JPH0255383B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a stable iron hydroxide colloidal solution;
More specifically, water is stable even at slightly alkaline pH, which is almost the same as human blood, has a high iron utilization rate, has almost no side effects, and is useful as an intravenous iron agent for the treatment of iron deficiency anemia, etc. It relates to iron oxide colloidal solutions.

A highly bioavailable iron colloid solution has been developed for intravenous administration as a drug for the treatment of iron deficiency anemia in humans due to impaired iron absorption, and to date, the results of experiments on iron utilization have shown that dextran is a protective colloid. A colloidal solution of iron hydroxide is widely used mainly in the United States [Goodman
and Gilman: The pharmacological basis of
therapeutics, MacMillan, New York 1980,
See p1325-1326]. Furthermore, in Japan, chondroitin sulfate colloidal solution is used, which has few side effects and a high iron utilization rate [Seno, Awai and
Ose：Iron Metabolism in Rabbits After the
Intravenous Introduction of a Ferric
Colloid, Proceedings 3rd Intern.Cong.
Hematology vol.2, 1961, Pan-Pacific,
Tokyo, p. 1257-1258], and in Europe, iron-poly(sorbitol gluconate) complex salts are used [Goodman and Gilman, cited above.
[Refer to the report]. Although these iron preparations have relatively high bioavailability, those using polymeric protective colloids often cause headaches, nausea, fever, rashes, and anaphylaxis.
There have been reports of side effects such as anaphylaxis, and even death due to anaphylaxis [mentioned above].
See article by Goodman and Gilman].

On the other hand, low-molecular complex salts, such as iron citrate complex salts,
Although it does not exhibit the side effects mentioned above, the bioavailability of iron is low and most of it is excreted as is, so a sufficient therapeutic effect cannot be expected.

Therefore, the present inventor discovered that iron has a high bioavailability and
Moreover, as a result of intensive research to develop an intravenous iron colloid preparation with extremely few side effects,
Iron hydroxide colloidal solution can be stabilized with tricarboxylic acid or its salt without worrying about side effects,
Moreover, the stabilized colloidal solution is extremely stable even in the slightly alkaline PH range, which is approximately the same as the PH of blood, and was found to be promising as an intravenous iron preparation, leading to the completion of the present invention.

Therefore, according to the present invention, there is provided an iron hydroxide colloidal solution that is stabilized by tricarboxylic acid or a salt thereof and is stable in neutral to weakly alkaline conditions, particularly in the pH range of 7.0 to 8.5. be done.

A colloidal solution of iron hydroxide can be prepared, for example, by dropping an aqueous solution of ferric chloride into boiling distilled water [for example, Yutaka Sano:
"Histochemical Research Methods," Nanzando, Tokyo, 1976, p. 461], or by adding a dilute alkaline aqueous solution to a ferric chloride aqueous solution at room temperature.

The colloidal particles in the colloidal solution of iron hydroxide prepared in this way have a positive charge and have a pH of 1.5.
Although it is stable in the range of ~2.0, it becomes unstable when the pH exceeds about 3, and completely precipitates at a pH of 7. These colloidal solutions of iron hydroxide are used to adjust the PH of human blood.
As mentioned above, protective colloids such as dextran and chondroitin sulfate have been used for stabilization in order to maintain stability even in weak alkalinity, which is almost the same as When an iron colloid solution is administered intravenously to humans, the above-mentioned side effects occur, which is not preferable.

Therefore, the present inventor conducted repeated studies on various compounds in order to find a substance effective in stabilizing iron hydroxide colloidal solution from among low-molecular-weight compounds that are free from such side effects and have no toxicity problems. It has now been discovered that certain tricarboxylic acids or their salts are extremely useful in stabilizing iron hydroxide colloidal solutions.

The tricarboxylic acids that can be used in the present invention are particularly preferably aliphatic ones, such as citric acid, isocitric acid, tricarballylic acid, nitrilotriacetic acid, etc. Among them, citric acid and isocitric acid are preferred. be. These tricarboxylic acids can also be used in the form of salts, preferably pharmaceutically acceptable inorganic or organic salts, for example sodium salts, potassium salts, ammonium salts, etc. used.

Methods for stabilizing iron hydroxide colloidal solutions using these tricarboxylic acids or their salts include:
A method of adding tricarboxylic acid or its salt to the iron hydroxide colloidal solution prepared in advance as described above, or adding these tricarboxylic acids or its salts (excluding tricarballylic acid) and a water-soluble iron compound such as ferric chloride. A method can be used in which a complex salt of the tricarboxylic acid and iron is formed in advance, and then the solution is made weakly alkaline and then heated to convert it into an iron hydroxide colloid solution.

