JP3339718B2 - Magnetic composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a magnetic composition, and more particularly, to an improved magnetic composition which can be administered to a living body by an injection method. The magnetic composition of the present invention is administered into a living body by, for example, an injection method, and can be applied to local hyperthermia. In addition, sustained release of various drugs can be performed together with hyperthermia.

[0002]

2. Description of the Related Art In recent years, hyperthermia (thermotherapy) has attracted attention as a method for treating cancer, and various proposals have been made for implant materials used for local hyperthermia. For example, Japanese Utility Model Laid-Open Publication No. 2-35750 discloses that a thermosensitive drug-containing polymer that releases a drug by heating is incorporated in an element body made of a magnetic material having a hole, and a drug that is released by heating. Has been proposed in which a drug is released to the outside through the hole. The above-mentioned drug release element is heated to an appropriate temperature by, for example, an induction heating device installed outside, and can release a drug in combination with Hypersaarmia.

[0003]

However, in local hyperthermia using a drug releasing element, a surgical operation such as incision is indispensable for placing the drug releasing element in a cancer site. The present invention has been made in view of the above circumstances,
Its purpose is to be able to administer in vivo by injection method, and by distributing it to the specific affected area and its vicinity, mainly,
It is an object of the present invention to provide a magnetic composition suitable for treating a malignant tumor or the like caused by hyperthermia due to local magnetism, and a magnetic composition capable of locally releasing a drug by magnetism.

[0004]

That is, the first aspect of the present invention is as follows.
The gist lies in a magnetic composition characterized by comprising an amorphous alloy and a hydrophilic polymer, and the second gist of the present invention comprises an amorphous alloy, a hydrophilic polymer and a drug. A magnetic composition characterized by the following.

Hereinafter, the present invention will be described in detail. First, the magnetic composition of the present invention will be described. The amorphous alloy used in the present invention is not particularly limited, and various conventionally known amorphous alloys can be used. From the viewpoint of Hyperthermia, the Curie temperature is 42 to
It is preferred to use an amorphous alloy at 90C, preferably 60-75C.

As an alloy having the above Curie temperature range,
For example, an amorphous alloy proposed in JP-A-2-47243, that is, one or more transition metals of Fe, Ni and Co, and one or more of P, C, Si and B An amorphous alloy containing a metalloid and Cr and / or Mo may be used.

The composition of the above amorphous alloy is usually
Metalloid: 8 to 40 at%, preferably 10 to 30 at%, Cr and / or Mo: 10 to 15 at%, preferably 12 to 13 at% (total value when Cr and Mo are used together). The remainder is a transition metal, but may contain other atoms, for example, atoms constituting unavoidable impurities in a range of 10 atomic% or less. Typical amorphous alloys having such a composition include, for example, Fe
(66.8) Cr (13.2) P (13.2) C (6.
Fe-Cr-PC-based alloy such as 8), Fe (17.
3) Fe-Ni-Si-B alloys such as Ni (60.6) Si (9.7) B (12.4). The amorphous alloy is usually used as a powder, and the average particle size is usually 300 μm or less, preferably 200 μm.
m or less, preferably 100 μm or less.

The hydrophilic polymer used in the present invention is a polymer of a monomer having a hydrophilic group (hydroxy group, carboxyl group, etc.) or a salt thereof.
The solubility in water is 3 g / 100 ml or more, preferably 1
0 g / 100 ml or more of a water-soluble polymer or a salt thereof is preferably used. The water-soluble polymer may be either a natural or synthetic polymer, and specific examples thereof are as follows.

(1) Carboxyvinyl polymer (carbopol), water-soluble celluloses (for example, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), water-soluble chitin derivatives (for example, Carboxymethyl chitin, polyvinyl pyrrolidone, polyvinyl alcohol, ester gum, polybutene, etc.), water-soluble starch derivatives (eg, hydroxypropyl starch, carboxymethyl starch, etc.) polyvinyl ether, one or two of polyethylene oxide
More than species. Their average molecular weight ranges from 20,000 to 9,000,000, preferably from 100,000 to 700,000.

(2) Poly (meth) acrylic acid or a metal salt such as a sodium salt or a potassium salt thereof having an average molecular weight of about 30,000 or more, preferably 50,000 to 10,000,000. (3) hyaluronic acid, sodium alginate, atelocollagen, gluten, soluble starch, gum arabic, mannan, dextrin, pullulan, dextran, tragacanth, amylopectin, xanthan gum, karaya gum, kelgam, locust bean gum, casein, pectin,
One or more natural polymers such as agar and fibrin glue.

