JPH0430374B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a urine alkalizing agent composition. More specifically, the present invention provides citric acid,
The present invention relates to a urine alkalizing agent composition containing sodium citrate and potassium hydrogen phosphate.

Traditionally, it has been used to treat hyperuricemia, which occurs in patients suffering from gout, urinary stones, renal dysfunction, etc.
It is known to administer drugs such as baking soda and sodium citrate. In other words, in hyperuricemia, the urine tends to be acidic, and uric acid precipitates in the kidneys and urinary tract, often resulting in stones. Therefore, in treating hyperuricemia, it is necessary to promote uric acid excretion and reduce the amount of urine in the urine. It is desired to prevent precipitation of uric acid by increasing the solubility of uric acid. This precipitation of uric acid can be prevented by alkalinizing the urine by administering the above-mentioned sodium bicarbonate, sodium citrate, or the like. Furthermore, by alkalizing the urine, it becomes possible to dissolve uric acid or uric acid stones that have already precipitated in the body.

However, when administering the above-mentioned sodium bicarbonate, sodium citrate, etc., although it is possible to alkalinize the urine, it also leads to excessive intake of sodium, which disrupts the balance of the Na ⁺ /N ⁺ ratio in the blood.
As a result, there is a problem in that it causes side effects such as high blood pressure.

Furthermore, in recent years, drugs containing citric acid and an alkali salt of citric acid have been proposed as auxiliary drugs for the treatment of hyperuricemia. For example, on pages 56-63 of Uric Acid Vol. [Product name: Uraritz-U
(CG-120), manufactured by Dr. Madaus Co., Ltd.] has been experimentally proven to be useful as an auxiliary drug for the treatment of hyperuricemia, and its effectiveness has been suggested. When this composition is administered, the balance of the Na ⁺ /N ⁺ ratio in the blood is almost never disrupted as described above, but this time, because the potassium citrate contained in the composition has deliquescent properties. However, the disadvantage is that the composition itself has poor storage stability.

As a result of intensive research into auxiliary drugs for the treatment of hyperuricemia, the present inventor discovered that the composition ratio (molar ratio) of citric acid, sodium citrate, and potassium citrate was 1:2:2. We have discovered that the above drawbacks can be overcome by using a composition containing citric acid, sodium citrate, and potassium hydrogen phosphate in a certain range of composition ratios instead of a composition containing citric acid, and have arrived at the present invention. did.

That is, an object of the present invention is to provide a pharmaceutical composition that brings about alkalinization of urine without disturbing the balance of the Na ⁺ /K ⁺ ratio in the body and therefore without affecting blood pressure. .

Further, the present invention provides a pharmaceutical composition that causes urine alkalization and does not have deliquescent property and hygroscopic property, or at least has its deliquescent property and hygroscopic property improved to such an extent that it does not pose a problem in practical use. It is also an object to provide pharmaceutical compositions.

The above purpose consists of citric acid, sodium citrate and potassium hydrogen phosphate, the composition ratio of which is x:y:z (citric acid:sodium citrate:
Potassium hydrogen phosphate, a mixture with a molar ratio of 80
A composition containing in the range of ~100% by weight,
and x, y and z representing the composition ratio of the mixture are 1.7≦x≦2.8, 1.0≦y≦3.0 and 2.1, respectively.
This can be achieved by the urine alkalizing agent composition of the present invention having a numerical value in the range of ≦z≦3.8.

Next, the present invention will be explained in detail.

The present invention uses potassium hydrogen phosphate instead of potassium citrate in conventionally known urine alkalizing agent compositions, and furthermore, by setting the composition ratio within the above range, the composition which has been a problem in the past can be solved. This product improves the deliquescent properties of urine and alkalinizes urine without disrupting the balance of the Na ⁺ /K ⁺ ratio in the body.

That is, the urine alkalizing agent composition containing citric acid, sodium citrate and potassium hydrogen phosphate of the present invention has not only deliquescent properties but also almost no hygroscopic properties. Therefore, when used regularly, there is no problem with its shelf life, and no special molding process is required for use as a drug.

In addition, by mixing these components, especially sodium citrate (Na ₃ C ₆ H ₅ O ₇ ) and potassium hydrogen phosphate (K ₂ HPO ₄ ) in the composition ratio within the above range, Na ⁺ in the blood can be reduced. It can alkalinize urine and increase the solubility of uric acid in urine without disturbing the balance of the /K ⁺ ratio. Therefore, since it has almost no effect on blood pressure, it can be used even in patients with hypertension.

