JP4120848B2 - Hemostasis or tissue adhesive for living body - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a hemostatic or tissue adhesive for a living body that is useful during use and has a stable color tone during storage. More specifically, it comprises a paste component mainly composed of a gelatin protein, a collagen protein partial hydrolyzate such as gelatin and a polyphenol compound, and a hardening component composed of aldehydes, and is useful in use and has a color tone upon storage. Relates to a hemostatic or tissue adhesive for living organisms which is stable and has good biocompatibility.
[0002]
[Prior art]
In recent years, hemostatic or tissue adhesives for living bodies comprising an aqueous paste component mainly composed of a collagen protein partial hydrolyzate and a polyhydric phenol compound and a hardening component mainly composed of formaldehyde have been developed and already clinically applied. Yes. However, at present, no particular attention has been paid to the ease of use of the adhesive when urgent is required.
[0003]
When a gas-permeable plastic container is filled with the above-mentioned collagen protein partial hydrolyzate and polyphenol compound as the main components, the collagen protein partial hydrolyzate and polyhydric phenol, which are constituents thereof, are used. Although no increase in color was observed, which would be a problem when each compound was present alone, the paste containing both compounds had a marked brown color when subjected to ethylene oxide sterilization and deethylene oxide treatment after preparation. Increases coloration. Although the detailed mechanism is not clear, it often happens that the degree of coloration further increases during storage.
[0004]
When the above-described coloring occurs, the viscosity increases due to cross-linking, or handling as an adhesive becomes difficult by pulling a thread, and the living body is affected by the influence of coloring-causing substances such as oxides. There is also a problem in terms of safety. The development of a paste that can cope with an emergency without causing such an increase in coloration is an important issue.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a hemostatic or tissue adhesive for living organisms which is excellent in operability during use, has a stable color tone upon storage, and is excellent in biocompatibility.
[0006]
[Means for Solving the Problems]
As a result of diligent research in view of the above problems, the inventors of the present invention immediately filled an adhesive component and a curing agent component in a gas permeable plastic container and packaged together with an oxygen scavenger, so that it can be immediately performed in an emergency. It has become possible to cope with this, and it has been found that coloring does not occur after gas sterilization and degassing treatment, and the present invention has been achieved. That is, the present invention is a container filled with a gelatin protein partial hydrolyzate sterilized by ethylene oxide and a paste component mainly composed of a polyhydric phenol compound and a curable component mainly composed of aldehydes, and enclosed in a sterile bag. Furthermore, it is a hemostatic or tissue adhesive for living bodies characterized in that it is sealed in a packaging material made of an oxygen-impermeable material together with an oxygen scavenger.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, gelatin and / or glue is preferably used as the collagen protein partial hydrolyzate. Resorcin is preferably used as the polyhydric phenol compound. The weight ratio of collagen protein partial hydrolyzate / polyhydric phenol compound in the paste component is usually preferably in the range of 1/1 to 10/1. The weight ratio of the solid content (the sum of the weights of the collagen protein partial hydrolyzate and the polyhydric phenol compound) to water is usually preferably 10 to 70% by weight.
[0008]
As the aldehydes, aliphatic dialdehydes such as formaldehyde, glyoxal and glutaraldehyde are used, but glutaraldehyde and / or glyoxal are particularly preferable in view of low toxicity. The said aldehyde is used in the state of aqueous solution, The density | concentration is 5 to 40 weight% normally. A paste component mainly composed of a collagen protein partial hydrolyzate and a polyhydric phenol compound is prepared by mixing a collagen protein partial hydrolyzate and a polyphenol compound in an aqueous solution with heating in a conventional manner. Prepared.
[0009]
The prepared paste component and hardener component are preferably filled in a container that can be used in an emergency. In the present invention, the container is not particularly limited, but examples of the form thereof include a tube form, a vial form, a syringe barrel form, a spoid form, and an ampule form. Among these, considering the ease of use, it is particularly preferable to fill the syringe-shaped container.
[0010]
The container material is preferably a plastic container. Furthermore, it is more preferable that the gas permeability is excellent. Here, examples of the plastic container include existing containers mainly made of polypropylene, polyester, polyethylene, polycarbonate, polyvinyl chloride, etc., among which polyethylene, polypropylene, and polyester are preferable. Preferably, it is an injection cylindrical container which does not use rubber as a sealing material for the cylinder part, and examples thereof include a polypropylene cylindrical part / polyethylene cylinder part.
[0011]
In the present invention, the oxygen scavenger is not particularly limited, and a generally known oxygen scavenger can be used. However, non-toxicity is required for use in medical applications, as well as oxygen absorption. Those that sometimes do not generate other gas components are preferred. Specifically, those having active iron oxide as a main component are particularly preferable. Here, the active iron oxide refers to an iron compound having oxygen absorbability or an iron or iron compound subjected to chemical or physical treatment. The shape of the active iron oxide is not particularly limited, but is preferably powdered or granular from the viewpoint of absorption efficiency of oxygen or the like.
[0012]
In the present invention, the packaging material obtained from the oxygen-impermeable material is not particularly limited, and general known materials can be used. The oxygen permeability of the packaging material is preferably 20 ml / m ² · atm · 24 hr or less, and more preferably 10 ml / m ² · atm · 24 hr or less.
