JP4230005B2 - Active vitamin D metabolism improver - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an agent for improving 1α, 25-dihydroxycholecalciferol metabolism and an agent for inhibiting bone loss. The above-mentioned metabolism improving agent according to the present invention can be effectively used for the treatment of diseases related to the metabolism of 1α, 25-dihydroxycholecalciferol (especially its activation disorder), for example, renal osteodystrophy. it can.
[0002]
[Prior art]
Active vitamin D ₃ that plays an important role in bone metabolism in vivo, namely 1α, 25-dihydroxycholecalciferol [1α, 25-dihydroxy-vitamin D ₃ ; hereinafter referred to as 1α, 25- (OH) ₂ -D ₃ )] is produced via activation by liver 25-hydroxylation and kidney 1α-hydroxylation. Therefore, when the liver function or kidney function is lowered, the concentration of 1α, 25- (OH) ₂ -D _{3 in} the blood is lowered. For example, a decrease in 1α, 25- (OH) ₂ -D ₃ concentration associated with a decrease in renal function is due to a decrease in 1α-hydroxylase activity in the proximal tubule due to the influence of hyperphosphatemia associated with impaired phosphorus excretion. This is because it is further attenuated and the 1α-position hydroxylation failure occurs. In particular, when end-stage renal failure occurs, the concentration of 1α, 25- (OH) ₂ -D ₃ in plasma becomes extremely low.
The deficiency of active vitamin D ₃ in renal failure, that is, 1α, 25- (OH) ₂ -D ₃ , leads to decreased intestinal calcium absorption and decreased bone responsiveness to parathyroid hormone (PTH), Causes hypocalcemia. Secondary hyperparathyroidism is caused by the stimulation caused by hypocalcemia and the decrease in the inhibitory action of active vitamin D ₃ directly on parathyroid hormone. These are the main causes of renal osteodystrophy. It is believed that.
[0003]
Renal osteodystrophy is classified according to its origin and bone histology into fibro-osteitis type, mixed type, low turnover type, and mild change type, etc. Unlike osteoporosis where bone mass decreases. It was considered a disease that changed bone quality. From the observation of bone biopsy material, it is considered that most cases of renal failure have an abnormality although there is a difference in the degree of bone lesion.
On the other hand, recent progress in bone mass measurement technology using single-wavelength photon energy has enabled quantitative treatment of bone mass. Unlike conventional X-ray findings and bone tissue findings, this method can measure the bone mass of the entire bone quantitatively, and is highly clinically useful. As a result of using this bone mass measurement technique, it was also revealed that patients with renal osteodystrophy have bone loss. However, there are still unclear points regarding the pathophysiology, including the relationship with inorganic components, organic components, and hormones in the blood, and further studies must be clarified.
[0004]
[Problems to be solved by the invention]
As conventional treatment for renal osteodystrophy, active vitamin D ₃ preparation, calcium preparation, calcitonin preparation and the like have been administered. However, none of the conventional therapeutic agents alone can improve bone quality without causing side effects or show an effect of suppressing bone loss, and bone quality is highly safe in renal bone dystrophy. The development of a drug that suppresses bone loss as well as improvement has been desired.
Japanese Patent Laid-Open No. 7-10661 discloses a renal osteodystrophy-improving agent containing 24,25-dihydroxycholecalciferol as an active ingredient. , Worked on the development of a new renal osteodystrophy improvement agent.
Under such circumstances, the present inventor worked on the development of a new safe renal osteodystrophy ameliorating agent using renal failure model rats. It was found that the activation disorder of 1α, 25- (OH) ₂ -D _{3 in} the disease was improved and the decrease in bone mass was suppressed. The present invention is based on these findings.
[0005]
[Means for Solving the Problems]
Therefore, 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 a bone mass loss inhibitor, a renal osteodystrophy ameliorating agent, and a 1α, 25-dihydroxycholecalciferol activation disorder ameliorating agent 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 mass reduction inhibitor” according to the present invention, and the “renal bone dystrophy according to the present invention”. The “symptom improving agent” and the “1α, 25-dihydroxycholecalciferol activation disorder improving agent” according to the present invention are collectively referred to as “the pharmaceutical preparation of the present invention”.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The activated carbon that is an active ingredient of the pharmaceutical preparation of the present invention is not particularly limited as long as it is an activated carbon that can be used for medical purposes, but activated carbon for oral administration, that is, for internal use for medical purposes. Preferred is activated carbon capable of
For example, powdered activated carbon or spherical activated carbon can be used as the activated carbon. As the powdered activated carbon, known powdered activated carbon that has been conventionally used in medicine as an antidote can be used. However, since it may cause constipation as a side effect, it is preferable to use spherical activated carbon.
