WO2017183640A1

WO2017183640A1 - SHEET-LIKE HEMOSTATIC MATERIAL EMPLOYING POLY-γ-GLUTAMIC ACID, AND METHOD OF MANUFACTURING SAME

Info

Publication number: WO2017183640A1
Application number: PCT/JP2017/015604
Authority: WO
Inventors: 友亮中村; 吉克菅原; 和久松田
Original assignee: ニプロ株式会社
Priority date: 2016-04-20
Filing date: 2017-04-18
Publication date: 2017-10-26

Abstract

A sheet-like hemostatic material (10A to 10E) is provided with: an adhesive layer (11) which is a sheet formed from at least poly-γ-glutamic acid (γ-PGA) and which serves as a surface for affixing to a bleeding site; and a covering layer (12) which is a sheet formed from at least one biodegradable material (covering material) other than γ-PGA, and which serves as the opposite surface to the affixing surface. At least one of the adhesive layer (11) and the covering layer (12) is a single sheet. If the adhesive layer (11) is a single sheet, the adhesive layer (11) should be a sponge-like sheet, and if the adhesive layer (11) is a partial layer, the adhesive layer (11) should be a sponge-like sheet or a nonporous layer. Alternatively, in another sheet-like hemostatic material, a sheet which is formed from at least poly-γ-glutamic acid (γ-PGA) and to which at least one of a saccharide and collagen has been added is provided as the adhesive layer.

Description

Sheet-like hemostatic material using poly-γ-glutamic acid and method for producing the same

The present invention relates to a sheet-like hemostatic material using poly-γ-glutamic acid that can be suitably used for local hemostasis, and a method for producing the sheet-like hemostatic material.

For example, when local bleeding occurs during surgery or the like, the use of a sheet-like hemostatic material is known as one of the methods for hemostasis treatment. The sheet-like hemostatic material is configured by molding a medical material that can be decomposed in a living body into a sheet shape. The materials used for the sheet-like hemostatic material are typically animal protein-derived materials (animal materials), polysaccharide-derived materials (polysaccharide materials), and synthetic polymer-derived materials (polymer materials). Etc. Animal materials typically include fibrin, collagen, etc., polysaccharide materials typically include cellulose-based and starch-based materials, and polymer materials include polyacrylic acid-based materials. Are known.

As a typical sheet-like hemostatic material that is commercially available, “Taco Seal” (registered trademark, CSL Behring Co., Ltd.) using animal materials, and “Surge Cell” (registered trademark, Johnson End Johnson, Inc.) is known. Taco seal is a slightly hard sponge-like sheet containing human-derived fibrinogen and thrombin, and has high adhesive strength and excellent hemostatic performance. Surge cells are made of regenerated oxidized cellulose derived from wood pulp, and include gauze type, cotton type, and knit type (new knit). In particular, the knit type is suitably used as a sheet-like hemostatic material.

Furthermore, recently, as disclosed in Patent Document 1 or 2, it has also been proposed to improve the flexibility of the sheet-like hemostatic material. The sheet-like hemostatic material described in these patent documents is a fiber molded body composed of biodegradable polymer fibers such as polylactic acid, a sheet on which fibrinogen is immobilized, and fiber molding composed of biodegradable polymer fibers, It consists of a sheet on which thrombin is fixed. By holding fibrinogen and thrombin on separate fiber molded bodies, hemostasis is improved. Further, by changing the density of the bulk density of the fiber molded body (Patent Document 1), or by forming a fiber molded body by combining fiber structure layers having different bulk densities (Patent Document 2), The flexibility of the fiber molded body is improved.

JP 2014-004066 A JP 2014-005219 A

By the way, recently, the use of a sheet-like hemostatic material has been studied for hemostasis treatment in laparoscopic surgery. However, the conventional sheet-like hemostatic material has not been sufficiently flexible or handleable (or both) for use in laparoscopic surgery.

In laparoscopic surgery, an instrument having a cylindrical portion called a trocar is first inserted into the abdomen, and a laparoscope and a surgical instrument are inserted into the trocar. Since the operative field (the site to be operated on) taken with the laparoscope is enlarged and displayed on the monitor, the surgeon performs the operation using the surgical instrument while observing the monitor. Since the inner diameter of the trocar is usually about 5 to 12 mm, the sheet-like hemostatic material is required to be flexible enough to be folded or rolled so that it can be inserted into such a small hole. In addition, a surgical instrument used for laparoscopic surgery is operated in a small space in the abdominal cavity via a trocar. Therefore, the sheet-like hemostatic material is also required to have good handleability.

Although the above-mentioned octopus seal has good hemostatic performance, it has a slightly hard sponge shape as described above, and is not flexible enough to be inserted into a trocar. In addition, the sheet-like hemostatic material disclosed in Patent Documents 1 and 2 together with the octopus seal contains fibrinogen. Fibrinogen becomes fibrin by the action of thrombin, and this fibrin reacts biochemically to realize hemostasis. Therefore, the sheet-like hemostatic material containing fibrinogen is firmly fixed once applied within the abdominal cavity, and it becomes difficult to peel off and reattach. In laparoscopic surgery, since it is necessary to perform surgery by making full use of surgical instruments through a trocar, it is possible to apply a hemostatic material at an appropriate position, unlike normal surgery performed by the operator's own hands. Often not. Therefore, it is difficult to say that the fibrinogen-based sheet hemostatic material has sufficient handleability when used in laparoscopic surgery.

Here, the surge cell new knit described above is an oxidized cellulose-based hemostatic material, is more flexible than octopus seal, and does not use fibrinogen, so it is not firmly attached. However, the surge cell achieves hemostasis by contacting with blood to form a gelatinous clot. Therefore, after pasting on the hemostatic site, it is necessary to hold down for several minutes until a clot is formed. Therefore, it can hardly be said that the surge cell new knit has sufficient handleability for use in laparoscopic surgery.

Also, since the fibrinogen-based sheet hemostatic material is a preparation (blood preparation) using human-derived components, there is a risk of infectious diseases and the like. Therefore, in use, it is necessary to exchange risk explanations and consent forms with humans (patients) for being human-derived products (blood products). Furthermore, since fibrinogen is a reactive protein and thrombin is an enzyme, it needs to be stored at a low temperature of 10 ° C. or less in the case of tachoseal. Although the main component of the surge cell is oxidized cellulose, it must be stored at 25 ° C. or lower. Therefore, it is difficult to say that any of the commercially available sheet-like hemostatic materials that are commercially available have sufficient handling properties in terms of restrictions on transportation and storage.

The present invention has been made to solve such problems, and in a sheet-like hemostatic material, realizes a good hemostatic performance without the need to use fibrinogen, and also realizes a good flexibility and handleability. The purpose is to do.

In order to solve the above-mentioned problems, the sheet-like hemostatic material according to the present invention is configured to include an adhesive layer that is provided on the attachment surface to the bleeding site and is composed of at least poly-γ-glutamic acid.

According to the above configuration, since the adhesive surface of the sheet-like hemostatic material is an adhesive layer composed of poly-γ-glutamic acid (γ-PGA), animal material such as fibrinogen is added by γ-PGA of the adhesive layer. Without using it, it is possible to achieve good adhesion to living tissue and good hemostatic performance. In addition, since γ-PGA has good adhesiveness without causing a biochemical reaction, for example, even when a hemostatic material cannot be applied at an appropriate position, Unlike a hemostatic material, it can be re-applied to a living tissue.

The sheet-like hemostatic material having the above structure further includes a coating layer provided on the opposite surface of the sticking surface and made of at least one biodegradable material excluding the poly-γ-glutamic acid. And the structure that at least one of the said coating layers is a single sheet | seat may be sufficient.

According to the above configuration, an adhesive layer made of poly-γ-glutamic acid (γ-PGA) is provided on the affixing surface, and a biodegradability other than γ-PGA is provided on the non-affixing surface. A coating layer made of a material (coating material) is provided. Therefore, γ-PGA of the adhesive layer can realize good adhesion to living tissue and good hemostatic performance without using animal materials such as fibrinogen, and the coating material of the coating layer It is possible to effectively suppress the sheet-like hemostatic material from inadvertently adhering to a tissue or a surgical instrument other than the pasted portion.

Further, according to the above configuration, since at least one of the adhesive layer and the coating layer is a single sheet, the adhesive layer and / or the coating layer can function as a base material for the sheet-like hemostatic material. Furthermore, since the adhesive layer is γ-PGA, it is possible to store at room temperature for a long period of time as compared with a conventional sheet-like hemostatic material by appropriately selecting a coating material to be a coating layer.

Further, in the sheet-like hemostatic material having the above-described configuration, when the adhesive layer is the single sheet, the adhesive layer may be a sponge-like sheet. Alternatively, in the sheet-like hemostatic material having the above-described configuration, when the adhesive layer is a partial layer that is not the single sheet, the adhesive layer is a sponge-like sheet composed of at least poly-γ-glutamic acid, or non- It may be a porous layer.

According to the above configuration, if the adhesive layer is sponge-like or the adhesive layer is a non-porous partial layer, the adhesive layer can achieve moderate flexibility or good flexibility. In addition, since the covering layer can also realize flexibility, it is possible to realize good flexibility as the sheet-like hemostatic material. Therefore, even if the sheet-like hemostatic material is rolled or bent, the hemostatic material can be effectively prevented from being damaged. Moreover, according to the said structure, since it has the characteristic of favorable softness | flexibility, re-sticking, and storage at room temperature, favorable handleability can be implement | achieved.

In the sheet-like hemostatic material having the above-described configuration, the coating layer may be a sponge-like sheet composed of at least crosslinked collagen.

In the sheet-like hemostatic material having the above structure, both the adhesive layer and the coating layer are a single sheet, or the coating layer is a partial layer partially provided on the opposite surface. It may be a configuration.

Further, in the sheet-like hemostatic material having the above-described configuration, the adhesive layer and the coating layer may be configured such that at least a part thereof has a different color.

Further, the sheet-like hemostatic material having the above-described configuration may be configured such that the weight ratio of the adhesive layer is within a range of 10 to 90% by weight of the total weight of the sheet-like hemostatic material.