[0013]
Examples of the packaging material include polyethylene film, polyester, stretched polypropylene, ethylene vinyl alcohol copolymer, stretched polyvinyl alcohol, polyvinylidene chloride, stretched nylon, polyacrylonitrile, an aluminum foil, an aluminum vapor deposition layer, or What comprised the silica vapor deposition layer etc. is preferable. In particular, a polyester / aluminum / polyethylene laminate sheet, that is, an outer layer made of polyester, an intermediate layer made of an aluminum foil or an aluminum vapor-deposited layer, and an inner layer made of polyethylene is preferred from the viewpoint of oxygen impermeability. In this case, the thickness of the outer layer and the inner layer is preferably in the range of 5 to 70 μm, and more preferably in the range of 10 to 50 μm. The thickness of the intermediate layer is preferably in the range of 3 to 30 μm, more preferably in the range of 5 to 15 μm.
[0014]
The degree of coloration of the hemostasis or tissue adhesive of the present invention is preferable when the color difference value of reflected light measured using a standard white plate as a control sample is quantified with a color difference meter, and the smaller the value, the less the degree of coloring. In general, it is preferably 85.0 or less, and more preferably 80.0 or less. If the quantitative value is 90.0 or more, the thread is pulled, which is not preferable.
[0015]
【Example】
Hereinafter, the present invention will be described in detail by way of examples. In addition, this invention is not specifically limited by an Example.
[0016]
<Example 1>
14.0 parts by weight of reagent-grade resorcin was dissolved in 75 parts by weight of distilled water for injection in a mixing container, and then 46.7 parts by weight of food gelatin powder was added, followed by stirring and mixing in a 50 ° C. warm bath for 60 minutes. 3 ml of the obtained gelatin / resorcin glue was placed in a glass cell having a diameter of 30 mm and a depth of 12 mm, and the color difference of reflected light measured using a standard white plate as a control sample using a Z-300A color difference meter manufactured by Nippon Denshoku Industries Co., Ltd. The value was 75.30.
[0017]
The obtained gelatin / resorcin paste was filled into a 10 ml polypropylene / polyethylene syringe, sealed in a sterilized bag, sterilized with ethylene oxide by a conventional method, and then deethylene oxide treated at 40 ° C. for 72 hours. Went. Subsequently, a laminating sheet of polyester / aluminum / polyethylene (size: 220 mm × 300 mm; thickness of each layer) in the presence of an oxygen scavenger (trade name: Ageless Z-PT200; manufactured by Mitsubishi Gas Chemical Co., Inc.) : 12 μm, 7 μm and 40 μm, respectively, sealed in packaging materials obtained from AGELESS / bag), sealed, stored at 4 ° C. for 30 days, and the measured color difference value was 78.50 (light yellow )Met.
[0018]
<Example 2>
The same treatment as in Example 1 was performed except that the storage temperature was 40 ° C. in Example 1. After storage for 30 days, the measured color difference value was 81.69 (light brown, practically problematic in physical properties) There was no).
[0019]
<Comparative Example 1>
After the gelatin / resorcin glue prepared in Example 1 was filled in a 10 ml capacity polypropylene / polyethylene syringe in the same manner as in Example 1, ethylene oxide sterilization and deethylene oxide treatment were performed in the same manner as in Example 1. The color difference measured after storage for 30 days at 4 ° C. without using a packaging material obtained from an oxygen scavenger and a polyester / aluminum / polyethylene laminate sheet was 85.16 (brown brown, increased viscosity). I admit).
[0020]
<Comparative example 2>
After the gelatin / resorcin glue prepared in Example 1 was filled in a 10 ml capacity polypropylene / polyethylene syringe in the same manner as in Example 1, ethylene oxide sterilization and deethylene oxide treatment were performed in the same manner as in Example 1. The color difference measured after storage for 30 days at 40 ° C. without using a packaging material obtained from an oxygen scavenger and a polyester / aluminum / polyethylene laminate sheet was 96.50 (almost blackish brown, The rise was recognized and the thread was pulled).
[0021]
【The invention's effect】
According to the present invention, a hardening comprising a paste component and aldehydes mainly composed of a collagen protein partial hydrolyzate and a polyhydric phenol compound filled in a gas permeable container and enclosed in a gas permeable sterilization bag. After the agent component is sterilized with ethylene oxide, it is sealed in a packaging material obtained from an oxygen-impermeable material together with an oxygen scavenger, making it easy to handle in terms of operability during use and suppressing coloration during storage. A living hemostatic or tissue adhesive can be obtained.

Claims (6)

The gelatin protein partially hydrolyzed substance sterilized by ethylene oxide and the paste component mainly composed of polyhydric phenol compound and the curing component mainly composed of aldehydes are filled in separate containers and sealed in a sterilized bag. Further, a hemostatic or tissue adhesive for living bodies, which is sealed in a packaging material made of an oxygen-impermeable material together with an oxygen scavenger.   The hemostatic or tissue adhesive for living body according to claim 1, wherein the collagen protein partial hydrolyzate is gelatin or glue.   The hemostatic or tissue adhesive for living body according to claim 1 or 2, wherein the polyhydric phenol compound is resorcin.   The hemostatic or tissue adhesive for living body according to any one of claims 1 to 3, wherein the oxygen scavenger is mainly composed of active iron oxide.   The hemostatic or tissue adhesive for living body according to any one of claims 1 to 4, wherein the container to be filled contains at least one selected from the group consisting of polyethylene, polypropylene and polyester as a component.   The hemostatic or tissue adhesive for living body according to any one of claims 1 to 5, wherein the oxygen-impermeable material is a laminate of polyester / aluminum / polyethylene.