Liquid medical materials

Abstract

To provide a liquid medical material that maintains a sol state at ordinary temperature and furthermore has a high function as a hemostatic material than fibrin glue, is safe, and can be manufactured inexpensively.SOLUTION: A liquid medical material includes: gelatin aqueous solution which includes calcium of a concentration of 0.2 M or more and 1.0 M or less, and has a concentration of 5 wt.% or more and 20 wt.% or less, and has an average molecular weight of 80,000 or more and 120,000 or less, and a molecular weight distribution of 20,000 or more and 300,000 or less; and thrombin. The ratio of the calcium concentration [M] to the gelatin weight concentration [wt%] in the gelatin aqueous solution is preferably 0.005 to 0.040 [M / wt%].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a liquid medical material. [Background technology]

[0002] Tissue occlusion, which prevents leakage of bodily fluids (blood, tissue fluid, etc.) due to tissue damage in the body, is of great clinical importance in surgery, etc. Effectively preventing leakage of bodily fluids from the damaged area leads to maintaining the patient's life during surgery and improving the quality of life (QOL) after surgery.

[0003] In clinical practice, hemostasis is important for the following reasons: 1. Blood loss is one of the major causes of death, and causes of blood loss include severe trauma, aneurysms, ulcers in the esophagus or stomach, and rupture of esophageal varices. The risk of death is particularly high when emergency hemostatic treatment is not available. 2. Bleeding during surgery is one of the major concerns in surgery, as it can lead to systemic infections and organ dysfunction. Not only does bleeding impede the surgical field, but the removal of bleeding blood can delay the operation. 3. Bleeding can be a problem even when minimally invasive surgery (e.g., laparoscopic surgery) is performed, and may require conversion to open surgery if bleeding cannot be adequately controlled.

[0004] Existing methods for hemostasis include the following: 1. Direct pressure on the blood vessels at the bleeding site (compressive hemostasis). The disadvantages of this method of hemostasis are that it takes time and effort, the pressure must be maintained, and there is a risk of hematoma forming in the patient. 2. Other physical methods of hemostasis include clamping or clipping the area near the bleeding site, and placing a plug or sponge on the bleeding site. The disadvantage of these hemostasis methods is that they are difficult to handle when bleeding occurs from many small blood vessels. 3. A method in which heat is used to coagulate the blood and cauterize the bleeding blood vessel (electric scalpel). The drawbacks of this method are that it causes thermal damage to the surrounding tissue, making it highly invasive to the patient, and that it requires medical equipment and expertise (it cannot be used outside of medical institutions).

[0005] Existing hemostatic materials include the following: 1. Alginic acid 2. Gelatin sponge 3. Collagen fibers 4. Fibrin glue. 5. Self-assembly of synthetic peptides Of the above, collagen fibers and fibrin glue are often used clinically as effective hemostatic materials.

[0006] Vascular suturing is sometimes required not only in cardiac and vascular surgery, but also in general intraperitoneal surgery. Since a small amount of blood leaks from the vascular suture site after surgery, there is a demand for a hemostatic material that can continuously suppress this leakage.

[0007] Biliary fistula and pancreatic fistula are symptoms that occur when bile or pancreatic juice leaks due to biliary surgery, pancreatitis, pancreatic surgery, etc., and adversely affect other organs. Currently, there are no known substances that can effectively suppress bile or pancreatic juice leakage and are clinically applicable, and there is a need for a safe and effective method to prevent biliary fistula and pancreatic fistula.

[0008] There are known conditions in the lungs where air leaks out due to spontaneous pneumothorax, which occurs when the alveolar sac ruptures, or traumatic pneumothorax, such as rib fractures or catheter puncture. Depending on the symptoms, there is no choice but to wait for natural healing, but a method that can adhere to the lung tissue by simply layering it on top of the affected area and close the hole in the sac is considered to be one of the simplest and safest ways to treat pneumothorax.

[0009] With the development of endoscopic technology, techniques for endoscopically resecting lesions have been developed. In particular, surgical methods for endoscopically resecting lesions such as polyps and early cancers (superficial cancers that are thought not to metastasize to lymph nodes) in the digestive tract, including the esophagus, stomach, or intestines, have been established. In endoscopic mucosal resection, hypertonic saline or the like is generally injected into the submucosa including the lesion to elevate the lesion, and the tissue including the lesion is resected using an electric scalpel while grasping the part to be resected. In this procedure, a solution such as hypertonic saline is injected into the submucosa to separate the lesion from the proper muscularis layer. However, there is a problem in that low-viscosity solutions such as saline cannot maintain the elevation of the lesion during surgery, and there is a demand for an injection solution that can maintain the elevation of the affected area during surgery.

