JPH09165327A - Microsphere and composition for medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a microsphere high in blood vessel closing effect, enabling an effective cancer closure treatment. SOLUTION: A dripping solution containing both a water-soluble phosphate and an organic polymer compound is dripped into a sclerosing solution containing both a water-soluble salt of a metal capable of forming a water- insoluble salt with phosphoric acid and water to precipitate a globule containing both a water-insoluble metal phosphate and an organic polymer compound. The prepared globule is baked and the organic polymer compound is removed to give a microsphere consisting essentially of the water-insoluble metal phosphate (hydroxyapatite or calcium tertiary phosphate, etc.) and having 0.01-10mm average particle diameter. The microsphere is useful as a blood vessel closing agent. A composition for a medicine is obtained by incorporating the microsphere.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to metal phosphate-based microspheres useful for the treatment of cancer obstruction.

[0002]

BACKGROUND OF THE INVENTION Cancer is one of the unsolved serious diseases facing humanity nowadays when infectious diseases have been overcome by the advent of antibiotics. Various chemical substances have been developed to overcome cancer, but there is little difference between the toxicity to cancer cells and the toxicity to normal cells, and it is not possible to raise the dose to a level that can treat cancer or side effects. Many problems remain with chemotherapy, such as cancer that can be treated but does not lead to life-prolonging effects.

Radiation therapy has been carried out for the purpose of complementing this chemotherapy, but radiation, like anticancer agents, also has a problem of side effects. Further, in radiation therapy, there is no other specification for coping with deep cancer such as liver, pancreas, spleen, etc. than intraoperative irradiation. Since intraoperative irradiation imposes a great burden on the patient, it is difficult to adapt to patients with weak physical strength, and the number of simultaneous irradiations is limited, so that the effect is often limited.

Under these circumstances, various efforts have been made to improve the effects of chemotherapy and radiation therapy. For example, a missile therapy in which an anti-cancer cell monoclonal antibody or the like is bound to an anti-cancer agent to enhance the cancer orientation, or an anti-cancer agent occlusion therapy that blocks the nutrient blood vessels of cancer with an iodized oil such as Lipiodol and also seals the anti-cancer agent in a cancer-bearing organ. And so on. However, missile therapy suffers from drug release when it reaches cancer, while occlusion therapy lacks materials that can occlude sufficiently, for example because it is a synthetic chemical such as Lipiodol, There are problems such as lack of biocompatibility and inability to perform complete occlusion.

On the other hand, regarding water-insoluble metal phosphates such as hydroxyapatite, its amorphous powder is used as a carrier for anti-cancer agents, etc. for cancer treatment, as a heat support for hyperthermia, and as an obstructive agent for cancer feeding blood vessels. Although it was known to be used, it was not known to process the inner wall of blood vessels into small spheres that are not easily scratched and to use such small spheres as an occluding agent.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of such circumstances, and an object of the present invention is to provide a microsphere having a high vascular occlusion effect which enables effective treatment of cancer occlusion.

[0007]

In view of such circumstances, the present inventors have earnestly sought a material having a high occlusion effect and biocompatibility, which is useful for effective cancer treatment, especially occlusion therapy for deep cancer. As a result of repeated research, they found that small spheres having a constant particle size and containing a water-insoluble metal phosphate such as hydroxyapatite as a main component were effective, and completed the invention.

That is, the present invention relates to small spheres containing water-insoluble metal phosphate as a main component and having an average particle size of 0.01 to 10 mm. This small sphere is preferably a drop solution containing a water-soluble phosphate, an organic polymer compound and water in a hardening solution containing a water-soluble salt of metal capable of forming a water-insoluble salt together with phosphoric acid and water. It is obtained by firing the spherical body containing the precipitated water-insoluble metal phosphate and the organic polymer compound.

The microspheres of the present invention effectively block the nutrient blood vessels of the cancer in the affected area, inhibit the supply of nutrients to the cancer, and at the same time, stop the anticancer drug administered to this area without leaking it to others. Therefore, by using this, cancer treatment can be efficiently performed.

In the microspheres of the present invention, the metal phosphate such as hydroxyapatite, which is the main component, is a biological component,
It can be expected that no foreign body recognition reaction will occur. Further, since the shape thereof is a spherical shape which has not been heretofore known, it can be expected that the blood vessel will not be damaged during the injection.