[0007]
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 is preferably excellent in adsorption capacity. Therefore, the spherical activated carbon is preferably spherical activated carbon having a diameter of 0.05 to 2 mm, more preferably 0.1 to 1 mm. Also, preferably the specific surface area of 500~2000m ² / g, more preferably spherical activated carbon 700~1500m ² / g. Further, spherical activated carbon having a pore radius of 100 to 75000 angstroms and a pore volume of 0.01 to 1 ml / g, more preferably 0.05 to 0.8 ml / g is preferable. In addition, said specific surface area is the value measured by the methanol adsorption method using the automatic adsorption amount measuring apparatus. The amount of voids is a value measured with a mercury intrusion porosimeter. The spherical activated carbon is advantageous in that it does not scatter when taken compared to powdered activated carbon and does not cause constipation even when used continuously. When the diameter is less than 0.05 mm, there is no sufficient effect for removing side effects such as constipation, and when it exceeds 2 mm, not only is it difficult to take, but the intended pharmacological effect is not rapidly manifested.
The shape of the spherical activated carbon is one of the important factors, and it is important that it is substantially spherical. Among the spherical activated carbons, spherical activated carbon derived from petroleum pitch, which will be described later, is particularly preferable because it is close to a true sphere.
[0008]
For the production of the spherical activated carbon, any activated carbon raw material such as sawdust, coal, coconut shell, petroleum-based or coal-based pitches, or organic synthetic polymer can be used. Spherical activated carbon can be manufactured, for example, by a method of activating after carbonizing a raw material. As the activation method, various methods such as steam activation, chemical activation, air activation, or carbon dioxide activation can be used, but it is necessary to maintain the purity acceptable for medical treatment.
[0009]
Examples of the spherical activated carbon include granulated activated carbon from carbonaceous powder, spherical activated carbon baked with organic polymer, and spherical activated carbon derived from petroleum hydrocarbon (petroleum pitch).
Granulated activated carbon from carbonaceous powder, for example, is obtained by granulating carbonaceous powder raw material into small spherical shapes with a binder such as tar, pitch, etc., and then calcining by heating and firing at a temperature of 600 to 1000 ° C. in an inert atmosphere. Then, it can obtain by activating. As the activation method, various methods such as water vapor activation, chemical activation, air activation or carbon dioxide activation can be used. The steam activation is performed at a temperature of 800 to 1100 ° C. in a steam atmosphere, for example.
[0010]
The organic polymer baked spherical activated carbon is disclosed in, for example, Japanese Patent Publication No. 61-1366 and can be manufactured as follows. A curing agent, a curing catalyst, an emulsifier, and the like are mixed with a condensation-type or polyaddition-type thermosetting prepolymer, emulsified in water with stirring, and reacted while continuing stirring at room temperature or warming. The reaction system is first in a suspended state, and the thermosetting resin spheres appear by further stirring. This is recovered, heated to a temperature of 500 ° C. or higher in an inert atmosphere, carbonized, and activated by the above-described method to obtain a spherical activated carbon fired with an organic polymer.
The activated spherical carbon from petroleum pitches has a diameter of preferably 0.05 to 2 mm, more preferably 0.1 to 1 mm, specific surface area is preferably 500~2000m ² / g, more preferably 700~1500m ² / g, The amount of voids having 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.
[0011]
The first method is described in, for example, Japanese Patent Publication No. 51-76 (U.S. Pat. No. 3,917,806) and Japanese Patent Application Laid-Open No. 54-89010 (U.S. Pat. No. 4,761,284). First, pitches in the form of small spheres in a melted state are infusible with oxygen, then heated and fired at a temperature of 600 to 1000 ° C. in an inert atmosphere, and then carbonized in a water vapor atmosphere at 850 to 1000 ° C. It is a method of activation by temperature. As described in Japanese Patent Publication No. 59-10930 (U.S. Pat. No. 4,420,433), for example, the second method first crushes pitch-like pitches in a molten state, In this method, the mixture is spheroidized and then infusible with oxygen, and then carbonized and activated under the same conditions as in the first method.
[0012]
In the present invention, (1) spherical activated carbon that has been subjected to ammonia treatment, (2) spherical activated carbon that has been subjected to oxidation and / or reduction treatment, and the like can be used as the active carbon spherical activated carbon. 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 spherical activated carbon baked with organic polymer.
