JPH06329542A - Composition for local vascular hemostatis and composition for arterial chemical embolus containing insoluble aliginic acid salt particle - Google Patents

Abstract

PURPOSE:To obtain a composition having local vascular hemostatic action, a composition usable for arterial chemical embolic therapy and a contrastradiographic composition. CONSTITUTION:The local hemostatic composition and the composition for arterial embolus contain insoluble alginic acid salt particles. Since the particles having the objective particle diameter is readily prepared and an anticancer agent or a contrast medium can be contained in the composition, the compositions are effectively used for treating cancer by the arterial chemical embolic therapy.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a composition for local vascular hemostasis and a composition for arterial chemoembolization containing insoluble alginate particles. Further, the present invention relates to a sustained-release composition and an imaging composition, wherein the insoluble alginate particles contain a drug or an imaging agent.

[0002]

2. Description of the Related Art Arterial embolization therapy is a therapeutic method in which a blood vessel catheter is inserted into a target artery and an embolization substance is injected through the catheter to embolize the target blood vessel, thereby treating a lesion by ischemia.

Tumor tissue needs to be supplied with a large amount of oxygen due to its vigorous growth and growth, and as a matter of course, the tumor tissue receives nutrition from arteries. Therefore, when an arterial occlusive substance is injected through an angiocatheter that is selectively inserted into an artery feeding the tumor tissue to embolize the artery, the tumor tissue is blocked by blood flow, resulting in ischemic necrosis.

Further, at this time, when an anticancer agent is contained in the embolus substance, in addition to the effect of blocking the tumor by the embolism of the artery,
By retaining the anticancer agent at a high concentration in the local area of the tumor, the effect of efficient chemotherapy can be expected. The application of such arterial chemoembolization has significantly improved the prognosis of unresectable liver cancer.

It is desirable that the chemoembolic substance used in arterial chemoembolization has the following properties.

1. Being safe for the living body.

2. A sufficient embolus that can be maintained for a certain period of time.

3. Adjustable so that the release rate of the anticancer drug from the embolic material can be controlled to some extent.

At present, the main substances used as embolic substances in arterial chemoembolization are gelatin sponge strips, gelatin sponge powder, oil contrast agent Lipiodol, etc. Of these, the most frequently used are gelatin sponge ( Sponzel). The effect of injecting the embolic material depends on the properties and size of the embolic material. For example, in the case of a gelatin sponge, it was necessary to cut it into small pieces or to take out pieces of a desired size when used.

[0010] However, the fine cutting and sorting during the operation are troublesome, and fine cuttings are likely to occur, and a difference easily occurs between facilities and between operators. That is, the gelatin sponge has different fine cuts depending on the individual who performs fine cut, and it is difficult to make the sizes uniform, and the sizes are not uniform. Further, when performing fine cutting and sieving at the time of operation, it is disadvantageous that preparation of the embolic substance takes time, and there is a drawback that impurities such as rubber gloves are easily mixed during fine cutting.

In addition, in arterial chemoembolization, it is effective to contain an anticancer agent and a contrast agent in the embolization substance, but the gelatin sponge contains the anticancer agent for sustained release, or contains the contrast agent. It is difficult to do.

[0012]

From the above, the present invention is a composition for local hemostatics and a composition for arterial embolization, which can easily prepare particles having a target particle size, and is an anticancer agent. Alternatively, it is an object to provide a novel composition that can contain a contrast agent.

[0013]

SUMMARY OF THE INVENTION The present invention provides a composition for topical vascular hemostasis and arterial embolization comprising insoluble alginate particles.

The insoluble alginate particles used in the present invention can be obtained by contacting a water-soluble alginate solution with a solution containing an appropriate polyvalent metal ion. As the water-soluble alginate, for example, sodium alginate can be used. Further, as the polyvalent metal ion, calcium ion, iron ion or the like can be used.

The insoluble alginate particles used in the present invention can be prepared in various sizes by changing the production conditions. Specifically, the size of the particles can be adjusted by changing the nozzle diameter when dropping sodium alginate. In free fall, particles with a diameter of 1.5 to 7 mm can be produced by changing the nozzle inner diameter to 0.2 to 7 mm. Further, in the method of spraying with an air stream, etc., particles of 0.2 to 1.5 mm can be produced by using a nozzle of 26 G to 14 G. Also, by using a vibrating nozzle,
It is known that the particle size can be adjusted.

Generally, the size of the required particles varies depending on the place of hemostasis and the purpose of embolization, but the above-mentioned particles can be freely controlled in size according to the purpose.
Uniform particles of the required size can be made. Furthermore, since the preparation is simple, it can be easily prepared by clinical preparation at the clinical site. In addition, it is possible to easily include a required amount of substances such as an anti-cancer agent and an angiographic agent as described below during the operation.

The composition for local vascular hemostasis of the present invention can obtain a hemostatic effect by being introduced into a blood vessel.
In particular, by injecting the above particles into a local blood vessel with a catheter, only the target portion of the blood vessel can be stopped, so that it can be used as a hemostatic substance for a local blood vessel by catheter surgery.

