JPS6229526A - Remedy and preventive for hypercalciuria - Google Patents

Abstract

PURPOSE:To obtain the titled agent by neutralizing an acidic aqueous solution of a phytic acid salt in the presence of a component selected from amino acids, peptides and water-soluble proteins, and using the resultant precipitate as an active component. CONSTITUTION:An acidic aqueous solution of a phytic acid salt (e.g. a double salt of phytic acid and a cation composed mainly of magnesium and potassium) is neutralized in the presence of one or more components selected from amino acids (e.g. glycine, alanine, valine, methonine, serine, asparagin, etc.), peptides (e.g. glycylglycine, glycylglycylglycine, etc.) and water-soluble proteins (e.g. albumin, casein, etc.), and the precipitate is used as an active component of the objective remedy and preventive for hypercalciuria. It is administered in the form of powder, tablet, etc., at a dose of 600-800mg in terms of the phytic acid salt orally after meal.

Description

DETAILED DESCRIPTION OF THE INVENTION (Objectives of the Invention) (a) Field of Industrial Application The present invention relates to a therapeutic and preventive agent for hypercalciuria.

Patients with hypercalciuria have consistently high levels of calcium in their urine, making them susceptible to urolithiasis, a condition in which stones formed in the kidney become lodged in the ureter or urethra, causing severe pain. , these stones are mostly composed of calcium.

When administered orally, the drug of the present invention captures and insolubilizes calcium in the gastrointestinal tract, thereby lowering the calcium concentration in the urine and suppressing stone formation (-therefore, it is an excellent agent for treating and preventing hypercalciuria). It is effective.

←) Prior art There have already been two attempts to utilize phytic acid for the treatment and prevention of hypercalciuria.

For example, Bruce and Force a-(C
allow), phytin binds to calcium in the intestines,
It has been reported that it suppresses the absorption of calcium in the body.

[Biochemical Journal
-al Journal Volume 28, 517-528
Page, 1934, Henneman
) etc. administered sodium phytate to stone patients (two doses,
It has been reported that urinary calcium concentration decreased during the administration period, and no exacerbation of stones was observed. [New England Journal of Medicine (Ne
w England Journal of Med
icine) Volume 259, pp. 802-807, 1
In 958, Kainosho administered rice bran or defatted rice bran to stone patients,
They reported that the urinary calcium concentration was significantly reduced, that this effect was caused by phytin, which is contained in large amounts in rice bran or defatted rice bran, and that no side effects were observed. [Journal of Neurology, Vol. 75, 1-2
4 pages.

1984,] (/9 Problems to be Solved The present inventors have demonstrated that phytates can be expected to be therapeutic agents for hypercalciuria, and that they are contained in a wide range of foods such as rice bran and rice germ. Since it is a natural ingredient with high safety, we conducted research into formulating it as a pharmaceutical product.

During the course of this research, we discovered that the in-vivo calcium capture ability of phytin preparations has an unexpectedly large difference depending on the preparation method.

That is, when formulating phytin, phytin is dissolved in an acidic aqueous solution, and then the solution is neutralized to precipitate a precipitate to obtain gel-like phytin.

When this is made into a syrup-like aqueous suspension without going through the drying process, it shows almost the same stable and high calcium trapping ability in the acidic site and the alkaline site (up to) even after long-term storage. Once dried and made into a solid preparation, the calcium capture ability is significantly affected by the area of action.
In the strongly acidic range (WD), it shows almost the same value as the formulation before drying.

It was found that in the neutral to alkaline range (2), there was a significant decrease.

The purpose of the present invention is to provide a therapeutic and preventive agent for hypercalciuria, which is based on phytate salts that have a stable and high calcium-trapping ability without being affected by one site of action by improving the formulation. be.

(Structure of the Invention) The present invention provides that ``an acidic aqueous solution of phytates is mixed with one or two components selected from amino acids, peptides, and water-soluble proteins.
A therapeutic and preventive agent for hypercalciuria, characterized in that it contains as an active ingredient a precipitate that is neutralized and precipitated in the coexistence of more than one species. ” and “An agent for the treatment and prevention of hypercalciuria characterized by containing as an active ingredient a precipitate precipitated by neutralizing an acidic aqueous solution of phytates without undergoing a drying process.” It is something.

Phytic acid exists in large amounts in various plants, especially seeds, as a double salt (phytin) with calcium, magnesium, caritum, etc.