Further, the sheet-like hemostatic material having the above-described structure further includes at least one intermediate layer interposed between the adhesive layer and the coating layer, and these layers are integrally fixed. Also good.

Further, in order to solve the above problems, the method for producing a sheet hemostatic material according to the present invention includes a first layered body composed of at least poly-γ-glutamic acid, and at least excluding the poly-γ-glutamic acid. A step of laminating a second layered body composed of one kind of biodegradable material to form a layered body, and an adhesion composed of at least poly-γ-glutamic acid by bonding or pressure-bonding the layered body And a step of forming a sheet-like hemostatic material comprising a layer and a coating layer composed of the biodegradable material.

In the method for producing a sheet-like hemostatic material having the above-described configuration, the first layered body is a first sponge-like porous body composed of at least poly-γ-glutamic acid, and pressure is applied to the first sponge-like porous body. The resulting sponge-like first sheet, or a first partial sheet that is composed of at least poly-γ-glutamic acid and is not a single sheet, the first partial sheet being non-porous or not sponge-like or sponge-like And the second layered body is a second sponge-like porous body composed of the biodegradable material, a sponge-like second sheet obtained by applying pressure to the second sponge-like porous body, or The structure which is comprised with the said biodegradable material and is a 2nd partial sheet | seat which is not a single sheet | seat may be sufficient.

In the method for producing a sheet-like hemostatic material having the above-described configuration, first, the second sponge-like porous body is pressurized to form the sponge-like second sheet, and then laminated on the first sponge-like porous body. The structure which forms the said laminated body by crimping | bonding may be sufficient.

Further, another sheet-like hemostatic material according to the present invention is configured to include, as an adhesive layer, a sheet made of at least poly-γ-glutamic acid and further added with saccharides in order to solve the above-described problems.

According to the above configuration, the adhesive layer is composed of a sheet containing poly-γ-glutamic acid (γ-PGA) as a main component and added with saccharides. A γ-PGA sheet substantially composed only of γ-PGA is not flexible and will be damaged when it is deformed. However, a γ-PGA sheet containing saccharides exhibits good flexibility. Can do. Therefore, γ-PGA of the adhesive layer can realize good adhesion to living tissue and good hemostatic performance without using animal material such as fibrinogen, and can also roll sheet-like hemostatic material. Even if it bends, damage to the adhesive layer can be effectively suppressed.

Furthermore, since γ-PGA has good adhesiveness without causing a biochemical reaction, it can be reattached to a living tissue as compared with a conventional sheet-like hemostatic material. In addition, since the adhesive layer is γ-PGA, it can be stored for a long time at room temperature as compared with a conventional sheet-like hemostatic material. That is, according to the said structure, since it has the characteristic of favorable softness | flexibility, re-sticking, and room temperature preservation | save, favorable handleability can be implement | achieved.

In the sheet-like hemostatic material having the above-described configuration, the saccharide may be a monosaccharide, an oligosaccharide, or a polysaccharide.

In the sheet-like hemostatic material having the above-described structure, the saccharide may be added so as to be in the range of 10 to 90% by weight with respect to the total weight of the sheet.

Further, the sheet-like hemostatic material having the above-described structure may further have a structure in which collagen is added to the sheet.

Furthermore, the present invention also includes a sheet-like hemostatic material comprising at least a sheet made of poly-γ-glutamic acid and further having collagen added thereto as an adhesive layer.

In addition, in order to solve the above-mentioned problem, the method for producing a sheet hemostatic material according to the present invention includes adding at least one of saccharides and collagen to poly-γ-glutamic acid and forming the sheet into a sheet shape. It is the structure including the process of forming.

The above object, other objects, features, and advantages of the present invention will become apparent from the following detailed description of preferred embodiments with reference to the accompanying drawings.

In the present invention, with the above configuration, in the sheet-like hemostatic material, it is possible to realize good hemostatic performance without the need to use fibrinogen, and further, it is possible to realize good flexibility and handleability. Play.

1A and 1B are schematic cross-sectional views illustrating a schematic structure of a sheet-like hemostatic material according to Embodiment 1 of the present disclosure. 2A, 2B, and 2C are schematic cross-sectional views showing modifications of the sheet-like hemostatic material according to Embodiment 1. FIG. 3A, FIG. 3B, and FIG. 3C are schematic plan views showing an example of the surface opposite to the application surface of the sheet-like hemostatic material shown in FIG. 2A.

The sheet hemostatic material according to the present disclosure is configured using at least poly-γ-glutamic acid. Specifically, it is provided on the surface to be attached to the bleeding site and has an adhesive layer composed of at least poly-γ-glutamic acid, at least composed of poly-γ-glutamic acid, and further added with saccharides The thing of the structure provided with a sheet | seat as an adhesive layer is mentioned. The sheet-like hemostatic material having each configuration will be specifically described.

(Embodiment 1)
The sheet-like hemostatic material according to the present disclosure may be provided with an adhesive layer that is provided on the attachment surface to the bleeding site and includes at least poly-γ-glutamic acid, but preferably, in addition to the adhesive layer, A coating layer formed on at least one of the biodegradable materials excluding the poly-γ-glutamic acid, and at least one of the adhesive layer and the coating layer is a single layer. Any configuration that is a single sheet may be used. Hereinafter, a typical embodiment of the present disclosure will be specifically described.

[Sheet hemostat]
FIG. 1A or FIG. 1B schematically shows a cross-sectional structure of a sheet-like

hemostatic material

10A or 10B as a representative example of the sheet-like hemostatic material according to the present disclosure. 2A to 2C schematically show cross-sectional structures of sheet-like hemostatic materials 10C to 10E as other examples of the sheet-like hemostatic material according to the present disclosure. These sheet-like hemostatic materials 10A to 10E are provided with an adhesive layer 11 and a coating layer 12. As described above, the adhesive layer 11 may be a sheet containing poly-γ-glutamic acid (γ-PGA) as a main component. In this embodiment, as shown in FIG. 1A, FIG. 1B, FIG. 2A or FIG. 2B, the adhesive layer 11 is a sponge-like (porous) sheet, or as shown in FIG. Any non-sponge-like non-porous shape may be used as long as it is a partial layer described later. The coating layer 12 may be a sheet mainly composed of a biodegradable material other than γ-PGA. In the present embodiment, as will be described later, the coating layer 12 is a sponge sheet mainly composed of crosslinked collagen. . In the following description, biodegradable materials other than γ-PGA are referred to as “coating materials” for convenience.

The adhesive layer 11 constitutes an affixing surface (back surface) for adhering the sheet-like hemostatic materials 10A to 10E to bleeding sites such as living tissue, and has good adhesion to living tissue. As shown in FIG. 1A, FIG. 1B or FIG. 2A, the adhesive layer 11 may be provided as a single layer covering the entire surface of the pasting surface, or as shown in FIG. 2B or FIG. It may be provided as a partial layer to be formed. Similarly, the covering layer 12 is provided on at least a part of the opposite surface (surface) that is the opposite side of the application surface when the sheet-like hemostatic material 10A is applied to the bleeding site. The covering layer 12 may be provided as a single layer covering the entire opposite surface as shown in FIG. 1A or 1B, or as a partial layer partially covering the opposite surface as shown in FIG. 2A. May be.

Whether the cover layer 12 is a single layer or a partially covered structure, unlike the adhesive layer 11, it does not have adhesiveness to a living tissue or the like, or has a sufficiently lower adhesiveness than the adhesive layer 11. It has become. In other words, the coating layer 12 only needs to be configured so that the opposite surface of the adhesive layer 11 can be a “non-adhesive surface”. Thereby, when the sheet-like hemostatic materials 10A to 10E are to be attached to the bleeding site, it is possible to effectively suppress the possibility that the sheet-like hemostatic materials 10A to 10E are inadvertently attached to a site other than the bleeding site or a surgical instrument. That is, the covering layer 12 has a function of covering the other surface and suppressing the adhesiveness so that only one surface of the sheet hemostatic materials 10A to 10E becomes the pasting surface.

As described above, the adhesive layer 11 is a sponge-like sheet composed of γ-PGA in the case of the sheet-like hemostatic materials 10A to 10D shown in FIG. 1A, FIG. 1B, FIG. 2A or FIG. Any sheet may be used as long as it is made of a coating material, and at least it can exhibit flexibility when the sheet-like hemostatic materials 10A to 10E are formed. However, the covering layer 12 is also preferably a sponge-like sheet made of a covering material. If the coating layer 12 is a sponge-like sheet, it is possible to impart good flexibility to the coating layer 12 regardless of the specific type of coating material.

Here, the sponge sheet may be a flexible porous sheet, and its specific configuration is not particularly limited. The specific structure of the sponge is a porous material in which compartments having a large number of gaps (such as pores or vacuoles) of uniform or non-uniform size are dispersed continuously or discontinuously as determined visually or under a microscope. Can be mentioned (porous body). The non-sponge-like non-porous layer or sheet is integrally formed into a sheet shape or a layer shape by γ-PGA or a composition containing the same as a main component, and the plurality of gaps (pores or vacuoles). Etc.) can be mentioned in a state where there is substantially no compartment (even if it is slightly present, it can be substantially ignored).

Further, the method of processing at least γ-PGA or γ-PGA and a coating material into a sponge sheet is not particularly limited, and a known method can be suitably used. Specifically, for example, a solution of γ-PGA or a coating material (or a composition thereof) is poured into a mold having a predetermined shape, and a sponge-like porous body is obtained by a drying method such as natural drying, vacuum drying, or vacuum freeze drying. And forming a sponge-like sheet by applying pressure to the sponge-like porous body. Among these, from the viewpoint of more uniformly forming the porous material, a vacuum freeze-drying method can be exemplified, but the method is not limited thereto.

As the vacuum freeze-drying method, from the viewpoint of ease of production, for example, a solution of about 0.05 to 30% by weight of γ-PGA or a coating material is about 10.6 Pa (about 0.08 Torr) after preliminary freezing. Although the method of drying below is mentioned, it is not limited to this. After freeze-drying, a sponge-like porous body that is a molded product can be obtained by removing it from the mold. Moreover, the method of forming the sponge-like porous body into a sheet is not particularly limited, and examples thereof include a method of compressing with a press.

