RU2732754C1 - Method for preparing a complex infusion preparation and use thereof for correcting hyperphosphatemia and reducing vascular impermeability in patients with renal insufficiency - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the field of medicine, namely to a complex infusion preparation and a method for its preparation, which involves preparing the drug solution by dissolving the following preparation components in pre-treated and purified water for injections: sorbitol, sodium lactate, sodium chloride, potassium chloride, magnesium chloride or magnesium chloride hexahydrate, calcium gluconate, with the following ratio of components, wt. %: sorbitol - 5.0–7.0; sodium lactate in terms of dry substance - 1.6–2.2; sodium chloride - 0.5–0.7; potassium chloride - 0.025–0.035; magnesium chloride or magnesium chloride hexahydrate in terms of dry substance - 0.006–0.016; calcium gluconate - 0.015–0.025; water for injection is balance; at that, the method includes the following stages: a) water is injected into reactor for injection with temperature of 80–95 °C in amount of not more than 70 % of calculated amount; b) loading gluconate into the calcium reactor, stirring, cooling solution to 40–45 °C; c) charging sodium chloride into the reactor, stirring; d) charging a chloride or magnesium chloride hexahydrate into a magnesium reactor, stirring; e) loading potassium chloride into reactor, stirring; f) loading sorbitol into reactor, stirring; g) loading lactate into a sodium reactor, stirring; h) bringing solution volume with water for injections to 100 %, cooling solution to 20–25 °C, stirring and circulating a solution for at least 30 minutes; i) holding the solution while stirring for at least 1 hour for stabilization; j) filtering the solution in three steps; k) packing the preparation solution into bottles; l) sterilized bottles with solution of preparation and also refers to application of infusion complex preparation for correction of hyperphosphatemia and reduction of vascular impermeability in patients with renal insufficiency.

EFFECT: group of inventions provides an improved method of preparing and adapting the composition of the infusion preparation in order to obtain a new complex pharmaceutical preparation used for a new purpose - for correcting hyperphosphatemia and reducing vascular impermeability in patients with renal insufficiency.

6 cl, 5 tbl, 6 ex

Description

FIELD OF TECHNOLOGY

The invention relates to the field of pharmaceutics, namely to a method for the manufacture and use of a complex preparation intended for infusion therapy for correcting hyperphosphatemia and reducing vascular impermeability in patients with renal insufficiency.

Preparations for infusion therapy are used in medicine for blood loss, which can be caused by wounds, trauma and surgery, as well as, if necessary, the use of treatment methods related to the regulation of blood volume, blood composition and other blood characteristics. Preparations for infusion therapy have such a formulation as infusion solutions.

Hyperphosphatemia is one of the most significant complications of chronic kidney disease.

Disorders in phosphorus excretion begin to occur in patients with chronic kidney disease early in the preclinical stages of the renal continuum, which initially leads to compensated hyperphosphatemia. Then, with the inevitable aggravation of renal dysfunction, this process becomes decompensated.

Long-term maintenance by the kidneys of the level of phosphorus in the body within normal limits (compensated hyperphosphatemia) is possible due to an increase in the production and enhancement of receptor interactions of such phosphaturic hormones as fibroblast growth factor-23 (FGF-23), thyrocalcitonin (calcitonin) and parathyroid hormone (PTH).

Chronic hyperphosphatemia together with hypocalcemia and deficiency of active forms of vitamin D (calcitriol) leads to the development of secondary and tertiary hyperparathyroidism in patients with renal insufficiency, as a result of which the overproduction of PTH becomes uncontrolled.

FGF-23, and especially PTH, are significant and, in some cases, the leading factors of uremic intoxication in patients with renal failure and directly correlate with the severity of clinical manifestations and mortality from this pathology.

Even a complete cessation of phosphorus intake at the clinical stage is not able to significantly affect the severity of secondary / tertiary hyperparathyroidism. Therefore, control over the balance of phosphorus in the body should be started at the early stages of the disease.

For this purpose, the following therapeutic tactics are used: reducing the intake of phosphorus from food (special "renal" diets and phosphate binders) and increasing its elimination by the kidneys (nephroprotective therapy, the use of certain loop diuretics).

To control the severity of hyperparathyroidism and its consequences in patients, it is possible to use a PTH antagonist - calcitonin and antiparathyroid drugs.

Currently, scientists and practicing nephrologists are looking for new pharmaceuticals to correct hyperphosphatemia and reduce vascular impermeability in patients with renal insufficiency, as well as continue active research on various mechanisms of the pathological effect on the body of previously discovered toxic substances and compounds, the accumulation of which occurs in the body of patients as at the clinical and, which is especially important, preclinical stages of renal failure.

Of particular interest are the mechanisms of development and the possibility of correction in patients with renal insufficiency of the mineral bone syndrome (MCS) (CKD-MCS) and the inextricably linked phenomena of compensated and decompensated hyperphosphatemia and secondary / tertiary hyperparathyroidism.

