DE1792341C3 - Injectable, aqueous, stable alpha-escin solutions - Google Patents

Description

Aqueous aescin solutions are relatively unstable. They tend to get theirs after some time of storage reduce biological effectiveness, and precipitations occur due to hydrolytic processes, in which the two acids present in aescin in ester bond, acetic acid and angelicic acid or Tiglic acid, split off by saponification. This is expressed in a decrease in the hemolytic (biological) effectiveness as well as in a precipitation of the water-insoluble cleavage products.

It is therefore desirable to prevent the acyl groups of the aescin from splitting off, or so far to inhibit that sufficiently stable solutions result for therapeutic use.

The therapeutically interesting concentrations for the parenteral use of aescin solutions lie in the range between 0.05 and 0.2% and are thus higher than the critical micelle concentration (CMC), which, according to our own investigations, depends on pH values between 4.0 and 5.5 and of salt or buffer additives can be between 0.003 and 0.03%.

At pH values between 4.0 and 5.5, our own studies have shown that the hydrolytic splitting off of the two acids is lowest in all concentration ranges. In addition, it was found in these investigations that solutions of aescin, which are in their concentration below the C ^- MC, have a relatively greater stability than the solutions with higher concentrations, an unusual fact, because in general in an aqueous solution of an unstable substance, the hydrolytic cleavage is promoted rather than inhibited by dilution.

It has now been found that certain additions hydrotropic substances, namely water-soluble theophylline or theobromine derivatives «-Escin solutions, the concentration of which is above the CMC, ratios are created that match those correspond to how they are present below the CMC, so that stable solutions are obtained through these additives can be. According to the invention, therefore, the injectable, aqueous, stable-aescin solution has one pH from 4.0 to 5.5 and contains 1 to 5% water-soluble theophylline or theobromine derivatives. Hydroxyethyl theophylline and hydroxypropyl theophylline or hydroxyethyl theobromine are preferred used as stabilizers.

This stability effect by preventing micelle formation is completely surprising. From the German Patent specification 944 816 is even known that the stability of aqueous solutions of oxyalkylk-rten theophylline and theobromine solutions are not particularly good, which is why one according to the method of this Patent specification as a solubilizer theophylline and / or caffeine should add if you already have Oxoalkyldimethylxanthine derivatives according to German Auslegeschrift 1 250968 as solubilizers of sparingly or insoluble therapeutically active substances, it is evident that one could not infer from the prior art that the theophylline to be used according to the invention or theobromine derivatives have a stabilizing effect on the aqueous solution, a substance such as -Escin, especially since -escin itself has good water solubility. Of some water-soluble xanthine derivatives due to solubilizing effect can therefore in the stability effect, which is primarily based on the effect, Preventing the formation of micelles of the aescin does not play a role here. Except for this stabilizing one The additives used according to the invention still have the desired effect, namely precipitation vcn cleavage products of the aescin, so that the solution is less even if it is present Quantities of degradation products remain clear and therapeutically applicable.

Although salts favor the formation of micelles per se, one that is necessary for setting pH values interferes The addition of buffers does not have the stabilizing effect of the hydrotropic substances used according to the invention.

Some application examples of the stability-increasing effect of water-soluble theophylline or theobromine derivatives are shown in the following table. For this purpose, solutions of (/ -aescin in the stated concentrations with the addition of about 0.3% sodium acetate buffer with a pH of 4.8 were filled into ampoules, ^{subjected to a heat treatment at 100 °} C. for preservation and then stored at the stated temperatures Percentages in the table indicate the decrease in the hemolytic activity of the solution to the specified amount. The occurrence of a precipitate is symbolized by the sign + + +.

Table I.

"■" "" "" ■ 0.1% H-escin concentration 25 ° C 0.2% «-escin 6OX 37 "C 37 "C 11 days: 87% 25'C Storage temperature 35 days: + + + additions 60 "C without addition 35 days: 95% 51 days: 27% 19 days: 77% 51 days: 84% 150 days: 17% 32 days: + + + 150 days: 25%

continuation

25-C 0.1% α-escin
37 ° C concentration nperature
25 ° C 0.2% α-escin
37-C 60 ° C 200 days: 97%
450 days: 95% 51 days: 98%
150 days: 99%
200 days: 92%
450 days: 87% Stores egg
ti0 ° C 35 days: 87% 4.4% hydroxyaryl
theophylline 41years: 91% 35 days: 90%
51 days: 80%
150 days: 62%
210 days: 56% 41 days: 87% 41 days: + + + 1% hydroxypropyl
theophylline 41 days: 81% 4.4% hydroxypropyl
theophylline 41 days: 88% 4.4% hydroxyethyl
theobromine 41 days: 93%

Table Ia Concentration: 0.1% α-escin

additions Storage temperature 25 ° C 97%
99% Storage temperature 37 C 94%
89% Storage temperature 60 ° C 1.8% dihydroxypropyl theophylline 70 days:
111 days: 100%
99% 70 days:
111 days: 95%
89% 70 days: 73%
Ul days: 63% 1.8% dihydroxypropyl theobromine 70 days:
111 days: 97%
100%
97% 70 days:
111 days: 97%
100%
83% 70 days: 73%
111 days: 60% 2.7% theophylline Na salicylate
1.5% ethyl theophylline 47 days:
30 days:
70 days: 96%
91% 47 days:
30 days:
70 days: 96%
88% 47 days: 85%
30 days: 90%
70 days: 76% 1.5% ethyl theobromine 30 days:
70 days: 100%
102%
96% 30 days:
70 days: 100%
100%
98% 30 days: 88%
70 days: 72% 2.2% 1 - (5'-oxyhexyl) -3,7-dimethyl-
xanthine 33 days:
56 days:
98 days: 33 days:
56 days:
98 days: 33 days: 89%
56 days: 87%
98 days: 71%

Claims (2)

Patent claims: 1. Injectable, aqueous, stable <_ <- aescin solutions of acidic pH, characterized that the aqueous aescin solution has a pH of 4.0 to 5.5 and 1 to 5% water-soluble theophylline or theobromine derivatives contains 2. Injectable solution according to claim 1, characterized in that it is hydroxyethyl theophylline or HydroxypropyltheophyHin contains