The present invention will be described in detail below.

(1) Small Sphere of the Present Invention The small sphere of the present invention is characterized by having a water-insoluble metal phosphate as a main component and having a spherical shape. Here, the sphere means a sphere or a shape having a smooth surface which allows a strain within 20% with respect to the sphere. Regarding the size, the average particle diameter (average diameter of spheres) is 0.01 to 10 mm, preferably 0.05 to 1 mm. When the average particle size is within this range, it can be administered intravascularly and can easily reach cancer.

The water-insoluble metal phosphate is not particularly limited to a metal, but is preferably a metal phosphate selected from the group consisting of calcium, strontium, zirconium and barium. Among them, calcium phosphate, which is abundant in the living body, is preferable. Furthermore, as such a metal phosphate, hydroxyapatite or tricalcium phosphate is preferable.

The microspheres of the present invention contain the above-mentioned water-insoluble metal phosphate as a main component, but may contain various optional components in addition to the extent that the effects of the present invention are not impaired. Examples of such other optional components include various inorganic salts such as calcium carbonate and calcium sulfate, silica, and the like.

The content of the water-insoluble metal phosphate in the microspheres of the present invention is preferably 70 to 100% by weight, more preferably 90 to 100% by weight. Among them, the preferred content of each component is 0.1 to 70% by weight of phosphoric acid in the microspheres, 0.1 to 70% by weight of metal, and more preferably 0.5 to 30% by weight of phosphoric acid. , The metal is 0.5-30
% By weight.

(2) Method for producing small sphere of the present invention The small sphere of the present invention can be produced by the following method. That is, a dropping solution containing a water-soluble phosphate, an organic polymer compound, and water is dropped into a hardening solution containing a water-soluble salt of metal and water capable of forming a water-insoluble salt together with phosphoric acid,
A precipitation step of precipitating a spherical body containing a water-insoluble metal phosphate and an organic polymer compound, and the organic polymer compound is removed by firing the spherical body obtained in the precipitation step to obtain a water-insoluble metal phosphate salt. And a firing step for producing microspheres containing as a main component.

In the deposition step, the dropping of the dropping liquid into the hardening liquid causes the hardening of the organic polymer compound and the formation of the water-insoluble metal phosphate, and further, the action of the surface tension of the organic polymer compound. A spherical body containing a water-insoluble metal phosphate and an organic polymer compound is deposited. When the dropping liquid is dropped into the hardening liquid, it is preferable to drop the dropping liquid with a syringe or the like so that the dropping particles become fine particles, although it depends on the size of the target small sphere.

The organic polymer compound used in the precipitation step may be any polymer compound which can be cured by a counter metal ion forming a water-insoluble salt of phosphoric acid,
Specifically, sodium alginate, xanthan gum,
Examples include locust bean gum, carboxydextran sodium, carrageenan, and pectin. Of these, sodium alginate is most preferred. The concentration of the organic polymer compound in the dropping solution is preferably 0.1
It is 4% by weight, more preferably 0.2 to 2% by weight.

Examples of the water-soluble phosphates contained in the dropping solution include organic amine salts such as diammonium hydrogen phosphate, ammonium phosphate and triethylammonium phosphate. Of these, diammonium hydrogen phosphate, Ammonium phosphate is particularly preferred. The concentration of the water-soluble phosphate in the dropping solution is preferably 2 to 10% by weight,
It is more preferably 3 to 8% by weight.

Examples of the water-soluble salts of metals contained in the hardening liquid which can form water-insoluble salts with phosphoric acid include water-soluble calcium salts such as calcium nitrate and calcium acetate, strontium nitrate, zirconium nitrate and barium nitrate. Can be exemplified, and of these, calcium nitrate is particularly preferable. The metal in this water-soluble salt forms the water-insoluble metal phosphate that constitutes the microspheres of the present invention, together with the phosphoric acid supplied by the dropping of the dropping solution. The concentration of the water-soluble salt in the curing liquid is preferably 4 to 15% by weight, more preferably 5 to 10% by weight. Also, the pH of the curing liquid is
It is preferably adjusted to about 9 to 11.

The spheres deposited in the curing liquid are recovered by filtration or the like.

