JPH0617312B2 - Vascular blocker - Google Patents

Description

TECHNICAL FIELD The present invention relates to a rod-shaped vaso-occlusive agent containing human fibrin as an active ingredient. More specifically, it relates to a medicinal use of human fibrin as an occluding substance in transarterial embolization.

[Prior art]

In recent years, transarterial embolization has been studied as one of cancer treatment methods. In this transarterial embolization, a catheter is inserted from the blood vessel of the thigh to the artery supplying nutrients to the cancer cells, that is, near the feeding artery, and the embolic substance is sent to the feeding artery through this catheter to feed this nutrient. This is a technique of occluding the artery, but as a result, the supply of nutrients to the cancer cells is cut off, and the growth of the cancer cells is suppressed or the cancer cells are killed.

Since this occlusive substance needs to be injected through a thin blood vessel catheter, it can be easily shredded, easily obtained, has no toxicity to tissues, does not show antigenicity or strong foreign body reaction, and has a proper period (usually Ideally, a substance that combines the conditions such as being absorbed after about 1 to 2 months). Traditionally, this embolic material is an autologous clot,
Muscle pieces, metal spheres, gelatin sponges, silicone spheres, polyvinyl alcohol sponges, cyanoacrylates, etc. have been used, but gelatin sponge has been most widely used, especially because it satisfies the above five conditions. Although gelatin sponge is non-antigenic, it is treated as a foreign substance in vivo. That is, after being injected into a blood vessel, thrombus formation centered on a gelatin sponge occurs and is then absorbed. When the effect of this gelatin sponge is examined by angiography, the blocked artery is recanalized in about 3 days to 1 week, so the ischemic effect is considered to be temporary, and it is a substance used for embolization of malignant tumors. As for, it is still considered insufficient.

[Problems to be solved by the invention]

An object of the present invention is to provide a vasoocclusive agent which satisfies the above conditions (1) to (3), is particularly excellent in biocompatibility, and is hardly absorbed by a foreign substance, and which is absorbed by a living body.

More specifically, the purpose of the present invention is to stop in a blood vessel for a certain period of time and block the blood vessel to block the nutrients to the cancer cells, and after the cancer cells die, they are decomposed and absorbed to recanalize the blood vessels. To provide a vaso-occlusive agent.

[Means for solving problems]

Therefore, the present inventors have studied embolic substances that satisfy the above conditions, utilizing the fact that human fibrin does not have foreign body reactivity and is excellent in tissue absorbability, and by processing it into a rod shape, The present invention has been completed by finding that it is useful as a vaso-occlusive agent.

That is, the present invention relates to a rod-shaped vaso-occlusive agent containing human fibrin (hereinafter abbreviated as fibrin) as an active ingredient.

The fibrin used in the present invention may have any shape so long as it can be inserted into the feeding artery and occludes the feeding artery. For example, for administration to a human feeding artery, a rod-shaped (cylindrical) one having a diameter of 0.3 to 3.0 mm and a length of 10 to 30 mm is preferable. Usually, a fibrin prepared in a rod shape (hereinafter referred to as a fibrin rod) is cut into an appropriate length before use.

The fibrin rod used in the present invention is prepared using fibrinogen obtained from human plasma as a raw material.
This is because it is more preferable to use fibrinogen obtained from human plasma as a raw material when targeting human from the viewpoint of biocompatibility. As such fibrinogen, medical dry fibrinogen manufactured according to the biological formulation standard (pages 201 to 203 of 1979) supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare can be used. -Midori "[Midori Cross Co.] powder. This is a mixture of dried fibrinogen with coagulation protein and sodium citrate as a stabilizer and monosaccharides such as glucose, fructose and mannitol. When used, distilled water for injection or a low salt concentration buffer solution of pH 6 to 7 is used. Dissolve in.

The fibrin rod is manufactured by adding thrombin and calcium chloride as a solidifying agent to human fibrinogen derived from human plasma to solidify, as described in detail below. More specifically, the fibrin rod used in the present invention is manufactured as follows.

The fibrinogen powder is dissolved in distilled water for injection, an appropriate buffer solution or the like to prepare a fibrinogen solution having a concentration of 1 to 4 w / v%, and the pH is adjusted to 5.3 to 6. Calcium chloride solution (final concentration 0.08-0.32M) and thrombin solution (final concentration 1-10u / ml) were added and mixed, and immediately placed in a tube having an appropriate inner diameter at room temperature for 2-3 hours, and then solidified. Push out the fibrin stick. At this time, the fibrin rod can be adjusted to a desired diameter by appropriately combining the concentration of the fibrinogen solution and the inner diameter of the tube.

The fibrin rod thus obtained is washed by leaving it in running water overnight to remove salts and the like, and then absorbs water in the fibrin rod by an appropriate method. For example, it is immersed in a cold ethanol aqueous solution whose ethanol concentration is gradually changed. The water-removed fibrin rod is subjected to heat sterilization at 121 ° C. for 15 to 60 minutes, preferably 121 ° C. for 20 minutes, particularly autoclave sterilization, in order to inactivate hepatitis virus and the like.

