Hyperosmolar compound solutions for infusion

Abstract

The present application relates to the field of medicine, and particularly relates to a high-osmotic parenteral medicine in a solution dosage form for infusion. The high-osmotic composite solution for infusion comprises polyhydric alcohol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate and water for infusion. The solution of the present application is effective for treating microcirculation and peripheral blood circulation disorders, has a faster alkalization effect, reduces the risk of taking excessive lactate ions, and has rheological, detoxification and anti-shock effects.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of medicine, in particular to a hypertonic parenteral pharmaceutical product in the form of a solution for infusion. BACKGROUND

[0002] Infusion solutions are pharmaceutical products for administration to the human body by intravenous infusion and using infusion systems. The main indications for infusion therapy prescriptions are:

[0003] - hypovolemia;

[0004] - deterioration of blood rheological properties;

[0005] - deterioration of water-salt and acid-base balance of blood;

[0006] - severe dehydration;

[0007] - poisoning, etc.

[0008] Depending on the therapeutic effect, infusion solutions are usually divided into several groups.

[0009] The first group of infusion solutions includes infusion solutions with hemodynamic effect. Hemodynamic infusion solutions (other terms in the literature - antishock and blood volume) can act as plasma substitutes and restore blood volume, hemodynamics and blood circulation in blood loss and shock. In hemodynamic infusion solutions, water-soluble polymers such as gelatin and hydroxyethyl starch (HES) are used as active pharmaceutical ingredients (API), the properties of which directly determine the therapeutic effect of the infusion solution (its circulation duration in the blood stream and hemodynamic effect). In current medical practice, medium and low molecular weight polymers are most often used, which are characterized by a small number of side effects.

[0010] However, hemodynamic infusion solutions have disadvantages such as limited therapeutic effect, etc. Therefore, they are used by people only for the main purpose of correcting the blood volume status of patients.

[0011] In addition, hemodynamic infusion solutions containing HES have the disadvantage of a significant negative impact on kidney function and other side effects. For example, the infusion solution "Voluven®" (see the web page https: / / compendium.com.ua / dec / 271727 / ) contains HES and sodium chloride, the average molecular weight of HES is 450,000 daltons, the molar degree of substitution is 0.7. In the case of using "Voluven®" infusion solution, cases of kidney pain occur, which leads to the termination of treatment and the impossibility of further use of the drug. In the case of using "Voluven®" infusion solution, cases of kidney pain occur, which leads to the termination of treatment and the impossibility of further use of the drug.

[0012] ​Furthermore, disadvantages of hemodynamic infusions containing gelatin include varying degrees of allergic reactions, even developing into anaphylactic shock. A well-known example of such a drug is GELOFUSINE infusion (see webpage http: / / likicontrol.com.ua / %D1%96%D0%BD%D1%81%D1%82%D1%80%D1%83%D0%BA%D1%86%D1%96%D1%8F / ?

[26777] ), which contains medium molecular weight (average molecular weight 30,000 Daltons) succinylated gelatin (as an API) and sodium chloride. Prescribing information for GELOFUSINE emphasizes that severe allergic reactions (Grade III or IV) are very rare (occurrence frequency <1:10,000). However, the risk of such serious side effects cannot be completely eliminated, therefore, continuous medical monitoring is required for patients receiving GELOFUSINE who experience allergic reactions.

[0013] The second category of infusion solutions includes those that regulate the water, electrolyte, and acid-base balance of the blood. These are used to replenish blood loss and stabilize circulating plasma volume, improve blood rheological properties, restore blood ion composition and pH to normal, and for routine fluid resuscitation and detoxification. In fact, these infusion solutions are saline solutions without polymer components.

[0014] A well-known example of the second class of infusion solutions is ACESOL infusion (see webpage http: / / likicontrol.com.ua / %D1%96%D0%BD%D1%81%D1%82%D1%80%D1%83%D0%BA%D1%86%D1%96%D1%8F / ?

[14778] ). Each 100 ml solution contains 200 mg sodium acetate trihydrate, 500 mg sodium chloride, and 100 mg potassium chloride. A disadvantage of this medication is its high potassium content, which can lead to hyperkalemia. During large-volume ACESOLUM infusions, patients may develop metabolic disturbances, requiring additional sodium medication to correct electrolyte imbalances in the blood.

[0015] Another well-known drug in the second category of infusion solutions is LACTASOL (see webpage https: / / www.piluli.kharkov.ua / drugs / drug / 1544 / ). By weight, LACTASOL contains 0.62% sodium chloride, 0.03% potassium chloride, 0.016% calcium chloride, 0.01% magnesium chloride, 0.336% sodium lactate, and 0.03% sodium bicarbonate. The ionic composition of this drug is as follows: Na... + -140.0 mmol / L, K + -4.0 mmol / L, Ca ++-1.5mmol / L, Mg ++ -1.0mmol / L, Cl - -116mmol / L, HCO3 - –4.0mmol / L, CH3CH(OH)SOO - -30.0 mmol / L, osmolarity -294 mOsm / L. Due to the presence of sodium bicarbonate, this drug becomes unstable after sterilization. Furthermore, the sodium lactate content in the drug is negligible. Therefore, when using LACTASOL to correct blood acid-base imbalance, large infusions are required, which can lead to excessive blood flow.

[0016] Another well-known drug is STEROFUNDIN ISO infusion solution (see webpage http: / / mozdocs.kiev.ua / likiview.php7id-24436), which contains a combination of an alkalizing component (such as sodium acetate) and L-malic acid, and contains sodium ions – 145.0 mmol / L, potassium ions – 4.0 mmol / L, calcium ions – 2.5 mmol / L, magnesium ions – 1.0 mmol / L, chloride ions – 127.0 mmol / L, acetate ions – 24.0 mmol / L and malate ions – 5.0 mmol / L.

[0017] STEROFUNDIN ISO infusion solution and the second type of infusion solution mentioned above are both isotonic saline solutions, therefore, their pharmacological effects are very limited.

[0018] Another known saline infusion, HARTMAN'S SOLUTION (see webpage http: / / likicontrol.com.ua / %D1%96%D0%BD%D1%81%D1%82%D1%80%D1%83%D0%BA%D1%86%D1%96%D1%8F / ?

[24214] ), contains sodium chloride, potassium chloride, sodium lactate, calcium chloride dihydrate, and magnesium chloride hexahydrate. 100 ml of the drug contains 0.6 g of sodium chloride, 0.04 g of potassium chloride, 0.303 g of sodium lactate, 0.2013 g of calcium chloride dihydrate, and 0.02 g of magnesium chloride hexahydrate. A disadvantage of HARTMAN'S SOLUTION is its low osmotic pressure. The drug is a hypotonic solution, which significantly limits its use because high doses can cause intracellular edema of visceral organs, primarily cerebral edema and increased intracranial pressure. In cases of severe hypoxia, Hartman's solution can worsen the condition, leading to lactic acidosis.