Although the sheet-like hemostatic material 10A illustrated in FIG. 1A has a two-layer structure including only the adhesive layer 11 and the coating layer 12, the present disclosure is not limited to this, and the sheet-like hemostatic material 10B illustrated in FIG. In addition, a multilayer structure of three or more layers may be used. That is, in the sheet-like hemostatic material according to the present disclosure, one surface (back surface) is a pasting surface composed of γ-PGA, and the other surface (front surface) is a coating material (biodegradation other than γ-PGA). The laminated structure is not particularly limited as long as it is a non-sticking surface (surface) covered with the adhesive material.

Since the sheet-like hemostatic material 10B shown in FIG. 1B includes the intermediate layer 13 between the adhesive layer 11 and the coating layer 12, it has a three-layer structure. The intermediate layer 13 may be a layer interposed between the adhesive layer 11 and the covering layer 12, and may be only one layer as in the sheet-like hemostatic material 10B, or may be two or more layers. The specific configuration of the intermediate layer 13 is not particularly limited as long as it can provide various functions and the like required for use in the sheet-like hemostatic material 10B.

For example, it is assumed that the sheet-like hemostatic materials 10A to 10E are sewn near the bleeding site. When the coating layer 12 is a sponge sheet composed of crosslinked collagen, the adhesive layer 11 is a sponge sheet composed of γ-PGA. It is not easy to sew to etc. Therefore, if a mesh composed of a thread material of biodegradable material is used as the intermediate layer 13 in the sheet-like hemostatic material 10B, it is easy to sew to a living tissue or the like. Examples of the other intermediate layer 13 include a fixing layer that improves the fixing state between the adhesive layer 11 and the covering layer 12, or a reinforcing layer that improves the strength of the sheet-like hemostatic material 10B. it can.

Furthermore, in the present disclosure, the adhesive layer 11 and the covering layer 12 are both configured as a single sheet as in the sheet-like hemostatic material 10A illustrated in FIG. 1A, but the present disclosure is not limited thereto. In the present disclosure, at least one of the adhesive layer 11 and the covering layer 12 may be a single sheet (both may be a single sheet), and the other may not be a single sheet.

The term “single sheet” as used herein means a single unitary planar member having a two-dimensional extension, and a plurality of planar members are configured as a partial layer described later. It does not mean a member assembly. Explaining as a layer constituting the sheet-like hemostatic materials 10A to 10E, the adhesive layer 11 or the covering layer 12 constituted as a “single sheet” is obtained when the sheet-like hemostatic materials 10A to 10E are attached to the hemostatic site. In addition, it means a layer of a planar member that can substantially cover the entire pasting surface or the opposite surface so that the hemostatic site can be appropriately stopped.

A configuration in which one of the adhesive layer 11 and the coating layer 12 is not a single sheet, that is, a configuration in which it is a partial layer will be specifically described. For example, like the sheet-like hemostatic material 10C shown in FIG. 2A, the coating layer 12 may be provided on the opposite surface as a plurality of partial coating layers (partial layers) 121 that partially cover the opposite surface. Or the adhesive layer 11 may be provided in the said adhesive surface as the some adhesive layer (partial layer) 111 which partially covers an adhesive surface like the sheet-like hemostatic material 10D shown to FIG. 2B. The partial adhesive layer 111 is a sponge sheet. Alternatively, like the sheet-like hemostatic material 10E shown in FIG. 2C, the adhesive layer 11 may be provided on the adhesive surface as a plurality of partial adhesive layers 141 that are non-porous layers. The sheet-like hemostatic materials 10A to 10E require a single sheet (base material layer) to be a base material in order to maintain the sheet shape. In the sheet-like

hemostatic material

10A or 10B, all layers are composed of a single sheet. However, since one layer is a partial layer in the sheet-like

hemostatic material

10C, 10D, or 10E, the other layer is based on the other layer. In order to become a material layer, it is necessary to be configured as a single sheet.

In addition, the adhesive layer 11 can exhibit flexibility as described later by being configured in a sponge shape. Therefore, even if the adhesive layer 11 is a single sheet as shown in FIG. 1A or FIG. 1B, even if the adhesive layer 11 is composed of a partial adhesive layer 111 as shown in FIG. Can be demonstrated. However, the present disclosure is not limited to this, and for example, as illustrated in FIG. 2C, if the adhesive layer 11 is configured as a partial layer, the adhesive layer 11 may not be a sponge.

A simple sheet composed of γ-PGA as a main component (that is, a non-sponge-like non-porous sheet) lacks flexibility as exemplified in Comparative Example 3 described later. However, even if the adhesive layer 11 is a non-porous material mainly composed of γ-PGA, if the adhesive layer 11 is formed as the partial adhesive layer 141, the partial adhesive layer 141 is supported by the coating layer 12. The adhesive layer 141 can exhibit flexibility. Therefore, the sheet-like hemostatic material 10E has sufficient flexibility.

In other words, the present disclosure includes (1) a sponge-like sheet (single sheet) composed of at least γ-PGA, excluding the adhesive layer 11 constituting the attachment surface to the bleeding site and γ-PGA. A sheet-like

hemostatic material

10A or 10B, which is a sheet (single sheet) composed of at least one biodegradable material, and includes a coating layer 12 constituting the opposite surface of the application surface; (2) The adhesive layer 11 that is a sponge sheet is provided as a single layer (single sheet) that covers the entire surface of the adhesive surface (constitutes the adhesive surface), and the covering layer 12 is partially provided on the opposite surface The sheet-like hemostatic material 10C configured as the layer 121, (3) the coating layer 12 is provided as a single layer (single sheet) covering the entire opposite surface of the adhesive layer 11 (constitutes the opposite surface), Adhesive layer 11 is partially on the application surface A sheet-like hemostatic material 10D configured as a sponge-like partial adhesive layer 111 provided on the surface, and (4) a coating layer 12 as a single layer (single sheet) covering the entire opposite surface of the adhesive layer 11 A sheet-like hemostatic material 10E is provided (which constitutes the opposite surface) and the adhesive layer 11 is configured as a non-porous partial adhesive layer 141 partially provided on the pasting surface.

In the present disclosure, if the adhesive layer 11 is a sponge sheet composed of γ-PGA, good flexibility can be achieved even if the adhesive layer 11 is a single sheet, such as the sheet-like

hemostatic material

10A or 10B. It can be demonstrated. Furthermore, like the sheet-like

hemostatic material

10C or 10D, one of the adhesive layer 11 or the coating layer 12 is configured as a base material layer made of a single sheet, and the other is configured as a partial layer. The flexibility can be made better. Moreover, even if the adhesive layer 11 is a non-sponge-like non-porous shape like the sheet-like hemostatic material 10E, sufficient flexibility can be exhibited if it is a partial layer.

The specific shape of the partial covering layer 121, the partial adhesive layer 111, or the partial adhesive layer 141 is not particularly limited, and may be configured as a partial layer (partial sheet) that is not a single sheet. For example, the partial covering layer 121 will be described as an example. As shown in FIG. 3A, the partial covering layer 121a may be a dot-like partial covering layer 121a, or as shown in FIG. 3B, a linear partial covering layer 121b may be used. As shown in FIG. 3C, it may be a shaded partial covering layer 121c or a shape other than these.

As described above, the partial layer or the partial sheet may be a member assembly (see FIG. 3A or FIG. 3B) in which a plurality of planar members are formed like dots or lines, or may be shaded. It may be a single planar member (see FIG. 3C) configured by forming a plurality of openings (or a plurality of through holes) like a shape, or a configuration in which these are combined (a plurality of openings A configuration in which a plurality of single planar members each having a shape are combined into a member assembly may be employed.

The partial coating layer 121 may be provided on the opposite surface so that the opposite surface of the adhesive layer 11 can be the above-mentioned “non-adhesive surface”, but the partial coating layer shown in FIGS. 3A to 3C As in the case of 121a to 121c, it is preferable that the partial covering layers 121 are dispersed and arranged so as to cover the entire opposite surface of the adhesive layer 11. The dispersive arrangement of the partial covering layer 121 may be irregular (random), but is more preferably regular as shown in FIGS. 3A to 3C. The partial covering layer 121 shown in FIG. 2A constitutes one layer having a two-layer structure as in FIG. 1A, but the partial covering layer 121 has a multilayer structure of three or more layers as illustrated in FIG. 1B. It may be provided as one layer.

Similarly, specific examples of the partial adhesive layer 111 or the partial adhesive layer 141 may also be dot-like, linear, and shaded like the partial covering layer 121 described above. The partial adhesive layer 111 or the partial adhesive layer 141 may be provided on the adhesive surface so as to be a “sticking surface” to be attached to a bleeding site such as a living tissue. The partial adhesive layer 111 or the partial adhesive layer 141 is preferably dispersed and arranged so as to cover the entire adhesive layer. The dispersed arrangement may be irregular, but is preferably regular.

In the sheet-like hemostatic material 10A having a two-layer structure, the adhesive layer 11 and the covering layer 12 may be integrally fixed to constitute one sheet. Similarly, in the sheet-like hemostatic material 10B having a structure of three or more layers, the adhesive layer 11, the one or more intermediate layers 13 and the covering layer 12 may be integrally fixed to constitute one sheet. .

In the sheet-like hemostatic material 10C, the coating layer 12 is constituted by a partial coating layer 121. The partial coating layer 121 is formed by punching or cutting out a sheet to be the coating layer 12 into a predetermined shape, and then the adhesive layer 11. What is necessary is just to adhere and form. Similarly, in the sheet-like hemostatic material 10D, the partial adhesive layer 111 may be formed by sticking to the covering layer 12 after punching out or cutting out a sheet to be the adhesive layer 11 into a predetermined shape. In the sheet-like hemostatic material 10E, since the partial adhesive layer 141 does not need to be processed into a sponge shape, a non-porous partial sheet made of γ-PGA formed in a predetermined shape is used as the adhesive layer 12. It may be formed by laminating and adhering.

The specific method for fixing these layers is not particularly limited, and a known method can be suitably used. If the coating layer 12 is a sponge-like sheet composed of cross-linked collagen, a method of pressing and bonding the adhesive layer 11 and the coating layer 12 (one or more intermediate layers 13 as necessary) as will be described later. It can be used suitably.

