UA145370U - CRYSTALOID INFUSION SOLUTION - Google Patents

Abstract

The crystalloid infusion solution containing polyhydric alcohol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate and water for injections, according to the utility model, further comprises sodium acetate and L-malate, in the following ratio, in terms of dry matter, in wt. %: polyhydric alcohol 4-7 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0.234-0.286 L-malate 0.120- 0.145 water for injections the rest.

Description

A useful model belongs to the field of medicine, namely to crystalloid hyperosmolar parenteral drugs in such a dosage form as infusion solutions.

Technical level

Infusion solutions are a type of medicine administered to the human body by intravenous infusion using infusion systems. The main indications for prescribing infusion therapy are: - insufficient blood volume. - violation of the rheological properties of blood. - violation of the water-salt and acid-base balance of the blood. - severe dehydration. - intoxication, etc.

According to their therapeutic effect, infusion solutions are conditionally divided into several groups.

The first group includes infusion solutions with a hemodynamic effect. Hemodynamic infusion solutions (other names found in the literature are anti-shock, volemic) perform the role of plasma substitutes and restore volume, hemodynamics and blood circulation in case of blood loss and shock. As an active pharmaceutical ingredient (API) in hemodynamic infusion solutions, water-soluble polymers such as gelatin and hydroxyethyl starch (HEC) are used, and the therapeutic effect of the infusion solution (duration of its circulation in the bloodstream and hemodynamic effect) directly depends on the characteristics of the polymer. In modern medical practice, medium- and low-molecular polymers are most often used, which are characterized by less pronounced side effects.

However, hemodynamic infusion solutions have disadvantages: they have a narrow therapeutic effect, so they are mainly used only to correct the volemic status of patients.

Additionally, the disadvantage of HEK-based hemodynamic infusion solutions is, among other adverse reactions, a pronounced negative effect on kidney function. For example, when using an infusion solution of STABIZOL (see the web page with the address porz//sotrepaitst.sot.tsa/des/271727/), which contains HEK with an average molecular weight of 450,000 Da and a degree of molar substitution of 0.7, and sodium chloride , very often there are cases of pain in the area of the kidneys, which leads to the termination of therapy and

Due to the impossibility of further use of the medicinal product.

Also, the disadvantage of hemodynamic infusion solutions based on gelatin is allergic reactions of varying degrees of severity, even before the development of anaphylactic shock. A well-known representative of the class is the infusion solution GELOFUSIN (see the web page with the address per /LiKisopitoY.sot.pa/zh601959696ro6vryahortyavv1950194068295019580950195839560095ВА95019586

For 1969690019068/2(26777|Y), which contains medium-molecular succinylated gelatin (average molecular weight 30,000 Daltons) and sodium chloride as an API. In the instructions for the drug HELOFUSIN, it is noted that severe anaphylactoid reactions (I or II degree) are very rare (frequency "1:10,000"). However, the risk of such severe adverse reactions cannot be excluded, therefore, patients receiving GELOFUZIN require constant supervision by a doctor for the occurrence of allergic reactions.

The second group includes infusion solutions for regulating the water-salt and acid-base balance of the blood. They are used to replenish blood loss in order to stabilize the volume of circulating plasma, improve the rheological properties of blood, normalize the ionic composition and pH of the blood, rehydrate and detoxify the body. In fact, the infusion solutions of this group are saline solutions and do not contain polymer components.

The following representatives of the second group of infusion solutions are known. Інфузійний розчин АЦЕСОЛЬ (див. веб-сторінку з адресою НЕр/ЛікісопігоІ.сот.ца/956019596950095809501958195019582 орі яовОо6рт1968395роО9вАЗЬОТ9086950195969501958Е/7І114778|Ї) на 100 мл розчину містить натрію ацетату тригідрату 200 мг, натрію хлориду 500 мг, калію хлориду 100 мг. The disadvantage of the drug is the high content of potassium salts, which can lead to the development of hyperkalemia. When carrying out massive infusions with the drug ACESOL, the patient may experience metabolic disorders, which leads to the need for the introduction of additional sodium drugs to correct the electrolyte balance of the patient's blood.

Another well-known infusion solution of the second group is LACTASOL (see the web page with the address pIrv:/Lymly.riishii.Knagkom.tspa/agidv/dgyd/1544/)u. LACTASOL contains sodium chloride 0.62 95 wt., potassium chloride 0.03 95 wt., calcium chloride 0.016 95 wt., magnesium chloride 0.01 95 wt., sodium lactate 0.336 95 wt., sodium bicarbonate - 0.03 95 mass Ionic composition of the medicinal product: Ma: - 140.0 mmol/l, K: - 4.0 mmol/l, Ca-- - 1.5 mmol/l, Mod" - 1.0 mmol/l, SI - 116 mmol /l, HCO3 - 4.0 mmol/l, CH3CH(OH)COO:- - 30.0 mmol/l, osmolarity - 294 mosm/l, because the drawback of the medicinal product is its instability after sterilization, due to the presence of sodium bicarbonate in the composition In addition, the amount of sodium lactate in the medicinal product is insignificant, and therefore, when using the medicinal product LACTASOL to correct the acid-base balance, it is necessary to transfuse significant volumes of the medicinal product, which leads to overloading of the vascular bed of the body.

The infusion solution STEROFUNDIN IZO is also known (see the web page with the address pEr//togdosv.Kiem.tsaliKimiem.ryr?id-24436), which contains a combination of the alkalizing component sodium acetate and I-malic acid, and contains sodium ion - 145 ,0 mmol/l, potassium ion - 4.0 mmol/l, calcium ion - 2.5 mmol/l, magnesium ion - 1.0 mmol/l, chloride ion - 127.0 mmol/l, acetate ion - 24.0 mmol/l and malate ion - 5.0 mmol/l. The STEROFUNDIN I5ZO infusion solution, as well as the infusion solutions of the second group listed above, are saline iso-osmolar solutions, and therefore have a very limited pharmacological effect.

Such a saline infusion solution is known as HARTMANN'S SOLUTION (see the web page with the address por /LiKisopygoY sot ma/ert1959655р095вровОт19581950195829501 96809501 968395009о

VAFRIT086900195969501908E/7 (242141), containing sodium chloride, potassium chloride, sodium lactate, calcium chloride dihydrate, magnesium chloride hexahydrate. 100 ml of medicinal solution contain: sodium chloride - 0.6 g; potassium chloride - 0.04 g; sodium lactate - 0.303 g; calcium chloride dihydrate - 0.02013 g; magnesium chloride hexahydrate - 0.02 g. A drawback of the medicinal product

HARTMAN'S SOLUTION is a low indicator of its osmolarity. The drug is a hypotonic solution, which significantly limits its use, because the use of this drug in large doses can lead to intracellular swelling of internal organs and, mainly, to cerebral edema and an increase in intracranial pressure in the patient. In case of severe oxygen deficiency, Hartmann's solution can worsen the developing lactic acidosis.