[0019] Another known saline infusion solution is DARROW'S SOLUTION (see webpage http: / / mozdocs.kiev.ua / likiview.php?ID=1526). 100ml of this solution contains 0.4g sodium chloride, 0.267g potassium chloride, and 0.594g sodium lactate. The application of DARROW'S SOLUTION is limited. Furthermore, a disadvantage of this solution is its high potassium content, which increases the risk of hyperkalemia, requiring strict control of serum potassium levels. DARROW'S SOLUTION is a non-equilibrium solution, containing only sodium and potassium ions as cations. This makes its composition significantly different from that of blood plasma; therefore, using a non-equilibrium solution for infusion can lead to acid-base and water-electrolyte imbalances.

[0020] The third category of infusion solutions includes those with combined (compound) effects. These solutions can be used as hemodynamic solutions, detoxifying solutions, and solutions for regulating the water-salt and acid-base balance of the blood. Currently, compound infusion solutions are the most promising because they can be used to treat a variety of diseases and pathological conditions.

[0021] One known compound infusion solution is The compound infusion solution (see webpage https: / / compendium.com.ua / dec / 267128 / ) contains, by weight, 6% polyol (e.g., sorbitol), 1.9% sodium lactate, 0.6% sodium chloride, 0.03% potassium chloride, 0.01% calcium chloride, and 0.02% magnesium chloride. The ionic composition of this drug is as follows: Na + -278.2mmol / L, K + -4.0 mmol / L, Ca ++ -0.9mmol / L, Mg ++ -2.1mmol / L, Cl - -112.7 mmol / L, CH3CH(OH)SOO - -175.5 mmol / L. The osmolarity of this drug is 891 mOsm / L. Its characteristics include plasma replacement and detoxification, and it is often used in the following situations:

[0022] —Treatment of microcirculatory disturbances in shock;

[0023] —Various peripheral circulatory disorders;

[0024] — Correction of water-salt balance;

[0025] —Comprehensive treatment of intestinal obstruction;

[0026] —Infectious diseases accompanied by severe poisoning, repeated vomiting, and diarrhea;

[0027] —In surgery to treat systemic inflammatory response syndrome (sepsis);

[0028] —Treatment of biliary tract diseases, such as gallbladder motility disorders and post-cholecystectomy syndrome;

[0029] —As part of combined conservative treatment for acute pancreatitis;

[0030] —In neurological practice, it is particularly used to treat cerebral ischemia and diabetic neuropathy.

[0031] Microcirculation—a general term encompassing blood and lymph flow within capillaries, various metabolic processes occurring through the capillary walls, and extravascular transport of fluids and substances. The primary function of microcirculation is metabolism. Continuous blood flow ensures the removal of waste products and the supply of nutrients to body tissues. Another important function of microcirculation is maintaining pressure by ensuring a balance of fluid flow in and out of tissues and blood vessels.

[0032] The microcirculation blood flow path consists of blood vessels (arterioles, venules, capillaries, etc.) with a diameter of no more than 100 μm.

[0033] Microcirculatory disorders can be classified into the following categories:

[0034] —Extravascular diseases, such as changes in perivascular transport of interstitial fluid, degranulation of basophils in tissues, and release of bioactive substances and enzymes into peripheral vascular tissues;

[0035] —Intravascular diseases, such as changes in blood viscosity and coagulation, changes in erythrocyte sedimentation and blood flow velocity;

[0036] —Microvascular wall diseases, such as changes in vascular permeability and leakage of blood cells.

[0037] Many diseases can cause microcirculatory disturbances, which are also dangerous because they lead to metabolic disorders and abnormal organ function. The main causes of microcirculatory disturbances include inflammation, hyperproteinemia, dehydration, hypoxia, acidosis, poisoning, hypovolemia, hypervolemia, and shock. Because some of these conditions can be life-threatening (e.g., shock), immediate treatment is necessary.

[0038] Shock is an acute pathological process that occurs due to insufficient blood supply to organs and tissues and can lead to death. Circulatory disturbances and shock can be caused by:

[0039] —(For example, due to blood loss) a decrease in total blood volume;

[0040] —Sudden dilation and increase in blood vessel volume (due to allergic reactions or pain);

[0041] —Heart disease (myocardial infarction);

[0042] —Inflammation (sepsis).

[0043] In the United States, approximately 1.2 million people enter the emergency room each year in a state of shock, with a very high risk of death, ranging from 20% to 50%.

[0044] Peripheral circulation is the movement of blood within an organ. The main peripheral circulatory disorders are as follows:

[0045] 1) Ischemia, which is caused by a decrease in blood flow to organs or tissues due to reduced arterial blood supply;

[0046] 2) Arterial congestion: Due to the dilation of arterial blood vessels, the blood flow through these vessels increases, leading to an increase in blood flow to organs or tissues;

[0047] 3) Venous congestion: Due to impaired blood flow through the veins, the amount of blood congestion in organs or tissues increases;

[0048] 4) Thrombosis, the deterioration of blood properties leading to the formation of clots within the blood vessel lumen;

[0049] 5) Embolism, caused by the movement of foreign substances (emboli) in the bloodstream, leading to the closure of the blood vessel lumen;

[0050] 6) Bleeding, caused by impaired vessel wall integrity or increased permeability, resulting in blood flowing out of the vessel.

[0051] A serious consequence of peripheral circulatory disorders is infarction, which means the necrosis of an organ or part of an organ, caused by circulatory obstruction within the organ.

[0052] Poisoning is the process of organ damage caused by the harmful effects of toxins and poisons. There are various causes of poisoning, such as the entry of harmful substances from outside the body or the formation of harmful substances within the body. Poisoning can also be caused by diseases, such as infectious diseases, when it is a product of the life activities of pathogens. One mechanism for combating the effects of poisoning is detoxification through the infusion of solutions into the bloodstream (accelerating the excretion of harmful substances from the body through the body's water).

[0053] Sepsis is an organ dysfunction resulting from the development of a systemic inflammatory response syndrome. It is an infectious disease caused by various pathogens, where sepsis occurs within the body. Effective treatments for sepsis include a combination of therapies such as intravenous detoxification, hemodynamic correction, parenteral nutrition, and blood transfusions.

