JP4989908B2 - Hemostatic material - Google Patents

Description

  The present invention relates to a hemostatic material. More specifically, the present invention relates to a hemostatic material excellent in hemostasis and bioabsorbability and excellent in handleability under moisture.

At the wound, the tissue is first damaged, and at the same time, the blood vessels are torn and bleeding occurs. Platelets contained in blood are activated by adhering to broken collagen fibers, and platelet aggregation occurs. Primary hemostasis occurs by closing the blood vessel with this platelet aggregate. Based on such hemostatic mechanism, various hemostatic materials have been studied so far. For example, hemostatic materials made of collagen, gelatin or oxidized cellulose are sold as commercial products.
Collagen comes into contact with blood to activate hemostasis by activating platelets. Gelatin is a sponge-like hemostatic material, and hemostasis is performed by absorbing blood into the sponge. Oxidized cellulose has an affinity for hemoglobin in blood, and hemostasis occurs by promoting blood aggregation. However, since collagen is a heterogeneous protein such as bovine and swine, it may cause an immune reaction. Gelatin is a solubilized collagen obtained by acid-alkali treatment. Therefore, since all are derived from animals, there is a risk of contamination with pathogens. For example, the causative substance of bovine spongiform encephalopathy is an infectious protein called prion. For this reason, in the manufacturing process of such hemostatic materials, safety measures such as raw material management and virus inactivation and removal treatment are carried out, but the risk of virus infection due to the use of foreign proteins as a material is completely eliminated. Since it cannot be denied, it must be used carefully.

As the oxidized cellulose, Surgecel (registered trademark) is sold by Johnson & Johnson. Patent Document 1 discloses a soluble wound healing hemostatic cellulose fiber using carboxymethylcellulose. These hemostatic materials also have the problem of promoting adhesions by containing blood and gelling. In addition, since both are soluble in water, there is a disadvantage that if the instrument or the like at the time of operation has adhesion of moisture or the like, it adheres to the hemostatic material and is difficult to handle.
Patent Document 2 describes an example in which a bioabsorbable film having a honeycomb structure is used as an adhesion preventing material. Further, Patent Document 3 discloses a porous hemostatic material composed of cellulose and polypropylene, but polypropylene is not bioabsorbable and therefore needs to be removed after hemostasis.
Japanese Patent No. 3057446 WO2004 / 084434 JP 2005-279074 A

  An object of the present invention is to provide a hemostatic material excellent in handleability under wet conditions. Moreover, the objective of this invention is providing the hemostatic material excellent in the hemostatic property. Furthermore, the objective of this invention is providing the hemostatic material excellent in the bioabsorbability. In addition, an object of the present invention is to provide a hemostatic material that does not contain animal-derived heterologous proteins.

  Therefore, as a result of intensive studies on the bioabsorbable material, the present inventor has found that a film having a concavo-convex portion only on one surface made of a bioabsorbable polymer containing phospholipid has excellent hemostasis and bioabsorbability, and is wet The present inventors have found that it is excellent in handleability below, and completed the present invention.

  Further, the present invention has been completed by finding that a film having a concavo-convex portion only on one specific surface promotes hemostasis by replacing plasma fibers and platelets into the film preferentially and replacing collagen fibers that activate platelets. . Furthermore, the inventors have found that a film having a concavo-convex portion on only one surface made of a bioabsorbable polymer is excellent in handleability without swelling even when wet, and thus completed the present invention. The phospholipid used in the present invention is a substance constituting a biological membrane system, and is inherently in vivo, and therefore has high biocompatibility.

That is, the present invention comprises 100 parts by weight of a bioabsorbable polymer and 0.1 to 100 parts by weight of a phospholipid, wherein the bioabsorbable polymer is an aliphatic polyester and the phospholipid is L-α-phosphatidylethanol. It is an amine and has a plurality of cells arranged adjacent to each other in a planar shape , and there are six cells around one cell, each cell communicates in the film, and each cell It is a hemostatic material made of a non-penetrating film having a circular opening only on one surface.

  The hemostatic material of the present invention has a very fine structure and serves as a substitute for collagen fibers that activate platelets. As a result, platelets are activated and hemostasis is promoted. Moreover, the phospholipid contained in the hemostatic material of the present invention promotes the adsorption of plasma proteins and provides an environment suitable for blood coagulation. Furthermore, since the hemostatic material of the present invention is composed of a bioabsorbable polymer, it does not swell even when wet, has excellent handleability, and can be used by being embedded in the body. Moreover, since the hemostatic material of the present invention does not contain animal-derived proteins, the risk of contamination with pathogens is small.

