JPH11292771A - Agent for improving metabolism of activated vitamin d - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 1α,25-dihydroxycholecalciferol metabolism-improving agent containing activated carbon as an active ingredient and capable of effectively treating renal osteodystrophia and vitamin D3 activation failure. SOLUTION: This 1α,25-dihydroxycholecalciferol metabolism-improving agent contains activated carbon, preferably spherical activated carbon, as an active ingredient. The spherical activated carbon preferably has a diameter of 0.1-1 mm, a specific surface area of 700-1,500 m<2> /g, a fine pore radius of 100-75,000 Åand a porosity of 0. 05-0. 8 ml/g. The spherical activated carbon includes granulated spherical activated carbon obtained from carbonaceous powder, spherical activated carbon obtained by calcining an organic polymer and spherical activated carbon originating from a petroleum-based hydrocarbon (petroleum- based pitch). The inhibitor is preferably orally administered. The improving agent is administered at a daily dose of 0.2-20 g (as the amount of the spherical activated carbon) with one or several portions for a human adult. The preparation of the activated carbon is preferably capsules, sticks or divided packages.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for improving 1α, 25-dihydroxycholecalciferol metabolism and an agent for suppressing bone loss. The metabolic improving agent according to the present invention,
It can be effectively used for treating diseases associated with metabolism of 1α, 25-dihydroxycholecalciferol (particularly, impaired activation thereof), for example, renal osteodystrophy.

[0002]

2. Description of the Related Art Active vitamin D ₃ plays an important role in bone metabolism in a living body, that is, 1α, 25-.
Dihydroxycholecalciferol [1α, 25-dihydroxy-vitamin D ₃ ; hereinafter, 1α, 25- (OH)
Sometimes referred to as ₂ -D _3] are 25-position in the liver - hydroxide and 1α-position in the kidney - are generated through activation by hydroxide. Therefore, when the liver function and the kidney function decrease, the concentration of 1α, 25- (OH) ₂ -D _{3 in} the blood decreases.
For example, 1α, 25- (OH) ₂ -D associated with decreased renal function
₍₃₎ The decrease in the concentration is because the decrease in 1α-hydroxylase activity in the proximal tubule is further attenuated by the effect of hyperphosphatemia associated with impaired phosphorus excretion, resulting in the impairment of 1α-hydroxylation. . In particular, when end-stage renal failure occurs, 1α,
The concentration of 25- (OH) ₂ -D ₃ is very low.
Active vitamin D ₃ in renal failure, ie 1α, 2
Deficiency of 5- (OH) ₂ -D ₃ is decreased and the calcium absorption in the intestinal tract, cause a decrease in reactivity of the bone for parathyroid hormone (PTH), resulting hypocalcemia. This and stimulation by hypocalcemia, active vitamin D ₃ decreased the inhibitory effect of direct parathyroid hormone by the like secondary hyperparathyroidism is induced, leading cause of renal osteodystrophy It is believed that.

[0003] Renal osteodystrophy is classified into fibrous ostitis type, mixed type, low turnover type, mildly altered type, etc. according to its etiology and bone histology, and osteoporosis in which bone mass decreases. Unlike this, it was considered a disease that caused changes in bone quality. Observation of bone biopsies suggests that most cases of renal failure patients have abnormalities, although the degree of bone lesions varies. On the other hand, recent advances in the technique of measuring bone mass using photon energy of a single wavelength have made it possible to treat bone mass quantitatively. This method is highly clinically useful because it can quantitatively measure the bone mass of the entire bone, unlike conventional X-ray findings and bone tissue findings. As a result of using the bone mass measurement technique, it was also revealed that patients with renal osteodystrophy have bone loss. However, there are still unclear points about its pathology, including its relationship with the inorganic and organic components in blood, and hormones, and further research must be elucidated.

[0004]

Conventional treatments for INVENTION Problems to be Solved] renal osteodystrophy, active vitamin D ₃ formulations, administration and calcium preparations, or calcitonin have been made. However, conventional therapeutic agents alone can improve bone quality without side effects,
There is no inhibitory effect on bone loss, and development of a drug that is highly safe in renal osteodystrophy and that suppresses bone loss as well as improving bone quality has been desired. Also, JP-A-7-107
No. 61 describes a renal osteodystrophy ameliorating agent containing 24,25-dihydroxycholecalciferol as an active ingredient, but the present inventor has proposed a new renal osteomyelitis from a different viewpoint. Worked on the development of dystrophic amelioration agents.
Under these circumstances, the present inventor worked on the development of a new highly safe renal osteodystrophy ameliorating agent using a renal failure model rat. 1α, 25- (OH) ₂ -D _{3 in} diseases
Activation disorder was improved, and bone loss was suppressed. The present invention is based on these findings.