The amount of tricarboxylic acid or its salt required for stabilizing an iron hydroxide colloid solution varies depending on the concentration of the colloid solution and the type of tricarboxylic acid or its salt, but in general, the amount of iron hydroxide colloid to be stabilized is It is appropriate to use the tricarboxylic acid or its salt in a proportion of 5 to 20 moles, preferably 10 to 15 moles, per gram atom of iron in the colloidal particles of the solution.

The iron hydroxide colloidal solution stabilized according to the present invention, when used as an intravenous iron preparation, has a 7.0
It is desirable to have a PH within the range of ~7.5, so if necessary, it can be adjusted within the above PH range by adding alkali or acid, and by adding sugar such as glucose, it can be adjusted to the same level as blood. It can also be stretched.

The stabilized iron hydroxide colloidal solution provided by the present invention is extremely stable in the PH range of 7.0 to 8.5, including the PH of human blood (approximately 7.3);
In addition, it has a high bioavailability of iron, and is safe without the risk of side effects unlike conventional colloidal iron solutions using polymeric protective colloids.As an intravenous iron preparation, it is useful for anemic patients suffering from abnormal symptoms due to iron deficiency. It is expected that it will be highly effective in treatment.

Next, the method for producing a colloidal solution of the present invention will be explained in more detail with reference to Examples.

Example 1 Add 1 volume of 0.1M ferric chloride aqueous solution to 9 volumes of boiling distilled water.
Add the distilled water gradually to the volume of the distilled water, being careful not to drop the temperature (while maintaining the boiling state). Once the addition is complete, cool the liquid to room temperature. 0.1M per volume of the obtained iron hydroxide colloid solution
After adding 5 volumes of aqueous sodium citrate solution and stirring thoroughly, adjust the pH of the solution to 7.3 with a 1N aqueous sodium bicarbonate solution, and then add glucose to make the osmotic pressure of the solution physiologically isotonic. . The colloidal solution thus obtained is extremely stable and 25
Even after being stored at ℃ for 6 months, there was no change and the original state of the colloidal solution was maintained.

In addition, instead of the above sodium citrate, ammonium citrate, sodium isocitrate,
A similarly stable iron colloid solution could be obtained when ammonium isocitrate, sodium tricarballylate, or ammonium tricarballylate was used.

Example 2 0.1M in 9 volumes of 0.1M sodium citrate aqueous solution
1 volume of ferric chloride aqueous solution is added to form a pale green aqueous solution of iron citrate complex salt. Next, 1N sodium hydrogen carbonate is added to this solution to adjust the pH to 8.5, and then boiled for 1 to 2 minutes. This gives a reddish-brown colloidal solution (final pH approximately 9.5). After adjusting the pH to 7.3 by adding 1N hydrochloric acid to this colloidal solution, glucose is added to make the solution physiologically isotonic. The colloidal solution thus obtained remained stable without any change even after being stored at 25°C for 6 months.

Example 3 Add 9 volumes of 0.1M sodium isocitrate aqueous solution
Add 1 volume of 0.1 M ferric chloride aqueous solution to form a pale yellow-green aqueous solution of iron complex salt of isocitrate.
Next, 1N sodium hydrogen carbonate aqueous solution is added to this solution to adjust the pH to 7.5, and then boiled for 1 to 2 minutes. This gives a reddish-brown colloidal solution (final pH approximately 8.8). After adjusting the pH to 7.3 by adding 1N hydrochloric acid to this colloidal solution, glucose is added to make the osmotic pressure of the solution physiologically isotonic. The colloidal solution thus obtained remained stable without any change even after being kept at 25°C for 6 months.

Example 4 5 volumes of 0.1M nitrilotriacetic acid aqueous solution was added to 1 volume of iron hydroxide colloidal solution obtained in the same manner as in Example 1, and after thorough stirring, 1N sodium bicarbonate aqueous solution was added. to bring the pH of the solution to 7.3.
The permeability of the solution is adjusted to physiological isotonicity by further adding glucose. The solution thus obtained was extremely stable, and no changes were observed even after storage at 25°C for 6 months.

Claims (1)

[Claims] 1. A neutral to weakly alkaline and stable iron hydroxide colloidal solution, which is stabilized by tricarboxylic acid or a salt thereof.