Another well-known saline infusion solution is DARROW'S SOLUTION (see the web page with the address NPEr://to2dosv.Kiem.tsalikimiemryr?ia-1526). 100 ml of the medicinal solution contain sodium chloride - 0.4 g; potassium chloride - 0.267 g; sodium lactate - 0.594 g. DARROW'S SOLUTION has a limited range of applications, and the drawback of the drug is the increased potassium content, which leads to a high risk of developing hyperkalemia in the patient and the need for strict control of the level of potassium in the patient's blood serum. DARROW'S SOLUTION is an unbalanced solution, as it contains only sodium and potassium ions as cations, thus the composition of the drug is significantly different from the composition of blood plasma, which can lead to acid-base and water-electrolyte disturbances during the use of this unbalanced infusion solution.

The third group of infusion solutions includes infusion solutions of combined action, which can be used as hemodynamic, detoxification solutions, and solutions for regulating the water-salt and acid-base balance of the blood. Currently, infusion solutions of combined action are the most promising, as they can be used for the therapy of a wide range of diseases and pathological conditions.

Thus, the known crystalloid infusion solution of the combined action REOSORBILACTF (see the web page with the address pIrz//sotrepait.sot.tsa/аес/267128/), which contains the polyatomic alcohol sorbitol in the amount of b 95 wt., sodium lactate - 1.9 95 wt., sodium chloride - 0.6 90 wt., potassium chloride - 0.03 Fo wt., calcium chloride - 0.01 95 wt., magnesium chloride - 0.02 95 wt. Ionic composition of the medicinal product: Ma: - 278.2 mmol/l, K: - 4.0 mmol/l, Ca": - 0.9 mmol/l, Mod": - 2.1 mmol/l,

SI - 112.7 mmol/l, SNNCH(OH)COOS. - 175.5 mmol/l. The osmolarity of the medicinal product is 891 mOsm/l. REOSORBILACTO has plasma-replacing and detoxifying properties, and is indicated for use in the following cases: - for the treatment of microcirculation disorders in shock; - with various disorders of peripheral blood circulation; - to correct the water-salt balance; - comprehensive treatment of intestinal obstruction; - with infectious diseases accompanied by severe intoxication, repeated vomiting and diarrhea; - in surgical practice for disorders causing systemic inflammatory response syndrome (sepsis); - for the treatment of diseases of the biliary tract, such as dyskinesia of the gallbladder, postcholecystectomy syndrome; - use as part of complex conservative therapy for acute pancreatitis; - in neurological practice, in particular for the treatment of cerebral ischemia and diabetic neuropathy. because microcirculation is a collective term that refers to blood flow and lymph flow in microvessels,

as well as a set of metabolic processes occurring through the walls of microvessels and extravascular transport of liquids and substances. The main function of microcirculation is exchange, the continuous movement of blood ensures the removal of waste products and the supply of nutrients to body tissues. Another important function of the microcirculation is to maintain pressure by ensuring the balance of fluid entering or leaving tissues and vessels.

The microcirculatory blood vessel consists of vessels whose diameter does not exceed 100 μm (arterioles, venules, capillaries, etc.).

Microcirculation disorders are divided into the following types: - extravascular disorders: changes in the perivascular transport of interstitial fluid, degranulation of tissue basophils and the release of biologically active substances and enzymes into the tissue surrounding the vessels; - intravascular disorders: changes in blood viscosity and coagulation, erythrocyte sludge, changes in the speed of blood movement; - violation of the walls of microvessels: changes in the permeability of blood vessels, diapedesis of blood cells.

Violation of microcirculation is a consequence of many painful conditions, and is a dangerous symptom, as it leads to disruption of metabolism and normal vital activity of tissues and organs. One of the main causes of microcirculation disorders is inflammatory processes, hyperproteinemia, anhydremia, hypoxia, acidosis, intoxication, hypovolemia, hypervolemia, and shock states. A number of these diseases require immediate therapy, as they pose a threat to the patient's life (eg, shock).

Shock is an acute pathological process that occurs due to insufficient blood supply to organs and tissues, and can lead to death. Violations of blood circulation in the body and shock can develop for the following reasons: 1) a decrease in the total volume of blood in the body (for example, as a result of blood loss); 2) sharp expansion of blood vessels and increase in their volume (due to allergic reactions, pain); 3) heart failure (myocardial infarction); 4) inflammatory processes (sepsis).

In the United States, about 1.2 million people go to the emergency department every year

From a state of shock, and the risk of death of patients is very high, and is from 20 to 50 95.

Peripheral circulation is the movement of blood within one organ.

Among the main disorders of peripheral blood circulation, the following are distinguished: 1) ischemia - a decrease in blood flow in an organ or tissue due to a decrease in blood supply by an artery; 2) arterial hyperemia - an increase in blood flow in an organ or tissue due to the expansion of the lumen of the artery and an increase in blood flow from it; 3) venous hyperemia - increased filling of an organ or tissue with blood as a result of weakened blood flow through the veins. 4) thrombosis - a violation of blood properties with the formation of a clot in the vessel lumen; 5) embolism - closure of the lumen of a vessel due to movement of extraneous substrates (emboli) in the vascular bed; b) bleeding - an outpouring of blood from the vessels due to a violation of the integrity or increased permeability of the vessel wall.

A serious consequence of a peripheral blood circulation disorder is a heart attack - necrosis of an organ or its part, which develops due to a blood circulation disorder in it.

Intoxication is the process of organ damage due to the harmful effects of poisons and toxins.

Intoxication can occur for various reasons: the entry of harmful substances into the body from the outside, or their formation inside the body. Intoxication can also be caused by diseases, for example, infectious diseases, when the poisoning of the body is caused by the products of the vital activity of the causative agents of the disease. One of the mechanisms of combating the consequences of intoxication is detoxification by introducing infusion solutions into the bloodstream (acceleration of the removal of harmful substances from the body by the body's water load).

Sepsis is a violation of the functioning of organs due to the development of a systemic inflammatory response syndrome. Sepsis occurs in the body as a result of infectious diseases caused by various pathogens. Effective methods of treatment of septic conditions include combined therapy, in particular, infusion drugs for detoxification, hemodynamic correction, parenteral nutrition, transfusion of blood products, etc.

