JPS58185519A - Antihyperphosphatemic agent - Google Patents

Abstract

PURPOSE:To prepare the titled drug capable of reducing the concentration of organic phosphorus in blood serum, useful for the remedy of chronic renal insufficiency, and having high safety, by using 24,25-dihydroxycholecalciferol as an active component. CONSTITUTION:The titled agent contains the 24,25-dihydroxycholecalciferol of formula I (e.g. 24R,25-dihydroxycholecalciferol of formula II) as an active component. The hyperphosphatemia is caused by the lowering of the secretion function of the kidney in chronic renal insufficiency, accessory thyroid hypofunction, acromegalia, acute osteanabrosis, etc. Since the patient of chronic renal insufficiency subjected to long-term dialysis is liable to be suffered by the complicates such as parosteosis, metabolic acidosis, etc. caused by the hyperphosphatemia, the use of a dialyzing solution having normal calcium concentration may results in osteomalacia, and the dialyzing solution having low calcium concentration has been used. The administration of the antihyperphosphatemic agent reduces the phosphorus concentration in the serum, suppresses the parosteosis, and improves the osteomalacia.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antihyperphosphatemic agent containing Q14+'124.25-dihydroxycholecalciferol.

In recent years, hyperphosphatemia has become a problem. Hyperphosphatemia 1.1,
In diseases such as chronic renal failure, hypoparathyroidism, acromegaly, and acute disuse, p occurs due to a decline in kidney function (increased reabsorption).

Recently, the number of patients with chronic renal failure who do not undergo long-term dialysis has been increasing, and these patients also develop symptoms such as ectopic 6-ash due to hyperphosphatemia and metabolic acidosis symptoms, so the amount of dialysis should be reduced. Phosphorus in blood is controlled by increasing the amount of phosphorus in the blood, limiting phosphorus in food, and administering aluminum gel as a phosphorus binder. Most dialysis patients are treated with aluminum gel, but recent research has revealed that aluminum caused by aluminum gel accumulates in the brain, making therapy using aluminum gel extremely dangerous. It has become clear that. As another treatment for hyperphosphoric hematuria, administration of calcitonin has been attempted.

Calcitonin is a peptide hormone.
Although the therapeutic effect is strong for about 3 hours, the duration of the effect is poor, and the difference in the internal state of the body between immediately after administration and when the Cal/Tone effect wears off is harsh for the patient. It is easy to treat.

Furthermore, administration of monobutide hormones derived from species (pig, eel) causes antibody production, which reduces the effectiveness of continuous administration (compared to initial administration), and there is a history of risks such as anaphylaxis. In addition, since calcitonin does not exhibit any medicinal efficacy when administered orally, it is administered by tEh injection, etc., which causes pain to the patient, making it difficult to find a safe therapeutic agent.

In view of the facts mentioned above, the development of safe antiphosphatemic agents has been eagerly awaited.

The present invention'4 was developed based on extensive research into endogenous and highly safe substances that exist in the healthy human body [24,
The present invention was achieved based on the knowledge that 25-dihydroxycholecalcifxa-py (hereinafter abbreviated as the present substance or 24,25-(OH)t-D) has a serum inorganic phosphorus-lowering effect.

All of these substances are known substances and have the following structure, for example, Pharmacia, 1o: 319-322°197
4K disclosed.

”, 25-(Oll)t-Ds 24
R,25(Okl)t-DaM However, the physiological activity of this substance is unknown to H, the discoverer.
, F, Deluca is 24.24-diflu n-0-2
Nine experiments comparing 5=hydroxyvitamin D and 25-hydroxyvitamin D revealed that 24R, 25-(OH) is responsible for the healing of rickets and the normal growth process of long bones in the absence of vitamin D.
s-DB is reported as not required (Endoc
tinol, 108 (612067~2071 (
1981).

Calif, Teasue Int, 33489~
497 (1981)), also A, W, Nor
man et al. used 24R925-(0)()s for egg curd.
-Ds is essential (Scl*nee, 2018:3
5-837 (1978)), and whether it is inactive or active form, %24R,25-(Ol(
)*-There are still many unknown points regarding the effects of Dt.

The inventors removed one kidney and the shaft of the remaining kidney.
KAIK
It was found that administration of 24R,25-(OH)s-Ds to nephrectomized rats that were induced to develop a hyperphosphatemic state caused a significant decrease in serum inorganic phosphorus levels. did. In addition, Sigma's 10 machine aminonucleosa 4)' (Purorrc/cin-1
The concentration of inorganic phosphorus in the serum was significantly reduced by administering 24R,25-(OH)m-Da to Wistar rats that had developed hyperphosphatemia due to the administration of uninonuclsoside* (hereinafter abbreviated as AN). I found out that.

