JP2017196406A - SHEET-LIKE HEMOSTATIC AGENT USING POLY-γ-GLUTAMIC ACID - Google Patents

Abstract

PROBLEM TO BE SOLVED: To realize good hemostatic performance dispensing with the usage of fibrinogen, and further realize good flexibility and handleability.SOLUTION: A sheet-like hemostatic agent 10A or 10B composed of at least poly-γ-glutamic acid includes an adhesion layer 11 becoming a patching surface for a bleeding part, and a covering layer 12 which is a sheet composed of at least 1 biodegradable material (covering material) except for γ-PGA and becomes an opposite surface of the patching surface. At least one of the adhesion layer 11 and the covering layer 12 is a single layer. When the adhesion layer 11 is a single layer, the layer may be a sponge-like layer. When a part layer, it may be a sponge-like layer or a nonporous layer. At least 1 layer of an intermediate layer 13 may be provided between the adhesion layer 11 and the covering layer 12.SELECTED DRAWING: Figure 1

Description

  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 in a surgical operation or the like, the use of a sheet-like hemostatic material is known as one method of 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

  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-described octopus seal has a good hemostatic performance, it has a slightly hard sponge shape as described above, and thus has no flexibility to be inserted into the 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 oxycellulose-based sheet-like hemostatic material, is more flexible than an octopus seal, and does not use fibrinogen and 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.

  Moreover, 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 provided on an attachment surface to a bleeding site and includes an adhesive layer composed of at least poly-γ-glutamic acid.

  According to the said structure, in order to make the sticking surface of a sheet-like hemostatic material into the contact bonding layer comprised by poly-gamma-glutamic acid (gamma-PGA), animal materials, such as a fibrinogen, are used by gamma-PGA of a contact bonding 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 pasted at an appropriate position, Unlike a hemostatic material, it can be re-applied to a living tissue.

  In the sheet-like hemostatic material having the above-described structure, the adhesive layer 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, the adhesive surface is provided with an adhesive layer composed of poly-γ-glutamic acid (γ-PGA) on the affixing surface, and biodegradability other than γ-PGA is provided on the opposite surface which is a non-adhesion surface. A coating layer made of a material (coating material) is provided. Therefore, by using γ-PGA of the adhesive layer, it is possible to realize good adhesion to living tissue and good hemostatic performance without using animal materials such as fibrinogen, and by 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.

  Moreover, according to the said structure, since at least one of an adhesion layer and a coating layer is a single sheet | seat, an adhesion layer or a coating layer, or both can function as a base material of a 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 as a coating layer.

  Moreover, 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 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.

  Moreover, 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.

  In the sheet-like hemostatic material having the above-described configuration, the weight ratio of the adhesive layer may be in the range of 10 to 90% by weight with respect to 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-like hemostatic material according to the present invention includes at least a first layered body composed of poly-γ-glutamic acid and at least excluding the poly-γ-glutamic acid. A step of forming a laminated body by laminating a second layered body composed of one kind of biodegradable material, and an adhesive composed of at least poly-γ-glutamic acid by adhering or pressing the laminated 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.

  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.

(A) And (B) is typical sectional drawing which shows schematic structure of the sheet-like hemostatic material which concerns on typical embodiment of this indication. (A)-(C) are typical sectional drawings which show the modification of the sheet-like hemostatic material which concerns on this Embodiment. (A)-(C) are typical top views which show an example of the opposite surface of the sticking surface in the sheet-like hemostatic material shown to FIG. 2 (A).

  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 And a coating layer made of at least one biodegradable material excluding the poly-γ-glutamic acid provided on the opposite surface of the sticking surface, wherein 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. 1 (A) or FIG. 1 (B) schematically illustrates 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 illustrate 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 10 </ b> A to 10 </ b> E include 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. As shown in FIG. 2C, if the adhesive layer 11 is a non-porous shape that is not sponge-like, it may be a partial layer described later. The coating layer 12 may be a sheet having a biodegradable material other than γ-PGA as a main component, and in the present embodiment, as will be described later, it is a sponge sheet having a cross-linked collagen as a main component. . In the following description, biodegradable materials other than γ-PGA are referred to as “coating materials” for convenience.

  The adhesive layer 11 constitutes a sticking surface (back surface) for attaching the sheet-like hemostatic materials 10A to 10E to a bleeding site such as a living tissue, and has good adhesiveness to the living tissue. As shown in FIG. 1 (A), FIG. 1 (B), or FIG. 2 (A), the adhesive layer 11 may be provided as a single layer that covers the entire surface of the sticking surface. As shown in FIG. 2C, it may be provided as a partial layer that partially forms the pasting surface. 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 surface of the opposite surface as shown in FIG. 1A or FIG. 1B, or the opposite surface may be provided as shown in FIG. It may be provided as a partial layer that partially covers.

  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 it is going to affix the sheet-like hemostatic material 10A-10E on a bleeding part, the possibility of adhering carelessly to parts other than a bleeding part or a surgical instrument etc. can be suppressed effectively. That is, the coating layer 12 has a function of covering the other surface and suppressing the adhesiveness so that only one surface of the sheet-like hemostatic materials 10A to 10E becomes the pasting surface.