Among the above water-soluble polymers, water-soluble celluloses are particularly suitable because they have been used as pharmaceutical carriers. The hydrophilic polymer is usually used in the form of a powder, and has an average particle size of usually 1 to 200 μm, preferably 1 to 100 μm, and more preferably 1 to 50 μm.

The drugs used in the present invention include antineoplastic agents, antibiotics, anti-inflammatory agents, various diagnostic agents and the like. In particular, examples of the anti-neoplastic agent include platinum derivatives such as cisplatin, bleomycins, futrafuls, doxorubicins, mitomycin and etoposide.

In the magnetic composition of the present invention, the mixing ratio of each of the above components is based on the total amount of the composition, and the ratio of the amorphous alloy is usually 10 to 95% by weight, preferably 30% by weight.
To 90% by weight, more preferably 50 to 85% by weight, and the proportion of the hydrophilic polymer is usually 5 to 90% by weight, preferably 1 to 90% by weight.
It is 0 to 70% by weight, more preferably 15 to 50% by weight. The ratio of the drug is usually 40% by weight or less, preferably 30% by weight or less, based on the total amount of the composition. Further, in the magnetic composition of the present invention, various modifying additives (such as pharmaceutical additives) can be included in the preparation of the composition, and the compounding ratio of such modifying additives is Is 40% by weight or less based on the total amount of the composition.

Next, a method for preparing the magnetic composition of the present invention will be described. The magnetic composition of the present invention includes, for example, (1)
A layer separation method in which the components are mixed in the first solvent as necessary, and precipitated using a second solvent that is not mixed with the first solvent,
(2) It can be prepared by a granulation method (a water addition method, a non-aqueous solvent addition method or a compression pulverization dry method) using a granulation solvent as necessary, by mixing the constituent components.

The magnetic composition of the present invention is obtained as a granular material, and the particle size is adjusted so that it can be well dispersed in water and pass through the catheter used. Specifically, 10
It is desirable to adjust the particle size in the range of 0 to 700 μm, preferably 100 to 400 μm. Hereinafter, preferred embodiments of each of the above preparation methods will be described.

(1) Layer separation method: A hydrophilic polymer is dissolved in a solvent, and the alloy powder is uniformly dispersed in a concentrated solution (when the hydrophilic polymer is a water-soluble polymer). To disperse or dissolve the drug. Then, the polymer solution is dropped into a precipitation solvent that does not dissolve the hydrophilic polymer and the drug as much as possible under stirring conditions to precipitate the magnetic composition. Next, a new solvent is added to the magnetic composition to sufficiently dehydrate and then dry. When the hydrophilic polymer is a water-soluble polymer, a hydrocarbon solvent such as benzene, toluene, xylene and hexane can be suitably used as the above-mentioned solvent for precipitation.
Further, the particle size of the magnetic composition can be adjusted by the kind of the precipitation solvent to be used, the stirring speed at the time of precipitation, and the like.

(2) Granulation method: After thoroughly mixing the hydrophilic polymer, the alloy powder and, if necessary, the respective powders of the drug, and further mixing an appropriate amount of ordinary pharmaceutical additives as necessary. After granulation and drying using a granulating solvent, granulation is performed, or the mixed powder is directly compressed into tablets or solidified by a roller compactor and then pulverized by a suitable crusher and then sieved to a predetermined particle size. Is separated. As the granulating solvent, water, lower alcohols (eg, methanol, ethanol, propanol, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, etc.), and mixtures thereof can be used. As the granulation method, for example, an extrusion method, a speed mill method, or the like can be adopted.

In the preparation of the magnetic composition of the present invention, various modifying additives can be used. For example, to further delay the disintegration or dissolution rate of the magnetic composition,
Ethyl celluloses, Eudraggids, chitin, polylactic acid, polyglycolic acid and polylactic glycolic acid copolymer can be used. In order to further enhance the hydrophilicity of the surface of the magnetic composition, various hydrophilic surfactants such as sucrose fatty acid ester, HCO-60e, and the like can be used.

In order to increase the lipophilicity of the surface of the magnetic composition, natural oils and fats derived from plants or animals such as petrolatum, paraffin, liquid paraffin, various phospholipids, hydrophilic ointments, purified lanolin, dextrin fatty acid esters, fatty acid glycerides, fatty acids, squalane And lanolin alcohol. In order to control the dissolution of the drug from the magnetic composition and improve the workability of preparing the magnetic composition, an extender such as lactose, mannitol, starch, and calcium phosphate can be used.

The above modifying additives can be used in combination of two or more, if necessary, and are added at the time of molding of the magnetic composition or used after coating after molding.
As described above, the used amount is 40% by weight or less based on the total amount of the composition as a total amount with the drug.
The content is preferably 0% by weight or less.

