JPH02200628A - Sustained-release antitumor agent and production thereof - Google Patents

Abstract

PURPOSE:To obtain a sustained release antitumor agent having high concentration of anti-cancer drug in tumor, suppressing systemic side effects, having affinity to organisms by embedding the agent in tumor part, by adding an antitumor agent to the interior of porous material of hydroxyapatite having open pore with specific particle diameter. CONSTITUTION:An antitumor agent is added to the interior of porous material of hydroxyapatite comprising granules having 100-400mum average particle diameter, having continuously connected open pore. The antitumor agent is produced by molding granules of hydroxyapatite having 150-500mum average particle diameter so as not to collapse the granules, calcining the molded hydroxyapatite at 1,100-1,300 deg.C and embedding an antitumor agent in the interior. Since the agent is directly embedded in tumor part by a surgical method, the agent acts as a bone filler after removal of malignant tumor of cartilage, advantageously restores erased bone to the original state and promotes formation of new bone.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a sustained-release antitumor agent using hydroxyapatite as a filler and a method for producing the same. The present invention relates to a sustained-release antitumor agent with stable effects and a method for producing the same.

BACKGROUND ART AND PROBLEMS TO BE SOLVED] Conventionally, cancer treatment has included surgical treatment methods and medical treatment methods, and various treatment methods have been used depending on the patient's condition. Among these, chemotherapy is the field that has made the most remarkable progress in recent years, and its therapeutic results are improving. On the other hand, however, this chemotherapy sometimes has to be discontinued due to its severe side effects.

Therefore, local administration of anticancer drugs has recently attracted attention, and efforts are being made to improve the therapeutic effect by administering them directly to cancer tissues and to avoid the serious side effects mentioned above. However, direct administration of antitumor agents has considerable side effects, and the anticancer agent disappears in a very short period of time, making it difficult to expect great effects. Development is required.

[Means for Solving the Problems] In view of the current situation, the present inventors conducted intensive studies to achieve the above object, and as a result, they used hydroxyapatite, which has excellent biocompatibility, and developed the compound. We have discovered that by using a sintered body with sufficiently controlled secondary particle size and pore size as a capsule for an antitumor agent, an antitumor agent that maintains stable effects over a long period of time can be obtained. It has been reached.

That is, the present invention provides a sustained-release antitumor agent characterized by having an antitumor agent inside a hydroxyapatite porous body consisting of particles with an average particle size of 100 to 400 μm and having continuously connected open pores, and Average particle size 150-500
This is a method for producing a sustained-release antitumor agent, which is characterized in that μm hydroxyapatite granules are molded without crushing, fired at a temperature of 1100 to 1300°C, and then an antitumor agent is embedded inside.

Used as a raw material for producing the sustained release anti-TTR ulcer agent of the present invention,
Granules having a hydroxyapatite composition with an average particle size of 150 to 500 μm have an atomic ratio of Ca/P of 1.45 to 1.
70 range of hydroxyapatite powder using a mold or rubber press, etc., to 1 kg/c+1! It is made by compression molding at a pressure higher than
It is sieved to obtain granules with an average particle size of 150 to 500 μm.

In addition, it is preferable for the granules to have a shape close to a spherical shape to make the product more uniformly porous and to prevent sharp edges from creating a uniform pore size after sintering. Granules with improved sphericity can be obtained by slowly rotating them in a bot mill containing . Also, the average particle size of the granules is 150μ
If the average particle size is less than 500 μm, the pore size of the resulting porous material will be small and the drug outflow rate will be too low, so no medicinal efficacy can be expected. The effect as a drug release agent is limited, and the strength of the porous body is also reduced.

Next, the granules are placed in a mold of the desired shape and molded under pressure.
The pressure can be freely selected depending on the required strength of the product and within a range that does not cause the granules to collapse too much.

If the granules are easily crumbled, they may be fired at a temperature below the final firing temperature to increase their strength, and then pressure molded. If molding is difficult, you can mold it by moistening it with water, or use organic binders such as ammonium polyacrylate, polyacrylic acid, polyvinyl alcohol, methyl polyacrylate, lactic acid, etc., or calcium phosphate powder. It may also be molded.