  As described above, the adhesive layer 11 is composed of γ-PGA if the sheet-like hemostatic materials 10A to 10D shown in FIG. 1 (A), FIG. 1 (B), FIG. 2 (A) or FIG. The covering layer 12 may be a sheet made of a covering material, and may be any sheet that can exhibit flexibility when at least 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.

  The spongy sheet here 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 or layer with γ-PGA or a composition containing the same as the main component, and the above-mentioned numerous 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).

  Moreover, 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 a 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 shown in FIG. 1 (A) has a two-layer structure including only the adhesive layer 11 and the covering layer 12, the present disclosure is not limited to this, and the sheet shown in FIG. 1 (B). As in the hemostatic material 10B, 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 an affixed 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 covering 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, the case where the sheet-like hemostatic materials 10A to 10E are sewn near the bleeding site is assumed. 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 each configured as a single sheet, as in the sheet-like hemostatic material 10A illustrated in FIG. 1A, but the present disclosure is limited to this. Not. 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. If it demonstrates as a layer which comprises the sheet-like hemostatic materials 10A-10E, when the adhesive layer 11 or coating layer 12 comprised as a "single sheet | seat" affixed the sheet-like hemostatic materials 10A-10E to a hemostatic location 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 covering layer 12 is not a single sheet, that is, a configuration in which it is a partial layer will be described in detail. 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 partial adhesive layer (partial layer) 111 which partially covers an adhesive surface like the sheet-like hemostatic material 10D shown to FIG. 2 (B). . 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 a softness | flexibility so that it may mention later by being comprised by sponge shape. Therefore, as shown in FIG. 1A or 1B, even if the adhesive layer 11 is a single sheet, the adhesive layer 11 is a partial adhesive layer 111 as shown in FIG. Even if constituted, good flexibility can be exhibited. 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 illustrated in Comparative Example 3 described later. However, if the adhesive layer 11 is formed as the partial adhesive layer 141 even if it is a non-porous material mainly composed of γ-PGA, 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, and excludes 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 partly applied The sheet-like hemostatic material 10D configured as the sponge-like partial adhesive layer 111 provided, and (4) the coating layer 12 is provided as a single layer (single sheet) covering the entire opposite surface of the adhesive layer 11 The sheet-like hemostatic material 10 </ b> E in which the adhesive layer 11 is configured as a non-porous partial adhesive layer 141 partially provided on the pasting surface is included.

  In the present disclosure, if the adhesive layer 11 is a sponge sheet composed of γ-PGA, good flexibility can be obtained even if the adhesive layer 11 is a single sheet, like 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 as long as it is configured as a partial layer (partial sheet) that is not a single sheet. For example, the partial coating layer 121 will be described as an example. As shown in FIG. 3A, the partial coating layer 121a may be a dot-shaped partial coating layer 121a, or as shown in FIG. The partial coating layer 121b may be used, or as shown in FIG. 3C, a shaded partial coating layer 121c may be used, or a shape other than these may be used.

  As described above, the partial layer or the partial sheet is a member assembly (see FIG. 3A or FIG. 3B) configured by a plurality of planar members such as dots or lines. Alternatively, 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 mesh shape. A configuration as combined (a configuration in which a plurality of single planar members having a plurality of openings are combined into a member assembly) may be employed.

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

  Similarly, specific examples of the partial adhesive layer 111 or the partial adhesive layer 141 can also be dot-like, linear, or 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 coating layer 12 may be integrally fixed to form a single 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. Further, in the sheet-like hemostatic material 10E, the partial adhesive layer 141 does not need to be processed into a sponge shape, so a non-porous partial sheet made of γ-PGA formed in a predetermined shape is used as the coating 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 coating layer 12 included in the sheet 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 by visual observation which surface is the sticking 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. Further, the method of adding a dye or the like is not particularly limited, and the dye or the like is added to 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). In addition, after the sheet-like hemostatic materials 10A to 10E are manufactured, any one of the adhesive layer 11 and the coating layer 12 may be colored with a pigment or the like. 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 preferable that it exists in the range of 10 to 90 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, although depending on the configuration of the sheet-like hemostatic materials 10A to 10E. Moreover, if the adhesive layer 11 exceeds 90% by weight, the covering layer 12 may not sufficiently exert the effect of suppressing the adhesiveness of the adhesive layer 11 depending on the configuration of the sheet hemostats 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 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-like hemostatic materials 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 here refers to the range of 1 to 30 ° C. defined by the Japanese Pharmacopoeia. The adhesive layer 11 showing hemostasis performance in the sheet-like hemostatic materials 10A to 10E is composed of γ-PGA as described above, but 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 the temperature usually exceeds 25 ° C. in summer. 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 of only 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 peptide-bonded by a carboxyl group at the γ-position and an amino group at the α-position, and a linear chain, and salts thereof. Examples of the salt of γ-PGA include 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”.

