JPS6259091B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antirheumatic agent containing 24,25-dihydroxycholecalciferol. Rheumatic diseases include systemic collagen diseases such as systemic lupus erythematosus, which can lead to death without proper treatment, as well as severe and malignant diseases such as rheumatoid arthritis, which has an extremely high incidence of physical disability, and deformation with a good prognosis. It includes a wide variety of diseases, including sexual arthropathy. Although the prevalence of rheumatic diseases as a whole, including these diseases, varies by country and by reporter, it is at least 5% of the population, and some reports exceed 15%, which has a significant social impact. is large. When it comes to treatment drugs for rheumatism, non-steroidal anti-inflammatory drugs,
Gold sols, steroids, etc. have been used, but there is currently no safe and effective treatment. The development of effective therapeutic agents that have few side effects and can be administered for a long period of time is eagerly awaited. As a result of intensive research on substances that are endogenous to healthy humans and have proven safety, the present inventors discovered 24,25-dihydroxycholecalciferol (hereinafter referred to as this substance or 24,25-dihydroxycholecalciferol). 25−
The present invention was achieved based on the knowledge that (OH) ₂ -D ₃ ) has an anti-rheumatic effect. This substance is 24R・25−(OH) ₂ −D ₃ , 24S・25−
(OH) ₂ -D ₃ or a mixture thereof may be used, but 24R.25-(OH) ₂ -D ₃ is particularly preferred. The antirheumatic agent of the present invention contains the above-mentioned present substance as an active ingredient and can be used in various formulations as shown below. The antirheumatic agent of the present invention can be administered orally, parenterally or rectally, although oral administration is preferred. Preparations containing this substance as an active ingredient are used in dosage forms such as tablets, powders, granules, suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions. As the oily solvent, triglyceride esters of intermediate fatty acids, corn oil, cottonseed oil, peanut oil, fish liver oil, oily esters, etc. are used.
Also preferred are cacao oil and glycerin. Other ingredients such as lactose, starch, talc, magnesium stearate, sorbic acid, salts of sorbic acid, sugar or derivatives thereof, alcohol, physiological saline, surfactants, antioxidants, etc. may be used in combination with this substance. The substance may be present in a unit dosage form in an amount of 0.00002 to 4% by weight, preferably 0.0002 to 1% by weight.
In addition, this substance is 0.1 to 100,000μ per day for adults.
g, preferably 0.5 to 10000 μg. Next, we will describe the results of investigating the acute toxicity of this substance. Acute toxicity: The substance was dissolved in ethanol, suspended in triglyceride ester of intermediate fatty acids to an ethanol concentration of 2%, and administered orally (po) to 10 male ICR mice (body weight 25±3 g). . The dose is 100mg/Kg. Symptoms of toxicity were observed for two weeks after administration, but all 10 animals survived without any abnormalities. After slaughter, blood biochemical tests, autopsy findings, and histopathological examinations were performed, but there was no difference from the control group to which only triglyceride ester of intermediate fatty acid containing 2% ethanol was administered. Therefore, the LD50 value of this substance for oral administration is 100 mg/Kg or more, so it can be said to be extremely safe. The present inventors basically confirmed the effect of 24R・25−(OH) ₂ −D ₃ on adjuvant arthritis, and found that 24R・25−(OH) ₂ −D ₃ is also effective for rheumatoid arthritis patients. Got the results. EXAMPLES The effects of the present invention will be specifically explained below with reference to Examples. In addition, 24R and 25 used in the examples
Structure confirmation of the optical isomer at position 24 of −(OH) ₂ −D ₃ is
Tetrahedron Letters No.26, pp2203-2206,
This was done with reference to 1975. Example 1 5 mg of 24R・25-(OH) ₂ -D ₃ was dissolved in 1 kg of triglyceride ester of intermediate fatty acid, which had been irradiated with a 400 W high-pressure mercury lamp for 72 hours under argon bubbling to eliminate impure reactive peroxides. , 0.5 of 24R・25−(OH) ₂ −D ₃ in one capsule
The following shell components were heated and dissolved so as to contain μg, and soft capsules were prepared by a conventional method using a soft capsule making machine. Shell formulation example Gelatin 10 parts by weight Glycerin 2 parts by weight Preservative (ethylparaben) 0.05 parts by weight Titanium White 0.2 parts by weight Water 0.2 parts by weight (final) Similarly, 1 μg, 2 μg, 5 μg in 1 capsule
Products containing μg or 10 μg were prepared, respectively. Example 2 24R/25 to 5-week-old male or female ICR mice
−(OH) ₂ −D ₃ in 1% ethanol-containing panacetate
The drug was dissolved in 810 at a predetermined concentration and administered by force orally to each group for 30 consecutive days at doses of 10, 100, and 1000 μg/Kg/day, respectively, and the following items were compared with the vehicle-only group. Shown below. According to the growth curve determined by body weight measurement, no significant difference in body weight change between groups was observed. The following organs were fixed with 10% formalin, stained with hematoxylin and eosin, and histopathologically examined, but no particular abnormalities were found. brain, heart, lungs, liver, kidneys, adrenal glands, spleen, pancreas, thyroid,
Pituitary gland, thymus, mesenteric lymph, testis, ovary, uterus, stomach, small intestine (jejunum, ileum, duodenum), large intestine (colon, cecum), eyeball, submandibular gland, bladder, back skin,
Muscle, sternum, thoracic bone marrow, femur, femoral bone marrow.

[Table] →: No change compared to control ↑: Increased compared to control

【table】

【table】

[Table] Example 3 Adjuvant Arthritis Suppressing Effect Mycobacterium tuberculosis (mycobacterium
tuberculosis), and on the 14th day, rats with similar hindlimb volumes were selected and were divided into groups of 10 rats.
From day 15, 24R・25−(OH) ₂ −D ₃ 1μg/Kg 7
After continuous oral administration between the eyes, the hindlimb volume was measured, and the control rate (IR) was calculated using the following formula. (1-T/C) x 100 = IR (%) T: Administration group average footpad volume C: Subject group average footpad volume 24R・25-(OH) ₂ -D ₃ administration group had an inhibition rate of 38.8% showed remarkable medicinal efficacy against adjuvant arthritis. Example 4 Rheumatoid arthritis (diagnosis name: Classical, Stage)
A 65-year-old woman diagnosed with the disease (Class 3) for 28 years took 10 μg of 24R・25-(OH) ₂ -D ₃ per day for 30 days, and as a result, her pain improved and her active joint index decreased. A reduction was observed, and the patient's impression was very positive, confirming the improvement effect.

【table】

Claims (1)

[Scope of Claims] 1. An antirheumatic agent containing 24,25-dihydroxycholecalciferol as an active ingredient. 2. The antirheumatic agent according to claim 1, wherein the 24,25-dihydroxycholecalciferol is 24R,25-dihydroxycholecalciferol.