(Bioabsorbable polymer)
Bioresorbable polymer is preferable from the viewpoint of solubility in organic solvents is an aliphatic polyester. As the aliphatic polyester, polylactic acid, lactic acid - glycolic acid copolymer, polyhydroxybutyric acid, polycaprolactone, polyethylene adipate, Ru and polybutylene adipate can be exemplified. These may be used alone, copolymers, or a mixture. Among these, polylactic acid, lactic acid-glycolic acid copolymer, and polycaprolactone are desirable from the viewpoint of availability, price, and the like.

(Phospholipid)
Phospholipids can be used regardless of their origin, whether extracted from animal tissue or artificially synthesized. Phosphorus lipid is Ri Ah with L-alpha-phosphatidyl ethanolamine, are good Mashiku L-alpha-phosphatidyl-ethanolamine - it is dioleoyl.
The phospholipid content is 0.1 to 100 parts by weight, preferably 0.5 to 10 parts by weight, based on 100 parts by weight of the bioabsorbable polymer. If the phospholipid is less than 0.1 parts by weight relative to 100 parts by weight of the bioabsorbable polymer, a uniform structure cannot be obtained, and if it exceeds 100 parts by weight, there is no self-supporting property, the cost is high, and the economy is poor. It is not preferable.

(Structure of hemostatic material)
The hemostatic agent of the present invention is a non-penetrating film having an uneven portion only on one surface. Here, the concavo-convex portion preferably has a structure in which a plurality of cells having openings only on one surface of the film are arranged adjacent to each other.
A preferred embodiment of the hemostatic material of the present invention will be described with reference to FIG. The film has a plurality of cells (1) arranged adjacent to each other in a planar shape. A cell is a space formed by evaporation of water droplets formed in a polymer and has a spherical shape.
Since the cells are formed by the closest packed water droplets, there are six cells around one cell. In addition, adjacent cells overlap each other in part. As a result, each cell communicates in the film. The communication part (2) is a fixed range centered on a straight line connecting the centers of the cells, which is a boundary between the cells. The shape of the communication part is circular or elliptical. The maximum diameter of the communicating part is preferably 0.5 to 5 μm, more preferably 1 to 3 μm. Due to the communicating portion, the adsorptivity of platelet plasma is improved.
The distance from one surface of the film to the lower end of the cell is called the hole depth. The depth of the hole is preferably 1 to 10 μm, more preferably 3 to 8 μm. The lower end of the cell has a non-penetrating bottom (3).

Each cell has a circular opening (4) only on one surface of the film. The diameter of the opening is preferably 1 to 10 μm, more preferably 3 to 8 μm. Six openings are arranged adjacent to each other around one opening. There is an edge (5) between adjacent openings. The width of the narrowest part of the edge is preferably 0.5 to 2 μm, more preferably 0.8 to 1.5 μm. That is, the shortest distance between the opening on one surface of the film and the adjacent opening is preferably 0.5 to 2 μm, more preferably 0.8 to 1.5 μm.
It can be said that the bottom part and the edge part are connected by the support column (6). There are six struts for each cell in a position surrounding each cell. The length of one side of the thinnest part of the column is preferably 0.1 to 1 μm. The support | pillar here shows the site | part which connects the film surface and the bottom face of a hole. Adjacent cells can be said to be holes formed by a bottom portion, an edge portion, and a support column.
The thickness of the film is preferably 10 μm or more, more preferably 10 to 100 μm. The thickness refers to the distance from one surface having an opening to the other surface. In order to enhance the support of the hemostatic material, other films, fiber bodies, porous bodies, etc. may be laminated. The hemostatic material of the present invention can have various shapes depending on the purpose, for example, a circle, an ellipse, a square, a rectangle and the like.

(Film production)
The hemostatic material of the present invention,
(1) a step of casting a dope containing a bioabsorbable polymer and an organic solvent on a substrate to form a liquid film;
(2) a step of evaporating the organic solvent and condensing water vapor to form water droplets on the surface of the liquid film in an atmosphere having a relative humidity of 50 to 95%; and (3) a step of evaporating the water droplets.
It can manufacture by the method which consists of.