[0010] With the development of catheter therapy, surgical methods have been established to eliminate tumors, myomas, etc. by occluding the arteries that flow into lesions controlled by the blood flow of tumors, myomas, etc. Specific examples include hepatic vein occlusion, uterine artery occlusion, and cerebral artery occlusion. In this procedure, liquids such as urethane precursors and ethylene vinyl alcohol are injected to block the artery, but they are undoubtedly toxic to the body and their use is limited unless the condition is severe. Therefore, there is a need to develop an injectable liquid that is free of the risk of infection and has low toxicity to the body. Furthermore, there is a demand for injectable solutions that can contain anticancer drugs and contrast agents.

[0011] In recent years, highly controlled self-assembling peptides have been attracting attention as new materials due to their physical, chemical, and biological properties (see Patent Document 1). Due to their amino acid sequence, they have the property of forming self-assemblies in which a large number of peptide molecules are regularly arranged. Self-assembling peptides have a structure in which charged hydrophilic amino acids and electrically neutral hydrophobic amino acids are arranged alternately, with positive and negative charges being distributed alternately, and they adopt a β structure at physiological pH and salt concentrations.

[0012] In the application of self-assembling peptides to hemostasis, continuous blood leakage was observed from the end of the incision in the liver, and complete hemostasis was not achieved. The reason for the incomplete hemostasis is presumed to be due to insufficient adhesion between the self-assembling peptide gel and the tissue. Therefore, further improvements are required to bring out the hemostatic effect of the self-assembling peptide to a level that can be used clinically.

[0013] Similar to fibrin glue, polyamine-aldehyde systems, which are used clinically and are made by adding cross-linking agents such as formaldehyde and glutaraldehyde to gelatin, are by no means satisfactory, as they may cause sequelae such as vascular occlusion and low molecular weight aldehydes are highly damaging to nerves and tissues.

[0014] In order to overcome these problems, many studies have been conducted. For example, adhesives based on cross-linked Schiff base formation using dextran and ε-poly-L-lysine (hereinafter also simply referred to as ε-PLL) made from food additives have been studied (see, for example, Patent Document 2).

[0015] Furthermore, as adhesives with high strength, tissue adhesives containing active ester derivatives of citric acid and proteins such as collagen as adhesive components are also being researched (see, for example, Patent Document 3).

[0016] In addition, a composition that can be used as a wound dressing and hemostatic material has been disclosed, which contains cross-linkable gelatin, transglutaminase, calcium, and urea in a solution combining an acetate buffer and a citrate buffer (see, for example, Patent Document 4).

[0017] In addition, an absorbent topical hemostatic material using gelatin containing human thrombin is commercially available. This hemostatic material is used by mixing granular cross-linked gelatin, dried human thrombin, and calcium chloride solution at the time of use. The mixture of cross-linked gelatin and thrombin solution is a viscous fluid. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] WO2010 / 041636 International Publication [Patent Document 2] International Publication No. 2009 / 057802 [Patent Document 3] JP 2004-261222 A Summary of the Invention [Problem to be solved by the invention]

[0019] However, although the tissue occluding agent described in Patent Document 1 is a self-assembling peptide, it has a problem in that it has a lower hemostatic effect than fibrin glue. Furthermore, the adhesive made from the ε-PLL raw material described in Patent Document 2 has a gel strength inferior to that of fibrin glue, which is a commercially available hemostatic agent, and there is concern about its insufficient strength as a hemostatic material. Furthermore, in the tissue adhesive described in Patent Document 3, the active ester compound is chemically unstable and cannot be stored in an aqueous solution for a long period of time, so that it must be dissolved in a solvent that carries the risk of adversely affecting the living body immediately before use. Furthermore, there is a problem in that when a doctor needs to use the tissue adhesive in an emergency, such as in a surgical operation, the tissue adhesive cannot be used immediately, which is highly likely to cause problems. Another problem is that these adhesives are very expensive.

[0020] Commercially available absorbable local hemostatic materials using gelatin containing human thrombin have the problem of undergoing a sol-gel phase transition at room temperature. Therefore, the gel is chopped into small pieces to improve fluidity even at low temperatures, but there is a limit to how much concentration can be increased, and at the same time, the system becomes non-uniform, making it difficult to apply the material evenly to the bleeding area when used in the surgical field. In addition, because the gel is opaque, there is also the problem that it is impossible to directly view the surgical field.

[0021] The present invention has been made with attention to these problems, and aims to provide a liquid medical material that maintains a sol state at room temperature, has better hemostatic function than fibrin glue, is safe, and can be produced at low cost. [Means for solving the problem]

[0022] In order to achieve the above object, the present inventors conducted extensive research and discovered that there are optimal gelatin types, gelatin concentrations, and calcium concentrations, leading to the completion of the present invention. That is, the liquid medical material according to the present invention contains a hydrophilic polymer compound containing calcium and thrombin. nothing. In particular, the liquid medical material according to the present invention contains a gelatin aqueous solution containing calcium and thrombin. nothing.