[0005]

SUMMARY OF THE INVENTION Accordingly, the present invention relates to an agent for improving 1α, 25-dihydroxycholecalciferol metabolism, comprising activated carbon as an active ingredient. The present invention also relates to an agent for suppressing bone loss, an agent for ameliorating renal osteodystrophy, and an agent for ameliorating 1α, 25-dihydroxycholecalciferol activation disorder, comprising activated carbon as an active ingredient. Hereinafter, in the present specification, the “1α, 25-dihydroxycholecalciferol metabolism improving agent” according to the present invention, the “bone loss inhibitor” according to the present invention, and the “renal bone dystrophy” according to the present invention Amelioration agent "and" 1α, 25-dihydroxycholecalciferol activation disorder ameliorating agent "according to the present invention.
Are collectively referred to as the "pharmaceutical formulations of the present invention."

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The activated carbon which is an active ingredient of the pharmaceutical preparation of the present invention is not particularly limited as long as it is an activated carbon which can be used for medical purposes. Activated carbon that can be used internally for medical purposes is preferred. As the activated carbon, for example, powdered activated carbon or spherical activated carbon can be used. As the powdered activated carbon, known powdered activated carbon conventionally used in medicine as an antidote can be used, but spherical activated carbon is preferably used because constipation may be caused as a side effect.

The spherical activated carbon is not particularly limited as long as it is a spherical activated carbon that can be used internally for medical purposes. This spherical activated carbon preferably has excellent adsorption capacity. Therefore, the spherical activated carbon preferably has a diameter of 0.
It is a spherical activated carbon having a diameter of 0.5 to 2 mm, more preferably 0.1 to 1 mm. Preferably, the specific surface area is 500 to 20.
00m ² / g, more preferably 700~1500m ² /
g of spherical activated carbon. Also, preferably, the pore radius is 10
0 to 75000 angstroms void volume is 0.01 to
1 ml / g, more preferably 0.05 to 0.8 ml / g
Is a spherical activated carbon. The above specific surface area is a value measured by a methanol adsorption method using an automatic adsorption amount measuring device. The void amount is a value measured by a mercury intrusion porosimeter. The above-mentioned spherical activated carbon is advantageous in that it does not scatter when taken, and does not cause constipation even when used continuously, as compared with powdered activated carbon. If the diameter is less than 0.05 mm, there is not enough effect to remove side effects such as constipation,
If it exceeds 2 mm, not only is it difficult to take the drug, but also the desired pharmacological effect is not rapidly exhibited. The shape of the spherical activated carbon is one of the important factors, and it is important that the shape is substantially spherical. Among the spherical activated carbons, a spherical activated carbon derived from a petroleum-based pitch described below is particularly preferable because it is close to a true sphere.

For the production of the spherical activated carbon, any activated carbon raw material, for example, 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. As the activation method, various methods such as water vapor activation, chemical activation, air activation or carbon dioxide gas activation can be used,
It is necessary to maintain medically acceptable purity.

Examples of the spherical activated carbon include granulated activated carbon from carbonaceous powder, spherical activated carbon obtained by firing an organic polymer, and spherical activated carbon derived from petroleum hydrocarbon (petroleum pitch). Granulated activated carbon from carbonaceous powder, for example, after granulating the carbonaceous powder raw material into small spheres with a binder such as tar, pitch, etc., is heated and calcined at a temperature of 600 to 1000 ° C. in an inert atmosphere to carbonize. , Followed by activation. Activation methods include steam activation, chemical activation,
Various methods such as air activation or carbon dioxide activation can be used. Steam activation, for example, in a steam atmosphere,
It is performed at a temperature of 800 to 1100 ° C.

[0010] Spherical activated carbon fired by an organic polymer is, for example,
It is disclosed in JP-B-61-1366, and can be manufactured as follows. A curing agent, a curing catalyst, an emulsifier, and the like are mixed with the condensation-type or polyaddition-type thermosetting prepolymer, emulsified in water with stirring, and reacted at room temperature or while heating while stirring. The reaction system is first in a suspended state, and a thermosetting resin spherical substance appears by further stirring. This is collected and placed in an inert atmosphere at 50
It can be heated to a temperature of 0 ° C. or higher for carbonization, and activated by the above-mentioned method to obtain a spherical activated carbon fired by an organic polymer. The spherical activated carbon derived from petroleum-based pitch preferably has a diameter of 0.05 to 2 mm, more preferably 0.1 to 1 mm,
The specific surface area is preferably 500~2000m ² / g, more preferably 700~1500m ² / g, pore radius 100
A void volume of ７５75000 Å is preferably 0.01-1 ml / g. This spherical activated carbon derived from petroleum-based pitch can be produced, for example, by the following two methods.