Thus, the combined effect of the well-known REOSORBILACTF infusion solution contributes to its multipurpose use in clinical practice. However, the drug REOSORBILACTF is not universal. Thus, general somatic contraindications for the use of the medicinal product REOSORBILACTF include alkalosis of any origin (respiratory, metabolic, etc.),

DVZ-syndrome, hemorrhages in the brain, gastrointestinal bleeding with unstable hemostasis, acute thrombophlebitis (due to the risk of thromboembolic complications). It is not recommended to use REOSORBILACT! for first aid for injuries until the final stop of bleeding (due to the ability to reduce blood viscosity, the drug may interfere with blood clot formation). Also, contraindications include severe forms of heart failure, acute renal failure (in the absence of hemodialysis).

Among the disadvantages of the well-known medicinal product are the following: - one of the components of the medicinal product REOSORBILACTF - sodium lactate is contained in a sufficiently large amount, which can cause an overload of the body with lactate and a load on the liver when a large amount of lactate is metabolized; - insufficiently fast onset of action of a known medicinal product; - the possibility of developing side effects when using a known medicinal product for the treatment of patients with fructose intolerance; - insufficient effectiveness of its action in the treatment of disorders of microcirculation and peripheral blood circulation.

The useful model is based on the task of creating an infusion solution that is effective and safe for the treatment of disorders of microcirculation, peripheral blood circulation, restoration of water-salt balance, rheological properties of blood, capillary tone, in various population groups, in particular, in patients with diabetes and fructose intolerance, it is characterized by a faster onset of alkalinizing action, a reduced risk of overdosing the patient's body with lactate ion, and can be used to implement a strategy of restrictive type infusion therapy.

The essence of the technical solution

The problem is solved by introducing two additional reserve alkalinity carriers into the composition of the infusion solution, which makes it possible to reduce the content of sodium lactate in the final composition of the infusion solution while maintaining the necessary osmolarity of the solution and achieve additional advantages that expand the spectrum of its action. As additional carriers of reserve alkalinity, it is proposed to use a mixture of sodium acetate and I-malate in the amount that was calculated for the purpose

To preserve the optimal value of the indicator of total osmolality of the hyperosmolar infusion solution. At the same time, an increase in the amount of lactate in the infusion solution was achieved by 4 times, compared to the existing analogues, and a decrease in the total amount of lactate compared to the nearest analogue, which allows solving the problem of using the infusion solution in situations where the patient is at risk of an overdose of lactate ion.

The task is also solved thanks to the balanced content of three reserve alkalinity carriers in the stated infusion solution. Since lactate ions are metabolized in the body in the liver, and acetate and malate ions are metabolized in the muscles, reducing the total amount of lactate ions in the infusion solution allows you to reduce the burden on the liver when using the stated infusion solution. In addition, the use of the components of the infusion solution containing acetate and malate anions as carriers of reserve alkalinity allows to minimize the consumption of oxygen in the tissues necessary for the formation of bicarbonate ions, which is very important for patients in a state of shock, in which respiratory failure is manifested.

In addition, additional tasks are also solved, such as: effective correction of metabolic acidosis and strengthening of the antihypoxant and detoxification effects of the infusion solution due to the successful use and scientifically selected and calculated amounts of malate and acetate ions introduced into the infusion solution, faster onset of action and manifestation of alkalizing effect due to the use of sodium acetate as one of the backup alkalinity carriers.

The problem is solved by creating a crystalloid infusion solution that contains polyhydric alcohol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate and water for injections, and additionally contains sodium acetate and I-malate, with the following ratio of components, in conversion to dry substance, wt. 90: polyhydric alcohol 4-7 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0234-0286

Y - malate 0.120-0.145 water for injections the rest.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution as a polyatomic alcohol contains sorbitol, xylitol or their mixture.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution contains calcium chloride, magnesium chloride, sodium lactate, sodium acetate in the form of anhydrous salts or crystal hydrates.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution contains I-malate in the form of I-malic acid or sodium salt of I-malic acid.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution contains sorbitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, I-malate and water for injections, with the following ratio of components, in terms of dry substance, mass 90: sorbitol 5-7 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0234-0286

Y - malate 0.120-0.145 water for injections the rest.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution contains xylitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, I-malate and water for injections, with the following ratio of components, in terms of dry substance, mass 90: xylitol 4-6 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0234-0286

Y - malate 0.120-0.145 water for injections the rest.

According to one of the variants of the implementation of the technical solution, the crystalloid infusion solution has an osmolality value in the range of 880-920 mOsm/l.

The main active pharmaceutical ingredients of the declared infusion solution are polyhydric alcohol - hexahydric alcohol sorbitol or pentahydric alcohol xylitol, reserve alkalinity carriers sodium lactate, sodium acetate (alkalizing components), I-malate and electrolytes.

Carriers of reserve alkalinity are substances that, as a result of metabolism in the human body, form bicarbonate ions, thus replenishing the buffer capacity of the blood.

Due to the fact that the known infusion solution REOSORBILACTO contains a sufficiently large amount of such a reserve alkali carrier as sodium lactate (19 mg/ml), it cannot be used for the treatment of patients with an increased level of lactate in the blood or diseases that cause lactic acidosis (hypoxic conditions, oncological, cardiovascular diseases, diabetes, etc.). Thus, the possibility of possible side effects when using a known infusion solution somewhat narrows its possibilities

For use in clinical practice.

To overcome the known disadvantages of the analogue, instead of introducing a large amount of sodium lactate into the composition of the infusion solution, it was proposed to change this alkalizing component to a combination of 3 reserve alkalinity carriers: sodium lactate, sodium acetate and I-malate. This allows you to avoid the negative consequences of an overdose of the patient's body with lactate ion during infusion therapy using an analogue, and makes the declared crystalloid infusion solution safer and more versatile in use, compared to the analogue.

At the same time, the qualitative and quantitative composition of the infusion solution according to the technical solution is developed in such a way that the total osmolality of the solution is kept at an effective level close to 900 mOsmol/l : 2 95.

The infusion solution, according to the technical solution, contains the reserve alkalinity carrier sodium lactate in a concentration of 1.5 95 (133 mmol/l), which is 4 times higher than its content in the most common iso-osmolar solutions (for example, in the medicinal product RINGER LACTATE SOLUTION - pEr//togdosv .Kiem.tsaliKimiem.ryr"ida-13629), but less than in the medicinal product

REOSORBILACTF (169.6 mmol/l). Sodium lactate contributes to the correction of the acid-alkaline balance of the blood plasma, and also participates in the reactions of carbohydrate-energy metabolism, restores and stimulates the functions of the cells of the reticuloendothelial system, liver and kidneys. In contrast to infusion solutions containing sodium bicarbonate, sodium lactate reserve alkalinity carrier has a neutral reaction. Sodium lactate belongs to carriers of reserve alkalinity of slow action.

