DE2127288A1 - Process for the production of infusion solutions - Google Patents

Description

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PATENT ADVOCATE

May 29, 1971 2127288 Application files: 75.362

PATENT APPLICATION

Applicant; Ceskoslovenskä academy ved., Praha 1, Narodni tr. 3

Title; Process for the preparation of infusion solutions

The invention relates to a method of manufacture of infusion solutions, which are mainly used as a replacement for Blood plasma can be used.

Blood "and blood plasma transfusions are today" already one of the main and most effective remedies in the treatment of major bleeding, burns and of states of schack, in exceptional circumstances However, this intervention is often associated with great difficulties, especially with regard to the difficult procurement of blood, and further

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possibly because of insufficient amounts of the required blood group. The impossibility of building up sufficient stocks because of the limited duration of preservation, their easy vulnerability, the great demands on their transport and storage, the need to determine the blood group and carry out a cross test. These are further disadvantages that were already clearly evident in the First World War the impulse to efforts made to replace blood and blood plasma by other solutions, although such attempts had been earlier but virtually unsuccessfully made (gum arabic, gelatin and "ä _{#} φ}

In 1878 Schäfer expressed the conviction that the replacement of blood with a physiological solution was of only limited importance in bleeding therapy. Starling then showed the fundamental difference between the effects of crystalloids and of blood or plasma and established that the therapeutic effectiveness especially from the colloidal-osmotic properties of Flüsigkeit used depends · in the hemorrhaging patient occurs mainly due to the replenishment of the blood volume and not to the replacement of lost Erytrocyten to _e These findings influenced the further Forschimgstätigkeit the Wisseit-

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ORfGfHAL INSPeCTED

scholars involved in the preparation of that Blood-plasma-replacing solutions, endeavored to improve their colloidal-osmotic properties should than with the previously used physiological solution · In the course of time, a. whole range of "substitute substances" of which but only a few have proven themselves.

Today all experts agree that colloidal infusion solutions are one indivisible part of the modern transfusion service and that they are one of the most important prerequisites for successful therapy for injuries, heavy bleeding, prophylaxis and the treatment of crouching are·

The great importance of infusion solutions can therefore no longer be in doubt today, especially not in situations under unusual circumstances, when a sufficient amount of blood or plasma is not immediately available (accidents, unforeseen Bleeding, accumulation of accidents and the like «,). In such cases, the rapid administration of an infusion solution in the required amount is decisive often about the further fate of the patient.

The invention is based on the object of an improved

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tes and cheaper process for the production of infusion solutions, which are mainly used as blood plasma substitutes; can be used to create.

This object is achieved according to the invention in that monoesters of acrylic or methacrylic acid and polyols with at least two OH groups, or amides of these acids themselves or substituted on the nitrogen with one up to two alkyl groups with 1 - 4 carbon atoms or with hydroxy ^ alkylene, optionally with polyhydroxyalkylene, which contain up to 6 carbon atoms, are polymerized or copolymerized, then the solution precipitated and the resulting polymer dissolved in physiological solution, preferably to a 0.3 l A solution with a viscosity of 2-3 cP.

A distribution of the molecular weights suitable for the application can be achieved by fractionation, wherein the lower and higher molecular weight fractions are separated from the polymer.

The preparation of infusion solutions, which are used according to the invention as blood plasma substitutes, goes with it Advantage of glycol methacrylates (starting with diglycol monomethacrylate), glycerol methacrylate, N-monosubstituted Methakrylamideh, Ν, Ν-disubstituted acrylamides and N-monosubstituted acrylic amides.

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For the preparation of infusion solutions, mixed polymers of these substances or copolymers can also be used with advantage with N-vinylpyrrolidone or N, N-disubstituted Methacrylamides are used. The condition for this is the water solubility of the resulting polymer. The glycol methacrylates can also contain the diester if the polymerization is carried out at high dilution will.

The polymers prepared according to the invention are completely non-toxic and do not cause allergic or other reactions before, have no antigenic effects, are very stable and record the determination of blood groups not.

All of the listed types of infusion solutions have been found to have had good success in healing hemorrhagic vision Shocks tested in rabbits.

In one case, e.g. B. used to sensitize the organism polytriglycol monomethacrylate. the Sensitization was carried out on 5 rabbits of the same sex with a mean weight of 2.5 kg in the way of five subcutaneous injections made at four day intervals with an amount of 2 ml of the polymer. The test results were determined on the one hand by biological tests and on the other hand by means of serological methods.

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after 30 days after administration the last sensitizing dose. As a control, non-sensitized rabbits were used for the biological tests and normal rabbit serum and a physiological solution used for serological methods.

Results:

a) Biological tests:

The Arthurian reaction was after the 30 day Interval of the sensitization caused by intracutaneous injection of 1 ml of the appropriate substance. During the histological examination of the puncture site no difference was found compared to the control groups during 4-48 hours and the Reaction had to be rated as negative.