Based on the above findings, III! When 248,25-(OH)s-Dst was administered to patients with chronic renal failure who had phosphatemia, it was found that the level of inorganic phosphorus in the serum decreased significantly to normal values. . Incidentally, it has been reported that the normal value of inorganic phosphorus in serum in adults is 2.5 to 5.5 q/di (Tsuyoshi Wajima, Clinical Chemistry Analysis).

U, Electrolyte, Tokyo Kagaku Doujin, Page 117.19
67).

In addition, the calcium component is 9 to 10 q/o! III [
24R,25-(OH)-D to chronic renal failure dialysis patients undergoing dialysis therapy using dialysate containing
It was found that when administered with I, the level of inorganic phosphorus in the serum significantly decreased to a normal value.

Incidentally, the serum calcium concentration contained in serum (1
1ki 8.8~1 0.4 Q/(14(Bio
logi@al handbooka andot
her body Flutda, Waahingt
ton, D., CUjLA.

19 (see also l), therefore, the calcium component-1 in the dialysate is preferably 9 to tOq/dj, or 9 to tOq/dj.
It has been found that continuing long-term dialysis therapy with a dialysate with a calcium content of 10/a/a that causes osteomalacia, lα-(OH)-D・ is used for bone softening therapy, but the calcium concentration of the dialysate is 9-10q/
Since dJ tends to produce high calcium blood sputum, dialysate with a calcium content S* of 6 to 7.5++ v/dl, which is lower than the normal value, has come to be used. However, 1α.

25-(OH)-Ds or Filα-(OH)-D
When s is used, bone resorption and/or intestinal absorption of not only calcium but also phosphorus is promoted, and blood phosphorus increases, so the above-mentioned aluminum gel is currently used in combination.

According to the present invention, if a dialysate containing 9 to 1 Oql of calcium component is used, and the hyperphosphatemia agent of the present invention is administered, blood serum As the phosphorus concentration decreased, ectopic calcification was also observed, and it was concluded that osteomalacia was improved without Egamma phosphorus concentration.

This substance is 24R, 25-(OH) Soritomi, 24S.

Although it may be 25-(OH)s-Da or a mixture thereof, 24R,25-(OH)m-Ds is particularly preferred. The antihyperphosphatemic agent of the present invention contains the above-mentioned substance as an active ingredient, and the antihyperphosphatemic agent of 0-bon Q light, which is used in the following formulations, can be administered orally or parenterally. Administration may be by the route or by the rectal route, but oral administration is preferred.

Preparations containing this substance as an active ingredient are used in dosage forms such as tablets, powders, 6-grain tablets, suppositories, capsules, alcohol solutions, oil-based preparations, and aqueous suspensions. In addition, as the oily melt, mono-liglyceride esters of intermediate fatty acids, corn oil, cottonseed oil, peanut oil, fish liver oil, oily esters, etc. are used.

Also preferred are cacao oil, guriron, etc. Other ingredients include lactose, starch, Merck, magnesium stearate, sorbic acid, and sorbic acid salts.

Glucose derivatives such as alcohol, physiological saline, interfacial viscosity agents, and antioxidants may be used in combination with this substance.

4-Substance is 6c2x1o-1' to 1 in positional dosage form
The substance may contain 0 weights per day, preferably 2 x 10'' to 1 weight per day.
x 10''iil, preferably 1 to 1 x 1Oμl.

The arrow indicates the results of examining the acute toxicity of this substance.

Acute toxicity: This substance was dissolved in ethanol using 10 ICR male mice (body weight 25±, 3II), and once ethanol
It was dissolved in triglycephyte ester of intermediate fatty acid so as to give orally administered (p, o,). Dosage is 50aw
I met /m. The animals were observed for poisoning symptoms for 2 weeks after administration, but all 10 animals survived without any abnormalities. After sacrifice, blood, biochemical examination, F9T autopsy, and histopathological examination were performed, but no differences were found between the control group and the control group in which only triglyceride ester of intermediate fatty acids containing 1% ethanol was administered. Therefore, the LDs of oral administration of this substance
.

Since the O value is 9 or more in 50q/, active vitamin D
This substance can be said to be extremely safe compared to lα-(OH)-Da, which is said to be an s analog (LDM for oral administration is 1q/1Kg or less).

EXAMPLES The effects of the present invention will be specifically explained below with reference to Examples. In addition, 24R825-(OH) used in the examples
The structure of the optical isomer at position 24 of m-Ds was confirmed using Tetra.
hedron Letters J626, pp
Please refer to 2203-2206.1975':)
is.

Example 1 A triglyceride ester of an intermediate fatty acid was irradiated with a 400W high-pressure water bath for 72 hours while bubbling argon to eliminate and remove reactive peroxides. 24R, 25-(OH), - D.

5～, 24R,25-(OH
)*-Da t 0.5μ? The following shell ingredients were dissolved by heating to contain the following ingredients [9.