The adhesive layer 11 and the covering layer 12 included in the sheet-like hemostatic materials 10A to 10E may have the same color, but preferably have different colors. Thereby, when using the sheet-like hemostatic materials 10A to 10E, it can be easily confirmed visually which surface is the affixing surface (adhesive layer 11). A method for imparting color to the adhesive layer 11 and the coating layer 12 is not particularly limited, and a known method can be suitably used. Generally, a known dye, dye or pigment is used for the adhesive layer 11 or the coating layer 12. And a method of coloring these layers by adding. Specific dyes include legal dyes known in the field of pharmaceuticals, for example, green 202, purple 201, blue 2 and the like, and specific pigments include, for example, iron sesquioxide. It is done.

The color may be applied to either the adhesive layer 11 or the coating layer 12, or may be performed only to one of the adhesive layer 11 or the coating layer 12. In other words, both the adhesive layer 11 and the coating layer 12 may be colored by adding different pigments, or only one layer is added by adding a pigment or the like only to the adhesive layer 11 or only the coating layer 12. It may be colored. Also, the method of adding a dye or the like is not particularly limited, and the dye or the like is added to the γ-PGA or the coating material in the process of forming the adhesive layer 11 or the coating layer 12 (manufacturing a sheet or a sponge-like porous body serving as these layers). Alternatively, either one of the adhesive layer 11 and the coating layer 12 may be colored with a dye or the like after the sheet-like hemostatic materials 10A to 10E are manufactured. Furthermore, the part to which the color is imparted is not particularly limited as long as the color is imparted to at least a part of the adhesive layer 11 or the covering layer 12. Of course, all of the adhesive layer 11 or the covering layer 12 (entire layer) may be colored.

In the sheet-like hemostatic materials 10A to 10E, the weight ratio of the adhesive layer 11 and the coating layer 12 is not particularly limited, but typically, the weight ratio of the adhesive layer 11 is the total weight of the sheet-like hemostatic materials 10A to 10E. It is preferably in the range of 10 to 90% by weight. If the adhesive layer 11 is less than 10% by weight, the adhesiveness due to the adhesive layer 11 may not be sufficiently exhibited, depending on the configuration of the sheet-like hemostatic materials 10A to 10E. Further, if the adhesive layer 11 exceeds 90% by weight, the coating layer 12 may not sufficiently exert the effect of suppressing the adhesiveness of the adhesive layer 11 depending on the configuration of the sheet hemostatic materials 10A to 10E. .

The size and thickness of the sheet-like hemostatic materials 10A to 10E are not particularly limited, and can be appropriately set according to the use conditions of the sheet-like hemostatic materials 10A to 10E. The sheet-like hemostatic materials 10A to 10E can be suitably used for laparoscopic surgery. In this case, the sheet-like hemostatic materials 10A to 10E may have a size of about several centimeters and widths in consideration of trocar passage. In addition, when used for surgery other than laparoscopic surgery, or for emergency hemostasis of trauma, a size larger than the above-mentioned length and width of about several centimeters can be used.

The sheet hemostats 10A to 10E can be stored at room temperature depending on the type of the covering layer 12 or the intermediate layer 13. The room temperature referred to here is in the range of 1 to 30 ° C. as defined by the Japanese Pharmacopoeia. The adhesive layer 11 showing hemostatic performance in the sheet-like hemostatic materials 10A to 10E is composed of γ-PGA as described above. However, γ-PGA can be stably stored even within a room temperature range. Further, for example, if cross-linked collagen is used as the coating layer 12, the cross-linked collagen can also be stably stored within a room temperature range. Therefore, if the sheet-like hemostatic material 10 </ b> A is composed of the adhesive layer 11 and the cross-linked collagen coating layer 12, it can be stably stored at room temperature. Similarly, if the intermediate layer 13 is made of a material that can be stored at room temperature, the sheet-like hemostatic material 10B can also be stored stably at room temperature. Of course, it can be stably stored at a low temperature as required.

In addition, a fibrinogen-based sheet hemostatic material such as Taco Seal (registered trademark) needs to be stored at a low temperature of 10 ° C. or lower. Further, an oxidized cellulose-based sheet hemostatic material, for example, Surge Cell (registered trademark) New Knit, needs to be stored at 25 ° C. or lower. The normal temperature is in the range of 15 to 25 ° C., but in summer, the temperature usually exceeds 25 ° C. Therefore, storage at 25 ° C. or lower means that storage at room temperature is substantially difficult.

[Poly-γ-glutamic acid]
As described above, the adhesive layer 11 is a sponge-like sheet or a non-porous partial sheet composed of at least poly-γ-glutamic acid (γ-PGA). Therefore, the adhesive layer 11 may be composed only of γ-PGA, or may be composed of a γ-PGA composition containing γ-PGA as a main component and other components.

The γ-PGA used as the adhesive layer 11 includes a polymer in which glutamic acid is linked by a peptide bond between a carboxyl group at the γ position and an amino group at the α position, and a salt thereof. An example of a salt of γ-PGA is sodium poly-γ-glutamate. The term “poly-γ-glutamic acid (γ-PGA)” used in the present embodiment basically includes “poly-γ-glutamic acid and / or a salt thereof”.

The γ-PGA used as the adhesive layer 11 is not specifically limited, but, for example, one having a molecular weight within a specific range can be suitably used. A preferred molecular weight range of γ-PGA is a weight average molecular weight Mw in the range of 200,000 to 13 million, more preferably in the range of 300,000 to 10 million. If the weight average molecular weight Mw of the γ-PGA is below the lower limit of 200,000 (less than 200,000), good adhesiveness on the application surface will depend on the configuration of the adhesive layer 11 or the sheet-like hemostatic materials 10A to 10E. May not be possible. The upper limit of the weight average molecular weight Mw of γ-PGA is not particularly limited, but is usually 13 million or less. This is because it is considered that it is difficult to produce a product having a weight average molecular weight Mw exceeding 13 million by a conventionally known production method.

As the γ-PGA used as the adhesive layer 11, one having a kinematic viscosity ν within a specific range can be suitably used. As a preferable kinematic viscosity ν of γ-PGA, the kinematic viscosity ν at 37 ° C. when dissolved in distilled water at a concentration of 0.05% by mass can be, for example, in the range of 2 cSt to 15 cSt. A preferable range is 2.5 cSt to 8 cSt.

If the kinematic viscosity ν of γ-PGA is below the lower limit of 2 cSt (less than 2 cSt), good adhesiveness on the application surface cannot be realized depending on the configuration of the adhesive layer 11 or the sheet-like hemostatic materials 10A to 10E. there is a possibility. The upper limit of the kinematic viscosity ν of γ-PGA is not particularly limited, but is usually 15 cSt or less. This is because it is considered that it is difficult to produce a product having a kinematic viscosity ν exceeding 15 cSt by a conventionally known production method.

In the present disclosure, the γ-PGA used for the adhesive layer 11 has a weight average molecular weight Mw within the above-mentioned range, or a kinematic viscosity ν within the above-mentioned kinematic viscosity range. Alternatively, both the weight average molecular weight Mw and the kinematic viscosity ν may be within the above-described ranges. Of course, it goes without saying that at least one of the weight average molecular weight Mw and the kinematic viscosity ν of γ-PGA may be out of the above-mentioned range depending on the configuration or use conditions of the adhesive layer 11 or the sheet-like hemostatic materials 10A to 10E. Yes.

The method for obtaining such γ-PGA is not particularly limited. For example, γ-PGA satisfying at least one of the aforementioned weight average molecular weight Mw and kinematic viscosity ν is commercially available as a food additive and the like, and sufficiently safe for living bodies (including human bodies). Further, for example, γ-PGA can be easily produced by a known method using a microorganism derived from the genus Bacillus such as Bacillus subtilis.

The adhesive layer 11 may be substantially composed only of γ-PGA except when it contains impurities that are unavoidable due to common technical knowledge, but is composed of a γ-PGA composition containing components other than γ-PGA. May be. Components other than γ-PGA (other components) may be those that have biocompatibility and biodegradability and do not hinder the adhesion of the adhesive layer 11 when blended with γ-PGA. Specifically, for example, other components include saccharides such as monosaccharides such as glucose, saccharides such as oligosaccharides and polysaccharides; collagen; glycerin; polyethylene glycol; and known additives (the above-mentioned pigments and the like). Yes, but not particularly limited. These other components may be used alone or in combination of two or more.

The amount of other components added to the γ-PGA composition is not particularly limited as long as the adhesiveness of the adhesive layer 11 is not hindered. Usually, the blending amount may be such that γ-PGA does not become less than 50% by weight of the total amount of the γ-PGA composition. If the γ-PGA composition is composed only of γ-PGA and other components, the other components may be less than 50% by weight. In addition, when the γ-PGA composition contains saccharides, the adhesive layer 11 can be given further flexibility, and further improvement in adhesiveness can be expected.

[Coating material]
As described above, the coating layer 12 is a sheet (preferably a sponge sheet) made of at least one biodegradable material (coating material) excluding γ-PGA. Therefore, the coating layer 12 may be composed of one type of coating material, or may be composed of two or more types of coating materials. Moreover, you may contain the other component which can be mix | blended in addition to a coating material.

The coating material may be any material that exhibits good biocompatibility when introduced into a living body together with γ-PGA and is decomposed and absorbed after a certain period of time. Usually, a polymer having biocompatibility and biodegradability can be mentioned. Examples of such a polymer include collagen, polylactic acid, and polyglycolic acid. Among these, collagen (Col) is particularly preferable. Collagen has almost no possibility of adversely affecting the living body after introduction into the living body, is excellent in degradability in the living body, and does not substantially exhibit adhesiveness compared to γ-PGA.

The specific structure of the collagen is not particularly limited, but preferred examples include collagen that has been treated so that it can be dissolved in a known solvent. Specific examples include solubilized collagen such as enzyme-solubilized collagen, acid-solubilized collagen, alkali-solubilized collagen, and neutral-solubilized collagen. Among these, preferred collagens include acid solubilized collagen from the viewpoint of handleability. In addition, atelocollagen that has been subjected to the removal treatment of the telopeptide that is an antigenic determinant can be preferably used from the viewpoint of further reducing the possibility of adverse effects on the living body.

