FI58072C - FOERFARANDE FOER FRAMSTAELLNING AV ETT TORRPREPARAT AV ETT ALKALIMETALLSALT AV DEHYDROEPIANDROSTERONSULFAT FOER PARENTERAL ADMINISTRATION - Google Patents

Description

For 2,58072 women in the 37th to 39th week of pregnancy, it improves the maturity of the birth canal and the oxytocin sensitivity of the uterine muscles, thus leading to a safe, normal birth. Thus, the clinical use of DHA-S has become of considerable importance. Unfortunately, the alkali metal salt of DHA-S is very unstable in water. For example, the sodium salt of DHA-S is hydrolyzed to partially free dehydroepian drosterone in a short time upon storage of its aqueous solutions at reflux temperature.

Similarly, its dosage forms must be sterile dry crystals or lyophilized powders in container packs which are dissolved in sterile water just prior to use. The above forms are not satisfactory because the crystals take a long time to dissolve in water and the lyophilized powders do not remain at room temperature long enough.

The present invention demonstrates that a stable preparation for parenteral administration of water-soluble DHA-S can be prepared by adding to a aqueous solution of an alkali metal salt of dehydroepiandrosterone sulfate as a stabilizing agent a neutral or basic naturally occurring amino acid, namely glycine, Glycine. , and that the amount of the stabilizing agent is 10 to 200% by weight of the amount of the alkali metal salt of dehydroepiandrosterone sulfate, after which the resulting mixture is sterile filtered and lyophilized.

The resulting powders remain stable for a long time and can be easily dissolved in sterile water before use and administered parenterally, such as by intravenous or intramuscular injection.

58072

The amount of stabilizing agents is at least 10%, preferably 20% to 200%, by weight of the DHA-S salt.

It has been found that the solubility of DHA-S is significantly increased in the presence of amino acids.

For example, the solubility of the sodium salt of DHA-S in pure water at room temperature is 1.4%, but in a 2% aqueous solution of glycine is 3.0%. Thus, ampoules are prepared, each containing 100 mg of the sodium salt of DHA-S, by dispersing 5 ml of the solution in a 2% glycine solution, whereas when 10 ml of pure water is required to dissolve the sodium salt of DHA-S. This greatly reduces the amount of water to be removed and also the time required for lyophilization.

In practice, the alkali metal salt of DHA-S is dissolved in a solution of the stabilizing agent and the solution is sterilized by filtration in the usual manner. The solution is dispensed into containers such as ampoules or vials and lyophilized in the usual manner. Finally, the container is sealed. Before use, reconstitute the container with a sufficient amount of sterile water.

The solubilities of DHA-S in 2% aqueous solutions of some amino acids are as follows:

Solubility of amino acid DHA-S at room temperature (%)

Without amino acid 1.4

Glycine (2-%) 3.0

Arginine (2-%) 2.7

Cystidine (2-%) 2.8

It is known from CA 78: 2S944j that the DHA-S injection can be stabilized in a solution containing sorbitol. Such an injection is stable for at least 12 weeks only when stored in a cold place. In practice, storing injections in a cold place is very difficult. In addition, sorbitol is not as effective a stabilizer of DHA-S as the amino acids of the present invention.

The results of the comparative experiment are presented below. The samples were prepared in the same way as in the examples. Each ampoule contained 100 mg of the sodium salt of DHA-S and 100 mg of each of said stabilizers.

* 58072 Residual sodium salt of DHA-S stored at 40 ° (¾) _ 30 days 90 days

After stabilization, D-sorbitol (100 mg) 76.4 57.1

Glycine (100 mg) 99.6 98.0

Without the stabilizer 78.5 58.9 sorbitol does not naturally increase the solubility of the DHA-S salt in water. j

German application 2,010,758 discloses that “an organic base stabilizes certain 2o and 3o-epithioandrostane derivatives.

The active ingredients, which decompose on storage, are completely different in structure from DHA-S and are insoluble in water.

Thus, in solutions for parenteral administration containing 2o and 3o <t-epithioandrostane derivatives, water cannot be a solvent.

None of the references provided disclose the advantages offered by the present invention, in particular the fact that according to the invention the solubility of the alkali metal salt of DHA-S is significantly increased. This is advantageous because the amount of water removed during lyophilization is reduced and the lyophilized product can be easily redissolved in situ before use.

The following examples illustrate the invention.

Example 1 40 g of glycine were dissolved in distilled water in a vessel with a volume of 2 liters. To the solution was added 40 g of the sodium salt of DHA-S under heating. The solution was diluted to 2 liters with distilled water.

The solution was sterilized by filtration in the usual manner and dispensed into glass ampoules, 5 ml each. The solution was then lyophilized and the ampoules sealed in the usual manner. Each ampoule contained 100 mg of the sodium salt of DHA-S and 100 mg of glycine. The procedure was repeated using varying amounts of glycine. The remaining amounts of sodium salt of DHA-S were determined, after 30 days and 90 days of storage; the results are shown in Table 1.

t S 58072

table 1

Glycine content Residual sodium salt of DHA-S mg / container (%)

30 days / 40 ° C 90 days / 40 ° C

0 78.5 58.9 20 95.7 94.6 50 98.4 97.3 100 99.6 98.0 150 98.2 97.1 200 99.0 98.4

Example 2

Example 1 was repeated except that glycine was replaced with L-arginine (free base). The amounts of sodium salt of DHA-S remaining in the shelf life test are shown in Table 2.

Table 2 Amount of L-arginine Residual sodium salt of DHA-S mg / container stored at 40 ° C,% 30 days 90 days 0 80.3 60.8 20 92.0 87.4 50 97.4 96.0 100 98.6 96.2 150 97.8 97.4 200 98.1 97.6

Example 3

Example 1 was repeated except that glycine was replaced with DL-alanine. The amount of sodium salt of DHA-S remaining in the shelf life test is shown in Table 3.

Table 3 Amount of DL-alanine Residual amount of DHA-S sodium salt mg / container when stored at 40 ° C,% 30 days 90 days 0 77.4 55.4 20 85.3 82.3 50 91.4 87.4 100 95.2 90.1 150 95.4 93.3 200 94.7 93.2