RU2229879C1 - Medicinal agent "asparkam-1" for regulation of metabolic processes and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention relates to a medicinal agent used for regulation of metabolic processes associated with deficiency of potassium and magnesium in body and representing the source of bioavailable potassium and magnesium cations. The proposed agent comprises di-(L-aspartate) magnesium, 7÷50 mg/ml; L-aspartate potassium, 11÷50 mg/ml; sorbitol or xylitol, 20÷50 mg/ml and apyrogenic water, pH 6.2÷7.4. Method for preparing the agent is carried out by dissolving L-aspartic acid, magnesium oxide, potassium hydroxide and sorbitol in water for injection at heating. The prepared solution with pH 6.2÷6.8 is subjected for sterilizing filtration, dosing and sterilizing in autoclave. Invention provides the higher bioavailability of potassium and magnesium cations and their assimilability with reducing loading on excretory system of body. EFFECT: improved preparing method, valuable medicinal properties of agent. 5 cl, 4 tbl, 1 dwg, 6 ex

Description

The invention relates to the field of medicine and the pharmaceutical industry and relates to a medicinal product for the regulation of metabolic processes associated with a deficiency of potassium and magnesium in the body.

Potassium and magnesium are the main intracellular ions. These ions play a significant role in the regulation of body functions. Potassium is involved in the regulation of conduction of impulses along nerve fibers, muscle contraction, the work of the heart muscle, and much more. Magnesium activates about 300 enzymes in the body, including enzyme systems involving ATP. Magnesium is a physiological calcium antagonist and helps to restrain spontaneous contractions of isolated smooth and transverse muscles. Both ions, potassium and magnesium, support the polarization of cell membranes.

The occurrence of a deficiency of these ions is associated with their increased excretion due to kidney and gastrointestinal diseases, the use of diuretics, alcohol abuse, etc., as well as due to a decrease in potassium and magnesium intake with food.

A consequence of a deficiency of potassium and magnesium ions in the body are, first of all, disorders of the cardiovascular system.

To regulate these processes, various potassium and magnesium preparations are used.

The closest in composition and therapeutic effect to the proposed drug are the well-known preparations “Panangin” of the company Gideon Richter, Hungary (Vidal Handbook, Astra Pharm Service, 1997, p.431), “Asparkam” of the company Pharmak, Ukraine (patent UA 14462) in the form solutions for injection. These preparations contain in 1 ml of 0.04 g of magnesium DL-asparaginate, and 0.045 g of potassium DL-asparaginate, sorbitol and pyrogen-free water. And also “Potassium magnesium asparaginate” (Berlin-Chemie, Germany), which is an infusion solution containing magnesium DL-asparaginate, potassium DL-asparaginate, xylitol and pyrogen-free water (Reference Vidal, Astra Farm Service, 1997, p.240) .

The disadvantages of the known drugs are lack of effectiveness and side effects on the renal system, a possible violation of myocardial conduction. These drawbacks are mainly caused by the use of a racemic mixture of aspartic acid enantiomers. It is known that asparaginate is a carrier of potassium and magnesium ions and contributes to their penetration into the intracellular space. Entering the cells, the asparaginate itself is included in the metabolic processes. Endogenous for the body are the L-enantiomers of amino acids, which have systems of transport into the intracellular space, are effectively included in cellular metabolism. D-enantiomers of amino acids are inactive for most of the enzyme systems of the body and are practically not absorbed by it.

Known methods for producing antiarrhythmic drugs based on potassium and magnesium asparaginates include the steps of dissolving D, L-aspartic acid, magnesium oxide, potassium hydroxide, sorbitol, maintaining at a temperature of about 100 ° C, cooling, filtering, packaging and sterilization in hot water (a. S. USSR No. 1635328, 03/27/1995, RF patent No. 2178296 C1, 01/20/2002).

The objective of the invention is to increase the bioavailability of potassium and magnesium ions, as well as increasing the digestibility of the components of the drug, reducing the load on the excretory system of the body and ensuring the stability of solutions.

This problem is solved by the proposed tool “Asparkam-L”, obtained on the basis of L-aspartic acid, in the form of a solution for parenteral administration, which contains magnesium di- (L-asparaginate), potassium L-asparaginate, sorbitol or xylitol and pyrogen-free water at pH 6.2-7.4.

Preferably, the solution contains magnesium di- (L-asparaginate) 7-50 mg / ml, potassium L-asparaginate 11-50 mg / ml, sorbitol or xylitol 20-50 mg / ml.

To obtain the agent, it is preferable to use L-aspartic acid obtained by biotransformation from ammonium fumarate using a biocatalyst containing the aspartate-ammonia lyase enzyme.

The parenteral forms proposed according to the invention provide high assimilation of potassium and magnesium ions and their rapid transport to cells. At the same time, the load on the kidneys and intestines is significantly reduced, which is important because, as already noted, a deficiency of potassium and magnesium can occur in diseases of these organs. These advantages are of particular importance in the case of the infusion route of administration, since the infusion solutions are administered for a long time in high concentrations, that is, their introduction is accompanied by an increased load on the excretory system.

The method of obtaining the agent consists in dissolving L-aspartic acid, magnesium oxide, potassium hydroxide, sorbitol or xylitol in water for injection when heated, the resulting solution with a pH of 6.2-6.8 is cooled, sterilized by filtration, dosing and sterilization in the autoclave. After autoclaving, the final product has a pH of 6.2-7.4. The solution can be administered both as an injection and as an infusion.

It is known that the stability of drugs is influenced by various factors: the physical state of the substance, the method of preparation, including the selection of excipients, temperature, light, packaging.

In the case of injection solutions, stability during sterilization and temperature conditions are of great importance. Currently, two stabilization methods are known - physical and chemical.