The molded product thus obtained was heated to 1100 to 1300°C.
A sintered porous body can be obtained by firing with.

In the present invention, since the particle size of the raw material granules is adjusted in advance, the secondary particles in the obtained sintered body still maintain a spherical shape, although the particle size decreases by about 80% due to sintering. , the width of the pore size distribution is very narrow, the porosity is about 30 to 40%, and the hydroxyapatite porous body has continuously connected open pores, and its secondary particle size is also 10%.
It is 0 to 400 μm.

The above-mentioned porous material is confirmed by measuring the pore size distribution with a mercury boron meter, or using an optical microscope or a scanning electron microscope. For example, when measuring the pore size distribution of a product using 280 μm granules, it is within ±20 μm around 40 μm. It was found that over 70% of the

In addition, the shape of the molded product obtained by the above manufacturing method can take various shapes such as spherical and hexahedral shapes, but the shape that is easy to mold is the hexahedral shape, considering that it is easy to implant into living organisms. It is appropriate that each side be several centimeters or less.

The method for embedding the anticancer drug is to drill a hole of an appropriate depth in the center of the molded body using a drill, etc., fill it with the anticancer drug, and then seal it with a biocompatible sealing material. good.

Examples of sequestrants include α-tricalcium phosphate (hereinafter referred to as
It is abbreviated as α-TCP. ), hydroxyapatite, nitric acid,
There are cement sealants made of a slurry of a mixture of common salt.

The anticancer agent is not particularly limited, but among them, cisplatin (hereinafter abbreviated as CDDP) is preferred.

As mentioned above, by controlling the secondary particle size of the raw material, it is possible to control the pore distribution and pore size within the sintered body, and the release rate of the drug can be kept constant, and the release rate can also be controlled. can.

The anticancer agent of the present invention increases the tumor white concentration of the anticancer agent by directly implanting it into the tumor site using a surgical method, suppresses systemic side effects, and has biocompatibility, so there is no need to take it out after surgery. It acts as a bone filler after curettage of malignant tumors or metastatic bone tumors, etc., returning the excised bone to its original state and at the same time promoting the production of new bone.

In addition, hydroxyapatite implanted in living bodies slightly dissolves in body fluids, which increases the calcium concentration at the tumor site, but these calcium ions also have the effect of suppressing tumor growth, and the overall effect of these ions is to The antitumor agent of the present invention exhibits extremely excellent antitumor effects.

[Examples] Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Hydroxyapatite powder with a primary particle size of about 15 μm was packed into a rubber bag, then rubber pressed at a pressure of 1'000 kg/aa, taken out, calcined at 700°C for 1 hour, lightly crushed, and sieved. Then, the bot mill was slowly rotated to perform a spheroidization operation to produce granules with an average particle size of 300 μm.

Next, ammonium polyacrylate of 1Δtχ was added to the granules of hydroxyapatite (hereinafter abbreviated as HAP) produced by the above-mentioned method as a binder, and Te5wt! The mixture is then molded into a hexahedron shape of 10 x 10 x 10 mm under a pressure of 2 to 3 kg/d, and baked at 1250°C for 2 hours. Next, place 6φ x 611I in the center of the tox 10 (+am) surface.
After drilling a hole of size l, CDDP: 1
00 mg into the hole, cement sealant [α-T
CP:HAP:4N-Nitric acid:IN-Saline (weight ratio) = 100 = 100: 0; 6: 70] was kneaded for about 30 seconds, then poured into the hole, sealed, and CDDP was poured into the hole. A capsule of hydroxyapatite was obtained.

Example 2 Hydroxyapatite powder with a primary particle size of about 15 μm was packed into a rubber bag, then rubber pressed at a pressure of 1000 kg/cJ, taken out, calcined at 700°C for 1 hour, lightly crushed, and sieved. , granules with an average particle size of 250 μm were produced.

