JPH08208491A - Agent for lowering nephrotoxicity of medicine - Google Patents

Abstract

PURPOSE: To obtain an agent for lowering nephrotoxicity of medicine such as platinum complex compounds, containing, spherical activated carbon, capable of retaining the antineoplastic action of platinum complex compounds, esp. of cisplatin as active ingredient and capable of markedly lowering the nephrotoxicity after administering such a compound without the need of forced water dose or any diuretic agent administration. CONSTITUTION: This nephrotoxicity lowering agent contains, as active ingredient, spherical activated carbon [for example, petroleum-based pitch-derived spherical activated carbon produced by infusibilizing pitch made finely spherical inn a molten state using oxygen followed by baking at 600-1000 deg.C in an inert atmosphere to effect carbonization followed by activation at 850-1000 deg.C in steam, having a diameter of 0.05-2 (esp. 0.1-1) mm, specific surface area of 500-2000 (esp. 700-1500) m<2> /g, and the content of voids each having 100-75000Å pore radius of 0.01-1 (esp. 0.05-0.8) ml/g]. It is preferable that the formulation of this nephrotoxicity lowering agent be capsules, stick or divided package.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to platinum complex compounds (particularly cisplatin) containing spherical activated carbon as an active ingredient.
Relates to a nephrotoxicity reducing agent.

[0002]

BACKGROUND OF THE INVENTION Cancer chemotherapy has made rapid progress in recent years. However, since the anticancer agent acts not only on the cancer tissue but also on the normal tissue, side effects are unavoidable. Therefore,
Various measures have been taken to reduce side effects.
Platinum complex compounds, especially cisplatin, is an excellent anticancer agent that can be expected to have a marked life-prolonging effect on testicular tumor, bladder cancer, renal cancer, renal pelvic and ureteral tumor, prostate cancer and ovarian cancer,
Its chemical name is cis-dichloro-diamine-platinum. The main side effects of cisplatin are nephrotoxicity, gastrointestinal disorders,
Hematological toxicity and neurotoxicity, and nephrotoxicity is a dose limiting factor in usual intravenous administration, intraarterial administration, or intraperitoneal administration. Nephrotoxicity is caused by cisplatin secreted into the renal tubules, and the higher the concentration of cisplatin is long-lasting, the more severe the renal damage is caused. The degree of renal damage is judged by creatinine clearance or the like. Sometimes it causes serious symptoms such as renal failure. Usually, cisplatin is administered in a diuretic state, and measures have been taken to reduce renal toxicity by lowering the cisplatin concentration in the renal tubules. The diuretic state is brought about by water addition and administration of a diuretic (mannitol or furosemide). Furthermore,
It is also known to use a blood adsorption column with activated carbon in combination to reduce systemic side effects of cisplatin administration. Feun et al. (Proc. Am. Asso
c. Cancer Res. , 1985, vol. Two
6, No. 1039) reported an experiment in which active charcoal was orally given to dogs by intravenous administration of cisplatin at the end of administration. Examples of the compound capable of reducing the nephrotoxicity of cisplatin include, for example, sodium thiosulfate, acetazolamide, selenium dioxide, sodium selenate, cysteine, 3-aminobenzamide, fosfomycin, and S-adenosyl-L-methionine (Japanese Patent Laid-Open Publication No. HEI-6 (1999)).
-192109) and the like have been reported.

[0003]

However, administration in a diuretic state or combined use of an activated carbon adsorption column causes a great deal of pain to the patient, and the effect of reducing renal toxicity is not sufficient. In addition, the report of Feun et al. Only describes the effect on life prolongation, and does not describe, for example, the reduction of nephrotoxicity. Furthermore, among the above-mentioned compounds known to be capable of reducing the nephrotoxicity of cisplatin, no compound has hitherto been clinically put into practical use. Therefore, a drug that clearly reduces the nephrotoxicity caused by cisplatin administration has been desired. The present invention has been made in view of such circumstances, and an object thereof is to perform forced water addition or diuretic administration without reducing the antitumor effect of platinum complex compounds, particularly cisplatin. Another object of the present invention is to provide a nephrotoxicity-reducing agent for platinum complex compounds, which has a clear effect of reducing nephrotoxicity upon administration of platinum complex compounds without causing pain to patients. In order to achieve the above-mentioned object, the present inventors have diligently studied an active ingredient different from conventional drugs, and as a result, oral administration of a medicinal activated carbon formulation at the time of cisplatin administration clearly reduces renal toxicity. We found that the effect appears. The present invention has been completed based on the above findings.