In the proposed production method, a sterilizing filtration step is introduced. The resulting solution is pyrogen-free and maintains stability for a long time. The resulting solution has an optimal pH value close to the pH of the blood plasma, which provides better tolerance during administration. In addition, it was found that the pH value affects the completeness of absorption of potassium and magnesium ions.

The possibility of carrying out the invention can be illustrated by the following examples.

Example 1

Anhydrous magnesium L-asparaginate - 40.00 g / l;

Anhydrous potassium L-asparaginate - 45.20 g / l;

Sorbitol - 50.00 g / l or xylitol - 41.7 g / l

Water for injection rest.

Example 2

Anhydrous magnesium L-asparaginate - 7.87 g / l;

Anhydrous potassium L-asparaginate - 11.59 g / l;

Sorbitol - 20.00 g / l or xylitol - 16.7 g / l;

Water for injection rest.

Example 3

Obtaining a solution for injection.

In an apparatus equipped with a stirrer, 90 l of water for injection is placed, heated to a temperature of 70 ° C. Download 0.559 kg of magnesium oxide, mix it for 20 minutes. At T = 70 ° C, 7.400 kg of L-aspartic acid are charged into the apparatus. Stirred for 30 minutes. 1.482 kg of potassium hydroxide are charged. Mix the solution until all components are completely dissolved within 30 minutes. Then cool. When the solution is cooled to 60 ° C, 5,000 kg of sorbitol are loaded into the apparatus. Stir until completely dissolved within 20 minutes. After that, the solution is cooled to 30 ° C. The volume of the resulting solution is adjusted to 100 l, the pH of the solution is 6.2-6.8. Sterilizing filtration is carried out through a filter material with a pore diameter of 0.22 μm. The filtered solution is poured into ampoules and sterilized in an autoclave.

Example 4

Obtaining a solution for infusion

In an apparatus equipped with a stirrer, 90 l of water for injection is placed. Heated to a temperature of 70 ° C. 0.11 kg of magnesium oxide is charged. Stir it for 20 minutes. At T = 70 ° C, 1,500 kg of L-aspartic acid are charged into the apparatus. Stirred for 30 minutes. 0.380 kg of potassium hydroxide is charged. Mix the solution until all components are completely dissolved within 30 minutes. The solution is cooled to 60 ° C and 2,000 kg of sorbitol are loaded into the apparatus. Stir until completely dissolved within 20 minutes. After that, the solution is cooled to 30 ° C. The volume of the resulting solution is adjusted to 100 l, the pH of the solution is 6.2-6.8. Sterilizing filtration is carried out through a filter material with a pore diameter of 0.22 μm. The filtered solution is poured into bottles, sealed with stoppers and sterilized in an autoclave.

Experiments on rats showed that potassium and magnesium salts of L-aspartic acid, in comparison with salts of racemate (DL-aspartic acid), and even more so with salts of D-aspartic acid, have a higher bioavailability of potassium and magnesium ions, as well as the completeness of assimilation of aspartate.

Below are the experimental data confirming the conclusions made.

Example 5

The effect of the injection form of the Asparkam-L preparation (injection preparation obtained according to Example 1) was studied in comparison with similarly prepared preparations containing the D and DL isomers of aspartic acid on the rate of replenishment of the level of potassium and magnesium in red blood cells and myocardium against the background hypomagnesemia and hypokalemia artificially caused by drug (digitalis and furosemide) intoxication.

Tables 1 and 2 show the effects of Asparkam-L, Asparkama-D and Asparkama-DL on the change in the magnesium content of rat erythrocytes against hypomagnesemia and hypokalemia artificially induced by two weeks of digoxin and furosemide administered to rats, respectively.

Tables 3 and 4 show the effects of Asparkama-L, Aspar-kama-D and Asparkama-DL on the rate of potassium replenishment, respectively, in rat erythrocytes and myocardium on the background of hypomagnesemia and hypokalemia, artificially caused by two weeks of digoxin administered intraperitoneally to rats.

Example 6

In another series of experiments, the dynamics of the excretion of amine nitrogen with urine was studied against a background of a single intravenous administration of Asparkam-L, Asparkam-D and Asparkama-DL. The drawing shows data from a series of experiments. The obtained dependence indicates a higher level of elimination of amine nitrogen in the urine with the administration of Asparkam-D and Asparkam-DL (which is associated with the elimination of D-asparaginate) than in the case of administration of Asparkam-L and, therefore, higher absorption of L-asparaginate.

Thus, we have obtained a new, more effective composition of the antiarrhythmic and metabolic normalizing agent, which can be recommended for widespread introduction into practice.

Claims (5)

1. A drug for parenteral administration that regulates metabolic processes associated with a deficiency of potassium and magnesium in the body, characterized in that it contains magnesium di- (L-asparaginate), potassium L-asparaginate, sorbitol or xylitol and pyrogen-free water, pH 6 , 2-7.4. 2. The tool according to claim 1, characterized in that it contains magnesium di- (L-asparaginate) 7 ÷ 50 mg / ml, potassium L-asparaginate 11-50 mg / ml, sorbitol or xylitol 20 ÷ 50 mg / ml and pyrogen-free water. 3. The tool according to claim 1 or 2, characterized in that it is a solution for injection. 4. The tool according to claim 1 or 2, characterized in that it is a solution for infusion. 5. A method for producing a drug for parenteral administration that regulates metabolic processes associated with a deficiency of potassium and magnesium in the body, characterized in that L-aspartic acid, magnesium oxide, potassium hydroxide, sorbitol or xylitol obtained in solution for dissolving in water for heating a solution with a pH of 6.2-6.8 is cooled, subjected to sterilizing filtration, dosage and sterilization in an autoclave.

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