DE1165606B - Process for the production of aqueous solutions of gelatin derivatives - Google Patents

Description

Process for the preparation of aqueous solutions of gelatin derivatives It is known that by reacting gelatin with glyoxal and then Oxidation with hydrogen peroxide an aqueous solution of high molecular weight polypeptide derivatives which can be used therapeutically as a blood substitute fluid. Even Reaction products of gelatin and acid anhydrides have been used for the same purpose already used. The two methods of making these blood substitute fluids have the disadvantage that you react the gelatin with very aggressive substances must and that the molecular weight of the reaction product in the course of these reactions is reduced far more than it is in the interests of sufficient residence time in the Organism is desirable.

It has now been found that it can be used therapeutically as a blood substitute fluid usable, water-soluble gelatin derivatives can be obtained if one in itself known way gelatine or its degradation products obtained by partial hydrolysis Reacts with vinyl methyl sulfone in aqueous alkaline solution. Then you can the salts or other low molecular weight fractions formed as by-products can be removed by dialysis.

It is true that the addition of ß-naphthylamine to the double bond of the Vinyl-p-tolylsulfons known, but it was not easily foreseen that obtained by reacting gelatin or its partial hydrolysis Decomposition products with vinyl methyl sulfone to water-soluble, well-tolerated in the organism Derivatives would come, in particular, the reaction of gelatin with aromatic Bis-vinyl sulfones is described as a process for hardening gelatin.

The inventive implementation of the gelatin or its partial Hydrolysis of the degradation products obtained with vinyl methyl sulfone enables the gelation temperature to reduce the solution so far, even with molecular weights between 30,000 and 60,000, that the solutions are liquid at room temperature and infused without difficulty can be.

According to a preferred method for the reaction, vinyl methyl sulfone is added dropwise in the well-stirred, adjusted to a px value of 8 to 9 with a little sodium hydroxide solution Solution of the gelatin at about 80'C. One can measure the course of the reaction track the viscosity of the solution and in this way also the viscosity of the Adjust the final solution to the desired value.

After the addition has ended, the salts formed are removed and low molecular weight fractions and the excess sodium hydroxide solution preferably through dialysis with water, with increased temperature to accelerate the process or mechanical movement can be applied. Cleaning can also be done by Precipitation reactions or similar known measures take place.

The dialyzed solution is adjusted to a content of about 3 to 80 % dry matter. For use as a blood substitute fluid, the addition of small amounts of inorganic salts is required. One gives z. B. 0.85% table salt or the corresponding amount of a physiological salt mixture. The finished solution can then be filled into ampoules under sterile conditions and stored in this form until use.

The solutions obtained have before the synthetic blood substitutes, z. B. the polyvinylpyrrolidone solution, the advantage that they are broken down in the organism after some time, provided that they have not been excreted. On the other hand, when preparations with a sufficiently high molecular weight are administered, the residence time in the body is so great that a sufficient therapeutic effect can be achieved over a sufficiently long time. Thus, in animal experiments (rabbits), the solutions obtained have a therapeutically beneficial longer residence time in the organism than the blood plasma replacement solution known from German Auslegeschrift 1038 239, which has been produced by reacting gelatin with N-methylglucamine.

EXAMPLE 1 50 g of gelatin are dissolved in 500 cc of water, the solution is adjusted to pH 9 by adding sodium hydroxide solution and the amounts of vinylmethylsulfone given in the table are added dropwise with stirring at 80 ° C. within a quarter of an hour. The reaction is over after about 3 hours. Vinyl- me- LDso iv thyl- 07, s (white notes sulfon mouse) G 1 0 0.0 - solidified during dialysis, unusable 2 5 2.6 10.0 contains 8.7% vinylmethyl sulfone in the dry Dimensions 3 10 3.5> 10.0 contains 10% vinyl methyl sulfone in the dry Dimensions After the reaction, the solutions were dialyzed in a cellophane tube with cold tap water for 48 hours and clarified by centrifugation and filtering through a disinfection filter. The amount of converted vinyl methyl sulfone was determined by determining the sulfur content of the dry matter. The yields are 40 g dry matter. Example 2 509 gelatin, which in a 5% solution has a relative viscosity of 1.94 and the gelling temperature of -1-11 ° C. and which, by dissolving 500 g of bone gelatin in 1000 ccm of water and with the addition of 65 g of 25% Sodium hydroxide solution at 90 ° C., neutralization with hydrochloric acid, filtration and precipitation by pouring the solution into alcohol are dissolved in 200 cc of water at 40 ° C. and a pH of 7.9 and 10 g of vinylmethylsulfone are added dropwise within 5 minutes . After one hour, the solution is heated to 60 ° C. for 5 minutes, neutralized with hydrochloric acid and the reaction product is precipitated by pouring it into alcohol.

Yield: 44 g dry substance with 1.950 / 0 S = 6.5% bound vinyl methyl sulfone. The 5% solution in physiological saline solution prepared under sterile conditions has il "= 2.09 and a gel point of -1-8 ° C.

Claims (1)

Claim: A process for the preparation of aqueous solutions of gelatin derivatives, characterized in that gelatin or its degradation products obtained by partial hydrolysis are reacted with vinylmethylsulfone in an aqueous alkaline solution in a manner known per se. Documents considered: German Patent No. 635 298; German Auslegeschrift No. 1038 239. When the application was announced, a test report (2 pages) was laid out.