JPS6221332B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a blood sugar regulator containing 24,25-dihydroxycholecalciferol. In recent years, various injections and oral medications have been developed to adjust the hyperglycemic state caused by diabetes to normal levels, but they have various problems, and the development of safer and more effective blood sugar regulators is long-awaited. It has been done. Symptomatic drugs for hyperglycemia include insulin drugs in the form of injections and sulfonylurea drugs in the form of oral drugs. Insulin drugs, in addition to regular insulin, which has a quick onset of effect but has a short duration, various proteins are added to prolong absorption into the body, and zinc is bound to reduce solubility in body fluids. There are depot insulin preparations available. On the other hand, antidiabetic agents in the form of oral medications have evolved from sulfonylurea-based drugs to biquanide-based drugs, and new types of sulfonylurea-based drugs are also emerging. Recently, long-term epidemiological studies have gradually established that microangiopathy in diabetic patients is correlated with the quality of blood sugar control. In other words, it is expected that by strictly regulating blood sugar and maintaining normal blood sugar levels, it will be possible to prevent the development of microvascular disorders. In current insulin therapy, the amount and number of doses of insulin are adjusted to maintain fasting blood sugar levels and daily urine sugar levels within the normal range as much as possible. However, since insulin is a peptide hormone, it has a short internal lifespan as mentioned above and has a strong effect, so even if various improvements are made, the diurnal fluctuations in blood sugar levels are still far from those of a healthy person. complete normalization is extremely difficult. Moreover, no pharmacological effects can be expected even if insulin is administered orally. In view of the above facts, the development of safe and stable blood sugar regulators has been eagerly awaited. As a result of intensive research into a substance that is endogenous to healthy humans and has been proven to be safe, the present inventors found that 24,25-dihydroxycholecalciferol (hereinafter referred to as this substance or 24,25-dihydroxycholecalciferol)
The present invention was achieved based on the finding that (OH) ₂ -D ₃ ) has the effect of regulating blood sugar. This substance is a known substance and has the following structure, for example, Pharmacia, 10: 319-322, 1974.
has been disclosed. The present inventors confirmed that urine sugar was positive by intraperitoneal administration of streptozotocin, and further showed a decrease in urine sugar and blood sugar by regular insulin administration, and that the levels rose again several days after discontinuing insulin administration. Using rats exhibiting urinary sugar and hyperglycemia as diabetic model animals, we investigated substances that have blood sugar regulating effects, and found that 24·25-(OH) ₂ -D ₃ has blood sugar regulating effects. The blood sugar regulator of the present invention is of an unprecedented type that has a hypoglycemic effect when administered orally in doses of several μg/Kg. Furthermore, when the blood sugar regulator of the present invention was administered to diabetic patients, it showed a significant drop in blood sugar. That is, the blood sugar regulating agent of the present invention can exert a blood sugar regulating effect even in humans. 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 blood sugar regulator of the present invention contains the above-mentioned substances as active ingredients, and can be used in various formulations as shown below. The blood sugar regulator of the present invention can 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: This 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 100
mg/Kg or more, this substance is extremely safe compared to 1α-(OH)-D ₃ , which is said to be an active vitamin D ₃ analog (LD ₅₀ for oral administration is 1 mg/Kg or less). It can be said to be a thing. 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, p2203-2206,
This was done with reference to 1975. Example 1 1 kg of triglyceride ester of intermediate fatty acid (hereinafter abbreviated as MCT) was irradiated with a 400 W high-pressure mercury lamp for 72 hours while purging argon to eliminate and eliminate peroxide.
Dissolve 5mg of (OH) ₂ -D ₃ and add 24R・
The following shell components were heated and dissolved to contain 0.5 μg of 25-(OH) ₂ -D ₃ and soft capsules were prepared in a conventional manner using a soft capsule making machine. Shell formulation example Gelatin 10 parts by weight Glycerin 2 Preservative (ethylbaraben) 0.05 Titanium white 0.2 Water 0.2 (Parts by weight in final form) Similarly, 1 μg, 2 μg, 5 μg in one capsule
Products containing μg or 10 μg were prepared, respectively. Example 2 60 mg/Kg of streptozotocin was intraperitoneally administered to 6-week-old male Wistar rats. One week after administration, positive urine sugar was confirmed, and regular insulin administration showed a decrease in urine sugar and blood sugar. In addition, only rats in which hyperglycemia and hyperglycemia were confirmed again several days after administration of insulin were used as diabetic model animals. In addition, rats to which physiological saline was intraperitoneally administered instead of streptozotocin were used as control rats. A normal solid feed (CE-2 manufactured by CLEA Japan) was given as feed. 24R・25−
(OH) ₂ -D ₃ was orally administered by force in a state dissolved in MCT containing 0.2% ethanol. Forced oral administration was performed once a day for 5 to 6 days per week, and continued for 4 weeks. After the administration, the rats were fasted for 24 hours and then sacrificed. Blood was collected from the abdominal descending vena cava into a test tube containing EDTA and NaF, and blood sugar was measured by an enzymatic method. Results first
Shown in the table.

[Table] Example 3 24R・25-(OH) ₂ -D ₃ was orally administered to three diabetic patients at a dose of 4 to 6 μg per day in the form of microcapsules obtained in Example 1 for three weeks. . Blood was collected at 11:00 the next morning after an overnight fast, and blood sugar was measured using an enzymatic method. The results are shown in Table 2.

【table】

Claims (1)

[Claims] 1. A blood sugar regulator containing 24,25-dihydroxycholecalciferol as an active ingredient. 2. The blood sugar regulator according to claim 1, wherein the 24,25-dihydroxycholecalciferol is 24R,25-dihydroxycholecalciferol.