[0054] Therefore, people are familiar with The combined mechanisms of action of infusion solutions facilitate their use in clinical practice to achieve multiple purposes. However, Medicine is not a panacea. Therefore, the use of... General contraindications for this medication include alkalosis of any cause (respiratory, metabolic, etc.), disseminated intravascular coagulation (DIC) syndrome, cerebral hemorrhage, gastrointestinal bleeding with unstable hemostasis, and acute thrombosis (due to the risk of complications from thromboembolism). It is not recommended to use this medication before final hemostasis. Use this medication for first aid of injured patients (because it can reduce blood viscosity and may interfere with blood clotting). Contraindications for this medication also include (in the absence of hemodialysis) severe heart failure and acute renal failure.

[0055] The drug also has the following drawbacks:

[0056] —— If a component of a drug (e.g., sodium lactate) is present in a sufficiently high amount, it can lead to excessive lactate levels in the body, which can overload the liver during the metabolism of large amounts of lactate.

[0057] —The onset of action is not fast enough;

[0058] —Side effects may occur when using known medications to treat patients with fructose intolerance;

[0059] —Its effectiveness in treating microcirculatory and peripheral blood circulation disorders is insufficient.

[0060] The objective technical problem to be solved by this invention is to develop an infusion solution formulation of a drug that has a synergistic effect, effectively and safely treating microcirculatory and peripheral circulatory disorders in different populations (including patients with diabetes and fructose intolerance), restoring water-electrolyte balance, blood rheological properties, and capillary tone; characterized in that the alkalization effect begins more quickly, reducing the risk of excessive administration of lactate ions to the patient's body; and, the drug is used to implement a restrictive infusion strategy. Summary of the Invention

[0061] The target technical problem is addressed by introducing two additional alkali reserve carriers into the infusion fluid composition. This reduces the sodium lactate content in the final infusion fluid composition while maintaining the required osmotic pressure and providing the additional benefit of expanding its range of action. As additional alkali reserve carriers, a calculated mixture of sodium acetate and L-malic acid is proposed to maintain the total osmotic pressure of the hypertonic solution for infusion at an optimal value. Furthermore, the infusion fluid disclosed in this invention contains 4 times more lactic acid than existing analogues and is comparable to the closest prototype. In comparison, the total amount of lactic acid in the infusion solution disclosed in this invention is lower, thus enabling the use of the infusion solution to achieve the purpose even when the patient is at risk of lactate ion excess.

[0062] The balanced content of the three base reserve carriers in the infusion solution of this invention also solves the target technical problem of this invention. Since lactate ions are metabolized in the liver, while acetate and malate ions are metabolized in muscles, reducing the total amount of lactate ions in the infusion solution when using this invention can alleviate the burden on the liver. Furthermore, using infusion solution components containing acetate and malate anions as base reserve carriers can minimize the oxygen consumption required for bicarbonate formation in tissues, which is crucial for patients in shock with respiratory failure.

[0063] Furthermore, by successfully using and scientifically selecting and calculating the amount of malate and acetate ions introduced into the infusion solution, this invention also solves other technical problems, such as effectively correcting metabolic acidosis and enhancing the anti-hypoxia and detoxification effects of the infusion solution; since sodium acetate is used as one of the alkali reserve carriers, the infusion solution of this invention takes effect faster and has a significant alkalization effect.

[0064] This invention relates to a hypertonic composite solution for infusion, comprising polyol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, and infusion water, and further comprising sodium acetate and L-malic acid. The dry weight ratio (wt.%) of each component is as follows:

[0065] Polyols 4-7

[0066] Sodium chloride 0.54–0.66

[0067] Potassium chloride 0.027–0.033

[0068] Calcium chloride 0.008–0.012

[0069] Magnesium chloride 0.017–0.023

[0070] Sodium lactate 1.35-1.65

[0071] Sodium acetate 0.234–0.286

[0072] L-malic acid 0.120–0.145

[0073] The remaining water was injected to 100%.

[0074] In various embodiments, the present invention provides a hypertonic composite solution for infusion containing sorbitol, xylitol, or mixtures thereof as a polyol.

[0075] One embodiment of the present invention provides a hypertonic composite solution for infusion, comprising calcium chloride, magnesium chloride, sodium lactate, and sodium acetate in anhydrous salt or hydrate form.

[0076] In various embodiments, the present invention provides a hypertonic composite solution for infusion containing L-malic acid or L-malic acid in the form of sodium L-malate.

[0077] Another embodiment of the present invention provides a hypertonic composite solution for infusion, comprising sorbitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, L-malic acid, and water for infusion, wherein the dry weight ratio (wt.%) of each component is as follows:

[0078] Sorbitol 5-7

[0079] Sodium chloride 0.54–0.66

[0080] Potassium chloride 0.027–0.033

[0081] Calcium chloride 0.008–0.012

[0082] Magnesium chloride 0.017–0.023

[0083] Sodium lactate 1.35–1.65

[0084] Sodium acetate 0.234–0.286

[0085] L-malic acid 0.120–0.145

[0086] The remaining water for infusion is increased to 100%.

[0087] Another embodiment of the present invention provides a hypertonic composite solution for infusion, comprising xylitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, L-malic acid, and water for infusion, wherein the dry weight ratio (wt.%) of each component is as follows:

[0088] Xylitol 4-6

[0089] Sodium chloride 0.54–0.66

[0090] Potassium chloride 0.027–0.033

[0091] Calcium chloride 0.008–0.012

[0092] Magnesium chloride 0.017–0.023

[0093] Sodium lactate 1.35–1.65

[0094] Sodium acetate 0.234–0.286

[0095] L-malic acid 0.120–0.145

[0096] The remaining water for infusion is increased to 100%.

[0097] Another embodiment of the present invention provides a hypertonic composite solution for infusion, the osmotic pressure of which ranges from 880 to 920 mOsm / L.

[0098] The main active pharmaceutical components of the infusion solution of the present invention are polyols (e.g., hexahydrol sorbitol or penthydrol xylitol), alkaline storage carriers (sodium lactate, sodium acetate (alkalizing component)), L-malic acid, and electrolytes.

[0099] Alkali reserve carriers are products of human metabolism that form bicarbonate ions, thereby restoring the blood's buffering capacity.

[0100] Due to known The infusion solution contains a sufficiently high amount of alkaline reserve carrier, such as sodium lactate (19 mg / ml), therefore it cannot be used to treat patients with high blood lactate levels or those suffering from conditions that lead to lactic acidosis (hypoxia, cancer, cardiovascular disease, diabetes, etc.). Thus, the potential for side effects when using known infusion solutions somewhat limits their application in clinical practice.

[0101] To overcome the known drawbacks of the prototype, the inventors propose not to introduce large amounts of sodium lactate into the infusion solution, but instead to transform this alkalizing component into a combination of three alkali reserve carriers, such as sodium lactate, sodium acetate, and L-malic acid. Compared to the prototype, this avoids the negative effects on patients caused by excessive administration of lactate ions during treatment with the prototype's infusion solution, and makes the hypertonic composite infusion solution of the present invention safer and more versatile in use. In this case, the qualitative and quantitative composition of the infusion solution of the present invention is formed as follows: the total osmolarity of the solution is maintained at an effective level of approximately 900 mOsmol / L ± 2%.