[0004]

The present invention relates to a nephrotoxicity-reducing agent for platinum complex compounds containing spherical activated carbon as an active ingredient.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below. The spherical activated carbon which is an active ingredient of the nephrotoxicity reducing agent of the platinum complex compounds of the present invention is not particularly limited as long as it is a spherical activated carbon that can be used internally for medical purposes. It is preferable that the spherical activated carbon has excellent adsorption ability. for that reason,
The spherical activated carbon preferably has a diameter of 0.05 to 2 mm,
More preferably, it is a spherical activated carbon of 0.1 to 1 mm. Further, preferably, the specific surface area is 500 to 2000 m ² / g,
More preferably, it is 700 to 1500 m ² / g of spherical activated carbon. Further, the pore radius is preferably 100 to 75,000.
A spherical activated carbon having an angstrom void volume of 0.01 to 1 ml / g, more preferably 0.05 to 0.8 ml / g. The specific surface area is a value measured by a methanol adsorption method using an automatic adsorption amount measuring device. The void volume is a value measured by a mercury penetration porosimeter.

[0006] Conventionally, powdered activated carbon, which has been conventionally used in medicine as an antidote, easily causes constipation as a side effect,
This was a major drawback because constipation during illness is particularly dangerous. The spherical activated carbon is advantageous as compared with the powdered activated carbon in that it does not scatter when taken, and does not cause constipation even when continuously used. If the diameter is less than 0.05 mm, there is not enough effect to remove side effects such as constipation,
When it exceeds 2 mm, not only is it difficult to take, but the desired pharmacological effect is not rapidly exhibited. The shape of the spherical activated carbon is one of the important factors for obtaining the effects of the present invention, and it is necessary that it is substantially spherical. Among the spherical activated carbon, spherical activated carbon derived from petroleum-based pitch, which will be described later, is particularly preferable because it is close to a sphere.

For the production of spherical activated carbon, any activated carbon raw material such as sawdust, coal, coconut shell, various petroleum-based or coal-based pitches or organic synthetic polymers can be used. Spherical activated carbon can be produced, for example, by a method of activating carbonized raw materials and then activating them. As the activation method, various methods such as steam activation, chemical activation, air activation or carbon dioxide activation can be used,
It is necessary to maintain the purity that is medically acceptable.

Examples of the spherical activated carbon include granulated activated carbon derived from carbonaceous powder, organic polymer fired spherical activated carbon, and spherical activated carbon derived from petroleum hydrocarbon (petroleum pitch). Granulated activated carbon from carbonaceous powder is carbonized by, for example, granulating a carbonaceous powder raw material into small spherical particles with a binder such as tar or pitch, and then heating and firing at a temperature of 600 to 1000 ° C. in an inert atmosphere. Then, it can be obtained by activating. As the activation method, steam activation, chemical activation,
Various methods such as air activation or carbon dioxide activation can be used. Steam activation is, for example, in a steam atmosphere,
It is performed at a temperature of 800 to 1100 ° C.

Spherical activated carbon of organic polymer firing is, for example,
It is disclosed in Japanese Examined Patent Publication No. 61-1366 and can be manufactured as follows. A condensation type or polyaddition type thermosetting prepolymer is mixed with a curing agent, a curing catalyst, an emulsifier and the like, emulsified in water with stirring, and allowed to react at room temperature or under heating with continuous stirring. The reaction system first becomes a suspension state, and the thermosetting resin spherical particles appear by further stirring. Collect this and in an inert atmosphere 50
It is possible to obtain a spherical activated carbon of organic polymer firing by heating to a temperature of 0 ° C. or higher for carbonization and activation by the method described above.

The diameter of the spherical activated carbon derived from petroleum pitch is preferably 0.05 to 2 mm, more preferably 0.1 to 2 mm.
1 mm, preferably with a specific surface area of 500 to 2000 m ² /
g, more preferably 700 to 1500 m ² / g, and the void volume with a pore radius of 100 to 75000 angstroms is preferably 0.01 to 1 ml / g. This spherical activated carbon derived from petroleum pitch can be produced, for example, by the following two methods.

