JPS6221328B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-inflammatory agent containing 24,25-dihydroxycholecalciferol as an active ingredient.

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). −
(OH) ₂ -D ₃ ) has been found to have numerous physiologically active effects, and has already been shown to have anti-hypercalcemic effects,
It has been found to have anti-ulcer effects, prevent immune function decline, regulate magnesium metabolism, anti-hyperphosphatemia, regulate blood sugar, and anti-tumor effects. After that, as a result of repeated research, it was discovered that it has an anti-inflammatory effect as described later, and the present invention was achieved.

As described below, this substance is a highly safe substance and has an anti-inflammatory effect, and is useful as an active ingredient of an anti-inflammatory agent.

All of these substances are known substances and have the following structures. For example, Anthony W.Norman, Vitamin
D; MOLECULAR BIOLOGY AND CLINICAL
NUTRITION, MARCEL DEKKER, INC. p.1~
92 (1980).

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 anti-inflammatory agent of the present invention contains the above-mentioned substances as active ingredients, and is used in various formulations as shown below. The anti-inflammatory agents of the invention may be administered orally, parenterally or rectally, with oral administration being 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 its derivative alcohol, physiological saline, surfactants, antioxidants, or other pharmaceutical agents are used in combination with this substance. It is possible.

The substance may be contained in a unit dosage form from 2x10 ^-5 to 4% by weight, preferably from 2x10 ^-4 to 1% by weight. In addition, this substance is 0.1 μg per day for adults.
1×10 ⁵ μg, preferably 0.5 to 1×10 ⁴ μg is administered.

Next, we will describe the results of investigating the acute toxicity of this substance.

Acute toxicity: The substance was dissolved in ethanol and triglyceride ester of intermediate fatty acids to give an ethanol concentration of 2%, and administered orally (po) to 10 male ICR mice (body weight 25±3 g). . The dose is 100mg/Kg. The animals were observed for symptoms of toxicity 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 in any way from the control group to which only triglyceride ester of intermediate fatty acid containing 2% ethanol was administered.
Therefore, the LD ₅₀ value for oral administration of this substance is 100mg/
1α-(OH)-D ₃ (orally administered), which is said to be an active vitamin D ₃ analogue.
(LD ₅₀ is less than 1 mg/Kg), this substance can be said to be extremely safe.

EXAMPLES The effects of the present invention will be specifically explained below with reference to Examples. The substance used in the examples is 24R・25-(OH) ₂ -D ₃ , and the structure of the optical isomer at position 24 was confirmed in Tetrahedron Letters No.
26, p. 2203-2206, 1975.

Example 1 Anti-inflammatory effect (1) Carrageenin edema suppressing effect According to the method of Van Arman et al. (1963),
100 μg/Kg of this substance dissolved in MCT (triglyceride ester of C ₈ to _{C 10} carboxylic acids) was orally administered by force to 10 rats per group.
After a period of time, 0.1 ml of a 1% Carrageenin saline suspension was injected into the footpad of the right hind paw, the paw volume was measured over time, and the inhibition rate was calculated using the following formula.

(1-T/C) x 100 = IR (%) T: Average footpad volume of this substance administration group C: Control group footpad volume (only MCT administered) As a result, the edema suppression rate of this substance was 15.4%. Ta.

(2) Granuloma suppression effect According to the method of Winter et al. (1963), two 30±1 mg cotton wool pellets were implanted subcutaneously on the back of each group of six rats symmetrically on the midline and dissolved in MCT. 10 μg/Kg of this substance was orally administered for 7 consecutive days, and on the 8th day, the granulation was removed, the dry weight was measured, and the inhibition rate was determined in the same manner as in (1) above, and the inhibition rate was 22.4%. .

(3) Anti-exudation effect According to the method of Baris et al. (1965), pouches were made by injecting air subcutaneously into the backs of 6 rats per group, and 0.5% of 1% Croton oil (in sesame oil) was placed in the pouches. Inject 10ml of this substance dissolved in MCT
μg/Kg was orally administered for 5 consecutive days, the amount of exudate in the pouch was measured on the 6th day, and the inhibition rate was determined in the same manner as in (1) above, and the inhibition rate was 17.8%.

These results demonstrate that this substance is useful as an anti-inflammatory agent.

Example 2 1kg of MCT was irradiated with a 400W high-pressure mercury lamp for 72 hours while bubbling argon to eliminate and eliminate peroxide, and 0.5 of 24R・25−(OH) ₂ −D ₃ was added to it.
The following skin components are dissolved by heating to contain μg,
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 (parts by weight in final form) Similarly, 1 μg, 2 μg, 5
Products containing μg or 10 μg were prepared, respectively.

Claims (1)

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