The phytate salts used in the present invention include:

There is no particular limitation as long as the cation that binds to phytic acid can replace calcium, but natural phytin whose main cations are magnencum and potassium is usually suitable.

When using natural phytin, it is most preferable to use phytin separated and purified from rice bran or defatted rice bran, which has a particularly high content among seeds.

In this case, phytin is obtained from rice bran or defatted rice bran at -12~
Extract with dilute hydrochloric acid from step 3 and neutralize the extract (from step 2, separate the precipitate, dissolve it in acid, neutralize, and precipitate if necessary. Repeat the procedure to separate the precipitate (from step 2, purify). and can be used.

In addition, as desired (from 2), phytic acid that has been separated and purified in advance is reacted with magnesium chloride, potassium chloride, etc. in a predetermined molar ratio in an acidic aqueous solution and then neutralized (from 2) containing magnecum, potassium chloride, etc. in a predetermined molar ratio. It is also possible to generate and utilize a precipitate of phytate salts.

Examples of the amino acids used in the present invention include alanine,
Examples include glycine, valine, methionine, serine, asparagine, lysine, arginine, aspartic acid, glutamic acid, etc., examples of peptides include glycylglycine, glycylglycylglycine, etc., and examples of water-soluble proteins include albumin, casein, etc. is exemplified.

It is appropriate to use the amino acid, peptide or water-soluble protein in a ratio of usually about 0.5 to 3 parts per 1 part of the phytates.

As for the acid used to dissolve these.

Any inorganic or organic acid may be used as long as it dissolves phytates, but hydrochloric acid is most preferred.

The acidic aqueous solution in which the predetermined components are dissolved is adjusted to -2 to 3 (:), and an alkali aqueous solution is added while stirring to raise the - of the solution to about 8, thereby precipitating a precipitate.

The precipitate obtained in this manner contains about 3 to 70% (in dry powder) of amino acids, peptides, or water-soluble proteins, and can be used as the active ingredient of the drug of the present invention without drying or drying. It can be used suitably.

The therapeutic and preventive agent for hypercalciuria of the present invention can be formulated into powders, fine granules, granules, 0 tablets,
It is formulated into capsules, aqueous suspensions, etc., and administered orally as phytate salts at a dose of 600 fff to 800 m9 (approximately 21 g/day) after each meal.

Hereinafter, the present invention will be further explained in detail with reference to Examples.

Example 1. (Glycine-containing phytin powder) Phytin powder 22y separated and purified from defatted rice bran is dissolved in 300 g of a 0.6% hydrochloric acid aqueous solution, and 30 g of glycine is added thereto and dissolved.

While stirring the solution at room temperature, 26 ml of aqueous caustic potassium solution is gradually added to maintain the solution at p) 18.0 to precipitate phytin. After standing for 1 hour, the precipitate was centrifuged to obtain paste-like phytin, which was stirred and dispersed in 300 d of distilled water, and the operation of centrifuging the phytin was repeated twice, followed by drying and pulverization to obtain 25% glycine-containing phytin powder. I got it. The glycine content in this powder was 18% (VjAN).

Example 2. (Phytic powder containing alanine) Defatted rice bran 10
0. Add 680 m of Fl20, 4-width hydrochloric acid, perform shaking extraction at room temperature for 3 hours, separate the extract, wash the residue with the same hydrochloric acid, combine the washings with the extract, and add this (:L- α−
Add and dissolve Alanine 12I.

While stirring this solution, gradually add 26 ml of caustic potassium solution (-
Add, maintain pH S, O+ to precipitate phytin, centrifuge 1. This was washed twice with 100 grams of distilled water and then dried and ground to obtain 8 g of alanine-containing phytin powder.

The alanine content in this powder was 13% (%).

Example 3. (Powder) Mix phytin powder and mannitol thoroughly according to the above recipe. To this, dissolve hydroxypropylcellulose in an appropriate amount of ethanol and add it.

After thorough kneading, the mixture was dried and ground to obtain a powder.

Example 4. (Granules) According to the above recipe, phytin powder, corn starch, and white sugar are thoroughly mixed.

To this was added pregelatinized starch dissolved in an appropriate amount of 304 ethanol, and kneaded thoroughly and uniformly.

The mixture was made into granules according to a conventional method.

Example 5. (Tablets) According to the above recipe, phytin powder and corn starch were thoroughly mixed, stearic acid was added, and flat tablets with a diameter of 8.5+w and a tablet weight of 250 cm were obtained by direct compression.