The origin of collagen is not particularly limited, and examples include cattle, pigs, birds, fish, rabbits, sheep, mice, and humans. The part of the animal species from which collagen is extracted is not particularly limited, and examples thereof include skin, tendon, bone, cartilage, and organ. Of these, those derived from pig skin can be preferably used from the viewpoint of availability. Furthermore, the type of collagen is not particularly limited, and examples thereof include type I, type II, and type III. Among these, type I and type III can be preferably used from the viewpoint of handleability.

A coating material such as collagen may be used for the coating layer 12 as it is, but is preferably subjected to a crosslinking treatment. That is, the covering layer 12 is preferably composed of cross-linked collagen (C-Col). Thereby, the strength of the covering layer 12 can be improved or stabilized, and the degradation time in the living body can be controlled by adjusting the degree of crosslinking. The crosslinking method of the coating material is not particularly limited, and examples thereof include a chemical crosslinking method, γ-ray irradiation, ultraviolet irradiation, electron beam irradiation, plasma irradiation, and thermal dehydration crosslinking treatment. In the case where the coating material contains at least collagen, among these crosslinking methods, a thermal dehydration crosslinking treatment can be exemplified.

In the thermal dehydration cross-linking treatment, first, collagen is formed into a sheet shape and air-dried. Thereafter, the sheet is placed in a vacuum dry oven and held at a predetermined temperature for a predetermined time under reduced pressure. This makes it possible to crosslink the collagen. In the thermal dehydration crosslinking treatment, the degree of crosslinking can be adjusted favorably by adjusting at least one of the crosslinking temperature and the crosslinking time.

In addition, when the coating layer 12 contains not only one or more types of biodegradable materials (coating materials) but also other components that can be blended in the biodegradable materials, that is, the coating layer 12 is composed of a coating material composition. In this case, other components can be blended within the range that does not interfere with the physical properties of the coating layer 12 in the same manner as the γ-PGA composition described above. Usually, the blending amount may be such that the coating material does not become less than 50% by weight in the total amount of the coating material composition. If the coating material composition is composed of only one or more types of coating materials and other components, the other components may be less than 50% by weight. In addition, examples of other components include known additives (such as the dyes described above), but are not particularly limited.

[Method for producing sheet hemostatic material]
The method for producing the sheet-like hemostatic material according to the present disclosure is not particularly limited as long as it can form an adhesive layer composed of at least γ-PGA and produce a sheet-like hemostatic material having sufficient flexibility. As described above, the sheet-like hemostatic materials 10A to 10E according to the present disclosure include the adhesive layer 11 and the coating layer 12, and may include the intermediate layer 13. Therefore, as a typical production method, an adhesive layer 11 which is a sponge-like sheet made of γ-PGA or a non-porous partial sheet, a coating layer 12 which is a sheet made of a coating material, and, if necessary, Any method may be used as long as the intermediate layer 13 interposed therebetween is laminated and integrally fixed as one sheet. Therefore, the adhesive layer 11, the covering layer 12, and the intermediate layer 13 may be formed simultaneously with the sheets serving as these layers, or an arbitrary sheet may be formed first, followed by another sheet. Good.

As a representative method for producing a sheet-like hemostatic material, for example, when both the adhesive layer 11 and the coating layer 12 are sponge-like sheets, a first sponge-like porous body composed of at least γ-PGA, or A sponge-like first sheet obtained by applying pressure to this and a second sponge-like porous body made of a coating material, or a sponge-like second sheet obtained by applying pressure thereto are laminated and laminated. Forming the body (lamination process), and laminating the first sponge-like porous body or sponge-like first sheet and the second sponge-like porous body or sponge-like second sheet (lamination) Step) and a step of forming the sheet-like hemostatic material 10A (or the sheet-like hemostatic material 10B) including the adhesive layer 11 and the covering layer 12 by bonding or press-bonding the laminate (integration) A degree), it can be mentioned a production method comprising a.

Also, the method for producing a sheet-like hemostatic material may include a step of forming a sponge-like porous body or sheet used in the lamination step. That is, in the present disclosure, in the laminating step, a sponge-like first sheet or sponge-like second sheet manufactured in advance (or commercially available) may be used, or the first sponge-like porous body or second sponge. A previously produced porous body may be used, or a sponge-like porous body or a sponge-like sheet may be produced from a raw material (γ-PGA or a coating material).

Specifically, the method for producing a sheet-like hemostatic material according to the present disclosure includes a step of lyophilizing at least γ-PGA to form a first sponge-like porous body (first sponge-like porous body forming step), Forming a sponge-like first sheet by applying pressure to one sponge-like porous body (sponge-like first sheet forming process), and forming a second sponge-like porous body by freeze-drying the coating material (second sponge) At least one of a step of forming a sponge-like second sheet by applying pressure to the second sponge-like porous member (sponge-like second sheet forming step).

In the first sponge-like porous body forming step or the second sponge-like porous body forming step, γ-PGA or a coating material may be formed into a sponge-like porous body using the various drying methods described above. When the coating layer 12 contains collagen, the second sponge-like porous body may be formed by a vacuum freeze-drying method. If the collagen of the coating layer 12 is cross-linked collagen, the sponge-like porous body before the sponge is formed is formed. What is necessary is just to give the bridge | crosslinking process mentioned above with respect to the state or sponge-like porous body after sponge-izing. Alternatively, the sponge-like porous body may be compressed to form a sponge-like sheet, and the above-described crosslinking treatment may be performed on the sponge-like sheet. Moreover, what is necessary is just to shape | mold a 1st sponge-like porous body or a 2nd sponge-like porous body in a sheet form by pressurizing using a press etc. as mentioned above.

In the lamination step and the integration step, a known lamination method, adhesion method, and pressure bonding method may be used. For example, a known press apparatus may be used as the crimping method. As a stacking method, not only a method of manually stacking by an operator but also a method of automatically stacking by a known robot or the like can be suitably used.

In the method for producing a sheet-like hemostatic material according to the present disclosure, the integration step can be performed only after the lamination step, but each step that can be performed before the lamination step, that is, the first sponge-like porous material The order of the body forming step, the second sponge-like porous body forming step, the sponge-like first sheet forming step, the sponge-like second sheet forming step, and the laminating step is not particularly limited. In addition, the sheet-like hemostatic material manufacturing method according to the present disclosure only needs to include at least a lamination step and an integration step, and if necessary, a first sponge-like porous body forming step, a second sponge-like porous body forming A process, a sponge-like first sheet forming process, a sponge-like second sheet forming process, and the like are included, but processes other than these processes may be included. For example, a sterilization process may be included after the integration process. Furthermore, in the manufacturing method of the sheet-like hemostatic material according to the present disclosure, any of a plurality of steps may be performed in parallel.

As a preferable example of the method for producing a sheet-like hemostatic material, for example, first, pressure is applied to the second sponge-like porous body to form a sponge-like second sheet, and then the first sponge-like porous body is laminated and pressure-bonded. The manufacturing method which forms the said laminated body can be mentioned. In this manufacturing method, after the sponge-like second sheet forming step, a laminating step is executed, and thereafter, the sponge-like first sheet forming step is executed. By this method, the sheet-like hemostatic material 10A having a two-layer structure shown in FIG. 1A can be efficiently produced.

In the case where the adhesive layer 11 or the covering layer 12 is a partial layer as in the sheet-like

hemostatic material

10C, 10D, or 10E, as a method for producing the sheet-like hemostatic material, before the lamination step, the adhesive layer 11 is used. Alternatively, a step (partial layer forming step) of punching out or cutting out the sheet to be the coating layer 12 into a predetermined shape may be executed. That is, the method for manufacturing a sheet hemostatic material according to the present disclosure may include a partial layer forming step in addition to the stacking step and the integration step. Alternatively, these partial layers may be formed as partial sheets from the beginning, instead of being formed as partial sheets by processing a single sheet.

Thus, in the method for producing a sheet-like hemostatic material according to the present disclosure, in order to form the adhesive layer 11, the first sponge-like porous body composed of at least γ-PGA, or the first A sponge-like first sheet obtained by applying pressure to a sponge-like porous body can be used, and a first partial sheet made of at least γ-PGA and not a single sheet can be used. Thus, for convenience, the layered member made of γ-PGA prepared for forming the adhesive layer 11 is referred to as a first layered body. The first partial sheet that is the first layered body may be in the form of a sponge or a non-porous form that is not in the form of a sponge.

Similarly, in order to form the coating layer 12, the above-described second sponge-like porous body made of a biodegradable material or a sponge-like first body obtained by applying pressure to the second sponge-like porous body is used. Not only can two sheets be used, but a second partial sheet composed of a biodegradable material and not a single sheet can be used. Thus, for convenience, the layered member made of a biodegradable material prepared for forming the coating layer 12 is referred to as a second layered body.

Therefore, as a representative example of a method for producing a sheet hemostatic material according to the present disclosure, a first layered body composed of at least γ-PGA and at least one biodegradable material excluding γ-PGA A step of forming a laminated body by laminating a second layered body comprising: a bonding layer comprising at least γ-PGA, and a biodegradable material by bonding or pressure-bonding the laminated body And a coating layer, and a step of forming a sheet-like hemostatic material.

Thus, according to the present disclosure, the sticking surface of the sheet-like hemostatic material is an adhesive layer composed of poly-γ-glutamic acid (γ-PGA), and the non-sticking surface is biodegradable other than γ-PGA. It is the coating layer comprised with material (coating material). Therefore, γ-PGA of the adhesive layer can realize good adhesion to living tissue and good hemostatic performance without using animal materials such as fibrinogen, and the coating material of the coating layer It is possible to effectively suppress the sheet-like hemostatic material from inadvertently adhering to a tissue or a surgical instrument other than the pasted portion.

Further, since the adhesive layer is a sponge sheet or a non-porous partial layer, it has good flexibility and the coating layer also has flexibility. Thereby, favorable softness | flexibility can be exhibited as the said sheet-like hemostatic material. Therefore, even if the sheet-like hemostatic material is rolled or bent, damage to the adhesive layer can be effectively suppressed. Further, by configuring one of the adhesive layer or the coating layer as a base material layer made of a single sheet and configuring the other as a partial layer, the flexibility of the sheet-like hemostatic material can be further improved. .