[0102] The infusion solution of the present invention contains a 1.5% (133 mmol / L) base stock carrier (i.e., sodium lactate), which is more common than the most common isotonic solutions (e.g., in RINGER'S LACTATE SOLUTION pharmaceuticals). http: / / mozdocs.kiev.ua / likiview.php?id=13629 The content in ) is 4 times higher, but lower than The drug (169.6 mmol / L). Sodium lactate helps correct plasma acid-base balance and participates in carbohydrate and energy metabolism, restoring and stimulating cellular function in the reticuloendothelial system, liver, and kidneys. Unlike infusions containing sodium bicarbonate, base reserve carriers such as sodium lactate are neutral in reaction. Sodium lactate is a slow-acting base reserve carrier. When sodium lactate is introduced into the bloodstream, it releases sodium, CO2, and H2O, and forms sodium bicarbonate, thereby increasing the blood base reserve. Correction of metabolic acidosis with sodium lactate is slow (because metabolism involves sodium lactate) and does not cause drastic fluctuations in blood pH. The effects of sodium lactate become apparent within 20-30 minutes after administration of the infusion solution of this invention.

[0103] This alkaline reserve carrier (e.g., sodium acetate) effectively corrects metabolic acidosis and is completely metabolized into an equal amount of sodium bicarbonate within 1.5–2 hours. Sodium acetate does not cause interstitial edema in brain cells, nor does it increase platelet and erythrocyte aggregation. Importantly, sodium acetate has a strong alkalizing effect while consuming minimal O2. Sodium acetate is primarily metabolized in muscle tissue by acetyl-CoA synthase, ultimately converting into carbon monoxide and water. The alkalizing effect of acetate is very rapid; within 15 minutes of the initial injection of acetate ions, HCO3- - Ion concentrations increase; 90% of the administered acetate ions are oxidized within minutes; 60%-80% of the acetate ions are expelled as CO2 through the lungs within 1-12 hours. Acetate metabolism, glucose, and insulin concentrations remain unchanged in diabetic patients. Acetate is an energy source, providing 209 kcal / mol. It also plays an important role in carbohydrate and lipid metabolism (acetate replaces fat as an oxidative fuel without affecting glucose oxidation).

[0104] Since malic acid is an energy substrate in the Krebs cycle and participates in the ornithine cycle of urea synthesis and the binding of ammonia in muscles, the inclusion of malate in the infusion solution of this invention can enhance anti-hypoxia and detoxification effects. The alkalizing effect of malic acid is much slower than that of acetate, which may contribute to the long-lasting effect of the infusion solution. Using acetate and malate anions as alkali reserve carriers can minimize the oxygen consumption required for the formation of bicarbonate ions in tissues.

[0105] Sorbitol is a hexahydrol, a sweet-tasting white crystalline powder. It is an energy source, metabolized independently of insulin (to fructose), and does not cause an increase in blood sugar levels. The presence of sorbitol in the blood helps normalize carbohydrate and energy metabolism. It stimulates fatty acid oxidation through non-ketogenic metabolism and promotes the use of ketone bodies in the tricarboxylic acid cycle, which has a positive effect on improving hepatocyte function. Because sorbitol has a direct effect on intestinal wall nerve receptors and promotes the synthesis and secretion of chorionic chorionic villus, cholecystokinin, and B vitamins, it enhances intestinal motility. The maximum dosage of sorbitol is 0.25 g / kg body weight / h. The infusion solution contains 6% isotonic sorbitol.

[0106] According to one embodiment, the infusion solution of the present invention contains a pentyl alcohol, such as xylitol, instead of sorbitol. Such pentyl alcohols have significant anti-ketogenic effects and can be used in a non-insulin-dependent manner, making the infusion solution safe for patients with diabetes and lactose intolerance. Furthermore, the effects of components such as sorbitol on the human digestive system (laxative effect, increased gas production, etc.) are known. For patients with gastrointestinal disorders, the xylitol-containing infusion solution of the present invention is more suitable to avoid potential side effects.

[0107] Xylitol is a pentyl alcohol, a colorless crystal with a sweet taste. It is an intermediate product of carbohydrate metabolism in humans and animals. The final product of xylitol oxidation is carbon dioxide, which is mainly expelled with exhaled air. When administered intravenously, xylitol is rapidly integrated into the body's metabolism, with 80% being absorbed by the liver and accumulated as glycogen. Xylitol has low toxicity, is well-tolerated, and does not cause a decrease in hepatic nucleotides (ATP, ADP, AMP), making it safe for patients with fructose intolerance. Because xylitol is a good energy source and its metabolism is independent of insulin, it has anti-ketogenic and lipid-promoting effects. Therefore, xylitol-containing infusions are recommended as a means of parenteral nutrition, especially for patients who have undergone gastrointestinal surgery. The maximum dosage of xylitol is 0.25 g / kg body weight / hour. The infusion solution contains xylitol at an isotonic concentration of 5%.

[0108] The infusion solution composition of the present invention contains an appropriate concentration of alkaline blood ions (Na+). + K + Ca ++ Mg ++ Cl -The balanced mixture of these components makes the infusion solution more physiologically compatible. Sodium chloride has a rehydration effect, supplementing sodium and chloride ion deficiencies in various pathological states. Calcium is essential for nerve impulse transmission, skeletal and smooth muscle contraction, myocardial activity, bone formation, and blood clotting. It reduces cell and blood vessel permeability, prevents the development of inflammatory responses, and increases the body's resistance to infection. Magnesium is required for many biochemical reactions, glucose uptake, protein synthesis, nerve signal transduction, and bone formation. Potassium restores electrolyte balance, has negative chronotropic and negative domain-varying effects, and high doses of potassium have negative inotropic, catalytic, and moderate diuretic effects. It participates in the transmission of nerve impulses, increases acetylcholine levels, and excites the sympathetic nervous system in the autonomic nervous system.

[0109] Within the range of selected components and their quantitative proportions, this invention belongs to the category of multi-component, multifunctional hypertonic solutions. The pharmacological effects of the infusion solution of this invention are related to the synergistic effects of its components, and, due to its hyperosmolarity being three times higher than that of plasma, the pharmacological effects of the infusion solution are also related to its additional properties. Following intravenous administration of solutions containing sorbitol and xylitol, the amount of fluid entering the bloodstream from tissues increases, hemodynamics is restored, blood microcirculation and rheological properties are improved, blood viscosity decreases, platelet aggregation is reduced, cardiac activity is enhanced, metabolic processes are strengthened, and liver detoxification function is improved. This allows the solution of this invention to be promoted as a means with hemodynamic, rheological, detoxifying, anti-ketogenic, anti-shock, energy, and alkalizing effects. The effective rheological and anti-shock effects of the infusion solution of this invention can reduce the amount of infusion fluid used during intravenous therapy, i.e., the infusion solution of this invention can be used for restrictive intravenous therapy.