(Dope)
The dope contains a bioabsorbable polymer, a phospholipid, and an organic solvent. The bioabsorbable polymer and phospholipid are as described above.
As the organic solvent, a water-insoluble one is used. This is because in the above method, it is essential that water vapor is condensed on the liquid film to form minute water droplet particles. Therefore, as organic solvents, halogen-based organic solvents such as chloroform and methylene chloride, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate and butyl acetate, water-insoluble ketones such as methyl isobutyl ketone, Examples include carbon disulfide. These organic solvents may be used alone or as a mixture of these solvents.
The total solute concentration of the bioabsorbable polymer and phospholipid in the dope is preferably 0.01 to 10% by weight, more preferably 0.05 to 5% by weight. If the solute concentration is lower than 0.01% by weight, the resulting film has insufficient mechanical strength, which is undesirable. On the other hand, if it exceeds 10% by weight, the solution concentration becomes too high and an optimum structure cannot be obtained. The phospholipid content is preferably 0.1 to 100 parts by weight, more preferably 0.5 to 10 parts by weight, and still more preferably 0.5 to 2 parts by weight with respect to 100 parts by weight of the polymer. Further, the dope may contain an amphiphilic polymer in addition to the polymer. The content of the amphiphilic polymer in the dope is preferably 1 to 50 parts by weight, more preferably 10 to 50 parts by weight, and further preferably 20 to 40 parts by weight with respect to 100 parts by weight of the polymer.

(Casting process)
This is a step of casting a dope on a substrate to obtain a liquid film. Such a process can be performed by pouring the dope onto the substrate. As the substrate, an inorganic material, a polymer, or a liquid can be used. Examples of the inorganic material include glass, metal, and silicon wafer. Examples of the polymer include polypropylene, polyethylene, polyether ketone and the like. Examples of the liquid include water, liquid paraffin, and liquid polyether. When water is used for the substrate, the film can be easily taken out from the substrate by taking advantage of the independence characteristic of the film.

(Organic solvent evaporation process)
In this step, the liquid film is allowed to stand in an atmosphere having a relative humidity of 50 to 95% to evaporate the organic solvent. The relative humidity is preferably 50 to 85%. If the relative humidity is less than 50%, condensation on the liquid film becomes insufficient, and if it exceeds 95%, it is difficult to control the humidity, which is not preferable. The temperature should just be the temperature which an organic solvent evaporates gradually, Preferably it is 10-30 degreeC, More preferably, it is room temperature.
In this step, the organic solvent evaporates and water vapor is condensed on the liquid film surface to form water droplets. This is because when the organic solvent evaporates, it takes away latent heat, the temperature of the liquid film surface decreases, and water vapor in the atmosphere condenses on the liquid film surface. The surface tension between the condensed water vapor and the organic solvent is reduced by the action of the hydrophilic group in the polymer, and the condensed water vapor is condensed to form fine water droplets. As the organic solvent evaporates, microscopic water droplets that are closely packed in a hexagonal arrangement are arranged on the liquid film surface. As the evaporation of the organic solvent progresses, the water droplets sink into the liquid film, and the surface of the liquid film has a structure in which the water droplets surrounded by the polymer are regularly arranged, and the organic solvent in the liquid film is completely evaporated, Form a film.

(Water droplet evaporation process)
After the organic solvent evaporates, water droplets generated by condensation are evaporated. As the water droplets evaporate, pores uniformly arranged on the polymer surface remain.

(Hemostatic action)
The hemostatic action of the present invention will be described. The hemostatic material of the present invention performs hemostasis by being applied to a wound. When the hemostatic material of the present invention is affixed to a wound, blood infiltrates into each hole made in the hemostatic material. The hemostatic material of the present invention containing blood adheres to the wound and closes the wound. While the hemostatic material of the present invention is applied to the wound, blood coagulation occurs inside the hemostatic material due to the self-healing ability, and complete hemostasis is achieved. In addition, since the hemostatic material of the present invention is composed of a bioabsorbable polymer, it can be used by being implanted in the living body, and after staying for a period necessary for hemostasis, it undergoes hydrolysis in the body, Because it is absorbed and decomposed, it does not stay as a foreign body in the body for a lifetime. Moreover, since it consists of a bioabsorbable polymer, it is needless to say that the risk of contamination with animal-derived pathogens can be reduced.
The hemostatic material of the present invention can be sterilized by, for example, ethanol sterilization, γ-ray sterilization, electron beam sterilization, ethylene oxide gas sterilization, and the safety can be improved by performing these treatments.