The first method is disclosed in, for example, Japanese Patent Publication No. 51-76.
(US Pat. No. 3,917,806) and JP-A-54-89010 (US Pat. No. 4,761,284).
First, as described in the specification, after the pitches made into small spheres in the molten state are made infusible with oxygen,
Heating and calcining to a temperature of 600 to 1000 ° C. in an inert atmosphere to carbonize, and then in a steam atmosphere to 850 to 100 ° C.
This is a method of activating at a temperature of 0 ° C. The second method is disclosed, for example, in Japanese Patent Publication No. 59-10930 (U.S. Pat. No. 442).
No. 0433), first, crushed string-like pitches in a molten state, then thrown into hot water to make them spherical, and then made infusible with oxygen, This is a method of carbonizing and activating under the same conditions as the first method.

In the present invention, the spherical activated carbon as an active ingredient includes (1) a spherical activated carbon treated with ammonia or the like;
(2) Spherical activated carbon 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-based pitch, granulated activated carbon of carbonaceous powder, and spherical activated carbon of organic polymer firing.

The above-mentioned ammonia treatment means, for example, that 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 activated spherical carbon is 2 to 10 at a temperature of 10 to 50 ° C. 0.
Consists of treating for 5 to 5 hours. The activated carbon obtained by subjecting the above-mentioned spherical activated carbon derived from petroleum pitch to ammonia treatment is disclosed in JP-A-56-5313 (US Pat. No. 476).
No. 1284). For example, the spherical activated carbon subjected to the ammonia treatment 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
000 angstrom void volume of 0.01 to 1 ml /
g and a spherical activated carbon having a pH of 6 to 8 can be exemplified.

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

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

An example in which the above-mentioned spherical activated carbon derived from petroleum pitch is subjected to an oxidation and / or reduction treatment is disclosed in
And spherical spherical carbonaceous adsorbents described in U.S. Pat. No. 4,681,764.
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 m.
m, specific surface area is 500 to 2000 m ² / g, preferably 700 to 1500 m ² / g, and pore radius is 100 to 7500.
Spherical activated carbon having a void volume of 0 angstroms of 0.01 to 1 ml / g is preferred.

The 1α, 25-dihydroxycholecalciferol metabolism improving agent of the present invention [ie, 1α, 25-
(OH) ₂ -D ₃ metabolism ameliorating agent] for the treatment of diseases associated with abnormalities of 1α, 25- (OH) ₂ -D ₃ metabolism in humans and other mammals (in particular, activation disorders thereof). Useful. Diseases associated with the 1α, 25- (OH) ₂ -D ₃ activation disorder include, for example, renal osteodystrophy. Other 1α, 25- (OH) ₂ −
D ₃ Metabolic abnormalities associated with the disease, may be, for example ,, malignancy.

The agent for inhibiting bone loss of the present invention is useful for treating diseases in which bone loss is observed in mammals including humans. Examples of the disease in which bone loss is observed include, in addition to the above-mentioned renal osteodystrophy, for example, osteoporosis.

The pharmaceutical preparation of the present invention is preferably administered orally. The dose depends on the subject (mammal, especially human), age, individual differences, and / or medical conditions.
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. Further, the administration may be performed once or divided into several times. The spherical activated carbon may be administered as it is, or may be administered 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.

[0020] The dosage form in the activated carbon preparation includes granules,
Any dosage form such as tablets, dragees, capsules, sticks, divided packages, or suspensions can be employed.
In the case of capsules, enteric capsules can be used, if necessary, in addition to ordinary gelatin capsules. When used as granules, tablets or sugar-coated tablets, it is necessary to break them down into the original microparticles in the body. The content of the spherical activated carbon in the activated carbon preparation is usually 1 to 100%. In the present invention, a preferred activated carbon preparation is a capsule, a stick or a divided package. For these formulations,
The spherical activated carbon is directly enclosed in a container.

[0021]

EXAMPLES The present invention will be described below in more detail with reference to examples, but these examples do not limit the scope of the present invention.

Example 1 << Preparation of spherical activated carbon >> Softening point generated by naphtha pyrolysis 182 ° C., quinoline insoluble content 10% by weight,
Naphthalene 25k for pitch 75kg with H / C = 0.53
g was introduced into a pressure-resistant container having an internal volume of 300 liters equipped with a stirring blade, heated and mixed at 210 ° C., cooled to 80 to 90 ° C., and adjusted to a viscosity suitable for extrusion spinning.
50 kg / cm ² from the lower base having 100 holes
The pitch mixture was extruded under a pressure of 5 kg / min. The extruded string pitch flows into a 10-25 ° C. cooling bath along a plastic gutter having a slope of about 40 °. The string pitch immediately after the extrusion is continuously stretched by flowing water having a flow rate of 3.0 m / sec into the gutter. String pitches having a diameter of 500 μm are accumulated in the cooling tank.
By leaving it in water for about 1 minute, the string-shaped pitch is solidified, and a string that can be easily broken by hand is obtained. This string pitch is put into a high-speed cutter and water is added. After stirring for 10 to 30 seconds, the crushing of the string pitch is completed, and the pitch becomes a rod pitch. When observed with a microscope, the ratio of the length to the diameter of the cylinder was 1.5 on average.