[0110] Therefore, the hypertonic composite solution for infusion of the present invention will fully exhibit its pharmacological properties within the range of the selected components and their quantitative proportions. Attached Figure Description

[0111] Figure 1 This is a wavelet analysis diagram of patient 1 before the infusion solution of the present invention was administered.

[0112] Figure 2 This is a wavelet analysis diagram of patient 1 taken 5 minutes after the infusion of the solution of the present invention.

[0113] Figure 3 This is a wavelet analysis diagram of patient 1 30 minutes after infusion of the infusion solution of the present invention.

[0114] Figure 4 This is a wavelet analysis diagram of patient 1 before the infusion of the control drug.

[0115] Figure 5This is a wavelet analysis diagram of patient 1 5 minutes after the infusion of the control drug.

[0116] Figure 6 This is a wavelet analysis diagram of patient 1 30 minutes after the infusion of the control drug.

[0117] Figure 7 This is a wavelet analysis diagram of patient 2 before the infusion solution of the present invention was administered.

[0118] Figure 8 This is a wavelet analysis diagram of patient 2 taken 5 minutes after the infusion of the solution of the present invention.

[0119] Figure 9 This is a wavelet analysis diagram of patient 2 taken 30 minutes after receiving the infusion solution of the present invention.

[0120] Figure 10 This is a wavelet analysis diagram of patient 2 before the infusion of the control drug.

[0121] Figure 11 This is a wavelet analysis diagram of patient 2 taken 5 minutes after the infusion of the control drug.

[0122] Figure 12 This is a wavelet analysis diagram of patient 2 30 minutes after the infusion of the control drug. Detailed Implementation

[0123] The manufacturing process of the infusion solution of the present invention includes the following stages: weighing appropriate mass of components, preparing solution, diluting solution to the required volume with infusion water, filtering, controlling physicochemical parameters, bottling, sterilization, repeated control of physicochemical parameters, labeling, and packaging.

[0124] The present invention is described through the following embodiments.

[0125] Example 1

[0126] The hypertonic composite solution for infusion containing sorbitol and L-malic acid of the present invention is prepared in the following manner.

[0127] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 60g sorbitol, 6g sodium chloride, 0.3g potassium chloride, 0.13g calcium chloride dihydrate, 0.43g magnesium chloride hexahydrate, 4.31g sodium acetate trihydrate, and 1.34g L-malic acid. Then, 15g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0128] The resulting infusion solution then undergoes filtration, packaging, sterilization, and quality control.

[0129] The solution obtained by liquid column filtration yields a filtrate. This filtrate is then filtered using filters with pore sizes of 1.2 μm (coarse purification) and 0.22 μm (fine purification). The first filtrate is then re-filtered. The filtered solution is checked for the absence of mechanical impurities and poured into 100 ml, 200 ml, or 400 ml bottles made of MTO or PSD grade glass used for blood, transfusion, and injection drugs. The bottles are sealed with rubber stoppers and capped with aluminum or aluminum-plastic caps. The bottles containing the solution are then steam-sterilized at 1.1 bar pressure and 121°C for 30 minutes. After checking for mechanical impurities, the sterile solution is labeled and packaged. The quality of the infusion solution is controlled according to the requirements of analytical and regulatory documents for all qualitative and quantitative indicators.

[0130] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0131] Example 2

[0132] The hypertonic composite solution for infusion containing sorbitol and sodium L-malate of the present invention is prepared in the following manner.

[0133] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 60g sorbitol, 6g sodium chloride, 0.3g potassium chloride, 0.13g calcium chloride dihydrate, 0.43g magnesium chloride hexahydrate, 4.31g sodium acetate trihydrate, and 1.56g sodium L-malate. Then, 15g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0134] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0135] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0136] Example 3

[0137] The hypertonic composite solution for infusion containing sorbitol and L-malic acid of the present invention is prepared in the following manner.

[0138] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 50g sorbitol, 5.4g sodium chloride, 0.27g potassium chloride, 0.11g calcium chloride dihydrate, 0.36g magnesium chloride hexahydrate, 3.88g sodium acetate trihydrate, and 1.22g L-malic acid. Then, 13.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0139] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0140] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0141] Example 4

[0142] The hypertonic composite solution for infusion containing sorbitol and sodium L-malate of the present invention is prepared in the following manner.

[0143] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 50g sorbitol, 5.4g sodium chloride, 0.27g potassium chloride, 0.11g calcium chloride dihydrate, 0.36g magnesium chloride hexahydrate, 3.88g sodium acetate trihydrate, and 1.42g sodium L-malate. Then, 13.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0144] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0145] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0146] Example 5

[0147] The hypertonic composite solution for infusion containing sorbitol and L-malic acid of the present invention is prepared in the following manner.

[0148] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 70g sorbitol, 7g sodium chloride, 0.33g potassium chloride, 0.16g calcium chloride dihydrate, 0.49g magnesium chloride hexahydrate, 4.74g sodium acetate trihydrate, and 1.47g L-malic acid. Then, 16.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0149] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0150] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0151] Example 6

[0152] The hypertonic composite solution for infusion containing sorbitol and sodium L-malate of the present invention is prepared in the following manner.

[0153] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 70g sorbitol, 7g sodium chloride, 0.33g potassium chloride, 0.16g calcium chloride dihydrate, 0.49g magnesium chloride hexahydrate, 4.74g sodium acetate trihydrate, and 1.71g sodium L-malate. Then, 16.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0154] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0155] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0156] Example 7

[0157] The hypertonic composite solution for infusion containing xylitol and L-malic acid of the present invention is prepared in the following manner.

[0158] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 50g xylitol, 6g sodium chloride, 0.3g potassium chloride, 0.13g calcium chloride dihydrate, 0.43g magnesium chloride hexahydrate, 4.31g sodium acetate trihydrate, and 1.34g L-malic acid. Then, 15g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0159] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0160] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0161] Example 8

[0162] The hypertonic composite solution for infusion containing xylitol and sodium L-malate of the present invention is prepared in the following manner.

[0163] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 50g xylitol, 6g sodium chloride, 0.3g potassium chloride, 0.13g calcium chloride dihydrate, 0.43g magnesium chloride hexahydrate, 4.31g sodium acetate trihydrate, and 1.56g sodium L-malate. Then, 15g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0164] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0165] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0166] Example 9

[0167] The hypertonic composite solution for infusion containing xylitol and L-malic acid of the present invention is prepared in the following manner.