When sodium lactate is introduced into the vascular bed, sodium, CO" and H2HO are released, which form sodium bicarbonate, which leads to an increase in the alkaline reserve of the blood. Correction of metabolic acidosis with the help of sodium lactate occurs slowly (as sodium lactate is incorporated into metabolism), and does not cause sharp fluctuations in blood pH. The effect of sodium lactate is manifested 20-30 minutes after the introduction of the solution for infusion according to the technical solution.

The reserve alkalinity carrier sodium acetate well corrects metabolic acidosis, and within 1.5-2 hours it is completely metabolized into an equivalent amount of sodium bicarbonate. Sodium acetate does not cause intracellular interstitial edema of the brain and increased aggregation of platelets and erythrocytes. It is important that sodium acetate has a high alkalizing effect with minimal O consumption. Sodium acetate is metabolized mainly in muscle tissues under the action of acetyl-coenzyme A-synthetase, and at the final stage is transformed into carbon dioxide and water. The alkalizing effect of acetate manifests itself very quickly: the concentration of HCO3 ions increases 15 minutes after the start of the infusion of acetate ions; 90 95 of the known amount of acetate ions is oxidized within a few minutes; from 60 95 to 80 95 acetate ions are excreted in the form of COg through the lungs in the interval from 1 to 12 hours. after the start of the introduction.

Acetate ion metabolism does not change in patients with diabetes, while there are no changes in glucose and insulin concentrations. Acetate is an energy source that supplies 209 kcal/mol. It also plays an important role in carbohydrate and lipid metabolism (acetate replaces fats as an oxidative fuel without affecting glucose oxidation).

The inclusion of malate ions in the composition of the stated infusion solution makes it possible to strengthen the antihypoxant and detoxification effects due to the fact that malate is an energy substrate of the Krebs cycle, participates in the ornithine cycle of urea synthesis and binding

From ammonia in the muscles. The alkalizing effect of malate is much slower than that of acetate, which may be useful for obtaining a long-term effect of the infusion solution. The use of acetate and malate anions as carriers of reserve alkalinity allows to minimize the consumption of oxygen in tissues, necessary for the formation of bicarbonate ions.

Sorbitol is a hexaatomic alcohol, has the appearance of a white crystalline powder with a sweet taste. Sorbitol is an energy source with insulin-independent metabolism - it is metabolized to fructose - which does not lead to an increase in the concentration of glucose in the blood.

The presence of sorbitol in the blood contributes to the normalization of carbohydrate and energy metabolism, stimulates the oxidation of fatty acids through the non-ketogenic pathway of metabolism and facilitates the easier use of ketone bodies in the Krebs cycle, which has a favorable effect on the improvement of the functional state of hepatocytes, in which the glycogen depot is renewed. Sorbitol enhances intestinal motility due to a direct effect on the nerve-receptor apparatus of the intestinal wall and increased synthesis and secretion of villikinin, cholecystokinin and B vitamins. The maximum utilization rate of sorbitol is 0.25 g/kg of body weight/hour. The composition of the infusion solution includes sorbitol in an isotonic 6.95% concentration.

According to one of the variants of implementation, the infusion solution according to the technical solution, instead of sorbitol, contains pentaatomic alcohol xylitol, which has a pronounced antiketogenic effect and is disposed of in an insulin-independent way, which makes possible the safe use of the infusion solution according to the technical solution in people with diabetes and fructose intolerance. In addition, such a component as sorbitol is known for its effect on the body's digestive system (laxative effect, increased gas formation, etc.). In cases where the patient has gastrointestinal disorders, it is more appropriate to use an infusion solution based on a technical solution based on xylitol in order to avoid possible side effects.

Xylitol is a pentaatomic alcohol, it has the appearance of colorless crystals with a sweet taste. It belongs to the intermediate products of carbohydrate metabolism in humans and animals. The end product of xylitol oxidation is carbon dioxide, which is released mainly with exhaled air. When administered intravenously, xylitol is quickly included in the general metabolism, 80 95 of the substance is absorbed in the liver and accumulates in the form of glycogen. Xylitol has low toxicity and good tolerance, does not cause a decrease in nucleotides (ATP, ADP, AMP) in the liver, and is also safe for administration to patients who cannot tolerate fructose. Since xylitol is a good energy source with insulin-independent metabolism,

it acts antiketogenic and lipotropic. Therefore, it is recommended to use infusion solutions containing xylitol as a means for parenteral nutrition of patients, especially those who have undergone operations on the gastrointestinal tract. The maximum utilization rate of xylitol is 0.25 g/kg of body weight/hour. Xylitol is included in the composition of the infusion solution in an isotonic 5-9% concentration.

The presence in the composition of the infusion solution according to the technical solution of a balanced mixture of the main blood ions (Ma, K", Bae, Ma", SI) in the appropriate concentrations makes the infusion solution more physiological. Sodium chloride has a rehydrating effect, replenishes the deficit of sodium and chlorine ions in various pathological conditions. Calcium is necessary for the process of transmission of nerve impulses, contraction of skeletal and smooth muscles, activity of the myocardium, formation of bone tissue, blood clotting. It reduces the permeability of cells and vascular walls, prevents the development of inflammatory reactions, and increases the body's resistance to infections. Magnesium is necessary for many biochemical reactions, assimilation of glucose, protein synthesis, transmission of nerve signals, building of bone tissue, etc. Potassium restores the water-electrolyte balance, has a negative chrono- and bathmotropic effect, in high doses - a negative ino-, dromotropic and moderate diuretic effect. Participates in the process of conducting nerve impulses.

Increases the content of acetylcholine and causes excitement of the sympathetic division of the autonomic nervous system.

Within the limits of the selected components and their quantitative ratio, the technical solution belongs to the group of multi-component polyfunctional crystalloid hyperosmolar solutions.

The pharmacological effect of the technical solution is due to the mutual potentiation of the action of its components, as well as additional properties of the infusion solution, caused by hyperosmolality, which is three times higher than the osmolarity of blood plasma. After intravenous injection of a solution made on the basis of sorbitol, as well as a solution based on xylitol, the evacuation of liquid from the tissues into the vascular bed increases, impaired hemodynamics is restored, microcirculation and blood rheological properties improve, blood viscosity decreases, platelet aggregation decreases, cardiac activity, metabolic processes increase, the detoxification function of the liver improves. This makes it possible to position the infusion solution according to the technical solution as a means of hemodynamic, rheological, detoxification, antiketogenic, antishock, energetic and alkalizing action.

The effective rheological and anti-shock action of the declared infusion solution allows to carry out infusion therapy of the patient using reduced amounts of the infusion solution, that is, the declared infusion solution can be used for infusion therapy of the restrictive type.