The anaphylactic reaction was also stopped after April 30 Days from the last sensitizing injection by injecting 20-50 ml of the substance directly into the ore evoked. There was none in the experimental animals Reaction.

b) Serological methods:

Of the serological methods, the agglutination tests were used. A drop of the polymer was with

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one drop of the serum from the unsensitized animals mixed. The control was carried out with normal serum and physiological solution. The results were read microscopically at 5, 10, 15 and 20 minutes. Agglutination could not be performed in any of the Tests are observed. "

The agglutination was tested in the test tube. In a conical 12 ml test glass was graduated o, 5, 1.2, 3 and 4 ml of the serum and 3 ml each of the polymer solution The control was carried out by comparison with normal serum and physiological solution. In these experiments, too, none of the reaction tubes did Agglutination.

As a further test method, double diffusion in two directions (Ouchterlony method) was used. The tested substance was placed in the middle reservoir (diameter 16 mm) of a petri dish filled with agar at a distance of 10 mm. reservoirs (diameter 12 mm) adjoining the middle reservoir are then filled with serum from unsensitized rabbits. The dishes were kept in the refrigerator for 4 days. A diffusion of the antisubstances was not observed.

In this experiment, active anafylaxis with polytriglycol monomethacrylate was followed on the animals. By

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the methods used (Deckglasagglutination, ^ robeglasagglutination, Gelddffusion, Arthur ¹ See response and eliciting a anafylaktisehen shocks) the formation of counter substances could not be detected *

In addition, the invention is applied to some implementation examples explained in more detail, the inventive The process is only illustrative, but by no means limit to this »

example 1

10 g of triethylene glycol monomethacrylate, 90 g of water and 0.009 g of azo - bis - methyl isobutyrate are weighed into a glass ampoule and blown with nitrogen for 1 hour. The ampoule is then melted shut and the contents polymerized for 10 hours at 60 _{° C. o} After cooling, the solution is precipitated by pouring into ten times the amount of acetone, the polymer is suctioned off, washed through and dried. The polymer is dissolved in water and a rough fractionation into three fractions is carried out in the acetone-water system. The middle fraction is used for the production of blood plasma substitutes. The polymer is filtered off with suction, washed through and dried in vacuo. The dry polymer, freed from all solvents, turns into a 0.5 # strength in physiological solution

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Solution (viscosity 2.3 cP) dissolved «The product is stored in the refrigerator and sterilized by boiling for 20 months,

Example 2

20gI-ethyl methacrylamide, 80 g water and 0.02 g Diisopropyl percariranate weighed into a glass ampoule and purge with nitrogen for 1 hour. The ampoule is sealed and the contents for 10 hours polymerized at 60 ° C. After cooling down, the solution becomes precipitated with acetone and the product sucked off, washed through and dried. th freed polymer is dissolved in physiological solution. The concentration is chosen such that the viscosity of the resulting solution corresponds to the viscosity of real blood plasma,

Example 3

20 g of a mixture of I - ethyl methyl acrylamide bit 1.1 - Whore thylmethacrylamide (oil ratio 5: 1), from 80 g of water and 0.02 g of diisopropyl percarbonate are weighed into a glass ampoule, blown with nitrogen for 1 hour and finally for a few hours. it polymerized at 70 ° C. The further processing took place as described in Example 2.

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Example 4

15 g N | B! - Dimethyl acrylamide, 84 g of water and 1 g of a 30% aqueous ELO® solution are polymerized in a glass ampoule for 10 hours at 60 ° C. Further processing was carried out as described in Example 2.

Example 5

20 g of a mixture of triethylene glycol monomethacrylate with N-vinylpyrrolidone C molar ratio 4: 1), 80 g of a mixture of ethyl alcohol - water (1: 1) and 0.01 g of azo - bis - isobutyronitrile is polymerized for 10 hours at 60 ° C »Further processing took place as described in Example 2.

Example 6

30 g of glycerol monomethacrylate, 70 g of lasser and 0 _f 01 g of diisopropyl percarbonate are polymerized at 60 ° C. for 10 hours. Further processing was carried out as described in Example 2.

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Example 7

20 g of a mixture of methyl methacrylate and Glyzerinmonomethakrylat (MolYerhältnis 7: 1), 80 g of water and 0 _f 01 g of azo - bis - isobutyronitrile 10 hours polymerized at 60 ° C ·

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Claims (2)

2127988 claims 1. Process for the production of infusion solutions, which are mainly used as blood plasma substitutes, characterized in that monoesters of acrylic or methacrylic acid and polyols with at least two OH "groups, or amides of these acids themselves or substituted with one on the nitrogen atom up to two alkyl groups with 1-4 carbon atoms or with hydroxyalkylene, optionally with polyhydroxyalkylene, which contain up to 6 carbon atoms, are polymerized or copolymerized, whereupon the solution precipitates and the resulting polymer is dissolved in physiological solution, 2. The method according to claim 1, characterized in that that the resulting polymer in physiological solution to a 0.3 - I ^ igen solution a viscosity of 2 - 3 oP is dissolved «, 3ο method according to claim 1, characterized in that that the lower and higher molecular weight fractions are removed from the polymer «, 10 9 8 5-1 / 1836