[0168] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 40 g xylitol, 5.4 g sodium chloride, 0.27 g potassium chloride, 0.11 g calcium chloride dihydrate, 0.36 g magnesium chloride hexahydrate, 3.88 g sodium acetate trihydrate, and 1.22 g L-malic acid. Then, 13.5 g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1 L) with infusion water and stirred to obtain the final infusion solution.

[0169] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0170] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0171] Example 10

[0172] The hypertonic composite solution for infusion containing xylitol and sodium L-malate of the present invention is prepared in the following manner.

[0173] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 40 g xylitol, 5.4 g sodium chloride, 0.27 g potassium chloride, 0.11 g calcium chloride dihydrate, 0.36 g magnesium chloride hexahydrate, 3.88 g sodium acetate trihydrate, and 1.42 g sodium L-malate. Then, 13.5 g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1 L) with infusion water and stirred to obtain the final infusion solution.

[0174] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0175] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0176] Example 11

[0177] The hypertonic composite solution for infusion containing xylitol and L-malic acid of the present invention is prepared in the following manner.

[0178] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 60g xylitol, 7g sodium chloride, 0.33g potassium chloride, 0.16g calcium chloride dihydrate, 0.49g magnesium chloride hexahydrate, 4.74g sodium acetate trihydrate, and 1.47g L-malic acid. Then, 16.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0179] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0180] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0181] Example 12

[0182] The hypertonic composite solution for infusion containing xylitol and sodium L-malate of the present invention is prepared in the following manner.

[0183] The infusion solution was prepared in an isolated storage room. Two-thirds of the infusion water was added to a metering mixer to dissolve 60g xylitol, 7g sodium chloride, 0.33g potassium chloride, 0.16g calcium chloride dihydrate, 0.49g magnesium chloride hexahydrate, 4.74g sodium acetate trihydrate, and 1.71g sodium L-malate. Then, 16.5g sodium lactate was added to the solution, and the solution was diluted to the nominal volume (1L) with infusion water and stirred to obtain the final infusion solution.

[0184] Then, as described in Example 1, the resulting infusion solution subsequently undergoes filtration, packaging, sterilization, and quality control stages.

[0185] The resulting solution is a colorless, transparent, and odorless liquid. The stability of the solution was tested under sterile conditions and during storage. The physicochemical properties of the solution were found to meet the requirements of analytical and regulatory documentation, indicating that the selected components and processes used to prepare the solution fully fulfilled the objectives of this invention.

[0186] The given embodiments of the present invention are not intended to limit the scope of protection of the claims, but are merely illustrative of the possibilities of implementation. It will be apparent to those skilled in the art that the hypertonic composite solution for infusion of the present invention can be implemented in other variations.

[0187] Example 13

[0188] Rabbit models were induced with toxic hepatitis after subcutaneous injection of carbon tetrachloride for 7 days. The specific activity of the infusion solution of this invention was investigated. Starting from the first day of the study, rabbit models were administered the infusion solution prepared according to Example 8 at a dose of 10 ml / kg body weight for 14 days. The results showed that, in the first 7 days of the study, in the context of carbon tetrachloride introduction, all rabbit models showed statistically significant increases in ALA (from 0.43 ± 0.04 to 1.39 ± 0.03 mmol / L x h), AST (from 0.30 ± 0.02 to 1.09 ± 0.02 mmol / L x h), and bilirubin (from 11.68 ± 0.95 to 21.60 ± 1.55 μmol / L). At the end of the study (i.e., day 14), these indicators decreased statistically significantly, but did not reach the initial levels (ALT decreased to 0.71 ± 0.02 mmol / L x h, AST decreased to 0.48 ± 0.02 mmol / L x h, and bilirubin decreased to 16.15 ± 1.30 μmol / L). Therefore, in the study of toxic hepatitis in a rabbit model, it was demonstrated that the infusion solution of the present invention at a dose of 10 ml / kg body weight has significant detoxification properties.

[0189] Example 14

[0190] The chronic toxicity study of the solution prepared according to Example 8 in rabbits (administered intravenously at a dose of 10 ml / kg body weight for 30 days) confirmed that the drug has no cumulative properties. Administration of the solution to rabbits did not cause any pathological changes in blood counts, hemostasis, electrolyte concentrations, biochemical blood parameters, or urine parameters. Pathological morphological studies showed that after repeated intravenous injections of the solution of this invention into rabbits, the internal organs of the study animals maintained normal structure without specific pathological changes, and there were no histological differences between the organs and those of the control group.

[0191] Example 15

[0192] In acute toxicity studies in animals, the infusion solution prepared according to Example 8 was found to be relatively safe when administered intraperitoneally to mice and rats. No animal death or symptoms of poisoning were observed after a single injection of the solution into mice at a dose of 50 ml / kg body weight, and into rats at a dose of 45 ml / kg body weight. Repeated intraperitoneal administration of the solution to mice and rats at the maximum possible overdose (180 ml / kg body weight for mice and 100 ml / kg body weight for rats) did not cause any animal death.

[0193] Example 16

[0194] A comparative study on the effects of the infusion solution of the present invention on microcirculation levels.

[0195] This study was conducted using a laser Doppler flowmeter (LDF) method with wavelet analysis. Results were recorded three times: before infusion (baseline recording), 5 minutes after infusion, and 30 minutes after infusion. Occlusion testing was performed by cuffing for 3 minutes and determining capillary flow reserve (CBFR).

[0196] The subject's microcirculation level was assessed based on the analysis of the following parameters.

[0197] Microcirculation score (MS) characterizes tissue blood flow and is the level of perfusion (blood flow) per unit volume of tissue per unit time. It reflects the volumetric red blood cell content in capillary blood and the number of simultaneously functioning capillaries within the study area.

[0198] Capillary flow reserve (CBFR) reflects the reserve capacity of microcirculatory channels in terms of increased microcirculatory rate during hyperemia following reactive occlusion.

[0199] We conducted an open-label prospective study involving two patients (one male and one female). The infusion solution was administered in two phases. The microcirculatory effects of the two infusion solutions (i.e., the infusion solution of the present invention and a control drug) were compared: 200 ml of the infusion solution of the present invention (composition: 100 ml solution contains 5 g xylitol, 0.6 g sodium chloride, 0.03 g potassium chloride, 0.01 g calcium chloride, 0.02 g magnesium chloride, 1.5 g sodium lactate, 0.26 g sodium acetate, and 0.134 g L-malic acid) and 200 ml of the control drug (e.g., ...). (Infusion solution) (Composition: 100ml solution contains 6g sorbitol, 1.9g sodium lactate, 0.6g sodium chloride, 0.01g calcium chloride, 0.03g potassium chloride, and 0.02g magnesium chloride). Microcirculation score (MS) and capillary flow reserve (CBFR) were measured before infusion, 5 minutes after infusion, and 30 minutes after infusion.