Wound Prescription Example Gelatin 10 parts by weight Glycerin 2 # Titanium Why 0.2 #1 and 1 capsule contains lpt, 2 pP+ 4
pt.

5sW, 6 pt, 8 pj'XId 10 pt
Containing materials (4bf) were prepared respectively.

Example 2 24 ft, 25- (0) 1) t-D, 1 (1■
was dissolved in 10 d of isopropyl alcohol, and then 1 ml of the obtained inonorobil alcohol solution (added to 11,100 ml of the obtained inonorobil alcohol solution with stirring). )vinegar,
Is the concentration of 241t, 25-(OH)l-DI IP? Composition for oral administration (hereinafter referred to as Composition A)
) and L = 1t-0, 24R, 25-
A composition for oral administration (hereinafter referred to as composition I3) was prepared in which the concentration of (OR)t-Da was o, ip t/ml and the amount of isopropyl alcohol was U, li.

Weight 200±30? One kidney of a Wistar ring-hund was completely removed, and six of the remaining kidneys were removed to prepare % nephrectomized rats. In addition, sham-operated Wistar ring rats of 200 ± 3 (l) were subjected to sham surgery as a control, and one month after the surgery, each group was treated with each composition on a submachine 6 times a week. Meyama was ingested for 9 weeks.In addition, 24R, 25-
(OH)*-Da administration 111rj, water intake per week was determined by m1, and the average dose per 11 was determined from the average value of water intake.
I asked for it. In addition, after a specified period of time, the amount of electricity was increased, blood was collected from the lower abdominal vein, and the concentration of inorganic phosphorus in the serum was measured using molybdenum bromide.
) Measured by colorimetric method. Yumikura 1st Fu-T.

Example 3 A solution with a concentration of 15 to % 1/2 was prepared by dissolving menstrual fluid (c). 4 times a day, add 15 liters of AN to 51 diluted bath liquid.
After 4 days of administration, 51 days of AN administration (W)
An AN body # intuition threshold of 2 weeks 1-'' was set. AN administration integrated prefecture cycle tt51i! After the start of AN administration in the same month, each group of 8 randos was given the orally administered composition ad libitum for 38 days in the same manner as in Example 2. After the completion of administration of the prescribed 381 cells, the animals were sacrificed, blood was collected from the abdominal descending vena cava, and the concentration of inorganic phosphorus in the fi beak was determined in the same manner as in Example 2. The results are shown in Table 2.

Implementation fi4: 18 in 8 patients with chronic renal failure who were not undergoing dialysis
Mushi 2-10 #PO24R,25-(OH)*-Da was orally administered in the form of Micro-Kaburu O obtained in Example 1 for 8 weeks. 24R,25-(O)I)ID
The concentration of inorganic phosphorus in the serum before administration and the concentration of inorganic phosphorus in the serum after administration for 8 times were measured using the Moripdenum Blue colorimetric method. The results are shown in Table 3.

Example 5 Eight patients with chronic renal failure were given 2 to 10μ of calcium per week using a dialysate containing 9 to 10 degrees of calcium each week. 024R, 2B-
(OH)t-D was orally administered for 6 weeks in the form of microcapsules obtained in Example N1. 24R, 25-
(0) 1) The concentration of inorganic phosphorus in the serum before administration of t-Di and the concentration of inorganic phosphorus in the serum after administration for 6 weeks were measured by the Moripdenam blue colorimetric method. The results are shown in Table 4. No ectopic calcification was observed in the X-rays, indicating osteomalacia, which was confirmed by a bone biopsy of a patient.

Table 4 Procedural Amendment May 1980 301] F, IIh Agency Director-General Kazuo Wakasugi], Indication of the case 1982 Patent Examination No. 62868 2, Title of the invention Anti-hyperphosphorus self-symptomatic agent 3, Make amendments Relationship to the patent case Patent applicant name (110) Kureha Chemical Industry Co., Ltd. 4, agent Yamada Building 5, 1-1-14 Shinjuku, Shinjuku-ku, Tokyo, date of amendment order Contents of Motto 8, Supplement 11 ( 1) In the specification, from the fourth negative to the third line fJr11. F
□e+uca J and 1°H, F, De 1uca
J and supplementary it-! Jru.

(2) In the specification, 2nd line from just below No. 10, 1-pp22
031 is corrected to rp 2203J.

Claims (1)

[Scope of Claims] An antihyperphosphatemic agent containing +1124.25-dihydroxy7cholecalciferol as an active ingredient. +2124.25-Dihydroxycholecalciferol is 24R,25-dihydro-xycholecalciferol, The antihyperphosphatemia agent described in Tokken-Kyu no Yokukei No. 1 JJI, characterized in that the 25-dihydroxycholecalciferol is 24R,25-dihydro-xycholecalciferol.