[0023] Furthermore, the liquid medical material according to the present invention comprises an aqueous gelatin solution containing calcium at a concentration of 0.2M to 1.0M, a concentration of 5% by weight to 20% by weight, an average molecular weight of 80,000 to 120,000, and a molecular weight distribution of 20,000 to 300,000, and thrombin. nothing. In the liquid medical material according to the present invention, it is preferable that the calcium has a concentration of 0.5 M or more and 0.7 M or less, the gelatin has a bloom of 160 or more and 250 or less, and the thrombin has an activity of more than 200 U / g and less than 1000 U / g.

[0024] In the liquid medical material according to the present invention, the ratio of the calcium concentration [M] to the gelatin weight concentration [wt %] in the aqueous gelatin solution is preferably 0.005 to 0.040 [M / wt %]. The liquid medical material according to the present invention is, for example, a biological tissue adhesive, a hemostatic material, a cell preservation solution, an organ preservation solution, an artificial ointment, an alveolar bone reconstruction agent, an agent for preventing adhesion of biological tissue, an agent for elevating mucous membranes, an agent for preventing post-bleeding, or an embolization material for intravascular treatment. The liquid medical material according to the present invention is particularly preferably an arterial hemostatic material. The liquid medical material according to the present invention maintains a sol state at room temperature, has a higher hemostatic function than fibrin glue, is safe, and can be produced at low cost. Effect of the Invention

[0025] According to the present invention, it is possible to provide a liquid medical material that maintains a sol state at room temperature, has a higher hemostatic function than fibrin glue, is safe, and can be produced at low cost. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Hereinafter, a liquid medical material according to an embodiment of the present invention will be described. The liquid medical material according to an embodiment of the present invention is characterized in that it contains a hydrophilic polymer compound containing calcium and thrombin. Examples of hydrophilic polymer compounds include collagen, gelatin, collagen peptide, hyaluronic acid, alginic acid, chitin, chitosan, cellulose, hydroxypropyl cellulose, and modified starch. In particular, it is preferable to use one or more combinations of collagen, gelatin, collagen peptide, and water-soluble cellulose, which can be dissolved in water and have excellent processability, as the hydrophilic polymer compound, and more preferably, it is made of collagen, gelatin, or collagen peptide with a molecular weight of 2,000 to 300,000 or hydroxypropyl cellulose with a molecular weight of 2,000 to 300,000, with reduced antigenicity, and particularly preferably a molecular weight of 30,000 to 100,000. The hydrophilic polymer compound may be made of a mixture of collagen peptide with a molecular weight of 2,000 to 10,000 or a molecular weight of 10,000 to 30,000 and gelatin or collagen with an average molecular weight of 30,000 to 100,000. The calcium may be, for example, calcium chloride or calcium carbonate, and is preferably, in particular, calcium chloride. In particular, the liquid medical material according to the embodiment of the present invention preferably contains an aqueous gelatin solution containing calcium and thrombin.

[0027] Furthermore, the liquid medical material of an embodiment of the present invention preferably contains an aqueous gelatin solution containing calcium at a concentration of 0.2 M to 1.0 M, a concentration of 5% by weight to 20% by weight, an average molecular weight of 80,000 to 120,000, and a molecular weight distribution of 20,000 to 300,000, and thrombin. In the liquid medical material according to an embodiment of the present invention, it is preferable that the calcium has a concentration of 0.5 M or more and 0.7 M or less, the gelatin has a bloom of 160 or more and 250 or less, and the thrombin has an activity of more than 200 U / g and less than 1000 U / g. In the liquid medical material according to an embodiment of the present invention, the ratio of the calcium concentration [M] to the gelatin weight concentration [wt %] in the aqueous gelatin solution is preferably 0.005 to 0.040 [M / wt %]. With this blend ratio, the composition has viscoelasticity while remaining deformable down to -10°C, and has high tissue adhesion to organs.