Hereinafter, although an example explains an embodiment of the present invention, these do not restrict the invention of the present invention.
[Example 1]
A glass substrate is prepared by mixing phosphatidylethanolamine-dioleoyl as a surfactant in a chloroform solution (5 g / L) of polylactic acid (manufactured by Shimadzu Corporation, Lacty (registered trademark), molecular weight 100,000) at a weight ratio of 200: 1. A film having a hole depth of about 4 [mu] m and a minimum edge width of about 0.7 [mu] m was prepared by casting on the substrate and allowing to stand under conditions of room temperature and humidity of 70% and gradually blowing off the solvent. An enlarged photograph of the obtained film is shown in FIG.

[Comparative Example 1]
A cast film was obtained by casting a chloroform solution (5 g / L) of polylactic acid (manufactured by Shimadzu Corporation, Lacty (registered trademark), molecular weight 100,000) on a glass substrate and allowing to stand at room temperature.

[Example 2] Adsorption amount evaluation of the amount of platelet plasma adsorbed The film obtained in Example 1 was cut into a 15 mm diameter sample and sandwiched between chambers to confirm the amount of platelet plasma adsorbed. That is, the sample was equilibrated in phosphate buffer for 12 hours. Next, the sample was contacted with a phosphate buffer solution containing 5% by weight of rat poor platelet plasma (PPP) at 37 ° C. for 1 hour to adsorb the platelet plasma. Next, the adsorbed platelet plasma was extracted with a 1 wt% SDS aqueous solution, and this extract was used for color development and spectroscopic quantification by the Micro BCA method to measure the amount of adsorbed platelet plasma. As a result, the amount of platelet plasma adsorbed was 24.4 μg / mL.

[Comparative Example 2]
The amount of platelet plasma adsorbed on the film obtained in Comparative Example 1 was confirmed in the same manner as in Example 2. As a result, the adsorption amount of platelet plasma was 12.1 μg / mL. As a result, it can be seen that the specific fine structure according to the present invention increases the amount of platelet plasma adsorbed and promotes blood coagulation.

[Example 3] Evaluation of the hemostatic effect of the hemostatic material The hemostatic material obtained in Example 1 was used for a wound prepared in the stomach of a rat as follows, and the hemostatic effect was confirmed. That is, the rat was surgically opened under anesthesia to expose the stomach, and a 1 cm × 1 cm epithelial exfoliation wound was prepared. A hemostatic material was pressed against the wound to confirm the hemostatic effect. As a result, blood was absorbed into the hole and adhered to the affected area, and a hemostatic effect was observed.

[Comparative Example 3]
Using the film obtained in Comparative Example 1, the hemostatic effect was confirmed in the same manner as in Example 3. However, since the hemostatic material of Comparative Example 1 does not have a fine structure on the film surface, leakage of blood is observed from the side of the hemostatic material, blood cannot be held, and finally exhibits a hemostatic effect I couldn't.

  The hemostatic material of the present invention can be applied to fields requiring hemostasis in the body such as surgery and wound treatment.

2 is an electron micrograph of the film obtained in Example 1.

Explanation of symbols

1 cell 2 communication part 3 bottom part 4 opening part 5 edge part 6 support | pillar

Claims (8)

100 parts by weight bioabsorbable polymer and 0.1-100 parts by weight phospholipid, wherein the bioabsorbable polymer is an aliphatic polyester, the phospholipid is L-α-phosphatidylethanolamine, A plurality of cells arranged adjacent to each other, and there are 6 cells around one cell, each cell communicates in the film, and each cell is only on one surface of the film. A hemostatic material comprising a non-penetrating film having a circular opening. The hemostatic material according to claim 1, wherein the distance from one surface of the film to the lower end of the cell is 1 to 10 µm. The hemostatic material according to claim 1, wherein the opening has a diameter of 1 to 10 μm. The hemostatic material according to claim 1, wherein six openings are arranged adjacent to each other around one opening. The hemostatic material according to claim 1, wherein the shortest distance between the opening on one surface of the film and the adjacent opening is 0.5 to 2 µm. The hemostatic material according to claim 1, wherein the aliphatic polyester is polylactic acid, lactic acid-glycolic acid copolymer, polycaprolactone, or a mixture thereof. The hemostatic material according to claim 1, wherein the phospholipid is L-α-phosphatidylethanolamine-dioleoyl. The hemostatic material according to claim 1, wherein the phospholipid content is 0.5 to 10 parts by weight with respect to 100 parts by weight of the bioabsorbable polymer.