[0200] The solution of the present invention was infused into patient 1. During baseline recording, MS = 3.27 perfusion units (pf.un.); at 5 minutes post-infusion, MS increased to 6.14 pf.un; and at 30 minutes post-infusion, MS increased to 9.51 pf.un. Therefore, during the infusion of the solution of the present invention, patient 1's MS increased from 3.14 to 6.14 at 5 minutes post-infusion and significantly stabilized at 9.51 at 30 minutes post-infusion. Five minutes after infusion of the solution of the present invention, capillary flow reserve decreased from 187% to 109%, and RCBF further decreased to 103.16% at 30 minutes post-infusion, indicating that a portion of the reserve capillaries were opened due to the infusion of the solution of the present invention.

[0201] On day 2, the control drug was infused into patient 1. During the baseline recording period, MS = 6.45 pf.un., which increased slightly to 8.13 pf.un. at 5 minutes post-infusion, and remained almost stable at 30 minutes post-infusion, for example, MS = 8.23 ​​pf.un., which is far below the fraction of the infusion solution of the present invention; and the control drug did not show a stable residual effect. In addition, RCBF decreased from 156% at baseline to 112% at 5 minutes post-infusion, and decreased slightly to 99% at 30 minutes post-infusion.

[0202] During examination of patient 2, the solution of the present invention was infused on day 1. At baseline, MS = 8.06 pf.un. At 5 minutes post-infusion, MS increased to 8.24 pf.un, and at 30 minutes post-infusion, MS increased to 10.56 pf.un. Therefore, the MS value increased slightly from 8.06 to 8.24 pf.un, and significantly to 10.56 pf.un at 30 minutes post-infusion. At 5 minutes post-infusion, RCBF decreased from 197% to 115%, and at 30 minutes post-infusion, it decreased to 106%.

[0203] On day 2, patient 2 received the control drug via infusion. At baseline, MS = 8.52 pf.un. At 5 minutes post-infusion, MS increased to 8.56 pf.un, and at 30 minutes post-infusion, MS increased to 9.01 pf.un. That is, the MS value slightly increased from 8.52 to 8.56 pf.un at 5 minutes post-infusion, and slightly increased to 9.01 pf.un at 30 minutes post-infusion. Simultaneously, the RCBF value decreased from 141% to 91% at 5 minutes post-infusion and decreased to 80% at 30 minutes post-infusion. The results are shown in Table 1.

[0204] Table 1

[0205] Results of a study on the effects of infusion fluid and control drugs on microcirculation scores and capillary blood flow reserve

[0206]

[0207]

[0208] Therefore, this study shows that when using the infusion solution of the present invention, two patients examined at 5 minutes post-infusion exhibited significantly increased microcirculatory function, and the effect remained stable and sustained at 30 minutes post-infusion, due to relaxation of the precapillary sphincter. This may be because the infusion compound solution of the present invention contains polyols, lactic acid, L-malic acid, and acetate ions, which activate A3 adenosine receptors. RCBF decreased at both 5 minutes and 30 minutes post-infusion, indicating that a portion of the reserve capillaries were opened due to the infusion of the solution of the present invention.

[0209] like Figures 1-3 As shown, due to the reduction in capillary muscle rigidity leading to relaxation of the precapillary sphincter, the infusion solution of this invention improves microcirculation. Furthermore, the maximum amplitude of respiratory mobilization is also increased.

[0210] like Figures 4-6 As shown, the use of the control drug slightly improved microcirculation due to increased exposure to the endothelial portion and reduced capillary muscle rigidity (leading to relaxation of the precapillary sphincter).

[0211] like Figures 7-12 As shown, compared with the control drug, the infusion solution of the present invention can stably increase the endothelial portion of microcirculation regulation and reduce capillary nerve tension, thereby improving microcirculation.

[0212] Example 17

[0213] To demonstrate the effectiveness and safety of the different components in the infusion solution of this invention, a series of three clinical trials were conducted. These clinical trials were designed identically and involved a total of 111 patients.

[0214] A randomized open-label parallel comparative study was conducted, compared with known... Compared with pharmaceuticals, studies have confirmed the effectiveness and safety of different components in the infusion solution of this invention.

[0215] The study included patients aged 18 to 60 with the following conditions:

[0216] —Traumatic, surgical, hemolytic, toxic, or burn shock;

[0217] —Burn-related diseases;

[0218] —Acute bleeding;

[0219] —Infectious diseases that accompany poisoning;

[0220] —Hepatitis worsened;

[0221] --septicemia;

[0222] —Thrombophlebitis.

[0223] Based on laboratory parameters, all of the above-mentioned conditions were accompanied by varying degrees of metabolic acidosis, blood electrolyte and rheological imbalances. Hemodynamic and microcirculatory abnormalities were observed according to the severity of the pathology. Patients with excessively high lactate levels were not included in this study.

[0224] According to the treatment protocol of the Ukrainian Ministry of Health, all patients received standard treatment for the aforementioned conditions. The infusion solution of this invention or... Different components of the control drug were used as hypertonic solutions.

[0225] To assess effectiveness, the following parameters were measured throughout the treatment process using the infusion solution of the present invention: the patient's general condition, subjective symptoms of the disease, routine blood tests, acid-base balance, coagulation profile, ionic and gaseous components of the blood, arterial and venous pressure, and diuretic dynamics.

[0226] The first study included 45 patients who were randomly assigned to three groups of 15 subjects each. Group 1 received treatment with the infusion solution of the present invention as a hypertonic solution, the composition of which is as follows (wt.%):

[0227] 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 L-malic acid 0.122 Water for injection The remainder to 100%

[0228] Group 2 was treated using the infusion solution of the present invention as a hypertonic solution, and the composition of the infusion solution was as follows (wt.%):

[0229]

[0230]

[0231] Group 3 was treated with a control drug as a hypertonic solution.

[0232] The second study included 30 patients who were randomly assigned to three groups of 10 participants each.

[0233] Group 1 was treated using the infusion solution of the present invention as a hypertonic solution. The composition of the infusion solution is as follows (wt.%):

[0234] 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 L-malic acid 0.134 Water for injection The remainder to 100%

[0235] Group 2 was treated using the infusion solution of the present invention as a hypertonic solution, and the composition of the infusion solution was as follows (wt.%):

[0236]

[0237]

[0238] Group 3 was treated with a control drug as a hypertonic solution.

[0239] The third study included 36 patients who were randomly assigned to three groups of 12 participants each.

