JPS61161220A - Closing agent for blood vessel - Google Patents

Abstract

PURPOSE:A closing agent for blood vessel having improved absorption properties in tissue free from admixture reactivity, containing human fibrin as an active ingredient. CONSTITUTION:A closing agent for blood vessel containing human fibrin (capable of being inserted into nutritive artery, having a shape enough to close nutritive artery; e.g., preferably cylindrical shape (circular cylinder) having 0.3-3.0mm diameter and 10-30mm length) as an active ingredient. Further, since the fibrin is decomposed and absorbed in a given period, the blood vessel is recirculated and no disorder is left. This agent is useful especially for closure operation through artery. The fibrin is obtained by solidifying fibrinogen derived from human with thrombin and calcium chloride as a solidifying agent.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a vascular occlusive agent containing human fibrin as an active ingredient. Regarding usage.

[Prior art]

In recent years, transarterial embolization has been studied as a cancer treatment method. Transarterial embolization involves inserting a catheter from the femoral blood vessel to the artery that supplies nutrition to cancer cells, that is, close to the feeding artery I1, and delivering embolic material to the feeding artery through this catheter. This surgical procedure involves occluding this feeding artery, but as a result, the supply of nutrients to cancer cells is cut off, resulting in either suppressed growth or death of cancer cells.

As this embolic material, it is easy to shred as it needs to be injected through a thin surface tube catheter, ■ it is easy to handle, ■ it is not toxic to MIliJ, and ■ it does not exhibit antigenicity or strong foreign body reactions. ■Appropriate period (usually 1 month to 2 months)
Ideally, a substance would be able to be absorbed after a period of about a month.

Conventionally, self-coagulated masses, muscle fragments, metal spheres, ceratin sponges, soricon spheres, polyvinyl alcohol sponges, and anoacrylate 1. - Gelatin sponges have been most widely used. Although gelatin sponge is non-antigenic, it is processed as a foreign substance in vivo. That is, after injection into a blood vessel, thrombus formation occurs centered on the gelatin sponge, which is then absorbed.

When the effect of this gelatin sponge was investigated using angiography, the blocked artery was recanalized in about 3 days to 1 week, so the ischemic effect was thought to be temporary. However, it is still considered to be insufficient.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a vasoocclusive agent that satisfies the conditions (1) to (4) above, has particularly excellent biocompatibility, hardly causes any foreign body reaction, and is absorbed by the living body.

To explain the purpose of the present invention more specifically, it stays in blood vessels for a certain period of time, occluding the blood vessels, cutting off nutrition to cancer cells, and after the cancer cells die, it is decomposed and absorbed, allowing the blood vessels to re-open. The object of the present invention is to provide a vasoocclusive agent.

[Failure to solve the problem]

Therefore, the present inventors conducted an investigation on embolic substances that met the conditions described in (-), and found that human fibrin has no foreign body reactivity and has excellent absorbability in Mi fabric, and has been developed to process human fibrin. The present invention was completed based on the discovery that the product is useful as a vascular occlusive agent by forming it into a rod shape.

That is, the present invention relates to a vasoocclusive agent containing human fibrin (hereinafter abbreviated as fibrin) as an active ingredient.

The fibrin used in the present invention may have any shape as long as it can be inserted into the feeding artery and has a shape sufficient to occlude the feeding artery. For example, for those administered to the feeding artery of a human, the cocoon has a diameter of 0.3 to 3.0 cm and a length of 10 to 30 m.
A rod-shaped (cylindrical) one is preferable. Usually, rod-shaped fibrin is cut into appropriate lengths for use.

The fibrin used in the present invention is prepared using fibrinokene obtained from human plasma as a raw material. This is because, from the viewpoint of biocompatibility, when the target is humans, it is more preferable to use fibrinokene obtained from 1-1IIL acids as a raw material. Fibrinoken is based on the Biological Products Standards supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare.
Dry fibrinoken for medical use manufactured according to the method (1979, pp. 201-203) can be used, and a commercially available powder is available under the trade name "Fibrinogen Mitri" (manufactured by Midori Juji Co., Ltd.). This is made by adding coagulating proteins and monosaccharides such as glucose, fructose, mannitol, etc. to dry fibrinoken as a coagulating protein and a stabilizer. Dissolve in liquid.

Fibrin is produced by adding thrombin and calcium chloride as anabolic agents to plasma-derived fibrinokene and solidifying it, as detailed below. More specifically, the fibrin used in the present invention is produced as follows.

Fibrinogen powder is dissolved in distilled water for injection, an appropriate buffer solution, etc., and the concentration of fibrinogen is 1 to 4 w/v%. The solution was prepared three times, and the pH was adjusted to 5.3 to 6 each time. Add to this a calcium chloride solution (final concentration 0.08-0.
32M) and l.rhombin solution (final concentration 1-10u/
ml), mix, and immediately leave to stand at room temperature for 2 to 3 hours in a tube with an appropriate inner diameter, and then extrude the solidified fibrin. At this time, the fibrin rod can be adjusted to a desired diameter by appropriately combining the concentration of the fibrinoken solution and the inner diameter of the tube.

The thus obtained fibrin rod is washed by leaving it in running water overnight to remove salts, and then the water in the fibrin is absorbed by an appropriate method. For example, it is immersed in a cold ethanol aqueous solution in which the ethanol concentration is changed stepwise. The fibrin from which water has been removed is subjected to heat sterilization, particularly autoclave sterilization, for 121'C115 to 60 minutes, preferably 121C for 20 minutes, in order to inactivate hepatitis viruses and the like.