Next, the rod-shaped pitch was filtered off, 100 g of the rod-shaped material was put into 1 kg of a 0.5% aqueous solution of polyvinyl alcohol heated to 90 ° C., melted, stirred and dispersed, and cooled to form spherical particles. . After filtering out most of the water, the obtained spherical particles were put into an extractor, and phthalic acid was passed through to remove naphthalene, followed by drying with ventilation. Next, using a fluidized bed, heated air was circulated and the temperature was raised to 300 ° C. at 25 ° C./Hr, and the mixture was kept at 300 ° C. for 2 hours to make it infusible.
Subsequently, the temperature is raised to 900 ° C. in steam,
The carbonization was activated by holding for a time to obtain a porous spherical activated carbon. The diameter of the obtained spherical activated carbon is 0.05 to 1.0 m
m, and the spherical activated carbon thus obtained is treated with a fluidized bed at 600 ° C. in an atmosphere having an oxygen concentration of 3% for 3 hours, and then heated to 950 ° C. in a nitrogen atmosphere, and then at 950 ° C. for 30 minutes. While holding, a spherical activated carbon (hereinafter, referred to as sample 1) derived from petroleum pitch subjected to oxidation and reduction treatment was obtained.
The diameter of the 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 (Yakusho No. 118). Was.

[0023]

Example 2 << Activated vitamin D by administration of spherical activated carbon
₃ and Increase in Bone Mass >> In this example, the sample 1 obtained in the above Production Example 1 was used as the spherical activated carbon. To an 8-week-old male Lewis rat, adriamycin (adriacin, Kyowa Hakko) was administered via tail vein at a dose of 3 mg / kg, and 2 weeks after that, adriamycin 2 mg / kg was administered via tail vein to produce a renal failure rat. . Two weeks after the second administration, the animals were divided into a control group (7 animals) and a spherical activated carbon administration group (7 animals). At this time, there was no gap between the two groups based on the amount of excreted urine protein. Over the following 24 weeks, the control group was fed the normal diet, and the spherical activated carbon-administered group was orally ingested spherical activated carbon in an amount of 0.4 g / day per 100 g body weight in addition to the normal diet. At week 24, blood was collected under anesthesia and serum biochemical analysis was performed. In addition, the femur was excised, and the bone mass at the proximal end of the femur was measured using a bone mass quantification device [dual energy X-ray absorption measurement method (DEXA)]. As a result, the amount of active vitamin D ₃ [1α, 25- (OH) ₂ -D ₃ ] in serum (mean ±
SD) were as follows: control group: 9.7 ± 2.6 (pg / ml), administration group: 18.3 ± 7.2 (pg / ml), and there was a statistically significant difference (p <0). .01).
The bone mass (mean ± SD) was 144 ± 6 (mg / cm ² ) in the control group and 152 ± 6 (mg / cm ² ) in the administration group, showing a statistically significant difference (p < 0.01).
That is, improvement was observed in the administration group as compared with the control group. As described above, serum activated vitamin D ₃ [1α, 25-
(OH) ₂ -D ₃ ] and bone mass were increased.

[0024]

[Preparation Example 1] << Preparation of capsules >> A capsule was prepared by enclosing 200 mg of the spherical activated carbon obtained in Production Example 1 above in a gelatin capsule.

[0025]

[Preparation Example 2] << Preparation of stick preparation >> Preparation Example 1
After filling 2 g of the spherical activated carbon obtained in the above into a stick made of a laminated film, it was heat-sealed to form a stick.

[0026]

The pharmaceutical preparation of the present invention is taken, for example, as an oral drug by patients suffering from renal osteodystrophy or vitamin D ₃ activation disorder. Dystrophy and vitamin D ₃ activation disorder can be effectively treated. Further, the pharmaceutical preparation of the present invention,
It can be used continuously for a long time.

Claims (5)

[Claims] 1. 1α, 25- containing activated carbon as an active ingredient
An agent for improving dihydroxycholecalciferol metabolism. 2. The improving agent according to claim 1, wherein the activated carbon is a spherical activated carbon. 3. An agent for suppressing bone loss, comprising activated carbon as an active ingredient. 4. An agent for improving renal osteodystrophy comprising activated carbon as an active ingredient. 5. 1α, 25- containing activated carbon as an active ingredient
An agent for improving dihydroxycholecalciferol activation disorder.