing a particle containing the crosslinked gelatin derivative, the average value of the sphericity of the particle containing the crosslinked gelatin derivative is 1.29 or less, and the standard deviation of the sphericity of the particle is 0.20 or less.

2. The manufacturing method according to claim 1, wherein, ultraviolet rays are also irradiated to the powder containing the particle containing the crosslinked gelatin derivative to hydrophilize the surface of the particle.

3. The manufacturing method according to claim 2, wherein, ultraviolet rays are irradiated to the powder for 3 hours to 6 hours.

4. A powder obtained by the powder production method according to any one of claims 1 to 3, comprising particles containing the crosslinked gelatin derivative, wherein the gelatin derivative has a structure represented by the following formula (1): GltnNH-L-CHR 1 R 2 … (1) In formula (1), Gltn represents a residue of gelatin, L represents -C(O)-, R 1 represents a hydrocarbon group having 6 to 12 carbon atoms, R 2 represents a hydrogen atom, the average value of the sphericity of the particle containing the crosslinked gelatin derivative is 1.29 or less, and the standard deviation of the sphericity of the particle is 0.20 or less.

5. The powder according to claim 4, wherein the water contact angle after 5 seconds of dripping is less than 70°, or the adhesion strength to the inner wall tissue of a pig stomach measured according to ASTM F-2258-05 after immersion in physiological saline for 5 minutes is reduced to 1 / 2 or less compared to before the immersion.

6. The powder according to claim 4 or 5, wherein the gelatin is an alkali-treated gelatin.

7. The powder according to claim 4 or 5, wherein the gelatin is a low-endotoxin-treated gelatin.

8. The powder according to claim 4 or 5, wherein, the gelatin is derived from a cold-water fish.

9. The powder according to claim 4 or 5, wherein, The cross-sectional area of the gel layer was 0.010 mm2from the following gel layer cross-sectional area measurement test 2 The above, gel layer cross-sectional area measurement test: for every 2.5 cm x 2.5 cm of the surface of an esophageal submucosal tissue, 100 mg of a powder to be measured is sprayed, a gel is formed on the surface of the tissue by keeping at 37°C for 48 hours, the gel is fixed by neutral buffered formalin to obtain a fixed gel, the fixed gel is observed with a phase contrast microscope, and the cross-sectional area of the gel layer is calculated in square millimeters based on the phase contrast microscope image thus obtained, the test is performed three times, and the arithmetic mean of the three tests is taken as the area of the gel layer.

10. The powder according to claim 4 or 5, wherein, the storage modulus G' measured after mixing with pig blood to which an anticoagulant has been added for 2 minutes and 30 seconds is 200 or more.

11. A wound covering material containing the powder of any one of claims 4 to 10.

12. An anti-adhesion material containing the powder of any one of claims 4 to 10.

13. A topical hemostatic material containing the powder of claim 10.

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