[0028] The liquid medical material according to the embodiment of the present invention is, for example, a tissue adhesive, a hemostatic material, a cell preservation solution, an organ preservation solution, an artificial ointment, an alveolar bone reconstruction agent, an agent for preventing adhesion of biological tissue, a mucous membrane protuberance agent, an agent for preventing post-bleeding, or an embolization material for intravascular treatment. The liquid medical material according to the embodiment of the present invention may be used for other purposes utilizing its film-forming properties, binding properties, and oxygen barrier properties. In particular, it is suitable for use in endoscopes, highly-regulated medical devices (Class IV), and catheters. The liquid medical material according to the embodiment of the present invention is particularly preferably an arterial hemostatic material. In the present invention, "blood" may be human blood or non-human blood. The liquid medical material according to the embodiment of the present invention maintains a sol state at room temperature, has a higher hemostatic function than fibrin glue, is safe, and can be produced at low cost. When the liquid medical material according to the embodiment of the present invention is mixed with blood, it instantly solidifies and forms a highly viscoelastic film. In the liquid medical material according to the embodiment of the present invention, a phenomenon occurs in which the hydrophilic polymer composition does not undergo a sol-gel transformation. EXAMPLES

[0029] The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In the following examples, "%" means % by weight.

[0030] (Test 1) The following gelatin / calcium aqueous solutions were prepared: Gelatin types: A: Average molecular weight 100,000 (distribution 20,000-300,000) acid-processed gelatin B: Alkaline-processed gelatin with average molecular weight of 100,000 (distribution: 20,000 to 300,000) C: Gelatin (polypeptide) with average molecular weight of 20,000 D: Gelatin with a molecular weight of approximately 100,000 (distribution 80,000 to 120,000) Gelatin concentration: 5-40wt% (5, 10, 20, 30, 40wt%) Calcium concentration: 0.0 to 1.0M (0, 0.2, 0.4, 0.5, 0.7, 1.0M) (1) 5, 10, 20, 30, and 40 wt% gelatin / water solutions of A, B, C, and D were prepared. At 25℃, gelatin solutions A, B, and D solidified at 5% concentration. Gelatin solution C did not solidify even at 40% concentration and remained in a fluid state. (2) For A, B, and D, aqueous gelatin / calcium solutions with the gelatin and calcium concentrations shown in Table 1 were prepared. The state of each gelatin / calcium aqueous solution was observed at 25°C and evaluated as either solidified, fluid, or highly viscous. Solidification: The aqueous solution does not move at all even when the sample is turned over. Flow: When the sample is inverted, the aqueous solution starts to move. Strong viscosity: When the sample is inverted, the liquid level begins to move slightly after a while.

[0031] [Table 1]

[0032] From the above results, an aqueous solution that is not solidified, i.e., highly viscous and fluid, at 25° C. is selected. The selection conditions are as follows: <Condition> A, B: 0% < suitable condition ≦ 40% gelatin < up to the concentration at which gelatin aqueous solution is created 0.2M calcium ≦ Suitable conditions ≦ 1.0M calcium ≦ Up to the concentration at which a calcium aqueous solution can be created C: 0% < suitable condition ≦ 40% gelatin < up to the concentration at which gelatin aqueous solution is created 0M calcium < suitable conditions < calcium aqueous solution concentration D: 0% < suitable conditions < 40% gelatin 0.2M calcium ≦ Suitable conditions ≦ 1.0M calcium ≦ Up to the concentration at which a calcium aqueous solution can be created

[0033] 100 μL of blood, 100 μL of 20% gelatin / 0.2 M calcium aqueous solution (material α) and 50 μL of thrombin (TB) were mixed and the solidification time was measured. The conditions and results are shown in Table 2.

[0034] [Table 2] TIFF0007625189000003.tif187136

[0035] As shown in Table 2, when the 20% gelatin / 0.2M calcium aqueous solution (material α) of B did not solidify at 25°C and was mixed with thrombin and blood, clots formed throughout the solution, resulting in a non-soft solution.

Claims

1. A liquid medical material comprising: an aqueous gelatin solution containing calcium at a concentration of 0.2 M to 1.0 M, a concentration of 5% by weight to 20% by weight, an average molecular weight of 80,000 to 120,000, and a molecular weight distribution of 20,000 to 300,000; and thrombin.

2. 2. The liquid medical material according to claim 1, wherein the calcium has a concentration of 0.5M or more and 0.7M or less, the gelatin has a bloom value of 160 or more and 250 or less, and the thrombin has an activity of more than 200 U / g and less than 1000 U / g.

3. 3. The liquid medical material according to claim 2, wherein the ratio of the calcium concentration [M] to the gelatin weight concentration [wt %] in the aqueous gelatin solution is 0.005 to 0.040 [M / wt %].

4. 4. The liquid medical material according to any one of claims 1 to 3, which is a biological tissue adhesive, a hemostatic material, a cell preservation solution, an organ preservation solution, an artificial ointment, an alveolar bone reconstruction agent, an agent for preventing adhesion of biological tissue, a mucous membrane elevation agent, an agent for preventing post-bleeding, or an embolization material for intravascular treatment.

5. 5. The liquid medical material according to claim 1, which is an arterial hemostatic material.

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