JPH0151266B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is an embolic agent for use in effective embolic therapy for malignant diseases such as cancer.

(Prior art and its problems) The number of deaths from cancer is increasing year by year, and there is a desire for early detection and the development of effective treatments for unresectable cases.

Therefore, intraarterial one-shot intraarterial injection therapy of anticancer drugs has become commonly performed using percutaneous vascular catheterization such as the Seldinger method, in order to deliver high concentrations of anticancer drugs locally. However, although one-shot arterial injection therapy can achieve a transient high drug concentration in the injected local area, the drug flows out through the bloodstream quickly and cannot maintain a high concentration in the injected local area for a long period of time. However, it is not necessarily an efficient method.

In addition, although embolization therapy using a gelatin sponge is an effective treatment, it may cause extracapsular invasion, daughter nodules,
Intraportal vein plugs have little effect, and in fact, the long-term prognosis is poor.

Therefore, there is a need for the development of an embolic agent that is diagnostically useful, compensates for the shortcomings of one-shot arterial injection therapy, and has an embolic effect to improve the therapeutic results of embolization therapy.

(Problems to be Solved by the Invention) The object of the present invention is to exhibit diagnostic utility in itself and to increase the concentration of the anticancer drug in the blood by using it in combination with other anticancer drugs. The object of the present invention is to provide an embolic agent with a high embolic effect, which maintains the anticancer agent and the yeast for a long period of time in contact with each other.

(Means for Solving the Problem) As a result of intensive research to achieve the above object, the present inventor discovered that a specific calcium phosphate sintered body becomes a microembolus and stagnates inside the body and blocks blood flow.
The present inventors have discovered that the anticancer drug used in combination can be sustained-released to exhibit remarkable anti-cancer effects, leading to the completion of the present invention.

That is, the embolic agent of the first aspect of the present invention is made of sintered fine particles of calcium phosphate such as sintered hydroxy calcium apatite (HAP) or sintered calcium triphosphate (TCP), and the firing temperature is 600-1350℃, average particle size 10-1000μm, and stoichiometric ratio Ca/P
is 1.0 to 2.0.

Further, the embolic agent of the second invention of the present invention is a hydroxyl compound having a firing temperature of 600 to 1350°C, an average particle size of 10 to 1000 μm, and a stoichiometric ratio Ca/P of 1.0 to 2.0.
It is characterized by adsorbing other anticancer agents such as adriamycin and mitomycin C to calcium phosphate such as calcium apatite sintered body (HAP) or tricalcium phosphate sintered body (TCP).

The hydroxy calcium apatite sintered body or tricalcium phosphate sintered body used in the present invention has an average particle size of 10 to 1000 μm. If the average particle size is less than 10 μm, there will be a problem that it will be washed away into the bloodstream during intraarterial injection and will easily clog the kidneys.
If it exceeds 1000 μm, the problem arises that intraarterial injection is difficult.

Furthermore, in the composition of the calcium phosphate sintered body used in the present invention, the content ratio of Ca and P is 1.0≦Ca/
It is preferable that P<2.0. When Ca/P is out of the above range, the problem arises that the solubility increases and the sustained release effect of the anticancer drug decreases.

Furthermore, when producing the calcium phosphate sintered body used in the present invention, the firing temperature is 600 to 1350°C.
It is preferable that If the firing temperature is less than 600℃, sufficient granulation will not be possible, resulting in the problem of decreased adsorption of monosites such as macrophages.
If the firing temperature exceeds 1350°C, the problem arises that the apatite itself decomposes and ceramics in an active state cannot be formed.

(Effect) When the embolic agent of the present invention is injected into an artery leading to a localized tumor such as cancer, it stagnates within the tumor as a microembolus, cutting off nutritional supply to the tumor and causing the concomitant anticancer drug to be localized. It is kept at high concentration for a long time to suppress the growth of soybean.

(Example) Hereinafter, examples will be given in which the present invention was applied to experiments and human liver malignancy.

Example 1 Transplanted into the right hind leg muscle of BALB/c mice
The effects of the apatite embolization chemotherapy of the first and second inventions were investigated using MethA.

The calcium phosphate used has a firing temperature of 700~
800℃, stoichiometric ratio Ca/P1.66…, average particle size 50~
It is 100μm hydroxy calcium apatite (pure apatite; HAP).

