JPS58118516A - Calcium adjusting agent containing 1alpha,25-dihydroxyvitamin d3-26,23-lactone - Google Patents

Abstract

PURPOSE:A calcium adjusting agent, containing 1alpha,2-,dihydroxyvitamin D3- 26,23-lactone as an active constituent, having the activity of reducing the calcium content in the blood serum, and useful for treating hypercalcemia, etc. CONSTITUTION:A calcium adjusting agent containing 1alpha,25-dihydroxyvitamin D3- 26,23-lactone as an active constituent. A compound expressed by the formula is used as the above-mentioned compound, and particularly 23(S)25(R)-1alpha,25-dihydroxyvitamin D3-26,23-lactone is suitable. The compound is capable of reducing the calcium level in the blood serum, and useful for treating hypercalcemia, etc. caused by the compound used in treating osteoporosis, osteomalacia, etc. Preferably, the compound can be administered by either one of the oral and parenteral routes, but preferably by the oral route.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a calcium regulator containing 23-lactone to la,25-dihydroxyvitamin Ds-2 as an active ingredient.

I! In detail #i The present invention is effective in treating pathological conditions caused by high calcium content in serum, such as hypercalcinemia. Calcinium joint agent K containing as
I'll do it.

Conventionally, as a compound useful for treating osteoporosis fatigue, osteomalacia, etc., for example, lI! , 25-dihydroxycholecalciferol, 1g-hydroxycholecalciferol,
let, z4-dihydroxycholecalciferol is known.

However, when the dose of these compounds is increased, there is a possibility that side effects such as hypercalcinilamemia and hypercalciniuria may occur.

Calcitonin is known as a therapeutic agent for hypercalculemia and the like, but calcitonin has the disadvantage that it cannot be administered orally.

On the other hand, recently, 1α,25-dihydroxyvitamin D3 was extracted from rat serum as a new metabolite of 1m-hydroxyvitamin Ds or in,25-dihydroxyvitamin D3. 23-lactone was isolated and identified (Mrch.

Biochem, Biophe, 204 317
~3111 (1918G): FICB8 Lff
iTTIR8,IX4 207~21t (19
81) ).

However, it costs 1g! ! The physiological activity of 23-lactone to i-dihydroxyvitamin Ds-2 is not yet known.

The present inventor has detailed the physiological activity of 23-lactone on la, 25-dihydroxyvitamin Ds-2.
Upon investigation, Ig, 25-dihydroxyvitamin D
s-2%N! - When lactone was administered to vitamin D-deficient rats and the calcium concentration in their serum was measured,
He also noticed a significant drop in calcium levels. The present invention has been achieved based on this knowledge. That is, la,25-dihydroxyvitamin Ds-2a23-lactone lowers calcium levels in serum, and therefore such compounds
The drug was found to be useful in the treatment of bulk calcinemia caused by the administration of ta, 2s-dihydroxyvitanin Da, etc., and was developed as Kinei fI14.

That is, the present invention provides 1 g, 25-dihydroxyvitamin D
Calcium regulator containing s-24"23-lactone as an active ingredient.

11! used in the drug of the present invention! , 25-dihydroxyvitamin Dm-26,23-lactone is a compound represented by the formula. The compound is Xa-hydroxyvitamin D
S or ta, zs-dihydroxyvitamin Ds is administered to rats or dogs in an amount within a toxically acceptable range by conventional means such as oral, intravenous, or intramuscular injection, and approximately 2 days after administration.
It was administered after approximately 50 hours had passed! --Hydroxyvitamin D, or Ig,! It is isolated and purified from rat or dog serum as a metabolite of 15-dihydroxyvitamin D8 (Arch.

Biochem, Biophs, 204.387-3
・1 (1980)).

Also la, 25-dihydroxyvitamin DI-2a2
3-lactone is a rat kidney homogenate and 2-lactone.
5-hydroxyvitamin Ds-26,23-lactoy
(Biochemistry, l Jl.

4775-478G (1G79): Tstrahs
droneL@tt.

21.46117-4670 (eyes] O))
B8 LITTKR8, 134, 207-211 (19
81)).

la, 25-dihydroxyvitamin Ds-2423-lactone has asymmetric carbon atoms at the 25th and 23rd positions, but in the present invention, the 25th and 23rd positions are R-
It may be either the coordination or the S-coordination, or it may be a mixture of the R-coordination and the 8-coordination in any proportion. Among them, 41%
2 3 (8) 25 (8)-1α, 2 which is naturally occurring in
5-dihydroxyvitamin Ds-2423-lactone is preferred because it has suitable physiological activity.

As mentioned above, the la, 25-dihydroxyvitamin D$-2 to 23-lactone of the present invention has the effect of lowering calcium concentration in serum, and therefore, diseases caused by high calcium levels in Arashisei. For example, it is useful in the treatment of hypercalcinillaemia caused by administration of vitamin D analogs, hypercalcinillaemia due to malignant tumors, hypercalciumuria, parathyroidism, Behcet's disease, etc.

1m! The administration of 21-lactone to S-dihydroxyvitamin Ds-2 may be either oral or parenteral, and parenteral administration may be intramuscular, subcutaneous, or intravenous.

Including rectal administration. Among these, oral administration is preferred.

