JP7625189B2 - Liquid medical materials - Google Patents

Description

The present invention relates to a liquid medical material.

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 and other procedures. Effectively preventing leakage of bodily fluids from the damaged area helps to maintain the patient's life during surgery and improves the patient's quality of life (QOL) after surgery.

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 (such as laparoscopic surgery) is being performed, and may necessitate conversion to open surgery if bleeding cannot be adequately controlled.

Existing methods for hemostasis include the following:
1. Direct pressure on the blood vessel at the bleeding site (compression 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, or placing a plug or sponge on the bleeding site. The drawback 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).

Existing hemostatic materials include the following:
1. Alginate 2. Gelatin sponge 3. Collagen fibers 4. Fibrin glue.
5. Self-synthesized peptides Among the above, collagen fibers and fibrin glue are often used clinically as effective hemostatic materials.

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.

Biliary fistula and pancreatic fistula are conditions in which bile or pancreatic juice leaks due to biliary surgery, pancreatitis, pancreatic surgery, etc., and can adversely affect other organs. Currently, there are no known substances that can effectively prevent 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.

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 condition, there is no option but to wait for natural healing, but a method that can adhere to the lung tissue by simply laying it on top of the affected area and seal the hole in the sac is considered to be one of the simplest and safest ways to treat pneumothorax.

With the development of endoscopic techniques, 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, and 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.

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.

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 form a β structure at physiological pH and salt concentrations.

When self-assembling peptides were applied to hemostasis, continuous blood leakage was observed from the end of the liver incision, 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.

The polyamine-aldehyde system, which is used clinically in the same way as fibrin glue and is made by adding crosslinking agents such as formaldehyde and glutaraldehyde to gelatin, is by no means satisfactory, as it has been pointed out that it may cause sequelae such as vascular occlusion and that low molecular weight aldehydes are highly damaging to nerves and tissues.

To overcome these problems, much research has been conducted. For example, adhesives based on cross-linked Schiff base formation using dextran and ε-poly-L-lysine (hereinafter simply referred to as ε-PLL), which are made from food additives, have been studied (see, for example, Patent Document 2).

In addition, tissue adhesives that use active ester derivatives of citric acid and proteins such as collagen as adhesive components are also being researched as strong adhesives (see, for example, Patent Document 3).

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

In addition, an absorbable local hemostatic material using gelatin containing human thrombin is commercially available. This hemostatic material is made by mixing granular cross-linked gelatin, dried human thrombin, and a calcium chloride solution at the time of use. The mixture of cross-linked gelatin and thrombin solution is a viscous fluid.

International Publication WO2010/041636 International Publication No. 2009/057802 JP 2004-261222 A

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 ε-PLL, as described in Patent Document 2, has a gel strength inferior to that of fibrin glue, a commercially available hemostatic agent, raising concerns 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.

Commercially available absorbable local hemostatic materials using gelatin containing human thrombin have the problem of undergoing a sol-gel phase transition at room temperature. For this reason, 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, which means that when used in the surgical field, it is not possible to apply the material evenly to the bleeding area. In addition, because the gel is opaque, there is also the problem that it is impossible to directly view the surgical field.

The present invention was made with a focus on these problems, and aims to provide a liquid medical material that maintains a sol state at room temperature, has better hemostatic properties than fibrin glue, is safe, and can be manufactured at low cost.

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 calcium-containing hydrophilic polymer and thrombin.
In particular, the liquid medical material according to the present invention contains an aqueous gelatin solution containing calcium and thrombin.

Furthermore, the liquid medical material according to the present invention comprises 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 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 the present invention, the ratio of calcium concentration [M] to 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.

The present invention provides a liquid medical material that maintains a sol state at room temperature, has better hemostatic properties than fibrin glue, is safe, and can be manufactured at low cost.

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 as the hydrophilic polymer compound, since they can be dissolved in water and have excellent processability, and more preferably, they are 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.

Furthermore, the liquid medical material according to 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 %].
At this blend ratio, the composition has viscoelasticity, yet is deformable down to -10°C, and has high tissue adhesion to organs.

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 that utilize 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.

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.

(Test 1)
The following gelatin/calcium aqueous solutions were prepared:
Types of Gelatin:
A: Average molecular weight 100,000 (distribution 20,000-300,000) acid-treated gelatin B: Average molecular weight 100,000 (distribution 20,000-300,000) alkali-treated gelatin C: Average molecular weight 20,000 gelatin (polypeptide)
D: Gelatin with a molecular weight of approximately 100,000 (distribution between 80,000 and 120,000) Gelatin concentration: 5 to 40 wt% (5, 10, 20, 30, 40 wt%)
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/aqueous solutions A, B, C and D were prepared.
At 25° C., gelatin aqueous solutions A, B and D solidified at a concentration of 5%. Gelatin aqueous solution C did not solidify even at a concentration of 40%, and remained in a fluid state.
(2) For A, B and D, aqueous gelatin/calcium solutions having 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 solidification, fluidity, or strong viscosity.
Solidified: The aqueous solution does not move at all even when the sample is inverted. Fluid: The aqueous solution starts to move when the sample is inverted. Strong viscosity: The liquid level moves little by little after a while when the sample is inverted.

From the above results, an aqueous solution that is not solidified, i.e., that is in a highly viscous and fluid state at 25° C., is selected. The selection conditions are as follows:
<Conditions>
A, B: 0% < suitable conditions < 40% gelatin < up to the concentration at which a gelatin aqueous solution is created 0.2M calcium < suitable conditions < 1.0M calcium < up to the concentration at which a calcium aqueous solution is created C: 0% < suitable conditions < 40% gelatin < up to the concentration at which a gelatin aqueous solution is created 0M calcium < suitable conditions < up to the concentration at which a calcium aqueous solution is created D: 0% < suitable conditions < 40% gelatin 0.2M calcium < suitable conditions < 1.0M calcium < up to the concentration at which a calcium aqueous solution is created

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

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 were formed throughout the solution, resulting in a non-soft solution.

Claims (5)

A liquid medical material characterized by comprising an aqueous gelatin solution containing calcium at a concentration of 0.2M to 1.0M, a concentration of 5% 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. 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. 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. 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. The liquid medical material according to claim 1, which is an arterial hemostatic material.