Therefore, the declared crystalloid infusion solution fully manifests its pharmacological properties within the limits of the selected components and their quantitative ratio.

List of drawing figures

The essence of a useful model is explained by drawings, where

Fig. 1 - Image of the graph of the wavelet analysis of patient 1 before the infusion with the infusion solution according to the technical solution.

Fig. 2 - Image of the graph of the wavelet analysis of patient 1 5 minutes after the infusion of the infusion solution according to the technical solution.

Fig. 3 - Image of the graph of the wavelet analysis of patient 1 30 minutes after the infusion of the infusion solution according to the technical solution.

Fig. 4 - Image of the graph of the wavelet analysis of patient 1 before the infusion of the comparator drug.

Fig. 5 - Image of the wavelet analysis plot of patient 1 5 minutes after the infusion of the comparator drug.

Fig. 6 - Image of the graph of wavelet analysis of patient 1 30 minutes after the infusion of the comparator drug.

Fig. 7 - Image of the graph of the wavelet analysis of patient 2 before the infusion with the infusion solution according to the technical solution.

Fig. 8 - Image of the graph of the wavelet analysis of patient 2 5 minutes after the infusion of the infusion solution according to the technical solution.

Fig. 9 - Image of the wavelet analysis graph of patient 2 30 minutes after the infusion of the infusion solution according to the technical solution.

Fig. 10 - Image of the graph of the wavelet analysis of patient 2 before the infusion of the comparison drug.

Fig. 11 - Image of the wavelet analysis graph of patient 2 5 minutes after the infusion of the comparator drug.

Fig. 12 - Image of the graph of the wavelet analysis of patient 2 30 minutes after the infusion of the comparator drug.

Information that confirms the possibility of implementing a technical solution

The technological scheme for the production of the infusion solution according to the technical solution includes the following stages: weighing the ingredients of appropriate quality, preparing the solution, bringing the solution to the required volume with water for injections, filtering, control of physicochemical indicators, bottling, sterilization, repeated control of physical - chemical indicators, labeling, packaging.

The technical solution is illustrated by the following examples.

Example 1.

The declared crystalloid infusion solution based on sorbitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 60 g of sorbitol, 6 g of sodium chloride, 0.3 g of potassium chloride, 0.13 g of calcium chloride dihydrate, 0.43 g of magnesium chloride hexahydrate, 4.31 g of sodium acetate trihydrate, 1.34 g of I-butric acid. After that, 15 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The resulting infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control.

The resulting solution is filtered under the pressure of a column of liquid to obtain a filtrate. Filters with a pore diameter of 1.2 μm (coarse cleaning) and 0.22 μm (fine cleaning) are used for filtering. The first portions of the filtrate are subject to repeated filtration.

The filtered solution is checked for the absence of mechanical inclusions, poured into 100, 200 or 400 ml glass bottles for blood, transfusion and infusion drugs made of MTO or NS glass, closed with corks made of a rubber mixture and crimped with aluminum caps or aluminum-plastic type caps. Bottles with the solution are sterilized in a steam sterilizer with steam under a pressure of 1.1 bar at a temperature of 121 "C for 30 minutes.

The sterile solution is labeled and packaged after checking for mechanical inclusions.

The quality control of the infusion solution is carried out in accordance with the requirements of the analytical-normative document for all qualitative and quantitative indicators.

The resulting solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the solution met the requirements of the analytical-normative document, that is, the choice of components and the solution manufacturing technology fully correspond to the task set in the technical solution.

Example 2.

The declared crystalloid infusion solution based on sorbitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 60 g of sorbitol, 6 g of sodium chloride, 0.3 g of potassium chloride, 0.13 g of calcium chloride dihydrate, 0.43 g of magnesium chloride hexahydrate, 4.31 g of sodium acetate trihydrate, 1.56 g of sodium I-malate. After that, 15 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 3.

The declared crystalloid infusion solution based on sorbitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 50 g of sorbitol, 5.4 g of sodium chloride, 0.27 g of potassium chloride, 0.11 g of calcium chloride dihydrate, 0.36 g of magnesium chloride hexahydrate, 3 .88 g of sodium acetate trihydrate, 1.22 g of I-malic acid. After that, 13.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution. because the finished infusion solution then goes through the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 4.

The declared crystalloid infusion solution based on sorbitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 50 g of sorbitol, 5.4 g of sodium chloride, 0.27 g of potassium chloride, 0.11 g of calcium chloride dihydrate, 0.36 g of magnesium chloride hexahydrate, 3 .88 g of sodium acetate trihydrate, 1.42 g of sodium I-malate. After that, 13.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 5.

The declared crystalloid infusion solution based on sorbitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 70 g of sorbitol, 7 g of sodium chloride, 0.33 g of potassium chloride, 0.16 g of calcium chloride dihydrate, 0.49 g of magnesium chloride hexahydrate, 4.74 g of sodium acetate trihydrate, 1.47 g of I-malic acid. After that, 16.5 g are added to the solution

From sodium lactate, bring the volume to the nominal (1 l) with water for injections and mix to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting solution for infusions is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 6.

The declared crystalloid infusion solution based on sorbitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 70 g of sorbitol, 7 g of sodium chloride, 0.33 g of potassium chloride, 0.16 g of calcium chloride dihydrate, 0.49 g of magnesium chloride hexahydrate, 4.74 g of sodium acetate trihydrate, 1.71 g of sodium I-malate. After that, 16.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting solution for infusions is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 7.

The declared crystalloid infusion solution based on xylitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 50 g of xylitol, 6 g of sodium chloride, 60 0.3 g of potassium chloride, 0.13 g of calcium chloride dihydrate, 0.43 g of magnesium chloride hexahydrate, 4, 31 g of sodium acetate trihydrate, 1.34 g of I-malic acid. After that, 15 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 8.

The declared crystalloid infusion solution based on xylitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 50 g of xylitol, 6 g of sodium chloride, 0.3 g of potassium chloride, 0.13 g of calcium chloride dihydrate, 0.43 g of magnesium chloride hexahydrate, 4.31 g of sodium acetate trihydrate, 1.56 g of sodium I-malate. After that, 15 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 9.

The declared crystalloid infusion solution based on xylitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 40 g of xylitol, 5.4 g of sodium chloride, 0.27 g of potassium chloride, 0.11 g of calcium chloride dihydrate, 0.36 g of magnesium chloride hexahydrate 3, 88 g of sodium acetate trihydrate, 1.22 g of I-malic acid. After that, 13.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 10.