Two weeks after transplantation, adriamycin (ADR 1.5 mg/Kg) was injected alone from the ipsilateral common iliac artery, apatite (HAP 20 mg/Kg) was injected alone, and apatite (HAP) and For the group in which adriamycin (ADR) was adsorbed and mixed and injected intraarterially, serum samples were collected over time from the fundus venous plexus.
The ADR concentration and the ADR concentration in the blood stream 30 minutes after intraarterial injection were measured (HPLC method), and the anti-inflammatory effect was determined, and each group was compared and studied.

Serum ADR concentration peaked 2 minutes after intraarterial injection in both groups, but in the HAP embolization chemotherapy group
Significant up to 10 minutes compared to ADR alone group (p<
The value was as low as 0.005). (Figure 1).

In addition, the intramuscular ADR concentration was significantly higher in the HAP-ADR embolization therapy group (p<0.001). In other words, it was thought that by performing HAP embolization chemotherapy, a higher concentration of ADR was captured within a day (Table 1).

The effect of embolization therapy on the growth of
ADR (1.5mg/Kg) injection alone had no anti-inflammatory effect. However, in the HAP-ADR chemotherapy embolization group, a significant effect on suppressing the growth of breast cancer was observed. Furthermore, HAP embolization therapy alone was more effective in suppressing the growth of breast cancer than ADR alone (Figure 2).

Example 2 The subjects were 15 cases of unresectable hepatocellular carcinoma.

The calcium phosphate used was pure apatite ADR as in Example 1.

In accordance with the Liver Cancer Handling Regulations, the spread of the tumor was examined using angiography and CT, and 5 cases within 2 areas, 3 cases within 3 areas, and 7 cases with 4 areas or distant metastasis.
These cases could be divided into 7 cases of massive type, 6 cases of nodular type, and 2 cases of infiltrative type.

The drug used was ADR (20 to 50 mg) mixed and adsorbed to HAP.

Since the safety of HAP-ADR injection into the gastroduodenal artery has not been confirmed, it was administered into the proper hepatic artery or the hepatic side thereof. The number of treatments was once.

The effectiveness of treatment was mainly determined by angiography, and the area reduction rate of the cyst was also determined with reference to ultrasound findings.

Regarding the treatment results, 7 cases showed a reduction of 50% or more (PR), and 4 cases showed a reduction of 20-50% (MR).
For example, there were 4 cases of reduction (NC) of 25% or less, and no increase of 25% or more (PD). In other words, the response rate of PR or better was 47%, and the reduction effect including MR or better was 73% (Figure 3).

(Effects of the Invention) As explained above, according to the present invention, calcium phosphate particles such as sintered hydroxy calcium apatite or sintered calcium triphosphate having a specific particle size are used as an embolic agent in embolization therapy. Compared to conventional embolization therapy, HAP embolization therapy improved the therapeutic effect with only one administration without stimulating the body. HAP stagnates in the tissue as microemboli, allowing the anticancer drug to be released in a sustained manner, and a significant anti-cancer effect was observed due to the synergistic effect with the blockage of blood flow by HAP. Furthermore, it is possible to increase the amount of anticancer drug.

The reason why the embolic agent of the present invention has excellent biocompatibility and does not stimulate living organisms is thought to be due to the fact that the calcium phosphate in the present invention is originally a substance that is the same as, or extremely similar to, bone components of vertebrates. Additionally, this substance is non-toxic and non-antigenic, so there are almost no side effects. Furthermore, it is possible to know the location and size of mustard particles that have a contrast effect, which is extremely useful in diagnosis.

[Brief explanation of drawings]

Figure 1 shows adreamycin (ADR1.5mg/
of mice in embolization chemotherapy using Kg)
Graph showing temporal changes in ADR blood concentration, 2nd
The figure is a graph showing the temporal change in the size of blood clots during embolization chemotherapy using adreamycin (ADR1.5mg/Kg). Figure 3 shows the change in the size of blood clots during embolization chemotherapy in humans. Graph showing 15 examples of temporal changes. FIG. 4 is a table of the ADR concentration in the throat 1 hour after embolization chemotherapy using adreamycin (ADR 1.5 mg/Kg).

Claims (1)

[Scope of Claims] 1. Sintered microparticles of calcium phosphate,
An embolic agent characterized in that the firing temperature is 600 to 1350°C, the stoichiometric ratio Ca/P is 1.0 to 2.0, and the average particle size is 10 to 1000 μm. 2. The anti-fouling agent is adsorbed onto sintered fine particles of calcium phosphate with a firing temperature of 600-1350℃, a stoichiometric ratio Ca/P of 1.0-2.0, and an average particle size of 10-1000μm. An embolic agent consisting of 3. The embolic agent according to claim 1 or 2, characterized in that the stoichiometric ratio Ca/P is 1.66.