Example 6. (Capsules) According to the above formulation, phytin powder and crystalline cellulose were thoroughly mixed, and then magnesium stearate was added to obtain hard capsules by a conventional method.

Example 7. (Aqueous suspension) 0.6 y of phytin powder 9y separated and purified from defatted rice bran
Dissolve the solution in a 100% hydrochloric acid aqueous solution, and gradually add 26% caustic potassium aqueous solution (:8) while stirring this solution at room temperature.
0 to precipitate phytin. After standing for 1 hour, the precipitate was centrifuged to obtain paste-like phytin, which was stirred and dispersed in distilled water at 100 °C, followed by centrifugation of the phytin, which was repeated twice. Ethyl 7~. Propyl paraoxybenzoate 5~. and 0.6 g of carboquine methylcellulose (to make a total volume of 100 ml): Purified water was added and mixed well to obtain an aqueous suspension.

(Effect of the invention) Test examples will be shown to explain the effects of the drug of the present invention.

Test example 1. (Calcium scavenging effect test with various...) (a) Test drug The test drug was a powder containing various amino acids, peptides, or water-soluble proteins prepared in the same manner as in Example 1 (&1 to 1 in Table 1 below) 15) and the aqueous suspension of Example 7 (&16 in Table 1).

The comparative drug was prepared in the same manner as in Example 1 except that no amino acids were added.

←) Test method: 50ml of test drug containing 1 mmol of phytic acid.
Suspend in distilled water and adjust the temperature of the suspension to 37°C, [)H2°4, 5, 6.7, and 8 by adding dilute hydrochloric acid while stirring and heating.

0, 12, prepared in advance for each suspension,
Add 50 ml of calcium chloride aqueous solution with stirring, and then oxidize with hydrochloric acid or seed hydroxide in a stirred tank at 37°C for 30 minutes) 6.
After stirring for 230 minutes at 37°C, the suspension was centrifuged (3500 rpm, 10 minutes), and the Ca+ concentration (final Ca+ concentration) of the supernatant was measured. The calcium uptake rate (ch) of the reagent was calculated.

Calcium capture rate (chi) (/9 Test results The results of this test are shown in Table 1.

During production (when not containing diamino acids, etc., the aqueous suspension (&16 in Table 1) showed stable calcium capture rates at various pH+=, but the dry powder formulation (comparative drug in the table) showed - Calcium uptake rate decreased significantly with increase.

In contrast, the dry powder formulations (&1 to A15) containing the amino acids of the present invention showed relatively stable calcium capture rates in various...

Table 1 Test Example 2. (Urinary calcium excretion inhibitory effect test) Test method Male Wistar rats were fed a high calcium diet containing 1.7 liters of calcium and served as a control group. .Ya 2,413 and Bian 14) and a comparative drug were added to 1.3-chi feed as phyton and reared.

Urine was collected over the course of one day during the fourth week of rearing, and urinary calcium was analyzed by atomic absorption spectrometry.

Test results The results of this test are shown in Table 2.

As is clear from the results in the table (2. Urinary calcium excretion was suppressed by 63.6 to 736 points in the group to which the drug of the present invention was added;
It showed a significantly higher inhibitory effect compared to 47.9% of the comparison drug addition group.

Table 2

Claims (6)

[Claims] (1) It is characterized by containing as an active ingredient a precipitate precipitated by neutralizing an acidic aqueous solution of phytates in the presence of one or more components selected from amino acids, peptides, and water-soluble proteins. A treatment and prevention agent for hypercalciuria. (2) The treatment of hypercalciuria according to claim 1, wherein the amino acid is selected from the group of glycine, alanine, valine, methionine, serine, asparagine, lysine, arginine, aspartic acid and glutamic acid; Preventive agent. (3) The agent for treating and preventing hypercalciuria according to claim 1, wherein the peptide is selected from glycylglycine and glycylglycylglycine, and the water-soluble protein is selected from albumin and casein. (4) A treatment and prevention agent for hypercalciuria, which contains as an active ingredient a precipitate precipitated by neutralizing an acidic aqueous solution of phytates without undergoing a drying process. (5) The agent for treating and preventing hypercalciuria according to claim 1 or 4, wherein the phytates are double salts of phytic acid and cations containing magnesium and potassium as main components. (6) The agent for treating and preventing hypercalciuria according to claim 1 or 4, wherein the phytates are natural phytin derived from rice bran or rice germ.