  Although it does not specifically limit as γ-PGA used as the adhesive layer 11, for example, those having a molecular weight within a specific range can be suitably used. As a preferable molecular weight range of γ-PGA, the weight average molecular weight Mw can be in the range of 200,000 to 13 million, and 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), good adhesiveness on the application surface may be obtained depending on the configuration of the adhesive layer 11 or the sheet-like hemostatic materials 10A to 10E. May not be possible. In addition, although the upper limit of the weight average molecular weight Mw of (gamma) -PGA is not specifically limited, Usually, it will be 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.

  Moreover, as γ-PGA used as the adhesive layer 11, 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. Preferably, it can be in the range of 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 affixing 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. In addition, although the upper limit of kinematic viscosity (nu) of (gamma) -PGA is not specifically limited, Usually, it will be 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 kinematic viscosity ν of γ-PGA may deviate from the above-mentioned range depending on the constitution 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 above-described 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 in terms of technical common sense, 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 blending amount of the other components with respect to the γ-PGA composition is not particularly limited as long as the adhesiveness of the adhesive layer 11 is not hindered. Usually, what is necessary is just a compounding quantity that (gamma) -PGA does not become less than 50 weight% among (gamma) -PGA composition whole quantity. 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 a (gamma) -PGA composition contains saccharides, while being able to provide the softness | flexibility to the contact bonding layer 11, the further improvement of adhesiveness can also be anticipated.

[Coating material]
As described above, the coating layer 12 is a sheet (preferably a sponge sheet) composed 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 only needs to exhibit good biocompatibility when introduced into a living body together with γ-PGA and be 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 being introduced into the living body, is excellent in degradability in the living body, and does not substantially exhibit adhesion compared to γ-PGA.

  Although the specific structure of collagen is not specifically limited, Preferably, the collagen processed so that it can melt | dissolve in a well-known solvent can be mentioned. 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, it is preferable that the coating layer 12 is comprised by crosslinked 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 crosslinking 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. If it is, other components can be blended within the range that does not interfere with the physical properties of the coating layer 12, as in the case of 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 a sheet-like hemostatic material according to the present disclosure is not particularly limited as long as it is a method capable of producing a sheet-like hemostatic material having sufficient flexibility by forming an adhesive layer composed of at least γ-PGA. As described above, the sheet hemostats 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 that is a sponge-like sheet made of γ-PGA or a non-porous partial sheet, a coating layer 12 that 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 typical 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 pressure-bonding the laminate (integration process). ) And it may include manufacturing method comprising the.

  Moreover, the manufacturing method of 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 freeze-drying 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. 1 (A) 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 that is composed of at least γ-PGA and is 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 the 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 constituted by, and an adhesive layer constituted by at least γ-PGA by bonding or pressure-bonding the laminated body, and a biodegradable material 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, by using γ-PGA of the adhesive layer, it is possible to realize good adhesion to living tissue and good hemostatic performance without using animal materials such as fibrinogen, and by 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.

  Moreover, since the adhesive layer is a sponge-like 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 accompanying 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.

  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. In addition, evaluation of the sheet-like hemostatic material in the following examples and comparative examples was performed 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 the sheet-like hemostatic material of Example or Comparative Example was applied. I attached. The hemorrhage performance was evaluated by confirming the state of bleeding after pasting. Further, it was also evaluated whether or not the sheet-like hemostatic material of the example or the comparative example could be re-applied after being applied to the bleeding site of the liver.

(Evaluation of trocar passability)
The sheet-like hemostatic material of the example or the comparative example was rolled into a roll shape, and it was evaluated whether it could pass through a trocar having a diameter of 5 mm (manufactured by Covidien Japan Co., Ltd., product name Step System Berserstep 5MM).

Example 1
A 1 wt% collagen aqueous solution was prepared, 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.), and then a compressor (stock) 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.). Thereby, 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 in which the γ-PGA sponge-like sheet as the adhesive layer and the cross-linked collagen sponge-like sheet as the coating layer were pressure-bonded was obtained.

  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 cross-linked 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 mg 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 of Examples and Comparative Examples)
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 not a sponge with a γ-PGA single layer, the γ-PGA sheet 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.

  It should be noted that the present invention is not limited to the description of the above-described embodiment, and various modifications are possible within the scope shown in the scope of the claims, and are disclosed in different embodiments and a plurality of modifications. Embodiments obtained by appropriately combining the technical means are also included in the technical scope of the present invention.

  INDUSTRIAL APPLICABILITY The present invention can be used widely and suitably in the field of sheet-like hemostatic materials and methods for producing the same.

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 (12)

It is provided on an adhesive surface to a bleeding site, and is provided with an adhesive layer composed of at least poly-γ-glutamic acid,
Sheet-like hemostatic material. Furthermore, provided on the opposite surface of the pasting surface, comprising a coating layer composed of at least one biodegradable material excluding the poly-γ-glutamic acid,
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 at least a sponge-like sheet composed of 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 laminated body is formed by laminating at least a first layered body composed of poly-γ-glutamic acid and a second layered body composed of at least one biodegradable material excluding the poly-γ-glutamic acid. 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.

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