In the manufacturing method of the present invention, next, the spherical body containing the water-insoluble metal phosphate produced and recovered in the precipitation step and the organic polymer compound is fired.
Through this baking step, the organic polymer compound is decomposed, and the microspheres containing the water-insoluble metal phosphate of the present invention containing no organic polymer compound are obtained. As the firing conditions, the temperature is about 900 to 1250 ° C., and the firing time is about 12 to 72 hours, although it depends on the amount of the small spheres.

By further dividing the thus obtained small spheres into spheres, small spheres having a desired particle size distribution can be obtained. Incidentally, other optional components such as calcium carbonate which may be contained in the above-mentioned microspheres of the present invention,
For example, it can be contained in the small spheres by a method such as being contained in the dropping liquid or the curing liquid in advance.

(3) Vascular occlusive agent and pharmaceutical composition of the present invention Since the microspheres of the present invention are made of a biocompatible material and are processed into a small spherical shape that is unlikely to damage the inner wall of the blood vessel, It can be used as an active ingredient of a vaso-occlusive agent such as a cancer-vegetative blood vessel occluding agent.

The composition of the present invention is characterized by containing such microspheres, and is suitable for use as a medicine. As a specific use, it can be used as an occluding agent in cancer obstruction therapy for cancer, especially deep cancer. Deep cancer includes pancreatic cancer, liver cancer, gallbladder cancer, and spleen cancer.

The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned microspheres, optional components used in the formulation of ordinary pharmaceutical compositions. As an optional component,
Excipients, fillers, binders, coating agents, sugar coating agents, stabilizers, disintegrating agents, coloring agents, lubricants, pH adjusting agents, solubilizing agents, dispersing agents, thickening agents, isotonic agents, etc. it can.

The administration route may be oral administration, rectal administration and the like, but administration by injection is most preferable, and therefore the pharmaceutical composition of the present invention is preferably in the form of injection. Examples of administration by injection include subcutaneous administration, intraperitoneal administration, arterial administration, and intravenous administration. Among these, arterial injection into the artery near the affected area or direct administration to the affected area is most preferable. It can also be administered using a fiberscope or the like.

The preferred dose of the pharmaceutical composition of the present invention is
Although it varies depending on the symptom, sex, age, and body type, it is preferable to administer 10 mg to 10000 mg per day for an adult in one to several divided doses. In addition, the pharmaceutical composition of the present invention is a biological substance or an analogue thereof, and therefore is excellent in safety. By administering the pharmaceutical composition of the present invention, the feeding blood vessels of cancer can be easily blocked, and the simultaneously administered anticancer agent can be stored for a long time.

In addition, the pharmaceutical composition of the present invention may contain various drugs used in the treatment of cancer.
Such agents include radiocontrast agents such as Lipiodol or vaso-occlusive agents, cisplatin, SMANC.
Anticancer agents such as S, adriamycin, actinomycin, neocarzinostatin, fluorouracil and its derivatives, apoptosis inducers such as etoposide, immunosuppressants such as steroid hormones and cyclophosphamide, and narcotics for pain relief such as morphine Etc. can be illustrated.

[0030]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

<Example 1: Production Example of Microspheres> A 0.1 M diammonium hydrogen phosphate aqueous solution containing 2% by weight of sodium alginate was prepared and used as a dropping solution. On the other hand, a 0.5M aqueous solution of calcium nitrate having pH adjusted to 9 by adding triethylamine as a hardening liquid was prepared, and the dropping liquid was dropped into this using a syringe (injection needle: 33G) to deposit a spherical body. Let The spheroids were collected by filtration and then calcined at 500 ° C. for 12 hours to remove alginic acid to obtain microspheres (small sphere 1). The electron micrograph revealed that the shape of the small sphere was a sphere having an average diameter of 400 μm. (Fig. 1)

<Example 2: Formulation example> Microsphere 1 obtained in Example 1
Was used to prepare an injection according to the formulation shown in Table 1.
That is, the formulation components shown in Table 1 were mixed and dispersed, filled in an ampoule, sealed, and then sterilized to obtain an injection.

