JPH05208917A - Blood vessel embolization agent - Google Patents

Abstract

PURPOSE:To provide a blood vessel embolization agent having an excellent blood vessel embolization action and effective for the treatment of blood vessel diseases such as aneurysm, varicosis, hemostasis, tumor, abnormal blood vessel formation, etc. CONSTITUTION:A blood vessel embolization agent comprises an aqueous calcium salt solution, an alginate salt solution, a thrombin solution and a fibrinogen solution.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a vascular embolic agent used when treating a vascular disorder such as aneurysm or arteriovenous malformation (AVM) by using a catheter without making an incision.

[0002]

2. Description of the Related Art At present, intravascular surgical treatment for treating vascular disorders by applying a vascular catheter without applying surgical invasion is being performed.

For example, in the treatment of cerebrovascular disorders, a minute catheter is superselectively placed in an affected area of a cerebral artery, and abnormal blood flow is blocked by an embolic substance introduced by the catheter to repair the blood vessel. , Cerebral aneurysm, arteriovenous malformation, etc. Cerebral aneurysm is 100 adults
It is an aneurysm that one person has in an arterial blood vessel, and the diameter is about 1 mm.
It has a wide shape distribution from about 20 mm to about 20 mm, and the generation site extends to multiple branches of the cerebral artery. Of these, about 30% passes without rupture, but about 70% causes rupture and is said to cause subarachnoid hemorrhage.

Arteriovenous malformations are the most common and well-known cerebrovascular malformation, consisting of a collection of blood vessels with arteriovenous anastomosis between tortuous, dilated inflow and outflow vessels.

[0005] Embolization is a treatment in which the affected area of the cerebral artery is occluded with an embolizing substance, the blood flow in the affected area is stopped to solidify the affected area, and if necessary, the solidified affected area is removed. ..

Cerebral blood vessels lack the outer elastic membrane and are thinner than other blood vessels, so the resistance to lateral pressure of blood flow is weak, and the blood vessels run intricately in the skull, leading to branching points. The stress is likely to cause a failure. Therefore, various embolic materials have been studied.

[0007] Conventionally, a cyanoacrylate-based material has been often used as a liquid for vascular occlusion (Journal of Biomaterials Research (J. Biome).
d, Matar. Res. ), 17, 167-177
(1983), MC Harp (MC Harp
ers and others)).

Recently, a solution of ethylene-vinyl alcohol copolymer in dimethylsulfoxide (DMSO) is used as a material for occlusion, DMSO is diffused in blood, and ethylene-vinyl alcohol copolymer is deposited to form blood vessels. It has been proposed to occlude (Medical Tribune, 26 October 1989, pp. 46-47).

On the other hand, a catheter is used to inflate a detachable balloon inside the aneurysm to close the aneurysm,
A method of placing a balloon in an aneurysm is also known (Journa of Neurosurgery).
l of Neurosurgery), 41, 125
-145 (1974), FA Serbinenko).

In addition to the above, polyvinyl alcohol (PVA) sponge, metal coil, alcohol, suture and the like have been used according to the purpose of treatment.

[0011]

With the conventional cyanoacrylate-based embolic agent, it is difficult to inject the embolic substance because it rapidly solidifies and polymerizes in the blood vessel, and the catheter must be removed all at once at the same time as the injection is completed. It is difficult to handle and cannot be reinjected even if the occlusion condition is insufficient. In addition, there is a problem that stimulation to the living body is large.

Since the solvent DMSO is a chemical substance, its clinical application may be limited (Proceedings of the 11th Annual Meeting of the Biomaterials Society of Japan (1989) 68, II).
-22 Hiroo Iwata et al.), And it is not a desirable solvent because it may damage the equipment made of resin.

When a balloon is used, since the reaction between the balloon and the inside of the aneurysm is weak, the cavity inside the aneurysm is not sufficiently filled, and there is a high risk of recurrence if a small lumen remains. Attempting to fill as many balloons as possible will change the shape of the aneurysm and there is a risk of aneurysm rupture.
There is also the problem that a pulling force must be applied when disconnecting the balloon from the catheter.

In addition, even when a material such as PVA is used, there are many therapeutic problems such as resistance when injecting into a blood vessel using a catheter.

The object of the present invention is to solve the problems in the prior art, and at the tip of the catheter, the lump has a certain degree of hardness and elasticity, breaks from one end and scatters, or is swayed by the blood flow and is unnecessary. The object is to provide a vascular embolus agent that does not move to the wall of the aneurysm, adheres to the wall of the aneurysm, fills the lumen without changing the shape of the aneurysm, and is easy to remove the catheter.