The declared crystalloid infusion solution based on xylitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 40 g of xylitol, 5.4 g of sodium chloride, 0.27 g of potassium chloride, 0.11 g of calcium chloride dihydrate, 0.36 g of magnesium chloride hexahydrate 3, 88 g of sodium acetate trihydrate, 1.42 g of sodium I-malate. After that, 13.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The finished infusion solution solution then passes through the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 11. The stated crystalloid infusion solution based on xylitol and I-malic acid is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 60 g of xylitol, 7 g of sodium chloride, 0.33 g of potassium chloride, 0.16 g of calcium chloride dihydrate, 0.49 g of magnesium chloride hexahydrate, 4.74 g of sodium acetate trihydrate, 1.47 g of I-malic acid. After that, 16.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The resulting infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and normative document, that is, the choice of components and the technology of manufacturing the infusion solution fully correspond to the task set in the technical decision.

Example 12.

The declared crystalloid infusion solution based on xylitol and sodium I-malate is prepared as follows.

Preparation of the infusion solution is carried out in an isolated, boxed room. 2/3 of water for injections is placed in a measuring cup-mixer, dissolve 60 g of xylitol, 7 g of sodium chloride, 0.33 g of potassium chloride, 0.16 g of calcium chloride dihydrate, 0.49 g of magnesium chloride hexahydrate, 4.74 g of sodium acetate trihydrate, 1.71 g of sodium I-malate. After that, 16.5 g of sodium lactate is added to the solution, the volume is brought up to the nominal volume (1 l) with water for injections and mixed to obtain a ready infusion solution.

The resulting infusion solution then undergoes the stages of filtration, packaging, sterilization and quality control according to Example 1.

The resulting infusion solution is a colorless, transparent, odorless liquid. The stability of the solution was tested under sterilization conditions, as well as during storage. It was established that the physico-chemical properties of the infusion solution met the requirements of the analytical and regulatory document, that is, the choice of components and the technology of manufacturing the infusion solution fully

They meet the task set in the technical decision.

The given examples of the implementation of a technical solution are not intended to narrow the scope of the declared technical solution and are given only for the purpose of explaining the possibilities of its implementation. For a specialist in this field, it is quite obvious that the claimed complex hyperosmolar infusion solution can also be embodied in other variants.

Example 13.

Research of the declared technical solution for specific activity was carried out on the model of toxic hepatitis in rabbits, caused by subcutaneous injections of carbon tetrachloride for 7 days. The infusion solution prepared according to the technical solution according to example 8 was administered at a dose of 10 ml/kg of body weight for 14 days, starting from the first day of the experiment. The results showed that in the first seven days of the experiment, a statistically significant (0.05) increase in AlAt (from 0.43-0.04 to 1.3940.03 mmol/lh), AsAT (from 0.30-0.02 to 1.0940.02 mmol/lh) and bilirubin (from 11.684-0.95 to 21.60-1.55 μmol/l). At the end of the experiment, on the 14th day, the activity of the indicated indicators decreased statistically significantly, but did not reach the initial level (AlAt to 0.7140.02 mmol/lh, AST to 0.4840.02 mmol/lh, bilirubin to 16 ,15--1.30 to 21.604-1.55 μmol/l). Thus, in an experiment on a model of toxic hepatitis in rabbits, it was shown that the proposed infusion solution at a dose of 10 ml/kg of body weight exhibits significant detoxification properties.

Example 14.

The results of an experimental study of the chronic toxicity of the solution prepared according to the technical solution according to example 8 on rabbits (when administered intravenously at a dose of 10 ml/kg of body weight for 30 days) confirmed that the drug does not have cumulative properties. Administration of the solution to rabbits does not cause pathological changes in hemogram indicators, hemostasis, electrolyte concentration, biochemical blood indicators, and urine indicators in animals. Pathomorphological studies indicate that after multiple intravenous injections of the medicinal product to rabbits, the internal organs of experimental animals retain their normal structure without specific pathological changes and do not differ histologically from the organs of control animals.

Example 15. 60 During an experimental study of acute toxicity on animals, it was established that the proposed infusion solution, made according to the technical solution of example 8, belongs to the class of relatively safe substances when administered intraperitoneally to white mice and white rats. With a single injection of the solution to white mice at a dose of 50 ml/kg of body weight and white rats at a dose of 45 ml/kg of body weight, the death of animals and symptoms of intoxication were not noted.

Multiple fractional intraperitoneal injection of the solution to white mice and white rats at the maximum possible excess dose (180 ml/kg of body weight for mice and 100 ml/kg for rats) did not cause death of the animals.

Example 16.

Comparative study of the influence of the infusion solution according to the technical solution on the level of microcirculation.

The research was carried out by the method of laser Doppler flowmetry (LDF) with wavelet analysis. Results were recorded three times: before infusion (background recording), 5 and 30 minutes after infusion. The occlusion test was carried out by applying the cuff for 3 minutes and determining the capillary blood flow reserve (RCC).

The assessment of the microcirculation level in the subjects was based on the analysis of the following indicators.

Microcirculation index (PM) - characterizes tissue blood flow, represents the level of perfusion (blood circulation) in a unit of tissue volume per unit of time. Displays the volumetric content of erythrocytes in capillary blood and the number of simultaneously functioning capillaries in the study area.

Capillary blood flow reserve (RCC) - reflects the reserve capabilities of the microcirculatory bed by the increase in the microcirculation index during reactive postocclusion hyperemia.

An open prospective study was conducted. 2 volunteer patients (1 man and 1 woman) took part in the study. Infusion of solutions was carried out in 2 stages. The microcirculatory effect of two infusion solutions was compared: the infusion solution according to the technical solution, 200 ml (composition: 100 ml of the solution contains xylitol 5 g, sodium chloride 0.6 g, potassium chloride 0.03 g, calcium chloride 0.01 g, magnesium chloride 0 .02 g, sodium lactate 1.5 g, sodium acetate 0.26 g, 1-malic acid 0.134 g), and the comparison drug - REOSORBILACTOF infusion solution, 200 ml (composition: 100 ml of solution contain sorbitol 6 g, sodium lactate 1 .9 g, sodium chloride 0.6 g, calcium chloride 0.01 g, potassium chloride 0.03 g, magnesium chloride 0.02 g). Determination of microcirculation index (PM), as well as capillary blood flow reserve (RCC) by performing an occlusion test, was carried out before infusion, 5 minutes later, and 30 minutes after infusion.

