JPH0375532B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a hypercholesterolemia improving agent useful for the prevention, treatment, and treatment of arteriosclerosis, and more particularly to a hypercholesterolemia improving agent containing calcitonin as an active ingredient. Calcitonin was discovered as a blood calcium-lowering hormone by Copp et al. in 1962, and in 1963
It was discovered by Hirsh et al. that it is secreted from the thyroid gland. This calcitonin exhibits a bone resorption inhibitory effect and a blood calcium lowering effect on bones, and is clinically used in the treatment of Paget's disease, osteoporosis, hypercalcemia, and the like. It is also known to have effects on the kidneys such as promoting the excretion of phosphorus, magnesium, potassium, and sodium, suppressing acid secretion on the stomach, increasing liver calcium content, and suppressing insulin secretion. Furthermore, it has been reported that calcitonin has an inhibitory effect on lipid degradation in normal rat adipose tissue in vitro [S.Werner et al.
al., Horm. Metab. Res. 6 (1974) 30-36], but
There are also reports that pure calcitonin does not inhibit lipid degradation [R. Ziegler et al.,
See Endokrinologie (1980), 75(1), 77-88]. However, it has not been previously known that calcitonin has an effect of improving hypercholesterolemia. Very recently, it has been discovered that one of the causes of hyperlipidemia in chronic renal failure is increased secretion of parathyroid hormone, which promotes bone resorption and reduces renal calcium excretion. were reported, and the present inventors thought that calcitonin, which antagonizes the above-mentioned bone resorption promoting effect, might be useful for the treatment of hyperlipidemia caused by chronic renal failure, and created and investigated an experimental animal model in rats. Coincidentally,
It was found that calcitonin significantly lowers blood cholesterol concentration. Furthermore, it was found that this serum total cholesterol lowering effect was not expressed in normal animals, but was expressed only in hypercholesterolemic animals, and normalized serum total cholesterol. Furthermore, calcitonin lowers low-density lipoprotein (hereinafter referred to as "LDL"), which has an effect of promoting arteriosclerosis, and high-density lipoprotein (hereinafter referred to as "HDL"), which has an anti-arteriosclerotic effect.
) - found that it has the effect of raising cholesterol. According to the present invention, there is provided a hypercholesterolemia improving agent characterized by containing calcitonin as an active ingredient. Calcitonin used as an active ingredient in the drug of the present invention has 32 amino acids and a molecular weight of approximately 3500.
It is a peptide hormone that has a cyclic structure with an S-S bond between the 1st and 7th amino acids, and human, rat, sheep, pig, cow, salmon, and eel calcitonin, etc. However, calcitonin in the present invention does not have an amino group at the 1-position and has S
Calcitonin homologues, which form a cyclic structure with _CH2 - _CH2 bonds instead of -S bonds and have the same physiological effects as calcitonin, can also be used. Therefore, calcitonin that can be particularly preferably used in the present invention includes salmon calcitonin, porcine calcitonin, and elcatonin. When calcitonin is used as a hypercholesterolemia improving agent according to the present invention, the dose is appropriately selected depending on the patient's age, weight, mildness of symptoms, etc.; however, in the case of parenteral administration, it is generally administered to adults. 10-200 IU (International Units) as a daily dose, preferably
A range of 20 to 80 IU is considered appropriate.
However, the above dosage range is just a guideline;
It should be understood that it is of course possible to administer doses beyond the above range based on a doctor's diagnosis or the like. When using the above calcitonin for the prevention and treatment of hypercholesterolemia, calcitonin is generally administered parenterally (intramuscular injection, intravenous injection, sublingual administration, rectal administration, etc.), and the dosage form suitable for each administration method is It can be prepared as follows. The drug of the present invention is particularly suitable for parenteral administration, and is particularly advantageous since it does not cause side effects such as gastrointestinal disorders that occur when conventional hypercholesterolemia improving agents are used for oral administration. When the drug of the present invention is prepared as an injection, it can be in the form of either a liquid or a lyophilized preparation. A solution can usually be prepared by adding a tonicity agent such as sodium chloride to a buffer and dissolving calcitonin in this solution. Buffers that can be used preferably include those having a pH of about 3.5 to about 5.5, such as acetate buffer, citrate buffer, and lactic acid buffer. Further, the liquid preparation may optionally contain a stabilizer, a preservative, and the like. The content of calcitonin in the liquid preparation is not particularly limited, but it is usually desirable to contain 5 to 200 IU of calcitonin per ampoule. Freeze-drying agents are generally prepared by adding excipients, such as saccharides such as lactose, mannitrate, and dextran, and amino acids such as glycine, to the above-mentioned buffer solution.
It can be prepared by dissolving calcitonin in this solution and then freeze-drying it. Note that the amount of excipients to be added is preferably such that the concentration is usually 2 to 3% relative to the buffer solution. On the other hand, when preparing the drug of the present invention as a suppository, for example, oils and fats, glycerin esters,
For suppository bases such as polyethylene glycols,
Calcitonin absorption enhancers such as acidic amino acids, ascorbic acids, citric acids, unsaturated fatty acids, and salicylic acids are kneaded, calcitonin is dispersed and mixed into this, and after being slightly heated, it is poured into a suppository mold and solidified. This can be done by letting Furthermore, when preparing the drug of the present invention as a sublingual tablet, the above-mentioned calcitonin absorption enhancer is added to a sublingual tablet base such as lactose, starch, hydroxypropylcellulose, polyacrylic acid copolymer, and magnesium stearate. This can be carried out by kneading, dispersing and mixing calcitonin, and then tableting. As mentioned above, the hypercholesterolemia-improving agent of the present invention has the effect of lowering blood cholesterol concentration, and is effective in preventing and treating arteriosclerosis, familial hypercholesterolemia, xanthomas, etc. It can be used for processing, etc. The excellent pharmacological effects of the hypercholesterolemia improving agent of the present invention can be demonstrated by the following animal experiments and clinical examples. Experimental Example 1 Effect in rats with chronic renal failure Two-thirds of one kidney of a 5-week-old Wistar male rat was removed, and one week later, the other kidney was removed. From the 10th postoperative day, administer 50 mIU/Kg of calcitonin for 3 days a week for 14 days.
Administered over a week. After administration, whole blood was collected and serum total cholesterol was measured using Cholesterol C-Test Wako (Wako Pure Chemical Industries, Ltd.). As shown in Table 1 below, calcitonin is
A dose of 50 mIU/Kg statistically significantly lowered serum total cholesterol.