The first method is, for example, Japanese Patent Publication No. 51-76.
U.S. Pat. No. 3,917,806 and Japanese Unexamined Patent Publication No. 54-89010 (U.S. Pat. No. 4,761,284).
As described in (Specification No.), first, the pitches in the molten state in the form of small spherical particles are infusibilized with oxygen, and then,
It is carbonized by heating at a temperature of 600 to 1000 ° C. in an inert atmosphere, and then 850 to 100 in a steam atmosphere.
This is a method of activation at a temperature of 0 ° C. The second method is, for example, Japanese Patent Publication No. 59-10930 (US Pat. No. 442).
No. 0433), first, crush the string-like pitches in a molten state, put them in hot water to make them spherical, and then make them infusible with oxygen, and then It is a method of carbonizing and activating under the same conditions as the first method.

The spherical activated carbon as an active ingredient in the present invention includes (1) spherical activated carbon which has been subjected to ammonia treatment,
(2) Spherical activated carbon that has been subjected to oxidation and / or reduction treatment can also be used. The spherical activated carbon that can be subjected to these treatments may be any of the above-mentioned spherical activated carbon derived from petroleum pitch, granulated activated carbon of carbonaceous powder, and organic polymer calcined spherical activated carbon.

The above-mentioned ammonia treatment is, for example, spherical activated carbon is an aqueous ammonia solution containing 1 to 1000 ppm of ammonia, and the volume ratio of the aqueous ammonia solution to the spherical activated carbon is 2 to 10 at a temperature of 10 to 50 ° C. 0.
It consists of treating for 5 to 5 hours. As the activated carbon obtained by subjecting the spherical activated carbon derived from petroleum pitch described above to ammonia treatment, there is disclosed in Japanese Unexamined Patent Publication No. 56-5313 (US Pat.
The spherical activated carbon described in No. 1284) can be mentioned. For example, the spherical activated carbon treated with ammonia has a diameter of 0.05 to 2 mm, preferably 0.1 to 2 mm.
1 mm, a specific surface area of 500~2000m ² / g, preferably 700~1500m ² / g, pore radius from 100 to 75
The void volume of 000 Å is 0.01-1 ml /
Examples thereof include spherical activated carbon having g and pH of 6 to 8.

The above-mentioned oxidation treatment means performing high-temperature heat treatment in an oxidizing atmosphere containing oxygen, and pure oxygen, nitrogen oxide, air or the like can be used as an oxygen source. The reduction treatment means performing high-temperature heat treatment in an atmosphere inert to carbon, and the atmosphere inert to carbon is formed by using nitrogen, argon, helium, or a mixed gas thereof. be able to.

The above-mentioned oxidation treatment is preferably 0.5 to 25% by volume oxygen content, more preferably 3 to 1 oxygen content.
The temperature is preferably 300 to 700 ° C., more preferably 400 to 600 ° C. in a 0% by volume atmosphere. The reduction treatment is preferably performed at a temperature of 700 to 1100 ° C, more preferably 800 to 1000 ° C in an inert atmosphere.

As an example of the spherical activated carbon derived from petroleum-based pitch subjected to oxidation and / or reduction treatment, Japanese Patent Publication No.
The spherical carbonaceous adsorbents described in JP-A-11611 (US Pat. No. 4,681,764) can be mentioned.
As another example, "Kremezin" (trade name: manufactured by Kureha Chemical Industry Co., Ltd.) can be mentioned, and as a capsule preparation thereof, "Kremezin Capsule 200" (product name: manufactured by Kureha Chemical Industry Co., Ltd .; 200 mg / cap) Is mentioned. Kremezin is a spherical fine-grained oral adsorbent composed of homogeneous porous carbon with a diameter of approximately 0.2 to 0.4 mm, and is effective in improving uremic symptoms and delaying the introduction of dialysis in progressive chronic renal failure. It is being used in clinical settings as a medicinal product.

The spherical activated carbon subjected to the oxidation and / or reduction treatment has a diameter of 0.05 to 2 mm, preferably 0.1 to 1 mm and a specific surface area of 500 to 2000 m ² /
g, preferably 700 to 1500 m ² / g, pore radius 1
0.01 to 75,000 angstrom void volume
Spherical activated carbon of ~ 1 ml / g is preferred.