The composition for local vascular hemostasis of the present invention also comprises
It is characterized in that a drug can be easily contained therein.
For example, adreamycin, mitomycin, cisplatin or the like can be used as the anti-cancer agent, and iopamidol, ioxablade or the like can be used as the contrast agent. When an anticancer agent is used, a sustained release chemotherapeutic composition,
When a contrast agent is used, it is possible to produce an excellent contrast composition for contrast-improving a local area.

The composition for local vascular hemostasis of the present invention is extremely useful as an embolic substance in embolization therapy because it has a hemostatic effect and also has an excellent property of containing a contrast agent. Furthermore, by containing an anticancer agent in the composition, the anticancer agent can be gradually released at the retention site of the composition. By this,
Since the anticancer drug can be locally administered at the same time as the vascular embolization, effective treatment of cancer by arterial chemoembolization is possible.

[0020]

【Example】

Example 1 Preparation of Micro Alginate Gel Beads Containing Contrast Agent and Anticancer Agent Pronova BLVG (sodium alginate) 100 mg, physiological saline 6 ml, Iopamilone 370 (vascular contrast agent) 6 ml, adriamycin (anticancer agent) 10 mg were obtained by mixing Suck 12 ml of solution into a syringe and pass through a 23 gauge needle to 0.5 M from the air.
A large number of alginate gel beads for chemical embolization (hereinafter referred to as beads) were prepared by continuously dropping them in 20 ml of a calcium chloride solution. The resulting beads have a diameter of 0.5 mm to 1.0 mm,
When the beads were placed on the film and X-rayed at 45 kv, 200 mA and a tube film distance of 1 m, the contrast capability of the beads was almost equivalent to 2 mm thickness of the aluminum step.

(Test Example 1) Effect of hepatic arterial chemoembolization in dogs Four hybrid dogs were randomly divided into a hepatic arterial chemoembolization group and a control group (saline administration).

Nembutal (pentobarbital) 50mg
/ Kg was administered intravenously and general anesthesia was performed. The surgically exposed left femoral artery was punctured with an elastor needle, a guide wire was advanced into the aorta, and a catheter was inserted. The aorta and common hepatic artery were imaged to identify the proper hepatic artery branches toward the medial left lobe, medial right lobe, lateral left lobe, lateral right lobe, square lobe, and caudate lobe. A catheter was superselectively inserted into the branch of the proper hepatic artery having a diameter of about 1 mm that circulates into the largest hepatic area among them. Approximately 0.6 ml of beads or saline under fluoroscopy according to the composition of the group
Injected at a rate of min.

After embolization, common hepatic arteriography did not image the arteries embolized with beads. This confirmed the embolic effect.

There was no difference in the general condition between the control group and the embolus group. Two weeks later, the liver, lungs, kidneys, and pancreas were excised and visually observed. No gross abnormalities were found in the control group and the embolus group.

Example 2 Elution of Adriamycin from Alginate Gel Beads Microalginate gel beads 2 prepared in the same manner as in Example 1
g was immersed in 60 ml of the dissolution test solution (0.9% NaCl), and the dissolution test was carried out in a shaking incubator at 37 ° C. for 120 strokes.
The amount of adriamycin (ADR) eluted at each time in the dissolution test solution is measured by spectrophotometer Ubest-30 type (manufactured by JASCO Corporation)
It was observed by measuring the absorbance at a maximum absorption wavelength of 480 nm using, and the elution ratio of ADR was calculated. The dissolution test solution had no absorption at a wavelength of 480 nm. Figure 1 shows the elution rate of ADR from alginate gel beads. The elution of ADR from the alginate gel beads was about 60% in 1 hour and about 75% in 2 hours.

Comparative Example 1 Elution of Adriamycin from Sponzel 0.5-1.0 mm ³ strips (0.012 g) obtained by slicing Sponzel, which is a plate-shaped preparation having a thickness of about 1 cm, was used in 1 ml of 0.9% NaC.
Sponzel strips were thoroughly soaked with ADR by soaking in 1 and 1 ml ADR mixture for 5 minutes. Then, soak in 60 ml of the dissolution test solution (0.9% NaCl) and incubate at 37 ° C in a shaking incubator.
The dissolution test was performed with 20 strokes. The elution rate of ADR was measured at a maximum absorption wavelength of 480 nm for each time of ADR eluted in the elution test solution. Figure 1 shows the elution rate of ADR from sponge strips. In the dissolution test solution, ADR was eluted from the sponzel strip in 75% for 15 minutes and nearly 100% in 30 minutes, and no retention was observed in the sponzel strip.

[Brief description of drawings]

FIG. 1 shows the change in the elution rate of ADR from alginate gel beads and Sponzel strips.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hidemi Kawada 1992-17 Kitakorozawa-machi, Tokorozawa-shi, Saitama Wing Court Tokorozawa P1-202

Claims (5)

[Claims] 1. A composition for local vascular hemostasis comprising insoluble alginate particles. 2. A composition for arterial embolization containing insoluble alginate particles. 3. An arterial chemoembolization composition comprising insoluble alginate particles and an anticancer agent. 4. A sustained-release composition comprising insoluble alginate particles, wherein the drug is contained in the particles. 5. An imaging composition, comprising insoluble alginate particles, wherein the particles contain a contrast agent.