Further, the vascular embolizing agent of the present invention is not limited to the above-mentioned embolizing substance in an aneurysm, and also provides an embolic agent suitable for treating vascular malformations such as arteriovenous malformations, arteriovenous aneurysms, hemostasis, and tumors. It is a thing.

[0017]

The above-mentioned problems can be solved by a vascular embolizing agent consisting of a water-soluble calcium salt solution, an alginate solution, a thrombin solution and a fibrinogen solution.

As the vascular embolizing agent of the present invention, each of a water-soluble calcium salt solution, an alginate solution, a thrombin solution and a fibrinogen solution may be used separately, but preferably either the water-soluble calcium salt or the alginate salt is used. As a solution of two kinds, a thrombin solution (solution A) to which either one of them is added and a fibrinogen solution (solution B) to which either a water-soluble calcium salt or an alginate which has not been added to the thrombin solution (solution A) is added To use.

The vascular embolic agent of the present invention is used by injecting a water-soluble calcium salt solution, an alginate solution, a thrombin solution and a fibrinogen solution into the affected area simultaneously or alternately through different routes such as using four catheters. To do.

Preferably, a solution of alginate and thrombin in sterile water or saline (solution A) and a solution of a water-soluble calcium salt and fibrinogen in sterile water or saline (solution B) are used for two catheters or It is used by simultaneous or alternating injection into the affected area through separate routes, such as with a multi-lumen catheter.

At this time, the water-soluble calcium salt and thrombin may be dissolved to be the solution A, and the alginate and fibrinogen may be dissolved to be the solution B. In other words, even if they are mixed with each other and do not cause gelation, they may be mixed together in advance, which requires a smaller number of catheters for guiding each solution to the affected area and facilitates the work. Is.

As the water-soluble calcium salt used in the vascular embolization agent of the present invention, water-soluble calcium salts such as calcium chloride, calcium acetate, calcium nitrate, calcium citrate and calcium gluconate are used. Among them, calcium acetate and calcium chloride are used. Calcium citrate is preferable in terms of toxicity.

At this time, the concentration of calcium salt is 1 mM to 1M.
Is preferred, and 5 mM to 500 mM is more preferred.

The alginate used in the present invention is a water-soluble alginate, and examples thereof include alkali metal salts, ammonium salts and amine salts of alginic acid. There is no particular limitation as long as it is a salt that does not cause the problem, and sodium alginate is preferable in view of cation toxicity and the like. It is also possible to use a salt of pectic acid, which is a structural variant of alginic acid.

The molecular weight of alginic acid used in the vascular embolizing agent of the present invention is preferably 5,000 to 1,000,000, and particularly 10,000 to 3
More preferably, 0,000. If it is more than 1 million, the viscosity when dissolved becomes too high, and it becomes difficult to inject it into the affected area through a catheter. If it is less than 5,000, the gel forming ability with calcium ions will be low, and the function as an embolic agent will be insufficient.

At this time, since the concentration of alginic acid is influenced by the molecular weight of alginic acid, it is preferable to adjust the concentration within a viscosity range that allows the catheter to pass through. In particular,
0.1 to 15% by weight is preferable, 1.0 to 3.0% by weight
Is more preferable.

The concentration of thrombin in the present invention is 0.1.
u / ml to 200 u / ml is preferable, and 1 u / ml to 2
0 u / ml is more preferred.

The fibrinogen concentration in the present invention is 1
-40% by weight is preferable, and 5-20% by weight.

The dose of each solution may be an amount suitable for the symptom so that each solution having the above-mentioned concentration becomes equal in the affected area.

The vascular embolizing agent of the present invention embolizes blood vessels by causing rapid gelation by alginic acid and calcium. Activation of the injected thrombin, fibrinogen, calcium ions and the blood coagulation system in autologous blood then completes a stronger embolus. Since these substances are not inflammatory and are organically organized, long-term stability is maintained.

Hereinafter, the present invention will be described in more detail with reference to examples.

[0032]

【Example】

(Example 1) Sodium alginate (Nacalai Textiles, Inc., 300 ops) and bovine thrombin (Sigma, Inc.) 8
0 μg was dissolved in 6.75 ml of sterile water to prepare a solution A containing 2.5% by weight of sodium alginate and 20 u / ml of thrombin.

Next, 55.49 mg of calcium chloride (special grade manufactured by Nacalai Tex Co., Ltd.) and 0.2 g of bovine fibrinogen (manufactured by Sigma) were dissolved in physiological saline, and solution B containing 50 mM calcium chloride and 20% by weight fibrinogen. Was adjusted.