Furthermore, since γ-PGA has good adhesiveness without causing a biochemical reaction, it can be reattached to a living tissue as compared with a conventional sheet-like hemostatic material. In addition, since the adhesive layer is γ-PGA, it is possible to store at room temperature for a long period of time as compared with a conventional sheet-like hemostatic material by appropriately selecting a coating material to be a coating layer.

(Embodiment 2)
Another sheet-like hemostatic material according to the present disclosure is configured to include at least a sheet made of poly-γ-glutamic acid and further added with a saccharide as an adhesive layer. Hereinafter, a typical embodiment of the present disclosure will be specifically described.

[Sheet hemostat]
As described above, the sheet-like hemostatic material according to the present disclosure has, as an adhesive layer, a γ-PGA sheet (saccharide-added γ-PGA sheet) containing poly-γ-glutamic acid (γ-PGA) as a main component and saccharide added thereto. It only has to have. By adding a saccharide to γ-PGA to form a sheet, flexibility can be imparted to the γ-PGA sheet without impairing adhesion to living tissue (see Examples described later).

The sheet-like hemostatic material may be a single-layer sheet composed only of a saccharide-added γ-PGA sheet, but may be a multilayer structure sheet of two or more layers in which other layers are laminated as necessary. . Other layers include, for example, a reinforcing layer that improves the strength of the sheet-like hemostatic material, and a coating on one surface of the saccharide-added γ-PGA sheet so that only the other surface is an adhesive surface (sticking surface). Although a layer etc. are mentioned, it is not specifically limited.

Other layers may have biocompatibility and biodegradability like γ-PGA, and the specific material is not particularly limited. As another typical layer, for example, a cross-linked collagen (C-Col) can be used for the coating layer. Moreover, the method of laminating other layers is not particularly limited, and a known method can be suitably used.

The size and thickness of the sheet-like hemostatic material according to the present disclosure are not particularly limited, and can be appropriately set according to the use conditions of the sheet-like hemostatic material. The sheet-like hemostatic material according to the present disclosure can be suitably used for laparoscopic surgery, but in this case, the sheet-like hemostatic material may have a size of about several centimeters in length and breadth in consideration of trocar passage. In addition, when used for surgery other than laparoscopic surgery, or for emergency hemostasis of trauma, a size larger than the above-mentioned length and width of about several centimeters can be used.

The sheet hemostatic material according to the present disclosure can be stored at room temperature because the adhesive layer is composed of a saccharide-added γ-PGA sheet. The room temperature here is within the range of 1 to 30 ° C. as appropriate in the Japanese Pharmacopoeia. The adhesive layer (saccharide-added γ-PGA sheet) showing hemostasis performance in a sheet-like hemostatic material contains γ-PGA as a main component and saccharide as a minor component, but both γ-PGA and saccharide are stable within a room temperature range. Can be saved. Of course, it can be stably stored at a low temperature as required.

The method for producing the sheet-like hemostatic material according to the present disclosure is not particularly limited, and an adhesive layer is formed by adding at least a saccharide to γ-PGA and forming it into a sheet shape (forming a saccharide-added γ-PGA sheet). Any manufacturing method including the step of performing the process may be used. When other layers are provided in addition to the adhesive layer, a saccharide-added γ-PGA sheet serving as the adhesive layer and a sheet serving as the other layer may be laminated and fixed by a known method such as pressure bonding. The method for adding saccharides to γ-PGA and the method for forming γ-PGA added with saccharides into a sheet are not particularly limited, and known methods can be suitably used.

In addition, the sheet-like hemostatic material according to the present disclosure only needs to include at least an adhesive layer, and the adhesive layer is a γ-PGA composition in which the saccharide-added γ-PGA sheet is composed of at least γ-PGA and saccharides. It is a sheet | seat obtained by shape | molding. Therefore, it can also be said that the method for producing a sheet hemostatic material according to the present disclosure is a method of preparing a γ-PGA composition and forming it into a sheet. In other words, in the present disclosure, the sheet-like hemostatic material can be easily produced by forming the γ-PGA composition into a sheet, and thus does not go through a complicated production process. For example, if the γ-PGA composition is formed into a sheet by a casting method, the thickness of the saccharide-added γ-PGA sheet can be controlled only by adjusting the amount of the liquid γ-PGA composition. It becomes possible.

[Poly-γ-glutamic acid]
The saccharide-added γ-PGA sheet serving as the adhesive layer may be any sheet having γ-PGA as a main component and saccharide as a subcomponent. The γ-PGA used for the adhesive layer includes a polymer in which glutamic acid is linked by a peptide bond at a γ-position carboxyl group and an α-position amino group, and a salt thereof in a straight chain. An example of a salt of γ-PGA is sodium poly-γ-glutamate. The term “poly-γ-glutamic acid (γ-PGA)” used in the present embodiment basically includes “poly-γ-glutamic acid and / or a salt thereof”.

The γ-PGA used as the adhesive layer is not particularly limited, but for example, those having a molecular weight within a specific range can be suitably used. A preferred molecular weight range of γ-PGA is a weight average molecular weight Mw in the range of 200,000 to 13 million, more preferably in the range of 300,000 to 10 million. If the weight average molecular weight Mw of γ-PGA is below the lower limit of 200,000 (less than 200,000), it may not be possible to achieve good adhesion on the application surface, depending on the configuration of the adhesive layer or sheet-like hemostatic material There is sex. The upper limit of the weight average molecular weight Mw of γ-PGA is not particularly limited, but is usually 13 million or less. This is because it is considered that it is difficult to produce a product having a weight average molecular weight Mw exceeding 13 million by a conventionally known production method.

As the γ-PGA used as the adhesive layer, those having a kinematic viscosity ν within a specific range can be suitably used. As a preferable kinematic viscosity ν of γ-PGA, the kinematic viscosity ν at 37 ° C. when dissolved in distilled water at a concentration of 0.05% by mass can be, for example, in the range of 2 cSt to 15 cSt. A preferable range is 2.5 cSt to 8 cSt. If the kinematic viscosity ν of γ-PGA is below the lower limit of 2 cSt (less than 2 cSt), it may not be possible to achieve good adhesion on the application surface, depending on the configuration of the adhesive layer or sheet-like hemostatic material. . The upper limit of the kinematic viscosity ν of γ-PGA is not particularly limited, but is usually 15 cSt or less. This is because it is considered that it is difficult to produce a product having a kinematic viscosity ν exceeding 15 cSt by a conventionally known production method.

The γ-PGA used for the adhesive layer in the present disclosure has a weight average molecular weight Mw within the above-mentioned range, or a kinematic viscosity ν within the above-mentioned kinematic viscosity range, or In addition, both the weight average molecular weight Mw and the kinematic viscosity ν may be within the above-described ranges. Of course, it goes without saying that at least one of the weight average molecular weight Mw and the kinematic viscosity ν of γ-PGA may be out of the above-mentioned range depending on the constitution or use conditions of the adhesive layer or the sheet-like hemostatic material.

[Sugar and other ingredients]
The saccharide contained in the saccharide-added γ-PGA sheet may be a polyhydric alcohol (monosaccharide) having a carbonyl group or a polymer thereof (oligosaccharide or polysaccharide). Specific types of monosaccharides, oligosaccharides and polysaccharides are not particularly limited, and known compounds can be suitably used. In particular, in the present disclosure, the sheet-like hemostatic material is used by being introduced into a living body and attached to a living tissue or the like. Therefore, saccharides are also added to γ-PGA unless they have incompatible properties with living bodies. be able to.

Specifically, as monosaccharides, for example, hexoses (hexoses) such as glucose, galactose, fructose, mannose; pentoses (pentoses) such as arabiose, xylose, ribose; glucosamine, galactosamine, N-acetylglucosamine Amino sugars such as N-acetylgalactosamine and sialic acid or derivatives thereof; sugar alcohols such as sorbitol and xylitol;

Examples of the oligosaccharide include disaccharides such as trehalose, maltose, sucrose, lactose, and melibiose; trisaccharides such as raffinose; tetrasaccharides such as stachyose;

Examples of polysaccharides include, for example, glucans such as amylose, amylopectin, dextran, dextrin, and icodextrin; examples of glycosaminoglycans include hyaluronic acid, alginic acid, heparan sulfate, chondroitin sulfate, chondroitin, dermatan sulfate, keratosulfate, and heparin. Non-glucan polysaccharides of dietary fiber such as alginic acid and salts thereof, inulin, carboxymethylcellulose, pectin, chitin, chitosan, carrageenan, fucoidan, and the like.

Only one of these monosaccharides, oligosaccharides, and polysaccharides may be added to the saccharide-added γ-PGA sheet, or a plurality of types may be appropriately combined and added to the saccharide-added γ-PGA sheet. The plurality of types herein may be a combination of monosaccharides, oligosaccharides, or polysaccharides, or a combination of monosaccharides and oligosaccharides, monosaccharides and polysaccharides, oligosaccharides and polysaccharides.

The amount of these saccharides to be added is not particularly limited, but in general, it may be in the range of 10 to 90% by weight with respect to the total weight of the saccharide-added γ-PGA sheet. If the added amount of saccharide is less than 10% by weight, the flexibility of the saccharide-added γ-PGA sheet cannot be obtained sufficiently, but warps or breaks, although it depends on the type of saccharide or the condition of γ-PGA (molecular weight, etc.). There is a risk of If the amount of saccharide added exceeds 90% by weight, the adhesion (function as an adhesive layer) of the saccharide-added γ-PGA sheet is sufficient, depending on the type of saccharide or the γ-PGA conditions (molecular weight, etc.). May not be obtained.

Furthermore, the saccharide-added γ-PGA sheet may contain other components in addition to γ-PGA and saccharide. Ingredients other than γ-PGA (other ingredients) have biocompatibility and biodegradability, do not interfere with the adhesion of the saccharide-added γ-PGA sheet when blended with γ-PGA, Any sugar-added γ-PGA sheet may be used as long as it does not hinder the flexibility. Specifically, for example, as other components, collagen, glycerin, polyethylene glycol, known additives (pigments, etc.) and the like can be mentioned, but are not particularly limited. These other components may be used alone or in combination of two or more. Further, the amount of other components added is not particularly limited as long as it does not hinder the adhesiveness and flexibility of the saccharide-added γ-PGA sheet.

