DE1467889A1 - Process for the production of stable heparin solutions - Google Patents

Description

fATfNTANWKU "

PROF.DR.DR.J.REITSTOtTfR Munich, June 15, 1964 DR.-INQ.W.BONTE _{M /} . " _Ofi MÖNCHEN 15. HAVDNSTRASSE 5 M / 7J 9 «- 1Λ67889

PROCESS FOR PRODUCING STABLE HEPARINE SOLUTIONS.

It is known that heparin is very easily soluble in water. It is also known to be heparin In the year it has already been inactivated by traces of acids and that its watery dissolving only sinks for a short time are permanent.

The solubility of heparin and the sluggishness of its emptying are particularly important properties if heparin is to be used in therapy because of its anticoagulant effect. Since heparin na.3u.llch vielt.ge; is lend ineffective when administered orally lt> i UAN angeviiesen on ^ ine oarenterale Verab-1 ¹ J ic hung. The parenteral pre-use of heparin :: iac.i ^J :!. "Made the production of adaptable solutions erible.

Ui.1 the olut coagulationGhe; riuiend3n effect of heparin ::.: ··. in the;. ': e handling of crane wheels rait lill-Cü ¹ ' / on;:]: to use erotlerenden means, one has to prove,.; ::. 1, riu..ir: alz des heparins, solved in \ Janser for Ia, 'οι ·;!, Ions before / ends. Since the action of heparin is not effective as a result of the ...

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^ß AD original

H67889

To prolong the effectiveness of the heparin, heparin was combined with e.g. gelatin and grape sugar without in this way, however, sufficient stabilization could be achieved.

The need to use a stable heparin solution is particularly evident in the treatment of Varicose veins. After the administration of sclerotic agents such as e.g. of sodium 2-methyl-7-ethyl-undecyl-4-sulfate, the sodium salts of the liquid fatty acids of psyllium oils or the pettic acids of liver oil and the like. an inflammation of the vein wall occurs, which causes the vein to grow together within a few minutes and thus become barren. In this case, however, the risk is very great that blood clots will be formed, which then have the known dangerous effects can trigger on the organism. In order to prevent the formation of such thromboses, heparin solutions are therefore injected before or after the injection of sclerotic agents. It is understood that the anticoagulant effect of the heparin for this treatment must be preserved for as long as possible. However, the results showed that despite After the administration of heparin, blood clots repeatedly appeared, which suggests that the anticoagulant end Effect of heparin because of its instability not in aqueous solution and partial absorption is fully exploited.

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BAD ORJGINAL

U67889

Attempts have therefore been made to administer heparin with the sclerotic agent to avoid both agents to let act at the same time. However, it has been found that a combination of the known sclerotic agents with heparin is not possible, because it precipitates develop. The solutions therefore had to be administered separately. However, it cannot be ruled out that such deposits can also arise within the treated veins, so that the effect of both compounds, the sclerotic compound and heparin, thereby but it is already diminished apart from other damages that may occur.

According to the present invention, it has now been possible, in a simple manner, to produce a stable heparin solution, the stabilizer of which at the same time has sclerotic properties. Namely, if you have heparin in a solution of at least 20% table salt loesuix; dissolves, a stable heparin leakage was obtained, which is excellently suited for the treatment of varicose veins. A saline solution of at least 2% from: ⁱ o :. '.: ^J. Memlich varicose veins just as good as the well-known, anti-inflammatory agents, without the nusfalls observed in the case of the combination with heparin, kccasal ^ loesvai ^ en of at least 2C; "have l.use ground ge ^ en j.e ':: ev eier, i-means used in the therapy of eramofaders the distribution that they do not

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U67889

cause toxic side effects such as allergies. In addition to these advantageous properties, at least 2Q saline solutions stabilize the heparin used so good that the heparin activity is maintained even after storage for several months and thus within which to veroedendon vein comes to full effect.

Surprisingly, it has been found that the effect of heparin as an anti-coagulant agent and table salt as a sclerotic agent in this combination, even far beyond the purely additive effect of the individual components goes out. The same effectiveness could not be achieved when both components were administered individually. Namely, if heparin was injected before the administration of the sclerotic agent, a loss of activity occurs Absorption into the circulation. If the heparin was injected after the administration of the sclerotic agent, comes the anticoagulant effect too late, as experience has shown Blood clots were observed before the heparin could be introduced. With simultaneous administration such as it is carried out according to the invention - the disadvantages are eliminated, so that full utilization of both effects is guaranteed. In addition, the heparin is as above executed in the saline solution used according to the invention so stable that no loss of activity occurs due to decomposition.

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BATH ORIGINAL '

U67889

The strength of the saline solution used for stabilization can be between 20% (about 20 g of sodium chloride in so much water that 100 ecm of solution are formed) and a saturated saline solution (about 35 g of sodium chloride in enough water to produce 100 ecm of solution). Vorzugswelse will a saturated or nearly saturated solution is used. The solution is preferably distilled Masser used. Becomes a praise prepared in this way that to achieve a sufficiently strong anticoagulant end Effect necessary heparin added. A minimum of 100 units of anticoagulant activity is recommended used in 100 ecm solution. Commercial heparin is standardized; it has 100 units of anticoagulant iU-activity per milligram of dry material. Therefore a minimum of 1 mg heparin per 100 ecm solution is used. Preferably, however, 3 to 5 mg of heparin in 100 ecm of saturated or nearly saturated Saline solution dissolved to provide a sufficiently strong anti-coagulant Exercise activity in the treatment of varicose veins. However, it is possible too Greater quantities due to saturated or nearly saturated ones To stabilize saline solutions. E.g. up to 10,000 units can be dissolved in 100 ecm saline solution and be stabilized.

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U67889

If the solutions prepared in this way are used for the treatment of varicose veins, 2 to 10 ecm of the the above solution is injected into the vein to be sclerosed «

In contrast to the means previously used in therapy, several veins can be treated at the same time. This was previously not possible because of the toxic side effects of the sclerotating agents.

Example:

100 mg heparin sodium, equivalent to 10,000 U.S, P. units, are dissolved in / 00 ecm of a 20% saline solution. the Solution can be kept for several months.

Example 2:

220 mg heparin sodium, equivalent to 22,000 U.S.P. units, are dissolved in 200 ecm of a 20 follow saline solution. the The solution obtained is diluted with distilled water to a volume of 2200 cc before use. diluted. The so on the salt content a heparin solution adjusted to an isotonic saline solution is well suited for intravenous drip infusion treatment, the rate of infusion being adapted to the rate of blood clotting.

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Claims (1)

H67889 Claim » Process for the production of stable heparin solutions, characterized in that heparin is dissolved in an aqueous, at least 20 "saline solution« 909827/1380