[0013]
The ammonia treatment is, for example, a spherical activated carbon, an ammonia aqueous solution containing 1 to 1000 ppm of ammonia, the volume ratio of the aqueous ammonia to the spherical activated carbon is 2 to 10, and the temperature is 10 to 50 ° C. Processing for ~ 5 hours. Examples of the activated carbon obtained by applying ammonia treatment to the spherical activated carbon derived from petroleum pitch include spherical activated carbon described in JP-A-56-5313 (US Pat. No. 4,761,284). For example, the diameter as the spherical activated carbon ammonia process has been performed is 0.05 to 2 mm, preferably 0.1 to 1 mm, a specific surface area of 500~2000m ² / g, preferably 700~1500m ² / g, pore radius Spherical activated carbon having a void volume of 100 to 75000 angstroms of 0.01 to 1 ml / g and pH of 6 to 8 can be exemplified.
[0014]
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 the oxygen source. The reduction treatment means that the high temperature heat treatment is performed in an atmosphere inert to carbon, and the atmosphere inert to carbon is formed using nitrogen, argon, helium, or a mixed gas thereof. be able to.
[0015]
The oxidation treatment is preferably performed in an atmosphere having an oxygen content of 0.5 to 25% by volume, more preferably an oxygen content of 3 to 10% by volume, preferably a temperature of 300 to 700 ° C., more preferably 400 to 600 ° C. Done in The reduction treatment is preferably performed in an inert atmosphere at a temperature of 700 to 1100 ° C, more preferably 800 to 1000 ° C.
[0016]
Examples of the spherical activated carbon derived from the above-mentioned petroleum pitch include oxidation and / or reduction treatment include the spherical carbonaceous adsorbent described in Japanese Examined Patent Publication No. 62-11611 (US Pat. No. 4,681,764). Can do.
The spherical activated carbon oxidation and / or reduction process is applied, 0.05 to 2 mm in diameter, preferably 0.1 to 1 mm, a specific surface area of 500~2000m ² / g, preferably 700~1500m ² / g, Spherical activated carbon having a pore radius of 100 to 75000 angstroms and a pore volume of 0.01 to 1 ml / g is preferred.
[0017]
L [alpha] of the present invention, 25-dihydroxy cholecalciferol metabolism improving agent _{[i.e., 1α, 25- (OH) 2} -D 3 metabolism improving agent] is, l [alpha] in a mammal, including humans, 25- (OH) ₂ -D ₃ metabolic abnormalities associated diseases (particularly, its activation disorder) are useful in the treatment of. Examples of diseases associated with 1α, 25- (OH) ₂ -D ₃ activation disorder include renal osteodystrophy. Other _{1α, 25- (OH) 2 -D} 3 metabolic abnormalities related diseases, for example, a malignant tumor.
[0018]
In addition, the bone mass loss inhibitor of the present invention is useful for treating diseases in which bone mass loss is observed in mammals including humans. Examples of diseases in which bone loss is observed include osteoporosis in addition to the above-mentioned renal osteodystrophy.
[0019]
The pharmaceutical preparation of the present invention is preferably administered orally. The dose depends on subjects (mammals, particularly humans), age, individual differences, and / or medical conditions. For example, the daily dose for humans is usually 0.2 to 20 g as the amount of spherical activated carbon, but the dose may be appropriately increased or decreased depending on symptoms. In addition, administration may be performed once or divided into several times. 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.
[0020]
As the dosage form in the activated carbon preparation, any dosage form such as granules, tablets, dragees, capsules, sticks, sachets or suspensions can be adopted. In the case of capsules, enteric capsules can be used as required in addition to ordinary gelatin capsules. When used as granules, tablets, or sugar-coated tablets, it is necessary to be unlocked into the original fine particles in the body. The content of spherical activated carbon in the activated carbon preparation is usually 1 to 100%. In the present invention, a preferable activated carbon preparation is a capsule, a stick or a packaged package. In the case of these preparations, the spherical activated carbon is enclosed in a container as it is.
[0021]
【Example】
EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
[Example 1]
<Preparation of spherical activated carbon>
25 kg of naphthalene is introduced into a pressure vessel having an internal volume of 300 liters equipped with a stirring blade, with a softening point of 182 ° C. generated by naphtha pyrolysis, a quinoline insoluble content of 10% by weight, and a pitch of 75 kg of H / C = 0.53. ° C. heat melting were mixed, cooled to 80-90 ° C. and adjusted to a suitable viscosity for extrusion spinning, the pitch mixture under a pressure of 50 kg / cm ² from a lower portion of the die having 100 holes of diameter 1.5mm Extrusion was performed at a rate of 5 kg / min. The extruded string-like pitch flows into a 10-25 ° C. cooling bath along a plastic ridge having an inclination of about 40 °. The string-like pitch immediately after extrusion is continuously stretched by flowing down water with a flow rate of 3.0 m / sec. A string-like pitch having a diameter of 500 μm is accumulated in the cooling tank. By leaving it in water for about 1 minute, the string-like pitch is solidified, and it can be easily broken by hand. Put this string-like pitch into a high-speed cutter and add water. When stirring for 10 to 30 seconds, crushing of the string-like pitch is completed, and a rod-like pitch is obtained. When observed with a microscope, the ratio of the length and diameter of the cylinders was 1.5 on average.