From the viewpoint of improving the handleability of the sheet-like hemostatic material according to the present disclosure, collagen is particularly preferable among the other components described above. By adding collagen to the saccharide-added γ-PGA sheet, breakage can be effectively suppressed even if the saccharide-added γ-PGA sheet (adhesive layer) is deformed by rounding or bending. Moreover, the saccharide-added γ-PGA sheet (adhesive layer) to which collagen is added is easily restored to its original shape even when deformed.

Therefore, if the sheet-like hemostatic material according to the present disclosure includes a saccharide-added γ-PGA sheet added with collagen as an adhesive layer, for example, a planar sheet-like hemostatic material is used when performing laparoscopic surgery. Even if the sheet is rolled and inserted into the trocar, the sheet-like hemostatic material is easily restored to the original planar shape after passing through the trocar. Therefore, since the work of applying a physical force to the sheet-shaped hemostatic material and then returning it to its original shape can be minimized, the handling property of the sheet-shaped hemostatic material can be greatly improved. it can.

Note that the sheet-like hemostatic material according to the present disclosure is a γ-PGA sheet (collagen-added γ-PGA sheet) to which only collagen is added and no saccharide is added as an adhesive layer when attention is focused on improving the handleability. The structure provided may be sufficient. That is, the present disclosure also includes a sheet-like hemostatic material configured to include at least a sheet made of poly-γ-glutamic acid and further added with collagen as an adhesive layer.

Here, the method for producing a collagen-added γ-PGA sheet and the method for producing a sheet-like hemostatic material comprising a collagen-added γ-PGA sheet as an adhesive layer are the same as the method for producing a saccharide-added γ-PGA sheet. The specific description is omitted. For example, although the amount of collagen added is not particularly limited, it may be within the range of 10 to 90% by weight with respect to the total weight of the collagen-added γ-PGA sheet, similarly to the amount of saccharide added to the saccharide-added γ-PGA sheet. Good.

As described above, in the sheet-like hemostatic material according to the present disclosure, the adhesive layer is constituted by a saccharide-added γ-PGA sheet in which saccharide is added with γ-PGA as a main component. A γ-PGA sheet substantially composed only of γ-PGA is not flexible and will be damaged when it is deformed. However, a γ-PGA sheet containing saccharides exhibits good flexibility. Can do.

Therefore, γ-PGA of the adhesive layer can realize good adhesion to living tissue and good hemostatic performance without using animal material such as fibrinogen, and can also roll sheet-like hemostatic material. Even if it bends, damage to the adhesive layer can be effectively suppressed. Furthermore, since γ-PGA has good adhesiveness without causing a biochemical reaction, it can be reattached to a living tissue as compared with a conventional sheet-like hemostatic material. In addition, since the adhesive layer is γ-PGA, it can be stored for a long time at room temperature as compared with a conventional sheet-like hemostatic material.

Further, in another sheet-like hemostatic material according to the present disclosure, the adhesive layer may be constituted by a collagen-added γ-PGA sheet to which collagen is added with γ-PGA as a main component. Thereby, the handleability of a sheet-like hemostatic material can be improved. Of course, in the sheet-like hemostatic material according to the present disclosure, it is needless to say that the adhesive layer may be a γ-PGA sheet containing γ-PGA as a main component and added with both saccharide and collagen.

The present disclosure will be described more specifically based on examples and comparative examples, but the present disclosure is not limited thereto. Those skilled in the art can make various changes, modifications, and alterations without departing from the scope of the present disclosure.

First, the sheet-like hemostatic material having the configuration described in Embodiment 1 will be specifically described based on Examples 1 to 3 and Comparative Examples 1 to 3. In the following Examples 1 to 3 and Comparative Examples 1 to 3, the sheet-like hemostatic material was evaluated as follows.

(Evaluation of hemostatic performance and reattachment)
The abdomen of a 40-week-old male rabbit (with a body weight of 3.0 kg) was incised under continuous anesthesia, the liver was exposed, the surface of the liver was incised and bled, and Examples 1 to 3 or Comparative Examples 1 to 3 were used. A sheet-like hemostatic material was pasted. The hemorrhage performance was evaluated by confirming the state of bleeding after pasting. In addition, it was also evaluated whether or not the sheet-like hemostatic material of Examples 1 to 3 or Comparative Examples 1 to 3 could be attached again after being attached to the bleeding site of the liver.

(Evaluation of trocar passability)
The sheet-like hemostatic material of Examples 1 to 3 or Comparative Examples 1 to 3 was rolled into a roll and evaluated whether or not it could pass through a trocar having a diameter of 5 mm (product name Step System Versa Step 5MM, manufactured by Covidien Japan Co., Ltd.). .

Example 1
A 1 wt% collagen aqueous solution was prepared, filled into a rectangular metal container, and frozen at −20 ° C. for about 12 hours. The obtained frozen product was freeze-dried under reduced pressure (about 13 Pa (1 Torr) or less) for about 24 hours in a freeze dryer (product name: FDU-2100, manufactured by Tokyo Rika Kikai Co., Ltd.) It was compressed at a pressure of 980 N / cm ² (100 kgf / cm ² ) by a company Masada Seisakusho, 15t press). The obtained freeze-dried product was subjected to thermal dehydration crosslinking under reduced pressure (about 13 Pa (1 Torr) or less) for about 24 hours in a vacuum dry oven (product name: VOS-300VD manufactured by Tokyo Rika Kikai Co., Ltd.). As a result, a crosslinked collagen (C-Col) sponge-like sheet was obtained.

Next, a 1% by weight γ-PGA aqueous solution was prepared, filled in a predetermined amount in a rectangular metal container, and frozen at −20 ° C. for about 12 hours to obtain a sponge-like porous body. Thereafter, this sponge-like porous body was freeze-dried under reduced pressure for about 24 hours, and then a crosslinked collagen sponge-like sheet was laminated and pressure-bonded. As a result, a sheet-like hemostatic material according to Example 1 was obtained in which the γ-PGA sponge sheet as the adhesive layer and the crosslinked collagen sponge sheet as the coating layer were pressure-bonded.

This sheet-like hemostatic material was 90 mg at 2.5 cm × 2.5 cm, and the weight ratio of the crosslinked collagen sponge sheet to the γ-PGA sponge sheet was 30:70. Using this sheet-like hemostatic material, the hemostatic performance and the reattachment performance were evaluated as described above. The results are shown in Table 1.

(Example 2)
The filling amount of the 1 wt% collagen aqueous solution and the 1 wt% γ-PGA aqueous solution into the metal container was changed so that the weight ratio of the crosslinked collagen sponge sheet to the γ-PGA sponge sheet was 25:75. Except for the above, a sheet-like hemostatic material according to Example 2 was obtained in the same manner as in Example 1. This sheet-like hemostatic material was 80 cm at 2.5 cm × 2.5 cm, and as described above, the weight ratio of the crosslinked collagen sponge sheet to the γ-PGA sponge sheet was 25:75. Using this sheet-like hemostatic material, the hemostatic performance and reattachment were evaluated as described above. The results are shown in Table 1.

(Comparative Example 1)
As a sheet-like hemostatic material according to Comparative Example 1, using a Surge Cell New Knit (registered trademark, Johnson & Johnson Co., Ltd.) having a size of 2.5 cm × 2.5 cm, the hemostatic performance and reattachment as described above. Evaluated. The results are shown in Table 1.

(Example 3)
A sheet-like hemostatic material according to Example 3 was prepared in the same manner as in Example 1 with a size of 3.0 cm × 2.5 cm. Using this sheet-like hemostatic material, trocar passage was evaluated as described above. The results are shown in Table 2.

(Comparative Example 2)
As the sheet-like hemostatic material according to Comparative Example 2, 3.0 cm × 2.5 cm octopus seal (registered trademark, CSL Bering Co., Ltd.) was used to evaluate trocar passage as described above. The results are shown in Table 2.

(Comparative Example 3)
A 1 wt% γ-PGA aqueous solution was prepared, and a 3.0 cm × 2.5 cm γ-PGA sheet was prepared by a casting method, and used as a sheet-like hemostatic material according to Comparative Example 3. Using this γ-PGA sheet, the trocar passage was evaluated as described above. The results are shown in Table 2.

(Comparison between Examples 1 to 3 and Comparative Examples 1 to 3)
With the sheet-like hemostatic material according to Examples 1 and 2, it was possible to exhibit good adhesiveness and hemostatic performance simply by being attached to a living tissue and lightly pressed. Moreover, it was possible to stick on a living tissue, and then peel off and put it on again. On the other hand, the surge cell new knit according to Comparative Example 1 was able to demonstrate hemostatic performance by pressing for 3 minutes after being applied to a living tissue, but unlike the sheet-like hemostatic material according to the present disclosure, it cannot be re-applied. It was.

Moreover, if it is the sheet-like hemostatic material which concerns on Example 3, it can pass a trocar easily by making it roll shape, However, in an octopus seal (comparative example 2), it can barely pass a trocar by making it a crushed roll shape. Things have been damaged. Furthermore, since the γ-PGA sheet (Comparative Example 3) was a γ-PGA single layer and was not sponge-like, it was not flexible and cracked when bent and could not be made into a roll.

As described above, the sheet-like hemostatic material according to the present disclosure is superior in hemostasis performance without using fibrinogen as compared with the conventional one, and can realize good flexibility and handleability.

Next, the sheet-like hemostatic material having the configuration described in Embodiment 2 will be specifically described based on Examples 4 to 8 and Comparative Examples 4 to. In the following Examples 4 to 8 and Comparative Examples 4 to 5, the sheet-like hemostatic material was evaluated as follows.

(Evaluation of sheet condition)
The sheet-like hemostatic material (saccharide-added γ-PGA sheet or γ-PGA sheet) produced in Examples 4 to 8 or Comparative Examples 4 to 5 was visually checked for warpage and the like and then bent.