Next, the features of the magnetic composition of the present invention will be described. The magnetic composition of the present invention can be administered into a living body by an injection method, and can be applied to local hyperthermia. That is, the temperature of the magnetic composition of the present invention rises to about 40 to 50 ° C. in a short time (depending on the composition and the like, but about several minutes to 15 minutes) by irradiation with electromagnetic waves. It is considered that such a temperature rise is caused by a change in the matrix structure of the magnetic composition.

The magnetic composition of the present invention can release various drugs in combination with hyperthermia. And, in the magnetic composition of the present invention, the hydrophilic polymer as a component thereof is generally non-melting, and in particular, although it does not melt at 70 ° C. or lower, it is clear from the test examples described below. As described above, the release of the drug can be remarkably enhanced by the irradiation of the electromagnetic wave, and the release can be restored by stopping the irradiation of the electromagnetic wave. Therefore, for example, in the case of the magnetic composition of the present invention containing an anticancer agent, a therapeutic effect of the anticancer agent together with hyperthermia can be expected by administering it locally to the cancer and irradiating it with electromagnetic waves.

Further, the magnetic composition of the present invention has a thickness of 100 μm
By adjusting the particle size to about 700 μm, preferably about 100 to 500 μm, a therapeutic effect by an embolic effect is also expected. As described above, the magnetic composition of the present invention is considered to be most suitable for anticancer treatment, but is not limited to use in anticancer treatment, and can be used as a diagnostic agent if a diagnostic agent is used as a drug.

[0024]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist of the present invention. In the following examples, the amorphous alloy has a composition of Fe (66.8 atomic%) Cr (13.2) P (13.2) C (6.8) and a particle size of 44 to 63 μm. , Curie temperature 64
An amorphous alloy having a crystallization temperature of 470 ° C. and a saturation magnetic flux density of 4200 G was used. The alloy is disclosed in
Amorphous flakes obtained by the same method as described in Example 1 of 7243 were pulverized and prepared.

Example 1 First, 1 part by weight of cisplatin (antineoplastic agent) powder (hereinafter abbreviated as "part"), 10 parts of an alloy, 3 parts of hydroxypropylcellulose (HPC) powder and 1 part of mannitol powder were sufficiently added. Mix. Next, 3 parts of a mixed solution of ethanol and hexane (1:10) that had been sterilized and filtered were added and kneaded well, and the kneaded product was granulated through a dry-heat sterilized 20-mesh stainless sieve (Japanese Industrial Standard Standard Sieve). And air-dry at room temperature for 15 hours. After drying, 42 mesh and 150
The particles were sized using a dry-heat sterilized stainless steel sieve to obtain a granular magnetic composition having a particle size range of about 100 to 350 μm.

Example 2 A particulate magnetic composition obtained in the same manner as in Example 1 was spray-coated with a xylene solution of ethylcellulose.
Xylene was completely removed by evaporation at 50 ° C. or lower to obtain a particulate magnetic composition coated with ethyl cellulose.

Example 3 Example 1 was repeated except that 1 part of the cisplatin powder was replaced by 0.5 part of cyano green powder and the amount of mannitol was changed to 1.5 parts. Similarly, a granular magnetic composition having a particle size range of about 100 to 350 μm was obtained. The granular magnetic composition of this example can be used for diagnosis of the size of a cancer site or the like by observing its spread with an optical fiber or the like after being administered locally in a living body.

Example 4 The procedure of Example 1 was repeated, except that the use of 1 part of the cisplatin powder was stopped and the amount of mannitol used was changed to 2 parts, to thereby obtain granules having a particle size range of about 100 to 350 μm. A magnetic composition was obtained.

Example 5 First, 2 parts of cisplatin powder, 10 parts of alloy, 6 parts of HPC powder, and 4 parts of ethylcellulose powder were uniformly mixed with 100 parts of ethanol to obtain a uniform suspension. Next, the suspension was gradually dropped into 100 parts of a mixed liquid (8: 2) of hexane and toluene which had been sterilized and filtered in advance to precipitate a granular magnetic composition. Dropping of the suspension was performed under stirring conditions of 500 rpm using a stirring blade. The obtained granular magnetic composition was collected by filtration through a glass filter, washed with anhydrous ethanol, dried, and sized using a dry-heat sterilized 42-mesh and 150-mesh stainless steel sieve. A granular magnetic composition having a particle size range was obtained.

<Evaluation Test> Test Example 1 (In-Vitro Test) A 200 ml beaker containing 150 ml of physiological saline was immersed in a constant temperature water bath at 37 ° C., and stirred at 50 rpm, while being stirred at 50 rpm. Was added, and the amount of the drug (cisplatin) eluted at each elapsed time was measured. At this time, data was measured from both sides, with and without applying a magnetic field strength of 7 KOe and a frequency of 185 KHz on the way. FIG. 1 shows the measurement results.

