US2134246A - Stable solutions of ascorbic acid salts of histidine and process for the manufacture of same - Google Patents

Description

Patented Oct. 25, 1938 UNITED STATES STABLE SOLUTIONS OF ASCORBIC ACID SALTS OF HISTIDINE AND PROCESS FOR THE MANUFACTURE OF SAME Franz Elger, Basel, Switzerland, assignor to Hollmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing.

Application June 21, 1937, Serial No. 149,548. In Switzerland July 9, 1936 6 Claims.

If ascorbic acid is neutralized with histidine base, the solutions of the resulting salts are not stable as is evident from the fact that they soon turn raspberry-red to dark orange-brown. If,

for instance, 3.1 grammes of histidine base W mol.) and 1.76 grammes of ascorbic acid mol.) are dissolved in 100 com. of water, the resulting solution of the salt has a pHof 6.0. It very rapidly changes color, first light pink,

10 then to raspberry-red, and finally becomes dark orange-brown. Solutions of other ascorbic acid salts, for instance of sodium ascorbate, or of other histidine salts, such as histidine hydrochloride, having the same pH, do not show this rapid change of color. This is a'property peculiar to the solutions of ascorbic acid salts of histidine. The constitution of the resulting colored compounds has not yet been ascertained.

This change of color can be completely inhibited if the utmost care is taken to prevent access of air during the preparation of the solutions of ascorbic acid salts of histidine and also to protect the finished solutions against access of air. This can be achieved, for instance, by dissolving ascorbic acid and histidine base. or ascorbates and salts of histidine, in the required proportions in water through which, for instance, carbon dioxide or nitrogen has been passed for some time, and preventing access of air to the solutions so prepared, which can be efiected by filling the containers with a gas free from oxygen, or by removing the air therefrom by evacuation.

The stable solutions of the. ascorbic acid salts of histidine are to be used in the treatment of gastroduodenal ulcers by injection. Both the histidine and the ascorbic acid radicals have proven valuable in the treatment of such ulcers as evidenced by the articles of I. F. Volina and R. F. McLaughlin in The Medical Record, New

York City, April 17, 1935. and in the Illinois Medical Journal, January 1936, and the article of P. B. Davidson in Journal of the American Medical Association, vol. 90, page 1014, and the article of Scale Harris, Journal American Medical Association," vol. 91, page 1452.

Example 1 310 parts by weight of histidine base and 1'76 parts by weight of ascorbic acid are dissolved in 5,000 parts of water through which a current 01' nitrogen is continuously passed, the water having previously been boiled to remove air and cooled in a current of nitrogen. The finished solution can, for instance, be filled into ampoules containing nitrogen which are immediately sealed. These solutions remain permanently colorless. They may even be heated (sterilized) in a current ofsteam without any appreciable change of color.

Example '2 209.5 parts'by weight of histidine mono-hydrochloride (containing 1 mol. of water of crystallization) and 199 parts by weight of sodium ascorbate are dissolved in 5,000 parts of water free from oxygen, nitrogen being introduced during dissolution. The air is removed from the containers in which the solution is to be stored by evacuation. The solutions remain colorless.

I claim:

1. A package comprising a solution of the ascorbic acid salts of histidine in oxygen free I water in a container excluding oxygen.

2. A package comprising a solution of the ascorbic acid salts of histidine in water containing gases free from oxygen in a container excluding oxygen.

A package comprising a solution ofthe ascorbic acid salts of histidine in water free from oxygen under nitrogen in a container excluding 6. A process for the manufacture of stable solutions of the ascorbic acid salts of histidine which comprises preparing a solution of said salts in oxygen free water and packaging said solutio in containers under nitrogen.

FRANZ ELGER.