The thus-prepared fibrin rod is cut into an appropriate length and used as it is as a vaso-occlusive agent, but it is usually immersed in a softening solution (for example, high-concentration ethanol etc.) and stored. It is preferable to further add an isotonicity agent (eg, sodium chloride), a bactericidal agent (eg, acriflavine, etc.) to the softening liquid.

〔The invention's effect〕

Since the vaso-occlusive agent obtained by the present invention contains human fibrin as an active ingredient, no foreign body reaction occurs and toxicity is reduced. In addition, workability, flexibility, and strength are extremely good,
Close the vessel by fitting it well. Moreover, after a certain period of time, the fibrin rods are decomposed and absorbed, so that the blood vessels do not recanalize and no obstruction remains.

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

For vascular occlusion, use a plastic catheter from the blood vessel at the optimal site of the body (femoral vein in most cases),
Insert it near the feeding artery supplying nutrients to the cancer cells,
A vaso-occlusive agent is sent to the preceding feeding artery via this catheter to occlude the feeding artery to stop the blood flow of cancer cells in the feeding artery. By keeping this vaso-occlusive agent in the blood vessel for a certain period of time, the supply of nutrients to the cancer cells is blocked for this certain period (about one month), thus suppressing the growth or killing of the cancer cells. And then, the vaso-occlusive agent may be decomposed and re-canalize the blood vessel.

Example 1 As a commercial product, 1 vial (containing 1 g of coagulating protein) under the trade name of "Fibrinogen-Midori" [Midori Cross Co.] was used.
Add 40 ml of distilled water for injection, heat to 37 ° C. and dissolve. After adjusting to pH 5.70 with 0.1N sodium hydroxide,
5 ml of 1.6 M calcium chloride solution and 5 ml of human thrombin solution 10 u / ml are added. The final concentration will be 2 w / v% fibrinogen, 0.16 M calcium chloride and 1 u / ml human thrombin. This mixed solution is quickly poured into a tube made of natural rubber and having an inner diameter of 4 mm, and allowed to stand at room temperature for 3 hours.
Remove the fibrin rod from the tube and run it under running water (tap water).
After leaving it in the room overnight, with a liquid volume four times the volume of the fibrin rod,
Cold ethanol (+5
C)). That is, the ethanol concentration is 10 v / v
% → 30 v / v% → 50 v / v% → 70 v / v% → 95
V / v% is changed stepwise. Next, soak this ethanol-treated fibrin rod in distilled water for injection for 12 hours,
It is left to stand for 1 hour in an environment of room temperature of 22 to 23 ° C. and humidity of 57 to 60% and air dried. Then, autoclave sterilization is performed at 121 ° C. for 20 minutes, and aseptically, the softening solution (ethanol 70 v / v%, sodium chloride 0.9 w /
v%, acriflavine 0.0005 w / v%), and stopper tightly. As a result, a uniform fibrin rod having a diameter of 1.67 mm was obtained.

Experimental Example 1 The properties of the vaso-occlusive agent obtained in Example 1 were examined.

Tensile Strength: A fibrin rod, which is a vaso-occlusive agent, is taken out from the softening solution, cut into 1.5 cm, and immersed in physiological saline at room temperature for 1 hour. Then, one of the fibrin rods is fixed, and a certain weight is applied to one of the fibrin rods to obtain the load at the time of rod rupture. The load per 1 mm ² of the cross section at the breaking point of this bar, that is, the tensile strength (g / mm ² ) is measured. The result was 40.2 g / mm ² .

Elasticity: A fibrin rod, which is a vaso-occlusive agent, is taken out from the softening solution, cut into 4.0 cm, and immersed in physiological saline at room temperature for 1 hour. Then, bend this rod in the middle and see if it has elasticity by breaking it. As a result, even if the fibrin rod was folded in two and both ends were attached, no rupture occurred.

Plasmin digestion resistance: A fibrin rod, which is a vaso-occlusive agent, is taken out from the softening solution, cut into 1.0 cm, and immersed in physiological saline at room temperature for 1 hour. This rod was immersed in a 4.5 CU / ml plasmin (Midori Cross) solution and incubated at 37 ° C. for 7 days, and then the plasmin solution was FDPL kit (manufactured by Teikoku Organ Co., Ltd. for humans) By law
FDP (fibrinogen and fibrin degradation product
s) The amount was determined. However, when this plasmin solution was not diluted and the undiluted solution was used as the test solution and the latex did not aggregate by this plasmin solution (fibrinogen concentration 5
ug / ml or less) was determined to be resistant to plasmin digestion, and when aggregated, it was determined to be not resistant to plasmin digestion. The sterilized vaso-occlusive agent did not aggregate even in the undiluted solution of plasmin solution, and it was judged to be resistant to plasmin digestion.

Experimental Example 2 When a fibrin rod having a diameter of 0.5 mm and a length of 2 cm was inserted into a rabbit's hip artery via a catheter and left in the hip artery, the fibrin rod was distal to the site where the fibrin rod was left. Since the blood flow in the hip artery was blocked and the blood vessels were not recanalized even one month later, it is expected to be sufficiently effective as a vaso-occlusive agent used in transarterial embolization.

Claims (1)

[Claims] 1. A rod-shaped vaso-occlusive agent containing human fibrin as an active ingredient.