[0033]

[Table 1] Table 1 ────────────────── Prescription ingredients Prescription ratio ─────────────────── Distilled water for injection 98.1% by weight Sodium chloride 0.9% by weight Small spheres 11% by weight ───────────────────

<Example 3: Formulation example> Microsphere 1 obtained in Example 1
Was used to prepare an injection according to the formulation shown in Table 2.
That is, the formulation components shown in Table 2 were mixed and dispersed, filled in an ampoule, sealed, and then sterilized to obtain an injection.

[0035]

[Table 2] Table 2 ──────────────────── Prescription component Prescription ratio ───────────────────── Distilled water for injection 97.1% by weight Sodium chloride 0.9% by weight Small spheres 11% by weight Neocarzinostatin 1% by weight ────────────────────

[0036]

Embodiments of the present invention will be described below.

[0037]

Example 1 <Reservability test> The retentivity of the microspheres of the present invention administered using rats was examined. That is, 5 male Wistar rats per group were anesthetized with pentobarbital, and the upper abdomen was incised in the midline. Then, the microsphere 1 which is the occluding agent of the present invention labeled with ³² P was intraperitoneally administered at 21 mg (28 d
pm / body weight (mg) was embedded and the abdomen was closed. This is slaughtered at regular intervals and each organ is taken out and homogenized,
A lysing agent was added and dissolved, and the radiation intensity of each organ was measured by a liquid scintillation counter.

This was divided by the organ weight, and the radiation intensity per unit weight was measured. Table 3 shows the results. Than this,
It can be seen that the microspheres, which are the occluding agent of the present invention, are well retained in the abdominal cavity, which is the administration site, and that no other radioactive substances have migrated. Therefore, it can be seen that the microspheres of the present invention can efficiently block the feeding blood vessels.

[0039]

[Table 3]

[0040]

EFFECTS OF THE INVENTION Since the microspheres of the present invention are made of a biocompatible material and are processed into small spheres that are less likely to damage the inner wall of blood vessels, they can occlude the feeding blood vessels of cancer well in the affected area. It has the effect of inhibiting the supply of nutrients to the area and at the same time stopping the anti-cancer agent administered to this part without leaking it to other parts, and can be effectively used as a vaso-occlusive agent.

Therefore, the pharmaceutical composition of the present invention containing such microspheres is useful for effective cancer treatment, especially for obstruction therapy for deep cancer, and contributes to efficient treatment of cancer such as pancreatic cancer and liver cancer. Can be expected.

[Brief description of the drawings]

FIG. 1 is an electron micrograph showing a particle structure of a small sphere obtained in Example 1 in an embodiment of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location B01J 13/14 B01J 13/02 H 13/10 G // (A61K 47/02 47:36)

Claims (9)

[Claims] 1. Small spheres containing water-insoluble metal phosphate as a main component and having an average particle diameter of 0.01 to 10 mm. 2. A dropping solution containing a water-soluble phosphate, an organic polymer compound and water is dropped into a hardening solution containing a water-soluble salt of a metal capable of forming a water-insoluble salt together with phosphoric acid and water. And obtained by firing a spherical body containing a water-insoluble metal phosphate and an organic polymer compound to be precipitated,
The small sphere according to claim 1. 3. The microsphere according to claim 1, wherein the water-insoluble metal phosphate is hydroxyapatite or tricalcium phosphate. 4. A vaso-occlusive agent comprising the microsphere according to any one of claims 1 to 3 as an active ingredient. 5. A pharmaceutical composition containing the vasoocclusive agent according to claim 4. 6. The composition according to claim 5, which is used for cancer obstruction therapy for deep cancer. 7. The composition according to claim 6, wherein the deep cancer is pancreatic cancer, liver cancer, gallbladder cancer, or spleen cancer. 8. The composition according to claim 5, wherein the dosage form is an injection. 9. A dropping solution containing a water-soluble phosphate, an organic polymer compound and water is dropped into a hardening solution containing a water-soluble salt of a metal capable of forming a water-insoluble salt together with phosphoric acid and water. , A precipitation step of precipitating a spherical body containing a water-insoluble metal phosphate and an organic polymer compound, and the organic polymer compound is removed by firing the spherical body obtained in the precipitation step to obtain a water-insoluble metal phosphate. The manufacturing method of the microsphere of Claim 1 including the baking process which produces | generates the microsphere which has a salt as a main component.