Furthermore, by using the urine alkalizing agent composition of the present invention, the amount of urine and the amount of uric acid excreted can be increased. That is, by alkalinizing the urine, it is possible to increase the concentration of uric acid in the urine and increase the amount of urine, thereby promoting the excretion of uric acid.

The urine alkalizing agent composition of the present invention having the excellent properties as described above has the following configuration.

The urine alkalizing agent composition of the present invention comprises citric acid,
Contains a mixture of sodium citrate and potassium hydrogen phosphate in the range of 80-100% by weight.

In this mixture, x, y, and z in the composition ratio (molar ratio) of citric acid: sodium citrate: potassium hydrogen phosphate (x:y:z) are 1.7≦x≦2.8, 1.0≦y≦3.0, and 2.1≦z≦
It is a number in the range of 3.8. From the viewpoint of hygroscopicity, etc.
Preferably 1.9≦x≦2.7, 1.5≦y≦2.5 and
It is a numerical value in the range of 2.4≦z≦3.2. Urine alkalinizing effect and blood electrolyte balance (Na ⁺ /
More preferably, 1.9≦x≦2.2, 1.8≦y≦ ^2.2 and 2.8≦
It is a numerical value in the range of z≦3.1, and the above composition ratio is 2:
Most preferably the ratio is 2:3.

This mixture is prepared, for example, by weighing citric acid, sodium citrate, and dipotassium hydrogen phosphate corresponding to the above composition ratios, dissolving them in water, and dehydrating and drying them.

In addition, various additives known as drug additives, such as excipients made of sugars such as fructose and lactose, stabilizers, and flavoring agents, may be added to the resulting mixture. When adding something other than the above three components to the composition, the content of the above mixture in the composition should be 80~
Keep it within 100% by weight. The content of said mixture is particularly preferably in the range 80-90% by weight.

Thereafter, it can be molded into any desired dosage form, such as granules or solids (pellets, etc.), using known formulation methods.

Next, Examples and Comparative Examples of the present invention will be described.
However, these examples do not limit the invention.

Example 1 Add 0.42 g of citric acid (C ₆ H ₈ O ₇ ), 0.588 g of sodium citrate (Na ₃ C ₆ H ₅ O ₇ ), and 0.522 g of potassium hydrogen phosphate (K ₂ HPO ₄ ) to 20 ml of distilled water. After dissolving, the mixture was stirred for 15 minutes at a temperature of 80°C in a hot water bath. Next, water in this solution is distilled off under reduced pressure at a temperature of 70 to 80°C, and dehydrated and dried to obtain a composition with a composition ratio of citric acid, sodium citrate, and potassium hydrogen phosphate of 2:2:3 (molar ratio). A crystalline composition was obtained.

Furthermore, only the molar ratio of citric acid was varied in the range of 1.0 to 3.3 to obtain various compositions consisting of citric acid, sodium citrate, and potassium hydrogen phosphate.

Example 2 Various citric acids, sodium citrate and A composition consisting of potassium hydrogen phosphate was obtained.

Example 3 Various citric acids and sodium citrate were prepared in the same manner as in Example 1 except that only the molar ratio of potassium hydrogen phosphate was changed in the range of 1.0 to 4.0. A composition consisting of potassium hydrogen phosphate and potassium hydrogen phosphate was obtained.

The hygroscopicity of each of the compositions obtained in Examples 1 to 3 was evaluated.

First, measure the weight of the composition immediately after drying under reduced pressure, then measure the weight after leaving it for 48 hours at a temperature of 24 to 32 degrees C and a humidity of 60 to 80%, and calculate the weight change (increase). did.

The obtained results are shown in FIGS. 1 to 3.

Figure 1 shows various compositions in which the composition ratio of citric acid, sodium citrate, and potassium hydrogen phosphate is x:2:3 (molar ratio), and the horizontal axis shows the molar ratio This is a graph showing the relationship when the weight change (%) is plotted on the vertical axis.

FIG. 2 shows that the composition ratio of the above composition is 2:y:3.
(molar ratio) of various compositions, the horizontal axis is the molar ratio y of sodium citrate, and the vertical axis is the weight change (%).

FIG. 3 shows that the composition ratio of the above composition is 2:2:z
(molar ratio) in various compositions, the horizontal axis is the molar ratio z of potassium hydrogen phosphate, and the vertical axis is the weight change (%).