The drug to which the nephrotoxicity-reducing agent of the present invention is applied is platinum complex compounds such as cisplatin, dichloro-ethylenediamine-platinum (II), 1,2-diamino-cyclohexyl-platinum (II) -malonate or Sulfate, carboplatin, diisopropylamino-trans-dihydroxy-cis-dichloro-platinum (IV), (-)-(R) -2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylate) platinum (II) -monohydrate Rate, cis-diamine glycolate platinum, etc., especially cisplatin, ie cis-
It is dichloro-diamine platinum. Moreover, the nephrotoxicity targeted by the nephrotoxicity-reducing agent of the present invention is a decrease in renal function due to renal cell injury.

Spherical activated carbon derived from petroleum pitch which has been subjected to oxidation and reduction treatment, which is a medical activated carbon preparation, was orally administered to normal rats upon administration of cisplatin, which is a platinum complex compound, and surprisingly, cisplatin nephrotoxicity was observed. There was a clear reduction effect on. Moreover, no side effect was observed with the administration of the spherical activated carbon. From these facts, it was found that the preparation containing spherical activated carbon as an active ingredient is useful as a nephrotoxicity reducing agent for platinum complex compounds. Since the administration route of the spherical activated carbon can be different from the administration route of the platinum complex compounds, its nephrotoxicity can be reduced without lowering the antitumor effect of the platinum complex compounds.

The nephrotoxicity-reducing agent for platinum complex compounds of the present invention is applied to humans who are adversely affected by renal toxicity or may be affected by administration of platinum complex compounds, particularly cisplatin. It is a mammal. The nephrotoxicity reducing agent of the platinum complex compounds of the present invention is preferably administered orally. The dose depends on the subject (mammal, particularly human), age, individual difference, and / or medical condition. For example, the daily dose for humans is usually 0.2 to 20 g as spherical activated carbon, but the dose may be appropriately increased or decreased depending on the symptoms. Also,
The administration may be performed once or in several divided doses. The spherical activated carbon may be administered as it is or as an activated carbon preparation. When the spherical activated carbon is administered as it is, it can be administered as a slurry in which the spherical activated carbon is suspended in drinking water or the like.

The time of administration of the reducing agent of the present invention and the time of administration of platinum complex compounds can be freely selected and combined. For example, they may be in tandem or may overlap. Moreover, you may overlap only a part of period. Furthermore, such administration schedules can be appropriately combined or repeated. The administration timing of the reducing agent of the present invention preferably overlaps with the administration timing of the platinum complex compounds over a part of the period or the entire period.

As the dosage form in the activated carbon preparation, granules,
Any dosage form such as tablets, dragees, capsules, sticks, sachets or suspensions can be adopted.
In the case of capsules, in addition to ordinary gelatin capsules, enteric-coated capsules can be used as necessary. When used as granules, tablets or dragees, it must be unlocked into the original microparticles in the body. The content of spherical activated carbon in the activated carbon preparation is usually 1 to 100%. In the present invention, the preferred activated carbon preparation is a capsule, a stick or a divided package. For these formulations,
The spherical activated carbon is directly enclosed in the container.

[0023]

The present invention will be described in detail below with reference to examples, but these examples do not limit the scope of the present invention. Production Example: Preparation of Spherical Activated Carbon Softening point generated by naphtha pyrolysis at 182 ° C., quinoline insoluble content 10% by weight, H / C = 0.53 pitch 75 kg
25 kg of naphthalene in an internal volume of 300 with a stirring blade
It is introduced into a liter pressure vessel, heated and melted and mixed at 210 ° C., cooled to 80 to 90 ° C. and adjusted to a viscosity suitable for extrusion spinning, and 50 kg / from a lower die having 100 holes with a diameter of 1.5 mm. 5 kg / pitch mixture under a pressure of cm ²
It was extruded at a rate of min. The extruded string pitch is about 4
10 along a plastic gutter with a 0 ° slope
It flows into a cooling bath at 25 ° C. Velocity of 3.0 m / se in the gutter
By flowing down the water of c, the string pitch immediately after extrusion is continuously stretched. String-like pitches having a diameter of 500 μm are accumulated in the cooling tank. The string-like pitch is solidified by leaving it in water for about 1 minute, and it can be easily broken by hand. Put this string pitch in a high speed cutter and add water. Crushing of the string-shaped pitch is completed by stirring for 10 to 30 seconds, resulting in a rod-shaped pitch. When observed under a microscope, the length-to-diameter ratio of the cylinder was 1.5 on average.