Patient 1 was infused with a solution according to a technical decision. On the background recording, a PM value of 3.27 perfusion units (pf. units) was obtained 5 minutes after the infusion

PM increased to a value of 6.14 p.o.d., 30 min after the infusion, PM increased to a value of 9.51 pf. unit

Thus, during the infusion of the solution according to the technical solution, an increase in PM from 3.14 to 6.14 at 5 minutes after the infusion and a significant persistent increase was noted in patient 1

PM to 9.51 at 30 minutes after infusion. 5 minutes after the infusion of the solution according to the technical solution, a decrease in the capillary blood flow reserve was recorded from 187 95 to 109 95, and a further decrease in the RCC index was observed to 103.16 95 30 minutes after the infusion, which indicates the opening of a part of the reserve capillaries due to the infusion of the solution according to technical solution.

On the 2nd day, patient 1 was given an infusion of the comparison drug. In the background recording, the value of PM-6b was obtained, 45 pf.units, 5 minutes after the infusion PM demonstrated a slight increase to 8.13 pf.units, after 30 minutes the indicator remained practically stable - PM 8.23 pf.units. , which is significantly lower than the indicators of the infusion solution according to the technical decision, and the comparison drug did not show a persistent residual effect. There was also a decrease in RCC from 156 95 on the background recording to 112 95 at 5 min post-infusion, and a slight decrease in RCC to 99 95 at 30 min post-infusion.

During the examination of patient 2, on the first day, the infusion of the solution was carried out according to the technical decision. On the background recording, a PM value of 8.06 pf.units was obtained, after 5 minutes after the infusion, the PM grew to a value of 8.24 pf.units, after 30 minutes after the infusion, the PM grew to a value of 10.56 pf. unit Thus, there was a slight increase in PM from 8.06 to 8.24 pf.units, as well as a significant increase in PM 30 min after infusion to 10.56 pf.units. A decrease in the RCC value from 197 95 to 115 95 at 5 min after infusion and to 106 95 at 30 min after infusion was registered.

On the 2nd day, patient 2 was given an infusion of the comparison drug. On the background recording, the PM value was 8.52 pf.units, after 5 minutes after the infusion, the PM grew to a value of 8.56 60 pf.units, after 30 minutes after the infusion, the PM grew to a value of 9.01 pf. unit That is, a slight increase in PM value from 8.52 to 8.56 pf.od was noted. for 5 min after the infusion, as well as a slight increase in PM to 9.01 pf.od. 30 min after infusion. At the same time, the value of the RKK indicator decreased from 141 95 to 91 95 at 5 min after infusion, and also to 80 95 at 30 min after infusion.

The results of the study are shown in Table 1.

Table 1

The results of studies of the influence of the infusion solution and the comparison drug on the values of indicators of microcirculation and capillary blood flow reserve ron ddenyayu t | Preparattorvnyanya and Preparat comparison decision 777171. | FonpM | 5 min 30 | Fonpm | 5 min. | 30 11111111 FonNRKK HER 77777777 | FonRKK HER 7/7 / | 77 777771711.171 187.80 | 10961 | 036 | 15647 | 11197 | 9920 7711111 0 FonNYM 17777777 | | FonpmM HER 11111111 FonNRKK HER 77777777 | FonRKK HER | SS 77111111 719704 | 11468 | 10644 | 14164 | 9089 | 80955

Thus, as a result of the study, a significant increase in the level of microcirculation was noted when using the infusion solution according to the technical solution in two examined patients 5 minutes after the infusion, as well as a stable long-term effect 30 minutes after the infusion, due to the relaxation of the precapillary sphincters. Probably, this is connected with the activation of the crystalloid infusion solution according to the technical solution containing polyatomic alcohol, lactate, malate and acetate ions, AZ adenosine receptors. At the same time, a decrease in the RCC index was registered at 5 and 30 min after the infusion, which indicates the opening of a part of the reserve capillaries due to the infusion of the solution according to the technical solution.

As shown in Figures 1-3, when the infusion solution is used according to the technical solution, the improvement of microcirculation due to the relaxation of the precapillary sphincters, caused by a decrease in capillary myotonus, is noted. An increase in the maximum amplitude of respiratory flexions was also noted.

As shown in Figures 4-6, when using the comparison drug, a slight improvement in microcirculation is noted due to an increase in the effect of the endothelial component, a decrease in capillary myotonus, which causes relaxation of the precapillary sphincters.

As shown in Figures 7-12, when used for infusions according to a technical solution, in contrast to the comparison drug, there is a steady increase in the endothelial component of microcirculation regulation, as well as a decrease in capillary neurotonus, which leads to an improvement in the microcirculation indicator.

Example 17.

To prove the effectiveness and safety of the infusion solution according to the technical solution in different versions of the composition, a series of three clinical studies was conducted with the same design and a total number of included patients - 111.

ZO Randomized open comparative studies were conducted in parallel groups, which confirm the effectiveness and safety of using the infusion solution according to the technical solution in various combinations of the composition in comparison with the well-known drug REOSORBILACTOF).

Patients aged 18 to 60 with the following pathological conditions were included in the study: - traumatic, operative, hemolytic, toxic or burn shock; - burn disease; - acute bleeding; - infectious diseases accompanied by intoxication; - exacerbation of hepatitis; - sepsis; - thrombophlebitis.

According to the results of laboratory indicators, all the above-mentioned conditions were accompanied by metabolic acidosis of various degrees of severity, electrolyte and rheological disorders of the blood balance, depending on the severity of the pathology, hemodynamic and microcirculatory abnormalities were noted. Patients with an excessively high lactate level were not included in the study.

All patients received standard treatment of the above-mentioned pathologies in accordance with the treatment protocols of the Ministry of Health of Ukraine. As hyperosmolar solutions, an infusion solution was used according to the technical decision in different versions of the composition or a comparison drug

REOSORBILACTF).

To evaluate the parameters of effectiveness, during the entire course of using the infusion solution, the following indicators were measured according to the technical decision: assessment of the patient's general condition, subjective signs of pathology, general blood analysis, acid-base balance, coagulogram, ionic and gas composition of blood, arterial and venous pressure , diuresis dynamics.

Study Mo 1 included 45 patients, who were randomized to group 3 of 15 subjects. Group 1 as a hyperosmolar solution in the composition of the treatment received an infusion solution according to the technical solution in the composition (wt. U): sorbitol 5.0 sodium chloride 0.54 potassium chloride 0.027 calcium chloride 0.008 magnesium chloride 0.017 sodium lactate 1.35 sodium acetate 0.234

And -malic acid 0.122 water for injections the rest.

Group 2 as a hyperosmolar solution in the composition of the treatment received an infusion solution according to the technical solution in the composition (wt. b): xylitol 4.0 sodium chloride 0.54 potassium chloride 0.027 calcium chloride 0.008 magnesium chloride 0.017 sodium lactate 1.35 sodium acetate 0.234

And -malic acid 0.122 water for injections the rest.