[Table] Experimental example 2 Effect on ventromedial hypothalamic nucleus disruption (VMH) in rats 10-week-old SD female rats were subjected to 2 mA and 20 seconds of electricity to disrupt the ventromedial hypothalamus. I did this. Calcitonin was administered at a dose of 50 mIU/Kg for 5 days a week for 4 weeks starting 2 weeks after the surgery. After administration, whole blood was collected, and serum total cholesterol was measured in the same manner as in Experimental Example 1. As shown in Table 2 below, calcitonin is
A dose of 50 mIU/Kg statistically significantly lowered serum total cholesterol.

[Table] Clinical example 10 units of salmon calcitonin was administered twice a week for 4 weeks to a hypercholesterolemic patient.
As shown in Table 3 below, calcitonin significantly lowered serum total cholesterol and ester cholesterol, but did not lower HDL-cholesterol.

[Table] Example 1 Dissolve 2.5 g of sodium chloride in 500 ml of 0.05M acetic acid-sodium acetate buffer, and dissolve 1.1 mg (4545 IU/mg) of salmon calcitonin in this solution.
The resulting solution is sterilized using a membrane filter (0.2 micron), filled into a 1 ml ampoule, purged with nitrogen gas, and then sealed. This results in
1 ml ampoule containing 10 units of calcitonin
You will get 500 pieces. Example 2 In Example 1, 4.4 mg of salmon calcitonin
Perform the same procedure except that calcitonin was added to 40
500 ampoules of 1 ml containing the unit are obtained.

Claims (1)

[Scope of Claims] 1. A hypercholesterolemia improving agent characterized by containing calcitonin as an active ingredient. 2. The hypercholesterolemia improving agent according to claim 1, wherein the calcitonin is salmon calcitonin. 3. The hypercholesterolemia improving agent according to claim 1, wherein the calcitonin is porcine calcitonin. 4. The hypercholesterolemia improving agent according to claim 1, wherein the calcitonin is elcatonin. 5. The hypercholesterolemia improving agent according to claim 1, which is in the form of an injection.