[0022]
Next, this rod-shaped pitch was separated by filtration, 100 g of rod-shaped material was put into 1 kg of 0.5% polyvinyl alcohol aqueous solution heated to 90 ° C., melted, stirred and dispersed, and cooled to form spherical particles.
After most of the water was filtered off, the resulting spherical particles were put in an extractor, and hexane was passed through to extract and remove naphthalene, followed by ventilation drying. Next, using a fluidized bed, heated air was circulated, the temperature was raised to 300 ° C. at 25 ° C./Hr, and further maintained at 300 ° C. for 2 hours to be infusible. Then, it heated up to 900 degreeC in water vapor | steam, and hold | maintained at 900 degreeC for 2 hours, and carbonization activation was performed, and the porous spherical activated carbon was obtained. The obtained spherical activated carbon has a diameter of 0.05 to 1.0 mm. The spherical activated carbon thus obtained was treated using a fluidized bed at 600 ° C. in an atmosphere having an oxygen concentration of 3% for 3 hours, and then a nitrogen atmosphere. Then, the temperature was raised to 950 ° C. and held at 950 ° C. for 30 minutes to obtain petroleum-based pitch-derived spherical activated carbon (hereinafter referred to as sample 1) that was subjected to oxidation and reduction treatment. The diameter of this spherical activated carbon was 0.05 to 1 mm.
In addition, in the acute toxicity test by oral administration to rats (Cpb: WU: Wister random), no abnormality was observed even at the maximum dose (5000 mg / kg of male and female rats) according to the toxicity test method guidelines (Yakusyu 118). It was.
[0023]
[Example 2]
《Activation of active vitamin D ₃ and bone mass by spherical activated carbon administration》
In this example, Sample 1 obtained in Production Example 1 was used as spherical activated carbon. 8 weeks old Lewis male rats were administered adriamycin (adriacin, Kyowa Hakko) at 3 mg / kg via the tail vein, and adrenamycin 2 mg / kg was administered via the tail vein two weeks later to produce renal failure rats. . When two weeks passed from the second administration, the control group (7 animals) and the spherical activated carbon administration group (7 animals) were divided. At this time, there was no gap between the two groups based on the amount of urinary protein excretion. Over the next 24 weeks, the control group was given normal food, and the spherical activated carbon-administered group was orally ingested with spherical activated carbon in an amount of 0.4 g / day per 100 g body weight in addition to the normal food. On week 24, blood was collected under anesthesia and serum biochemical analysis was performed. Further, the femur was removed, and the bone mass at the proximal end of the femur was measured with a bone mass quantification apparatus [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) is
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).
Also, bone mass (mean ± SD) is
Control group: 144 ± 6 (mg / cm ² ),
Administration group: 152 ± 6 (mg / cm ² )
And there was a statistically significant difference (p <0.01). That is, an improvement was observed in the administration group compared to the control group.
As described above, the active vitamin D ₃ [1α, 25- (OH) ₂ -D ₃ ] and bone mass in the serum were statistically significantly increased in the spherical activated carbon group.
[0024]
[Preparation Example 1]
<< Preparation of capsules >>
Capsules were prepared by encapsulating 200 mg of spherical activated carbon obtained in Production Example 1 in gelatin capsules.
[0025]
[Preparation Example 2]
<Preparation of stick agent>
After sticking the spherical activated carbon 2g obtained in the said manufacture example 1 to the stick made from a laminated film, it heat-sealed and it was set as the stick agent.
[0026]
【The invention's effect】
When the pharmaceutical preparation according to the present invention is taken as an oral medicine by a patient with renal osteodystrophy or a patient with impaired vitamin D ₃ activation, renal osteodystrophy or vitamins without causing any special side effects. D ₃ activation disorders can be effectively treated. Moreover, the pharmaceutical formulation of this invention can be used continuously for a long period of time.

Claims (5)

An agent for improving 1α, 25-dihydroxycholecalciferol metabolism comprising activated carbon as an active ingredient. The improving agent according to claim 1, wherein the activated carbon is a spherical activated carbon. Bone loss inhibitor containing activated carbon as an active ingredient. An agent for improving renal osteodystrophy, comprising activated carbon as an active ingredient. 1α, 25-dihydroxycholecalciferol activation disorder improving agent comprising activated carbon as an active ingredient.