[0240] Group 1 was treated using the infusion solution of the present invention as a hypertonic solution. The composition of the infusion solution is as follows (wt.%):

[0241] 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 L-malic acid 0.147 Water for injection The remainder to 100%

[0242] Group 2 was treated using the infusion solution of the present invention as a hypertonic solution, and the composition of the infusion solution was as follows (wt.%):

[0243] Sorbitol 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 L-malic acid 0.147 Water for injection The remainder to 100% Xylitol Sodium chloride Potassium chloride Calcium chloride Magnesium chloride Sodium lactate Sodium acetate L-malic acid Water for injection The remainder to 100%

[0244] Group 3 was treated with a control drug as a hypertonic solution.

[0245] Based on these three studies, the inventors recorded and analyzed the following results. Clinical and laboratory studies showed that the subjective complaints of patients in groups 1 and 2 disappeared earlier than those in group 3. Therefore, compared to the control group, patients receiving the infusion solution of this invention achieved normal body temperature, relief of general weakness, normal urination, and improved appetite 2-3 days earlier.

[0246] Notably, in Groups 1 and 2, hemodynamic parameters (including microcirculation) stabilized on average 5-6 hours after initiating combination therapy with the solution of this invention, and stabilized 6-8 hours after initiating combination therapy with the control drug. In all groups, hematological parameters, particularly red blood cell count, hemoglobin, hematocrit, and blood amylase levels, approached baseline values ​​24-48 hours after treatment initiation. Compared to the control group, white blood cell count, white blood cell structure, and ESR normalized 2-3 days earlier in Groups 1 and 2.

[0247] Furthermore, blood glucose parameters improved in group 2. This can be explained by the presence of xylitol in the solution of group 2. Unlike sorbitol, xylitol can be metabolized without insulin and does not convert into fructose, therefore it can be used freely even by patients with diabetes and fructose intolerance.

[0248] All patients had varying degrees of metabolic acidosis prior to treatment with the hypertonic solution studied. Alkalization was observed in all groups during treatment with the solution of this invention, but was more pronounced in groups 1 and 2. Patients' acid-base status normalized 36 hours after using the solution of this invention. For group 3 patients, acid-base status normalized 48–72 hours after using the control drug. This can be explained by the presence of acetate in the solution compositions of groups 1 and 2, which rapidly integrates into metabolism and releases HCO3- within 15 minutes after administration. - Ions. The rate at which blood acid-base parameters normalize when using the infusion solution of this invention at different concentrations is directly proportional to the concentration of the alkaline reserve carrier in the research drug.

[0249] No side effects were observed during the entire study when the infusion solution and control drug of the present invention were used.

[0250] Therefore, we can conclude that in the combined treatment of patients with the above-mentioned conditions, the infusion solution of the present invention used in various combinations has a positive effect on the reduction of clinical manifestations, the restoration of blood acid-base balance, hemodynamics and microcirculation scores, and the restoration of blood counts to normal.

[0251] Therefore, the hypertonic composite solution for infusion of the present invention can achieve the following effects: the hypertonic composite solution for infusion of the present invention is effective and safe to use, and can be used to treat various diseases such as microcirculation and peripheral blood circulation disorders; it can be used to treat different populations, including patients with diabetes and fructose intolerance; its characteristics include that the alkalization effect can be initiated more quickly, reducing the risk of patients taking excessive lactate ions; it can be used in small amounts, i.e., it is suitable for restrictive infusion therapy, and due to the different combinations and ratios of the components, it has multifunctional effects, namely rheological, detoxification and anti-shock effects.

Claims

1. A hypertonic compound solution for infusion, comprising a polyol, sodium chloride, potassium chloride, calcium chloride in anhydrous or hydrated form, magnesium chloride in anhydrous or hydrated form, sodium lactate in anhydrous or hydrated form, and water for infusion, and further comprising sodium acetate in anhydrous or hydrated form and L-malic acid or sodium L-malate, wherein the dry weight ratio (wt.%) of each component is as follows: Polyols 4% - 7% Sodium chloride 0.54% – 0.66% Potassium chloride 0.027% – 0.033% Anhydrous calcium chloride or calcium chloride in hydrated or crystalline form: 0.008% – 0.012% Magnesium chloride in anhydrous salt or hydrated form: 0.017% – 0.023% Sodium lactate in anhydrous salt or hydrated form: 1.35% - 1.65% Sodium acetate in anhydrous salt or hydrated form: 0.234% – 0.286% L-malic acid or sodium L-malate 0.120% – 0.145% The remaining water for injection is increased to 100%; The hypertonic compound solution for infusion contains sorbitol, xylitol, or a mixture thereof as a polyol.

2. The hypertonic compound solution for infusion according to claim 1, characterized in that, The hypertonic compound solution for infusion contains sorbitol, sodium chloride, potassium chloride, calcium chloride in anhydrous or hydrated form, magnesium chloride in anhydrous or hydrated form, sodium lactate in anhydrous or hydrated form, sodium acetate in anhydrous or hydrated form, L-malic acid or sodium L-malate, and water for infusion. The dry weight ratio (wt.%) of each component is as follows: Sorbitol 5% - 7% Sodium chloride 0.54% – 0.66% Potassium chloride 0.027%–0.033% Anhydrous calcium chloride or calcium chloride in hydrated or crystalline form: 0.008% – 0.012% Magnesium chloride in anhydrous salt or hydrated form: 0.017% – 0.023% Sodium lactate in anhydrous salt or hydrated form: 1.35% – 1.65% Sodium acetate in anhydrous salt or hydrated form: 0.234% – 0.286% L-malic acid or sodium L-malate 0.120% – 0.145% The remaining water is injected to 100%.

3. The hypertonic compound solution for infusion according to claim 1, characterized in that, The hypertonic compound solution for infusion contains xylitol, sodium chloride, potassium chloride, calcium chloride in anhydrous or hydrated form, magnesium chloride in anhydrous or hydrated form, sodium lactate in anhydrous or hydrated form, sodium acetate in anhydrous or hydrated form, L-malic acid or sodium L-malate, and water for infusion. The dry weight ratio (wt.%) of each component is as follows: Xylitol 4% - 6% Sodium chloride 0.54%–0.66% Potassium chloride 0.027% – 0.033% Anhydrous calcium chloride or crystalline hydrate form: 0.008%–0.012% Anhydrous magnesium chloride or crystalline hydrate form: 0.017% – 0.023% Sodium lactate in anhydrous salt or crystalline hydrate form: 1.35% – 1.65% Sodium acetate in anhydrous salt or hydrated form: 0.234%–0.286% L-malic acid or sodium L-malate 0.120% – 0.145% The remaining water is injected to 100%.

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