Next, the rod-shaped pitch was separated by filtration, 100 g of the rod-shaped material was put into 1 kg of a 0.5% aqueous polyvinyl alcohol solution heated to 90 ° C., melted, stirred and dispersed, and cooled to form spherical particles. . After filtering off most of the water, the spherical particles obtained were placed in an extractor, hexane was passed through to remove naphthalene by extraction, and air-dried. Then, using a fluidized bed, heated air was circulated to raise the temperature to 300 ° C. at 25 ° C./Hr, and the temperature was kept at 300 ° C. for 2 hours to infusibilize.
Subsequently, the temperature was raised to 900 ° C in steam and the temperature was raised to 900 ° C for 2
Carbonization activation was carried out by holding for a period of time to obtain porous spherical activated carbon. The diameter of the obtained spherical activated carbon is 0.05 to 1.0 m.
m, the spherical activated carbon thus obtained was treated in a fluidized bed at 600 ° C. in an atmosphere with an oxygen concentration of 3% for 3 hours, then heated to 950 ° C. in a nitrogen atmosphere, and at 950 ° C. for 30 minutes. A spherical activated carbon derived from petroleum-based pitch (hereinafter referred to as Sample 1) that had been held and subjected to oxidation and reduction treatment was obtained.
The diameter of this spherical activated carbon was 0.05 to 1 mm. In the acute toxicity test by oral administration to rats (Cpb: WU: Wistar random), no abnormality was observed even at the maximum dose (5000 mg / kg for male and female rats) according to the toxicity test method guideline (Pharmaceutical Trial No. 118). It was

Example: Cisplatin by administration of spherical activated carbon
In this example, the spherical activated carbon used was Sample 1 obtained in Production Example 1 above. Wist weighing 300-400g
ar male rats (22) were intraperitoneally administered with cisplatin at a frequency of 1 mg / kg / day twice a week for 13 weeks. At the beginning of the 14th week, the animals were divided into 2 groups (11 animals in each group) so that there was no bias between the groups. After that, for 10 weeks until the beginning of the 24th week, the control group was fed with the normal feed, and the spherical activated carbon administration group was fed with the sample 1 in addition to the normal feed.
It was orally administered in an amount of 1.0 to 1.4 g / day per animal. Further, both groups were intraperitoneally administered with cisplatin at a dose of 0.5 mg / kg / day twice a week for 10 weeks from the beginning of the 14th week to the beginning of the 24th week. Renal function was measured by creatinine clearance to assess nephrotoxicity at 24 weeks. In addition, since cisplatin causes renal tubular damage, the pathological morphological examination of renal tubules was performed. T-test was used for the statistical test between groups. The creatinine clearance (mean ± standard deviation) at 24 weeks was 0.63 ± 0.39 ml / m in the control group.
In, spherical activated carbon administration group 1.09 ± 0.48m
1 / min, statistically significant difference (p <0.05)
was there. That is, in the spherical activated carbon administration group, the renal function was observed to be statistically significant, and the renal toxicity due to cisplatin was reduced. As a result of pathological examination, renal tubular lesions were clearly suppressed in the spherical activated carbon administration group.

Formulation Preparation Example 1: Preparation of Capsule A capsule was prepared by encapsulating 200 mg of the spherical activated carbon obtained in Production Example 1 in a gelatin capsule.

Formulation Preparation Example 2: Preparation of Stick Agent A laminated film stick was filled with 2 g of the spherical activated carbon obtained in the above Production Example 1 and then heat-sealed to obtain a stick agent.

[0028]

As described above, by taking the nephrotoxicity-reducing agent of the present invention as an oral drug, for example, nephrotoxicity upon administration of platinum complex compounds can be clearly reduced.

Claims (3)

[Claims] 1. A nephrotoxicity-reducing agent for platinum complex compounds, which comprises spherical activated carbon as an active ingredient. 2. The nephrotoxicity reducing agent according to claim 1, wherein the platinum complex compounds are cisplatin. 3. The nephrotoxicity reducing agent according to claim 1, wherein the diameter of the spherical activated carbon is 0.05 to 2 mm.