Test Example 2 (In-Vivo Test) The granular magnetic composition obtained in Example 1 was dispersed in a physiological saline solution, and was intraarterially infused into a dog's right renal artery with a catheter.
(CDDP, 1 mg / kg) equivalent amount of the particulate magnetic composition was plugged. CDD in medulla, cortex and peripheral blood after embolus
The amount of P was measured. As a control, CDDP
The same measurement was performed by administering the same dose of CDDP to another dog using an injection solution (0.5 mg / ml). FIG. 2 shows the measurement results of the amount of CDDP (μg / g) in the medulla and cortex, and FIG. 3 shows the measurement results of the CDDP concentration (μg / ml) in peripheral blood. In addition, in arterial injection, no adhesion to the catheter or the like was observed, and it was confirmed that the granular magnetic composition of the present invention was a preparation that was easily injected.

<Test Results> (1) From the results of the in-vitro test, it was confirmed that the granular magnetic composition of the present invention could elute cisplatin, an antineoplastic agent, in a sustained release pattern. When a magnetic field was applied, it was confirmed that the granular magnetic composition rapidly disintegrated, and the dissolution of cisplatin was also rapidly increased.

(2) From the results of the in-vivo test, when the granular magnetic composition of the present invention was infused into the right renal artery, CDDP was observed for a long period of 7 days in local areas such as the medulla and cortex.
It was confirmed that the tissue concentration of can be maintained at a very high value as compared with the concentration in the case of the control CDDP injection solution or the concentration in peripheral blood. In addition, irradiation of electromagnetic waves from outside the body during the test (185 kHz, 7 kA / m, 45 mi)
According to n), the CDDP concentration in the peripheral blood showed a transient increase.

[0034]

The magnetic composition of the present invention as described above can be dispersed in physiological saline or Ringer's solution and injected into the affected area with a catheter, and can be stored locally to sustain the drug locally. Can be released. In addition, when a magnetic field is applied, the dissolution of the drug can be rapidly increased at the time of application, and the drug concentration in the body can be increased.
Moreover, it has a feature that it is easy to inject without being attached to the catheter.

[Brief description of the drawings]

FIG. 1 is a graph showing the time-dependent change in the drug dissolution rate of the granular magnetic compositions obtained in Examples 1 and 2.

FIG. 2 is a graph showing the change over time in the amount of CDDP (μg / g) in the medulla, cortex and the like of the granular magnetic composition obtained in Example 1;

FIG. 3 is a graph showing the change over time of the concentration (μg / ml) in the peripheral blood of the granular magnetic composition obtained in Example 1.

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61N 5/02 A61N 5/02 (72) Inventor Hidetoshi Matsuki 1-9-29 Yagiyama-Minami, Taihaku-ku, Sendai-shi, Miyagi (72) Invention Kazuo Kato 3-12 Namagi, Yagita, Fukushima City, Fukushima Prefecture No. 507 (72) Inventor Hiroshi Ninomiya 3-6-36 Shimorenjaku, Mitaka City, Tokyo (72) Inventor Sakae Minagawa 4-1-1, Suehiro, Kumagaya-shi, Saitama Pref. 4-14-1, Suehiro, Kumagaya-shi, Saitama Prefecture Rikken Kumagaya Office (56) References JP-A-2-47243 (JP, A) JP-A-4-180775 (JP, A) JP-A-4-116146 (JP, A) JP-A-54-52719 (JP, A) JP-A-63-41423 (JP, A) JP-A-5-49704 (JP, A) JP-A-5-137803 (JP, A) (JP, U) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 A61L 27/00-33/18 A61N 5/02

Claims (6)

(57) [Claims] 1. A magnetic amorphous alloy, water-soluble celluloses, and anticancer agents, antibiotics, anti-inflammatory agents and diagnostics.
Contains a drug selected from the group of drugs and has a particle size of 100 to 7
A particulate magnetic composition for sustained release of a drug, which is in the range of 00 µm . 2. The granular magnetic composition according to claim 1, wherein the Curie temperature of the magnetic amorphous alloy is 42 to 90 ° C. 3. The granular magnetic composition according to claim 1, wherein the drug is an anticancer drug. 4. The composition according to claim 1, wherein the proportion of the magnetic amorphous alloy is 10 to 95% by weight and the proportion of the water-soluble celluloses is 5 to 90% by weight based on the total amount of the composition. A granular magnetic composition according to any one of the above. 5. The method according to claim 5, wherein the ratio of the drug is 4
The granular magnetic composition according to any one of claims 1 to 4, wherein the content is 0% by weight or less. 6. is for hyperthermia claim 1-5
A granular magnetic composition according to any one of the above.