JPH09165328A - 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, having a fixed particle diameter, useful for a closing therapy especially for a deep cancer, by using both a water-insoluble metal phosphate and a prescribed compound. SOLUTION: This microsphere comprises both a water-insoluble phosphate such as hydroxyapatite and an organic polymer compound and has 0.01-10mm, preferably 0.05-1mm average particle diameter. The microsphere is obtained by dripping a dripping solution containing both the water-insoluble phosphate and the organic polymer compound 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. Calcium tertiary phosphate is preferable as the water-insoluble phosphate besides the above-mentioned compound. Sodium alginate, xanthan gum, locust bean gum, sodium carboxydextran, etc., are preferable as the organic polymer compound. The microsphere is effective for treating a deep cancer such as pancreatic cancer, hepatic carcinoma, gallbladder cancer and splenic cancer. The blood vessel closing agent is usable as an injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a microsphere containing a metal phosphate and an organic polymer compound, which is useful for the therapy of obstruction of cancer.

[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 of a certain particle size containing a water-insoluble metal phosphate such as hydroxyapatite and an organic polymer compound are effective,
Completed the invention.

That is, according to the present invention, a water-insoluble metal phosphate and an organic polymer compound are contained in an average particle size of 0.01 to
For a 10 mm globule. 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 dropping into water and precipitating small spheres containing a water-insoluble metal phosphate and an 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.

Since the metal phosphate such as hydroxyapatite which is one of the constituents of the microspheres of the present invention is a biological component, it can be expected that the microspheres will not undergo foreign body recognition reaction. 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 containing a water-insoluble metal phosphate and an organic polymer compound 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. The average particle size (average diameter of spheres) is 0.01-
It is 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 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 organic polymer compound may be any polymer compound which can be cured by a counter metal ion forming the above water-insoluble salt of phosphoric acid, but a polymer compound having hydrophilicity is preferably used. Specific examples include sodium alginate, xanthan gum, locust bean gum, carboxydextran sodium, carrageenan, and one selected from the group consisting of pectin,
You may use 2 or more types of these. Of these, sodium alginate is most preferred.

The microspheres of the present invention may contain various optional components in addition to the above, as long as 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 preferred content of each component in the microsphere of the present invention is 0.1 to 50% by weight of phosphoric acid and 0.1 of metal.
~ 50% by weight, 0.1 to 60% by weight of organic polymer compound
It is. More preferably, phosphoric acid is 0.5 to 30% by weight, metal is 0.5 to 30% by weight, and organic polymer compound is 0.5 to 40% by weight.

Since the microspheres of the present invention contain an organic polymer compound having hydrophilicity, they are excellent in impregnating a water-soluble drug to act. Therefore, it can be used not only as an occluding agent but also as a carrier for a water-soluble anticancer agent.

(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 the water-soluble phosphate, the organic polymer compound, and water is dropped into a hardening solution containing a water-soluble salt of metal capable of forming a water-insoluble salt together with phosphoric acid, and water. The target microspheres are obtained by precipitating the microspheres containing the insoluble metal phosphate and the organic polymer compound.

That is, 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 surface tension of the organic polymer compound causes the water-insoluble metal. The microspheres of the present invention containing a phosphate and an organic polymer compound are 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 concentration of the organic polymer compound in the dropping solution is preferably 0.1 to 4% by weight, more preferably 0.
It is 2 to 2% by weight. Examples of the water-soluble phosphate contained in the dropping solution include diamine ammonium hydrogen phosphate, ammonium phosphate, organic amine salts such as triethylammonium phosphate, and the like. Among these, diammonium hydrogen phosphate, ammonium phosphate Is particularly preferable. The concentration of the water-soluble phosphate in the dropping solution is preferably 2 to 10% by weight, more preferably 3 to 8% by weight.

Examples of the water-soluble salts of metals contained in the curing solution which are capable of forming 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. Moreover, it is preferable that the pH of the curing liquid is adjusted to about 9 to 11 in advance.

The small spheres deposited in the hardening liquid are recovered by filtration or the like. By further classifying the thus obtained small spheres, it is possible to obtain small spheres having a desired particle size distribution. Incidentally, other optional components such as calcium carbonate which may be contained in the above-mentioned microspheres of the present invention can be contained in the microspheres by a method such as being contained in a dropping liquid or a curing liquid in advance. .

(3) Vascular occlusion 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 microsphere that does not easily 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 small spheres, optional components used for the formulation used in 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.

Although oral administration, rectal administration and the like can be considered as administration routes, administration by injection is most preferable, and therefore the pharmaceutical composition of the present invention preferably has an injectable form. Examples of administration by injection include subcutaneous administration, intraperitoneal administration, arterial administration, and intravenous administration. this house,
Most preferred is arterial injection into the artery near the affected area or direct administration to the affected area. It can also be administered using a fiberscope or the like.

A suitable 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.

[0029]

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 0.5 M aqueous solution of calcium nitrate whose pH was adjusted to 9 by adding triethylamine as a hardening liquid was prepared, and the above dropping liquid was dropped into this using a syringe (injection needle: 33G) to deposit microspheres. Let This was filtered and collected, and the target small sphere was obtained (small sphere 1). The electron micrograph revealed that the shape of the small sphere was a sphere having an average diameter of 400 μm.

<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.

[0032]

[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.

[0034]

[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 ────────────────────

[0035]

Embodiments of the present invention will be described below.

[0036]

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.

[0038]

[Table 3]

[0039]

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.

Further, by using an organic polymer compound having hydrophilicity, it is possible to form small spheres which are excellent in impregnating a water-soluble drug to act, and therefore, not only as a blocking agent but also as a water-soluble drug. It can also be used as a carrier for anti-cancer drugs.

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.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C01B 25/32 B01J 13/02 G

Claims (10)

[Claims] 1. A small sphere having an average particle size of 0.01 to 10 mm, which contains a water-insoluble metal phosphate and an organic polymer compound. 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. , Obtained by depositing small spheres containing a water-insoluble metal phosphate and an organic polymer compound.
The described sphere. 3. The water-insoluble metal phosphate is hydroxyapatite or tricalcium phosphate.
The described sphere. 4. The microsphere according to claim 1, wherein the organic polymer compound is one or more selected from the group consisting of sodium alginate, xanthan gum, locust bean gum, sodium carboxydextran, carrageenan and pectin. . 5. A vaso-occlusive agent comprising the microsphere according to any one of claims 1 to 4 as an active ingredient. 6. A pharmaceutical composition containing the vasoocclusive agent according to claim 5. 7. The composition according to claim 6, which is used for cancer obstruction therapy for deep cancer. 8. The composition according to claim 7, wherein the deep cancer is pancreatic cancer, liver cancer, gallbladder cancer, or spleen cancer. 9. The composition according to claim 6, wherein the dosage form is an injection. 10. 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. The method for producing microspheres according to claim 1, comprising a precipitation step of precipitating microspheres containing a water-insoluble metal phosphate and an organic polymer compound.