Next, granules of IIAP produced by the above method were added to
5iutχ of wtX polyammonium acrylate was added as a binder, and 4
It is formed into a hexahedron shape of x4x3mm and baked at 1250°C for 2 hours. Next, after drilling a hole of 2φ x 2mm in the center of the 4 x 4 (all> surface,
DDP: 0.5 mg was placed in the hole, and cement sealant [α-TCP: 1 (AP-4N-nitric acid:IN-saline solution (weight ratio >= 100:100:0.6:70)] was added to the hole. After kneading for 30 seconds, put it into the hole, seal it, and CD
Hydroxyapatite capsules containing DP were obtained.

Example 3.4 The amount of CDDP was 1.0 mg in Example 3, and no CDDP was embedded in Example 4, and the other steps were carried out in the same manner as in Example 2 to obtain hydroxyapatite capsules. Ta.

Example 5 Two hexahedral hydroxyapatite capsules (referred to as Sample 1 and Sample 2) were produced by the method of Example 1.

), the capsules were placed in a petri dish containing 10 cc of synthetic culture medium HamF12, and then an elution test was conducted at 37°C. Table 1 shows the relationship between the CDDP concentration in the liquid and the number of days elapsed. The solution was replaced with a fresh one every day shown in Table 1. Therefore, in some cases, the solution was replaced with a new one within one day, and in other cases, it was replaced after being left for several days.

As can be seen from these results, although the elution rate naturally varies depending on the concentration of the surrounding liquid, the concentrations measured at the same daily intervals are almost the same, and the elution rate remains stable regardless of the number of days that have passed. You can see that

Example 6 The hydroxyapatite capsules produced in Examples 2 to 4 were directly administered to the BF transplanted tumor site of mice, and C0
The antitumor effect was compared with intraperitoneal administration of a large amount of DP (LD50 amount). To embed the capsule, first, the capsule was sterilized with ethylene oxide, and the surgical instruments were sterilized in an autoclave at 120° C. for 20 minutes. The mouse used was C311.

Surgery was performed when the tumors transplanted to both backs had a diameter of 1c+a. First, the mouse is fixed, the dorsal skin is disinfected with Hibitene alcohol, a skin incision is made at a position approximately 1 cm away from the tumor edge, the subcutaneous layer is peeled off, a capsule is placed on the surface of the transplanted tumor, and the skin incision is placed on the Flemen. It was closed. Judgment of antitumor effect is expressed by tumor volume, the tumor diameter is measured with a caliper, and the volume (v) - π x (longer axis x shorter axis x height) xi/6
And so.

On the other hand, intraperitoneal administration of a large amount of CD lobe (LD50 amount) was performed by intravenous injection (+, P,) when the tumor diameter reached approximately 1 cm. Mouse LD50.3DPg/Body.

Efficacy was similarly determined based on tumor volume.

The results are shown in Figure 1. C0DP 011g is Example 4
In Example 2, C0DP 0.51g is CDDP
1. Omg is the sustained-release antitumor agent obtained in Example 3, and its effect was investigated. As can be seen from the results, it was found that the effect of preventing tumor growth was remarkable compared to the case where no antitumor agent was added, and it was found to be more effective than the LD50 intraperitoneal injection. That is, it was found that direct administration to the tumor site by the method of this example was a sufficient amount, but on the other hand, the CDDP concentration in the living body was very low and was a sufficiently safe amount.

[Effects of the Invention] The sustained-release antitumor agent of the present invention is obtained by sintering hydroxyapatite granules with uniform particle sizes, so that the secondary particles have uniform particle sizes and are continuously connected. Because it has open pores, it exhibits a stable release rate, and when administered directly to the tumor site, it exhibits significant antitumor effects over a long period of time, and local administration is sufficient to ensure that the dose is safe for living organisms. Understood.

[Brief explanation of the drawing]

FIG. 1 shows the results of Example 6, and is a graph showing the relationship between the number of days after tumor implantation and tumor volume. 3° correction person 4,

Claims (2)

[Claims] (1) A sustained-release anti-tumor agent characterized by having an anti-tumor agent inside a hydroxyapatite porous body consisting of particles with an average particle size of 100 to 400 μm and having continuously connected open pores. (2) Hydroxyapatite granules with an average particle size of 150 to 500 μm are molded at 1100 to 1300°C without being crushed.
1. A method for producing a sustained-release anti-tumor agent, which comprises embedding the anti-tumor agent inside after firing at a temperature of .