Calcium regulators containing this compound as an active ingredient are available in tablets, powders, granules, suppositories, and capsules.

It is used in dosage forms such as alcoholic solutions, oily solutions, and aqueous suspensions. Suitable solvents for oily solutions include vegetable oils, such as corn oil, cottonseed oil, coconut oil, almond oil, peanut oil.

Fish liver oil, oily esters, etc. can be used. Other ingredients include lactose, starch, Merck, magnesium stearate, sugar, saline ice, surfactants, antioxidants, and the like.

In addition, to extend the shelf life of this compound,
Antioxidants such as ascorbic acid, butylated hydroxyanisole, hydroquinone, etc. can also be incorporated.

The dosage of 1g, 25-dihydroxyvitamin Dm-2a23-lactone is α o o o t 7-1. o'P
hZ days, preferably at a rate of ˜tsf/le/day.

The present invention will be explained in more detail below with reference to Examples.

Example 1 (1) Male pegle dog (weight t04) Icα2 T
riton X-100 solution 2011Lll! ni la-
Hydroxyvitamin Ds2119 was dissolved and administered orally. Eight hours after administration, the animals were anesthetized with Nemptal and blood was collected from the carotid artery. Serum 60G obtained from the blood was diluted with the same amount of water, and then diluted with twice the amount of σroform/methanol (1/1).
Extracted with.

The obtained extract was applied to a Se7 Adenx LH-20 column (L
5 x 25 ai ) using chloroform/n-hexane/methanol (75/23/2) as a developing solvent. Then Ig, 24
25-) Both parts of dihydroxyvitamin p are eluted as l
! Then, high performance liquid chromatography was performed using Solpax SL1 Katsum at a flow rate of 1-/i using dichloromethane containing Kame-5-methanol as a developing solvent. 111
One minute from which 1,25-dihydroxyvitamin Da-2a 23-lactone was eluted was further subjected to high performance liquid chromatography under the same conditions. The Ig, 25-
Shibitami 7Ds-26,23-lactone in dihydro was purified by high performance liquid chromatography using a Solpax Eli'1 column at a flow rate of 1117/win using n-hexane containing 18-inglobanol as a developing solvent.

11) Thus obtained 2,3@)25(2)-1
g.

Calcinium absorption capacity from the intestinal tract and calcium concentration in serum were measured using 25-dihydroxyvitamin D and -2423-lactone.

Weaned male Wistars were grown for 6 weeks on a diet deficient in Utwohitamine Ds and low in calcium.

After 6 weeks, weight I Q Of (Q) 6 rats received α2-Triton X-100 (Q solution
Dissolved 1 2 S nf LcL.

25-dihydroxyvitamin D, -26,23-lactone, l 25 nr of la, and 25-dihydroxyvitamin Ds were each administered intravenously.

After administration, the rats were sacrificed, and calcium absorption capacity from the intestinal tract and calcium IIIrtL in the serum were measured. Calcinium absorption capacity from the intestinal tract was determined using the De Roux method (
Am, J, physiol, 2 s t1351
-1359(196G))K, serum calcium concentration was determined using the OCPC method (Am, J, C11n.

pathol, 45. 290-296 (t966))
Measured from K.

The result of calcium absorption ability from the intestinal tract is 111th! lI
K. The results of calcium concentration in serum are shown in FIG.

From Figure 1, ia, zs-dihydroxyvitamin Ds-
It is found that 2423-lactone slightly enhances the ability to absorb calcium from the intestinal tract.

From Figure 2, 1m, 25-dihydroxyvitamin D*-2
a23-lactone is found to reduce calcium levels 24 hours after administration.

Example 2 Ia, 25-dihydroxyvitamin Ds-2423-lactone was dissolved in fatty oil to obtain an oily solution with a concentration of 7 μr/IIJ. 100 parts by weight of gelatin.

20 parts by weight of chrycerin, ethyl paraoxybenzoate α2
Parts by weight, 2 parts by weight of propyl α paraoxybenzoate, l
A coating composition consisting of 5 parts by weight of para-sulfophenylazo-2-naphthol-6-sulfonic acid disodium salt α and 80 parts by weight of purified water is dissolved by heating to prepare a coating material, and 1
la,25-dihydroxyvitamin Ds per capsule
Soft capsules were manufactured by applying a coating using a continuous soft capsule manufacturing machine so as to contain 1 st of 26,23-lactone.

[Brief explanation of drawings]

Figure 1 shows lel, 25-dihydroxyvitamin Ds21
Figure 2 shows the results of calcium absorption capacity of 423-lactone from the intestinal tract, and Figure 2 shows the results of calcium concentration in serum. Patent applicant Teijin Ltd.

Claims (1)

[Claims] L la, 25-dihydroxyvitamin Ds-2 to 2
A calcium joint agent containing 3-lacto/ as an active ingredient. @ 1m, 25-dihydroxyvitamin Da-2 to 2
3-Tuctone is 23@) 2B(2)-1g. 25-dihydroxyvitamin D zhen-2a 23-thictone O calcium regulator according to claim 1. λ The calcium regulator according to claim 1 or 2, for reducing the calcium content in serum. 4 Special tf1w end range 1st for hypercalcinemia
The calcium joint agent according to any one of Items 1 to 3. i Calcinium regulator according to any one of claims 1 to 94 in oral dosage form faK.