(Example 2) The basilar artery of pigs is
Because there is a physiological vascular malformation similar to venous malformation,
Using a porcine basilar artery as a human arteriovenous malformation (AVM) model, AVM occlusion was attempted with the vascular embolizing agent according to the present invention prepared in Example 1.

First, 10 ml of ketamine hydrochloride was subcutaneously injected into pigs to induce anesthesia, a mucus secretion inhibitor with atropine was added, the trachea was intubated, and maintenance anesthesia was performed with halothane.

After the pig was fixed in the dorsal position, the right external carotid artery was peeled off, the central side was tied, and a guide wire was directed toward the end through the introducer and X was placed on the right side of the brain at a position 25 to 30 cm from the insertion point. The catheter was inserted while being confirmed by fluoroscopy, and further, the catheter was inserted into the right basilar part along the guide wire.

The same operation was repeated and a total of two catheters were inserted. Then, the openings of the two catheters were positioned immediately before the anomalous vascular network on the right side of the fundus.

The first catheter was used for liquid A delivery prepared in Example 1 and the second catheter was used for liquid B delivery, so that the total amount of both liquids was 1.5 ml in the affected area. Both solutions were sent to the ectopic plexus of the right side of the brain for about 30 seconds.

Approximately 1 minute after the completion of the liquid feeding, one of the inserted catheters was taken out, and the remaining one was left in the affected area for the inflow of the vascular contrast agent. As a result of the inflow of the vascular contrast agent, the flow of the contrast agent was normal. Unlike that, it lost the pressure of the left carotid artery, or partly remained at the opening and showed irregular disappearance.

From this, it is clear that the vascular embolic agent of the present invention caused AVM occlusion. On this occasion,
No outflow of vasoembolic agents into the lungs or stomach was observed.

Example 3 For the purpose of confirming the effectiveness of the vascular embolizing agent of the present invention for obstructing vegetative blood vessels to tumor tissues, the mesenteric artery of the rabbit was occluded with the vascular embolizing agent, and control of this artery was performed. It was confirmed whether it could induce necrotic state of the intestinal mucosa.

Nembutal 25m
g / kg iv. After the rabbit was anesthetized by administration, the rabbit was fixed on a dorsal fixed table, the abdomen was shaved, a midline incision was made, and the abdominal digestive tract was spread on a saline-impregnated gauze so that the mesenteric artery was visible.

Under this condition, the common carotid artery of the rabbit is peeled off, a guide wire is inserted, the branch portion of the right bone artery is descended, and the distal end of the guide wire is placed on the branch portion of the mesenteric artery. Hemostasis was performed by pressing with a finger, the blood was placed on the blood flow, and a guide wire was sent to the branch portion of the mesenteric artery, and the catheter was positioned at the same site along the guide wire. The same operation was repeated and a total of two catheters were positioned at the same site.

The first catheter was used for feeding the liquid A prepared in Example 1, and the second catheter was used for feeding the liquid B, so that the total amount of both liquids was 1.5 ml in the affected area. Both solutions were sent to the ectopic plexus of the right side of the brain for about 30 seconds.

As a result, it was confirmed by X-ray fluoroscopic observation that liquid A and liquid B were in contact with each other and gelled in a short time.

After confirming sufficient gelation by palpation, the catheter was removed and the blood flow was restarted. However, no blood flow was observed at the thrombus site, and even after compression and hemostasis of the lower abdominal aorta. It didn't flow. That is, the vascular embolizing agent according to the present invention showed sufficient ability for nutrient obstruction around the tumor.

[0047]

INDUSTRIAL APPLICABILITY The vascular embolizing agent of the present invention is a gel which is rapidly gelated by alginic acid and calcium by flowing into the affected area by a catheter to embolize the blood vessel, and then by the injected thrombin and fibrinogen, it is more robust. Has an excellent vaso-occlusive action because the embolism is completed,
It is effective in treating blood vessels such as aneurysms, varicose veins, hemostasis, tumors, and vascular malformations.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31: 725 37:48 37:47) (72) Inventor Haruo Ishiyama 1500 Inokachi, Nakai-cho, Ashigarakami-gun, Kanagawa Prefecture Address Terumo Corporation (72) Inventor Akira Mochizuki 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Prefecture Terumo Corporation

Claims (1)

[Claims] 1. A vascular embolizing agent comprising a water-soluble calcium salt solution, an alginate solution, a thrombin solution and a fibrinogen solution.