DD138406B1 - PROCESS FOR PREPARING A HYPOTENSIZED HYPOTENSIVE PREPARATION FOR PARENTERAL APPLICATION - Google Patents

Description

Field of application of the invention

The invention relates to a process for the preparation of stable parenterally administrable preparations of disodium pentacyanonitrosylferrate (hereinafter called DNPF).

The compound is used in human medicine as an ideal hypotensive, with which acute hypertension crisis can be well controlled, as well as for controlled intraoperative hypotension.

Characteristic of the known technical solutions

The compound DNPF is the salt formed from the yellow blood lye salt by the action of nitric acid:

In Na ₂ CO., _R * | Pe (CN) ₆ J * 3 H ₂ O + HNO ₃ * -. * Na ₂ ^ Fe (CN) ₅ NO 2 * 2 H ₂ O

+ KNO ₃

In the past, this compound has found substantial use as a reagent for sulfide ions. Although the blood pressure-lowering effect of DNPF has been known for a long time, the high acute toxicity initially prevented clinical application:

LD ₅₀ : 9.4 mg / kg mouse

20.8 mg / kg dog 12.1 mg / kg cat

Only intensive studies on the detoxification mechanism in the organism enabled a clinical application of DNPF. In the organism, DNPF liberates cyanide, which is detoxified to thiocyanate in the presence of free sulfur by the enzyme rhodanase.

In normal metabolism, the organism can detoxify by 1 mg / kg cyanide. Only at high doses as a shock of existing sulfur in the organism is no longer sufficient to detoxify the resulting cyanide, and there are symptoms of cyanide poisoning.

The biological half-life strongly depends on the applied dose. Animal experiments showed after i. V. injections of 6.25 mg / kg still after 90 minutes, a blood level of 12.8% DNPF and a biological half-life of 28 minutes. After application of 0.4 mg / kg, only 19% DNPF was detectable in the blood after only 30 seconds, and the biological half-life could be calculated as 2.5 minutes.

Because of this low biological half-life and low therapeutic dose, DNPF has found its way into human medicine.

Of particular advantage is the good controllability of the antihypertensive effect, which is caused by the short biological half-life. A favorable dosage was suggested to be 3 to 13 g / kg with a total dose of about 15 mg DNPF per patient. The detoxification capacity of the human organism is never reached.

The problem with making an injectable DNPF preparation is the extreme instability of the compound. The originally yellow-brown solution turns dark red, green or blue after a short time, shows numerous unresolved impurities and thus becomes useless. Information is available in the literature according to which solutions stabilized with sodium citrate, citronic acid, acetic acid, acetate buffer or sodium diertate have a shelf life of 6 months under light protection.

This usability period is insufficient for industrial production. It would mean the production of very small batches and a separate supply to the hospitals.

Object of the invention

The aim of the invention is to produce a DNPF preparation which is stable over a longer period and parenterally administrable.

- 2 - 207 389 Explanation of the essence of the invention

The object of the invention is to produce a sufficiently stable, parenterally administrable disodium pentacyanonitrosylferrat preparation.

According to the invention, it has been found that a parenterally administrable DNPF preparation which is stable at room temperature over a prolonged period is obtained by adding a compound selected from acidic and neutral amino acids, sodium salts of weak organic or inorganic acids and / or mannitol to the aqueous solution of ONPF , makes a solution and then lyophilized. It has also been shown that the stability of the lyophilizate can be significantly improved if the potassium content of the DNPF used is between 5 and 50 mg%. The resulting lyophilizate is stable for a long time and, after dissolution in sterile 5% glucose solution, can be used for parenteral administration.

embodiments

1. 50 g Disodiumpentazyanonitrosylferrat, whose Flammenphotometrisch certain potassium content, which is due to impurities, is 5mg%, are dissolved with the addition of 20g of mannitol in 11 freshly distilled water. The resulting solution is sterile filtered and filled under aseptic conditions 1 ml each in amber glass ampoules and lyophilized.

2. Method analogous to Example 1 with the exception that instead of mannitol 1 g of sodium citrate is used.

3. Method analogous to Example 1 with the exception that in addition to the amount of mannitol used 2 g of sodium citrate is used.

4. Method analogous to Example 1 with the exception that is used instead of mannitol aminoacetic acid.

Claims (1)

-1- 207 389 Invention claim: A method for preparing a stable, parenterally administrable pharmaceutical composition of Dinatriumpentazyanonitrosylferrat by dissolving the active compound in water with the addition of stabilizing agents and subsequent Lyophiltsierung the solution, characterized in that the active ingredient a potassium ion content of between 5 × 10 ^-3 and 50 10 ~ ³ wt .-% It is necessary to use 2% amino acetic acid or 2.2% of a 10: 1 mixture of mannitol and sodium citrate.