The fibrin rod thus prepared is cut into appropriate lengths and used as is as a vasoocclusive agent, but is usually stored by immersing it in a softening solution (eg, high concentration ethanol). It is preferable that the softening liquid further contains an isotonic agent (for example, thorium chloride, etc.), a bactericide (for example, acriflavine, etc.), and the like.

〔Effect of the invention〕

Since the vasoocclusive agent obtained by the present invention contains human fibrin as an active ingredient, no foreign body reaction occurs and toxicity is reduced. It also has extremely good workability, flexibility, and strength.
It fits well into blood vessels and occludes them. Furthermore, after a certain period of time, fibrin is degraded and absorbed, so that there is no recanalization disorder in the blood vessels.

The vasoocclusive agent obtained according to the present invention is particularly useful in transarterial occlusion surgery.

For vascular occlusion, a plastic catheter is inserted into a blood vessel in the optimal part of the body (in most cases, the femoral vein).
Insert it close to the feeding artery that supplies nutrition to cancer cells,
A vasoocclusive agent is delivered to the feeding artery through this catheter to occlude the feeding artery and stop the blood flow to the cancer cells within the feeding artery. By keeping this vaso-occlusive agent in the blood vessel for a certain period of time, the supply of nutrients to cancer cells is blocked for a certain period of time (about one month), thus suppressing the growth or killing of cancer cells. The vaso-occlusive agent can then be degraded, allowing the blood vessel to recanalize.

Example 1 As a commercially available product, the product name is [Fibrinoken Midori] [
Made by Midori Jujisha] 1 vial (contains 1g of clotting protein)
Add 40 ml of distilled water for injection to the solution and heat to 37°C to dissolve. 0. After conditioning to pn5.7o with IN sodium hydroxide, chloride was added overnight 1.
5ml of 6M, 10u/ml of human tronin
Add 5ml of. The final concentration is fibrinoken 2w/
■%, calcium chloride 0.16M and human thrombin l
u/ml. This mixed solution is slowly poured into a tube made of natural rubber with an inner diameter of 4 ml, and left to stand at room temperature for 3 hours.

Remove the fibrin from the tube, leave it in running water (tap water) overnight, and add 12
Cold ethanol (→-5℃) whose concentration was changed stepwise over time
).

That is, the ethanol concentration was set to 10 v/v% - 30 v/v%.
-50 v/v% → 70 v/v% → 95 v/v%. Next, this ethanol-treated fibrin rod was immersed in distilled water for injection for 12 hours, and then
Leave to stand for 1 hour in an environment of 3°C and humidity of 57 to 60% to air dry. Then, autoclave sterilization was performed at 121°C for 20 minutes, and the softening solution (ethanol 70v/■%, sodium chloride 0.9w/
v%, Akuriwara 1 hun 0.0005 W/V%)
Soak in water and seal tightly. As a result, uniform fibrin rods with a diameter of 1.67 am were obtained.

Experimental example 1 The properties of the vasoocclusive agent obtained in Example 1 were tested.

■Hair heating: Remove the fibrin rod, which is a vasoocclusive agent, from the softening solution, cut it into 1.5 cm pieces, and soak it in physiological saline for 1 hour at room temperature. Then, one side of the fibrin rod is fixed, a constant weight is applied to the other side, and the load at which the rod breaks is determined.

The load per 1 m+i” cross section at the rupture point of this rod,
That is, the tensile strength (g/■12) is measured. Result is,
40.2 g/am''.

! Mansaku: Remove the fibrin rod, which is a vasoocclusive agent, from the softening solution. 4. Cut into Q cm pieces and soak in physiological saline for 1 hour at room temperature. Then, bend this rod in the middle and check whether it has elasticity or not by checking whether it breaks. As a result, no rupture occurred even when the fibrin rod was bent in half and the two ends were tied together.

Plasmin Digestion J [Mallability: Remove the fibrin rod, which is a vasoocclusive agent, from the softening solution.1. Cut into OcII+ and soak in physiological saline for 1 hour at room temperature. This rod was immersed in a 4.5 CU/ml plasmin (Midori Juji Co., Ltd.) solution and incubated at 37°C for 7 days.
Using the DPL kit (manufactured by Teikoku Kinki Co., Ltd., for human use), FDP (fib~rinoge
n and fibrin degradation
The amount of products) was determined. However, the undiluted plasmin solution was used as the test solution, and if the latex did not aggregate with this plasmin solution (fibrinokene concentration 5 Pg/n++ or less), it was resistant to plasmin digestion, and if it aggregated, it was resistant to plasmin digestion. It was determined that there was no such thing. The sterilized vasoocclusive agent did not aggregate even in the undiluted plasmin solution, and was judged to be resistant to plasmin digestion.

Experimental Example 2 A fibrin rope with a diameter of 9.5 IIm and a length of 2 cm was inserted into the femoral artery of Tsuzuki through a catheter. Blood flow in the distal femoral artery from the site of indwelling is obstructed, and -
Since the blood vessels did not recanalize even after several months, it is expected to be sufficiently effective as a vascular occlusive agent used in transarterial embolization.

Claims (1)

[Claims] A vascular occlusive agent containing human fibrin as an active ingredient.