Group C received a comparison drug as a hyperosmolar solution as part of the treatment.

Study Mo 2 included 30 patients, who were randomized to the 3rd group of 10 subjects.

Group 1 as a hyperosmolar solution in the composition of the treatment received an infusion solution according to the technical solution in the composition (wt. b): sorbitol 6.0 sodium chloride 0.6 potassium chloride 0.03 calcium chloride 0.01 magnesium chloride 0.02 sodium lactate 1, 5 sodium acetate 0.26

And -malic acid 0.134 water for injections the rest.

Group 2 as a hyperosmolar solution in the composition of the treatment received an infusion solution according to the technical solution in the composition (wt. b): xylitol 5.0 sodium chloride 0.6 potassium chloride 0.03 calcium chloride 0.01 magnesium chloride 0.02 sodium lactate 1, 5 sodium acetate 0.26

And -malic acid 0.134 water for injections the rest.

Group C received a comparison drug as a hyperosmolar solution as part of the treatment.

The Ministry of Health study included 36 patients who were randomized to the 3rd group of 12 subjects.

Group 1 as a hyperosmolar solution in the composition of the treatment received an infusion solution according to the technical solution in the composition (wt. b): sorbitol 7.0 sodium chloride 0.66 potassium chloride 0.033 calcium chloride 0.012 magnesium chloride 0.023 sodium lactate 1.65 sodium acetate 0.286

And -malic acid 0.147 water for injections the rest.

Group 2 as a hyperosmolar solution as part of the treatment received an infusion solution according to the technical solution in the composition (wt. b): xylitol 6.0 sodium chloride 0.66 potassium chloride 0.033 calcium chloride 0.012 magnesium chloride 0.023 sodium lactate 1.65 sodium acetate 0.286

And -malic acid 0.147 water for injections the rest.

Group C received a comparison drug as a hyperosmolar solution as part of the treatment.

According to the data of three studies, the following results were recorded and analyzed.

The obtained results of clinical and laboratory studies also indicate that the subjective complaints of patients in groups 1 and 2 disappeared earlier than in group 3. Thus, in the groups of patients who received the proposed solution for infusions, 2-3 days earlier, than in the comparison group, body temperature normalized, general weakness disappeared, diuresis normalized, appetite improved.

It was noted that the stabilization of hemodynamic indicators (including the state of microcirculation) occurs on average 5-6 hours after the start of the use of solutions in groups 1 and 2 as part of complex therapy, and after 6-8 hours after the start of the use of the comparison drug as part of complex therapy therapy Hematological indicators, in particular the content of erythrocytes, hemoglobin, hematocrit indicators, blood diastasis level approached the reference values after 24-48 hours. from the start of treatment in all groups. Indicators of leukocyte level, leukocyte formula and erythrocyte sedimentation rate (ESR) in patients of groups 1 and 2 normalized 2-3 days earlier than in patients of comparison groups.

In addition, improvement in glycemia was noted in groups 2. This can be explained by the presence of xylitol in the composition of Group 2 solutions, which, unlike sorbitol, is metabolized without the participation of insulin and is not transformed into fructose, and therefore can be safely used even in patients with diabetes and fructose intolerance.

Before starting the use of research hyperosmolar solutions, metabolic acidosis of various degrees was noted in all patients. During the course of application of the solutions, an alkalizing effect was noted in all groups, but it was more pronounced in patients of groups 1 and 2. The normalization of the acid-alkaline state occurred already 36 hours after the application of the solutions. For patients of group C, normalization of the acid-base status occurred 48-72 hours after the use of the comparison drug. This can be explained

With the presence in the composition of solutions of groups 1 and 2 of acetate, which is quickly incorporated into the metabolism and releases HSOZ ions already 15 minutes after administration to the patient. The speed of normalization of indicators of the acid-alkaline state of the blood when using the proposed infusion solution in different concentrations directly depends on the concentration of reserve alkalinity carriers in the studied drugs.

Manifestations of side effects during the use of the study drugs and the comparison drug were not observed during the entire period of the study.

Therefore, it can be concluded that the use of the proposed crystalloid infusion solution in various combinations in the complex treatment of patients with the above-mentioned pathologies has a positive effect on the rate of regression of clinical manifestations of the disease, normalization of the acid-alkaline balance of blood, indicators of hemodynamics and microcirculation, as well as normalization of the hemogram.

Thus, the use of the declared crystalloid infusion solution allows to achieve the following technical result: the proposed crystalloid infusion solution is effective and safe to use, and can be used for the therapy of a wide range of painful conditions, such as disorders of microcirculation and peripheral blood circulation,

can be used for the treatment of various population groups, in particular in patients with diabetes and fructose intolerance, is characterized by a faster onset of alkalizing action,

due to the reduced risk of overdosing the patient's organism with lactate ion, it can be used in smaller volumes, i.e. it is suitable for restrictive type infusion therapy and, thanks to the combination of constituent components and their quantitative ratio, has a multifunctional effect, namely: rheological, detoxification and anti-shock.

Claims (6)

USEFUL MODEL FORMULA 1. Crystalloid infusion solution containing polyhydric alcohol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate and water for injections, which is distinguished by the fact that it additionally contains sodium acetate and I-malate, with the following ratio of components , in terms of dry matter, wt. o: polyatomic alcohol 4-7 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0.234-0.286 Y -malate 0.120- 0.145 water for injections the rest. 2. Crystalloid infusion solution according to claim 1, which differs in that it contains sorbitol, xylitol or their mixture as a polyatomic alcohol. 3. Crystalloid infusion solution according to any of claims 1-2, which is characterized by containing calcium chloride, magnesium chloride, sodium lactate, sodium acetate in the form of anhydrous salts or crystal hydrates. 4. Crystalloid infusion solution according to any of claims 1-3, which differs in that it contains -malate in the form of I -malic acid or sodium salt of I -malic acid. 5. Crystalloid infusion solution according to any of claims 1-4, which is characterized by the fact that it contains sorbitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, I-malate and water for injections , with the following ratio of components, in terms of dry matter, wt. 9: sorbitol 5-7 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0.234-0.286 Y-malate 0.120-0.145 water for injections the rest. 6. Crystalloid infusion solution according to any of claims 1-4, which is characterized by the fact that it contains xylitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium Zo acetate, I-malate and water for other ektions, with the following component ratio, in terms of dry matter, wt. 9: xylitol 4-6 sodium chloride 0.54-0.66 potassium chloride 0.027-0.033 calcium chloride 0.008-0.012 magnesium chloride 0.017-0.023 sodium lactate 1.35-1.65 sodium acetate 0.234-0.286 Y-malate 0.120-0.145 water for injections the rest. 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