From Figures 1, 2, and 3, x, y, and z, which represent the composition ratios of citric acid, sodium citrate, and potassium hydrogen phosphate, are 1.7≦x≦, respectively.
2.8, 1.0≦y≦3.0 and 2.1≦z≦3.8, it is clear that the resulting composition is excellent in hygroscopicity. Furthermore, the above x, y and z are respectively 1.9≦x≦2.7 and 1.5≦
It has been found that when the values are in the ranges of y≦2.5 and 2.4≦z≦3.2, almost no hygroscopicity is exhibited.

Next, we will discuss the effect of the composition obtained in Example 1 in which the composition ratio of citric acid, sodium citrate and potassium hydrogen phosphate is 2:2:3 (molar ratio) on urine PH and the effect on urine volume. Evaluation was performed using the following measurement method.

(1) Effect on urine PH The above composition was administered to rats at 1000 mg/Kg and 1500 mg/Kg.
After oral administration of mg/Kg, 2 to 9 hours later urine
PH was measured.

(2) Effect on urine volume The above composition was administered to rats at 1000 mg/Kg and 1500 mg/Kg.
Urine volume was measured for 3 hours after oral administration of mg/Kg.

The obtained results are shown in FIG. 4 and FIG. 5, respectively, together with the measured values of rats to which the above composition was not administered at all (control group).

Figure 4 shows measurement time on the horizontal axis and urine pH on the vertical axis.
It is a graph showing the relationship when .

1: Rats administered 1000 mg/Kg (administration group) 2: Rats administered 1500 mg/Kg (administration group) 3: Rats not administered (control group) It is a graph showing the amount of urine for 3 hours.

As is clear from FIG. 4, when a composition in which the composition ratio of citric acid, sodium citrate, and potassium hydrogen phosphate is 2:2:3 (molar ratio) is administered to the present invention, as an example, In both cases, urine PH was higher than in the non-administered control group, indicating an alkalinizing effect.

Furthermore, from FIG. 5, it is clear that when the above composition was administered, the urine output from 0 to 3 hours after administration was increased compared to the control group that was not administered.

Example 4 The composition ratio of citric acid, sodium citrate and potassium hydrogen phosphate obtained in Example 1 was 2:
Fructose to 0.45 g of a composition with a 2:3 (molar ratio)
After mixing 0.05 g, pellet-like tablets were produced by a conventional method.

[Brief explanation of drawings]

Figure 1 shows various compositions in which the composition ratio of citric acid, sodium citrate, and potassium hydrogen phosphate is x:2:3 (molar ratio), and the horizontal axis shows the molar ratio x of citric acid. This is a graph showing the relationship when the weight change (%) is plotted on the vertical axis. Figure 2 shows the composition ratio of the compositions shown in Figure 1 being 2:y:3 (molar ratio), with the horizontal axis representing the molar ratio y of sodium citrate, and the vertical axis representing the weight. It is a graph showing the relationship when change (%) is taken. FIG. 3 shows the molar ratio z of potassium hydrogen phosphate on the horizontal axis and the vertical axis in various compositions in which the composition ratio of the composition shown in FIG. 1 is 2:2:z (molar ratio). It is a graph showing the relationship when weight change (%) is taken. Figures 4 and 5
In each figure, the horizontal axis shows measurement time, and the vertical axis shows urine.
These are graphs showing the relationship when taking PH, and graphs showing the urine volume between 0 and 3 hours after administration. 1: Rats administered 1000mg/Kg (administration group), 2:
Rats administered 1500 mg/Kg (administration group), 3: rats not administered (control group).

Claims (1)

[Claims] 1 Consisting of citric acid, sodium citrate and potassium hydrogen phosphate, the composition ratio of which is x:y:z
(molar ratio) in the range of 80 to 100% by weight, and x, y, and z representing the composition ratio of the mixture are each 1.7≦x≦
2.8, a urine alkalizing agent composition having numerical values in the range of 1.0≦y≦3.0 and 2.1≦z≦3.8. 2 x, y and z representing the composition ratio of the above mixture
are 1.9≦x≦2.7, 1.5≦y≦2.5 and
The urine alkalizing agent composition according to claim 1, characterized in that 2.4≦z≦3.2. 3 x, y and z representing the composition ratio of the above mixture
are 1.9≦x≦2.2, 1.8≦y≦2.2 and
The urine alkalizing agent composition according to claim 2, characterized in that 2.8≦z≦3.1. 4. The urine alkalizing agent composition according to claim 1, which contains the above mixture in an amount of 80 to 90% by weight. 5. The urine alkalizing agent composition according to claim 1, wherein the composition contains saccharide. 6. The urine alkalizing agent composition according to claim 1, wherein the composition is in solid form.