(Evaluation of trocar passability)
A sheet-like hemostatic material (saccharide-added γ-PGA sheet or γ-PGA sheet) having a size of 3.0 cm × 2.5 cm was prepared in Examples 4 to 8 or Comparative Examples 4 to 5, and this was rolled into a roll, and the diameter was 5 mm. It was evaluated whether or not it could pass through a trocar (product name Step System Berserstep 5MM, manufactured by Covidien Japan Co., Ltd.).

Example 4
Preparation of 1 wt% γ-PGA and 1 wt% glucose γ-PGA-sugar solution (1% γ-PGA 1% Glu solution) by adding glucose (Glu) to 1 wt% γ-PGA solution did. This γ-PGA-sugar solution is spread on a stainless steel plate as a base material and dried (cast method), whereby a saccharide-added γ-PGA sheet (γ-) as a sheet-like hemostatic material according to Example 4 is used. PGA 50% by weight, Glu 50% by weight).

The saccharide-added γ-PGA sheet was evaluated for sheet state and trocar passage by the methods described above. Table 1 shows the results of the sheet state, and Table 2 shows the results of the trocar passage.

(Example 5)
By adding glucose so as to be 2% by weight with respect to the 1% by weight γ-PGA solution, 1% by weight γ-PGA and 2% by weight glucose in γ-PGA-sugar solution (1% γ-PGA 2% Glu The saccharide-added γ-PGA sheet (γ-PGA 33.3% by weight, Glu 66.7% by weight) which is a sheet-like hemostatic material according to Example 5 was prepared in the same manner as in Example 4 except that the solution was prepared. Produced.

(Example 6)
By adding sucrose (Suc) to 1 wt% with respect to the 1 wt% γ-PGA solution, a 1 wt% γ-PGA and a 1 wt% sucrose γ-PGA-sugar solution (1% γ- A saccharide-added γ-PGA sheet (γ-PGA 50 wt%, Suc 50 wt%) as a sheet-like hemostatic material according to Example 6 was prepared in the same manner as in Example 4 except that a PGA 1% Suc solution was prepared. Produced.

(Example 7)
By adding 1% by weight hyaluronic acid (HA) to 1% by weight γ-PGA solution, 1% by weight γ-PGA and 1% by weight hyaluronic acid γ-PGA-sugar solution (1% γ-PGA1 A saccharide-added γ-PGA sheet (γ-PGA 50% by weight, HA 50% by weight), which is a sheet-like hemostatic material according to Example 7, was prepared in the same manner as in Example 4 except that the% HA solution was prepared. .

(Comparative Example 4)
A γ-PGA sheet (γ-PGA 100 wt.), which is a sheet-like hemostatic material according to Comparative Example 4, except that a 1 wt% γ-PGA solution was used instead of the γ-PGA-sugar solution. %). With respect to this γ-PGA sheet, the sheet state and trocar passage were evaluated by the methods described above. Table 1 shows the results of the sheet state, and Table 2 shows the results of the trocar passage.

(Comparative Example 5)
As a sheet-like hemostatic material according to Comparative Example 5, a octopus seal (registered trademark, CSL Bering Co., Ltd.) of 3.0 cm × 2.5 cm was used to evaluate trocar passage as described above. The results are shown in Table 2.

(Example 8)
A γ-PGA-HA aqueous solution was prepared so as to be 60% by weight of γ-PGA and 40% by weight of HA, filled in a predetermined amount in a rectangular metal container, and frozen at −20 ° C. for about 12 hours. The obtained frozen product was freeze-dried under reduced pressure (about 13 Pa (1 Torr) or less) for about 24 hours in a freeze dryer (product name: FDU-2100, manufactured by Tokyo Rika Kikai Co., Ltd.). This produced a saccharide-added γ-PGA sheet configured as a sponge-like sheet. A cross-linked collagen (C-Col) sheet as a coating layer was laminated on one surface of this saccharide-added γ-PGA sheet and pressure-bonded. The weight ratio between the saccharide-added γ-PGA sheet and the crosslinked collagen sheet was 70:30. Thereby, a sheet-like hemostatic material having a two-layer structure according to Example 8 was produced.

The adhesion and hemostasis performance were confirmed by animal experiments using this sheet-like hemostat. A pig was used as an experimental animal, and the chest of the pig was opened under continuous anesthesia to expose the heart. Then, the myocardial portion was partially incised and bled, and the sheet-like hemostatic material according to Example 8 was attached, and the subsequent bleeding situation was confirmed.

(Comparison of Examples 4 to 8 and Comparative Examples 4 to 5)
As is clear from Table 1, the sheet-like hemostatic materials according to Examples 4 to 7 were free from warping and cracking during bending, and had good flexibility. On the other hand, the sheet-like hemostatic material according to Comparative Example 4 was warped and cracked. Therefore, any saccharide such as monosaccharide (glucose), oligosaccharide (sucrose), and polysaccharide (hyaluronic acid) can be added to γ-PGA to form a sheet (sheet), thereby making the sheet flexible. Sex can be imparted. In addition, as a result of Example 8, it was confirmed that the saccharide-added γ-PGA sheet according to the present disclosure can realize good adhesiveness and hemostasis performance simply by being attached to a living tissue and lightly pressed.

Furthermore, as is apparent from Table 2, it can be seen that the sheet-like hemostatic material according to Examples 4 to 7 can easily pass through the trocar by making it into a roll shape, for example. On the other hand, the γ-PGA sheet to which saccharides were not added (Comparative Example 4) was not flexible and cracked when bent and could not be rolled. Moreover, in the octopus seal (Comparative Example 5), although it could barely pass the trocar by making it into the crushed roll shape, it was damaged.

As described above, the sheet-like hemostatic material according to the present disclosure is superior in hemostasis performance and adhesion performance without using fibrinogen as compared with the conventional one, and can realize good flexibility and handleability.

From the above description, many modifications and other embodiments of the present invention are apparent to persons skilled in the art. Accordingly, the foregoing description should be construed as illustrative only and is provided for the purpose of teaching those skilled in the art the best mode of carrying out the invention. The details of the structure and / or function may be substantially changed without departing from the spirit of the invention.

The present invention can be widely and suitably used in the field of sheet-like hemostatic materials and production methods thereof.

10A to 10E Sheet-like hemostatic material 11 Adhesive layer 12 Cover layer 13 Intermediate layer 111 Partial adhesive layer (sponge-like)
121 Partial coating layer 121a-121c Partial coating layer 141 Partial adhesion layer (non-porous layer)

Claims

Characterized in that it is provided on the surface to be attached to the bleeding site and comprises an adhesive layer composed of at least poly-γ-glutamic acid,
Sheet-like hemostatic material.
And a coating layer formed on at least one biodegradable material excluding the poly-γ-glutamic acid provided on the opposite surface of the application surface,
At least one of the adhesive layer and the coating layer is a single sheet,
The sheet-like hemostatic material according to claim 1.
When the adhesive layer is the single sheet, the adhesive layer is a sponge sheet,
The sheet-like hemostatic material according to claim 2.
When the adhesive layer is a partial layer that is not the single sheet, the adhesive layer is a sponge-like sheet composed of at least poly-γ-glutamic acid, or a non-porous layer,
The sheet-like hemostatic material according to claim 2.
The coating layer is a sponge sheet composed of at least crosslinked collagen,
The sheet-like hemostatic material according to any one of claims 2 to 4.
Both the adhesive layer and the covering layer are a single sheet, or
The covering layer is a partial layer partially provided on the opposite surface,
The sheet-like hemostatic material according to claim 2, 3 or 5.
The adhesive layer and the covering layer are characterized in that at least a part thereof has a different color.
The sheet-like hemostatic material according to any one of claims 2 to 6.
The weight ratio of the adhesive layer is in the range of 10 to 90% by weight of the total weight of the sheet-like hemostatic material,
The sheet-like hemostatic material according to any one of claims 1 to 7.
Furthermore, comprising at least one intermediate layer interposed between the adhesive layer and the coating layer,
Each of these layers is fixed integrally,
The sheet-like hemostatic material according to any one of claims 2 to 8.
A first layered body composed of at least poly-γ-glutamic acid and a second layered body composed of at least one biodegradable material excluding the poly-γ-glutamic acid are laminated to form a laminate. And a process of
Forming a sheet-like hemostatic material comprising: an adhesive layer composed of at least poly-γ-glutamic acid; and a coating layer composed of the biodegradable material by bonding or pressure-bonding the laminate. ,
Including,
A method for producing a sheet-like hemostatic material.
The first layered body is a first sponge-like porous body composed of at least poly-γ-glutamic acid, a sponge-like first sheet obtained by applying pressure to the first sponge-like porous body, or at least a poly- a first partial sheet composed of γ-glutamic acid and not a single sheet,
The first partial sheet has a non-porous shape that is not sponge-like or sponge-like,
The second layered body is a second sponge-like porous body made of the biodegradable material, a sponge-like second sheet obtained by applying pressure to the second sponge-like porous body, or the biodegradable material And is a second partial sheet that is not a single sheet,
The manufacturing method of the sheet-like hemostatic material according to claim 10.
First, the pressure is applied to the second sponge-like porous body to form the sponge-like second sheet, and then the laminate is formed by laminating and pressing the first sponge-like porous body. To
The manufacturing method of the sheet-like hemostatic material according to claim 11.
A sheet comprising at least poly-γ-glutamic acid and further containing a saccharide is provided as an adhesive layer.
Sheet-like hemostatic material.
The saccharide is at least one of a monosaccharide, an oligosaccharide, and a polysaccharide,
The sheet-like hemostatic material according to claim 13.
The saccharide is added so as to be in the range of 10 to 90% by weight with respect to the total weight of the sheet,
The sheet-like hemostatic material according to claim 13 or 14.
Furthermore, collagen is added to the sheet,
The sheet-like hemostatic material according to any one of claims 13 to 15.
A sheet comprising at least poly-γ-glutamic acid and further having collagen added thereto is provided as an adhesive layer,
Sheet-like hemostatic material.
Including a step of forming an adhesive layer by adding at least one of saccharide and collagen to poly-γ-glutamic acid and forming into a sheet shape,
A method for producing a sheet-like hemostatic material.