LEVEL OF TECHNOLOGY

From RF patent RU 2262340 C1, publ. 20.10.2005, a drug for infusion therapy is known, which is obtained by a method including such actions as obtaining a solution of the drug by dissolving in pyrogen-free distilled water heated to a temperature of 40-70 ° C solid components of the drug for infusion therapy - sodium salt and a colloidal substance of a polymeric nature, stirring the resulting drug solution for 30-60 minutes, temperature treatment of the drug solution by heating the resulting solution to a temperature of 90-100 ° C and holding at this temperature for 15-30 minutes, cooling the drug solution, filtering the drug solution sequentially through microfilters with a pore diameter 0.8 and / or 0.45 microns and sterilizing filters with a pore diameter of 0.22 microns, filling the drug solution in containers and sterilizing containers with the drug solution.

The closest in the claimed composition is the infusion preparation obtained by the method disclosed in the Eurasian patent No. EA 026248 B1, publ. 03/31/2017

The method of obtaining a drug for infusion therapy includes such actions as obtaining a solution of the drug by dissolving solid components of the drug for infusion therapy in a pyrogen-free distilled water heated to a temperature of 30-50 ° C, where sodium chloride, potassium chloride are used as solid components of the drug for infusion therapy , calcium chloride, magnesium chloride, sodium lactate and polyhydric alcohol, stirring the resulting solution for 20-30 minutes, cooling the drug solution, filtering the drug solution through a filter, filling the drug solution in a container and sterilizing containers with the drug solution. The drug for infusion therapy, which is obtained according to the method described above, has the following qualitative and quantitative composition in wt%:

polyhydric alcohol - 5.0-7.0;

sodium lactate - 1.6-2.2;

sodium chloride - 0.5-0.7;

potassium chloride - 0.025-0.035;

calcium chloride - 0.007-0.013;

magnesium chloride - 0.017-0.023;

pyrogen-free distilled water - the rest.

The objectives of the claimed invention are to improve the method of obtaining an infusion drug and the development of a new drug by changing its composition with the possibility of using it for a new purpose, namely for correcting hyperphosphatemia and reducing vascular impermeability in patients with renal failure.

DISCLOSURE OF THE INVENTION

One of the advantages of the claimed invention is the presence of calcium gluconate in solution. Calcium gluconate eliminates the deficiency of calcium ions. Calcium ions are necessary for the processes of transmission of nerve impulses, contraction of skeletal and smooth muscles, myocardial activity, bone formation, blood coagulation. Reduces the permeability of cells and the vascular wall, prevents the development of inflammatory reactions, increases the body's resistance to infections and can significantly enhance phagocytosis. Unlike calcium chloride, it does not increase the amount of chlorine introduced and does not irritate tissues when it enters the subcutaneous tissue.

In previously known similar infusion preparations, calcium chloride is present in the composition, which can be administered exclusively intravenously, since when it enters the subcutaneous tissue and muscles, it can lead to tissue necrosis. Whereas calcium gluconate can be administered not only intravenously, but also intramuscularly and subcutaneously. Therefore, the exclusion of calcium chloride from the composition and the introduction of calcium gluconate into the composition will make the infusion safer for the patient. Reduces the likelihood of pain along the veins at the time of rapid administration of the drug.

In addition, replacing calcium chloride with calcium gluconate will reduce the amount of chlorine introduced. An excessive amount of chlorine during massive infusions often provokes hyperchloremic acidosis, which is dangerous for the patient by an increase in the acidity of the body. Therefore, replacing calcium chloride with calcium gluconate will reduce the likelihood of such complications for the patient's health as hyperchloremic acidosis. The claimed invention is safe for hypertensive patients and patients with renal pathology.

Thus, the claimed pharmaceutical preparation is significantly safer for the patient, as well as for medical personnel. Calcium gluconate acts like calcium chloride, but in contrast to it, it has a weaker local irritant effect, is better tolerated, and is 2-4 times less toxic. The introduction of the drug based on the replacement of the above components corresponds to the basic principle of clinical pharmacology - maximum efficiency with maximum safety of the drug use.

As the studies below show, the claimed pharmaceutical preparation in the specified ratio of components helps to improve renal function, leads to the correction of hyperphosphatemia and a decrease in vascular impermeability in patients with renal failure, and also reduces the incidence of complications such as headaches, weakness, fatigue, decreased performance. decreased memory and attention, apathy, which significantly affect the quality of life of this category of patients.

The developers of the drug claimed in the present invention have found a new indication for use - correction of hyperphosphatemia and reduction of vascular impermeability in patients with renal failure.

The technical result of the invention is to improve the manufacturing method and adapt the composition of the infusion preparation in order to obtain a new complex pharmaceutical preparation used for a new purpose - to correct hyperphosphatemia and reduce vascular impermeability in patients with renal failure.

The specified technical result is achieved due to the developed composition and method of manufacturing a complex infusion preparation used not only to improve capillary blood flow for the prevention and treatment of traumatic, operational, hemolytic, toxic and burn shock, in acute blood loss, burn disease, infectious diseases, which are accompanied by intoxication, with exacerbation of chronic hepatitis, sepsis, for preoperative preparation and in the postoperative period, to improve arterial and venous circulation in order to prevent thrombosis, thrombophlebitis, endarteritis, Raynaud's disease, but also to correct hyperphosphatemia and reduce vascular impermeability in patients with renal failure, which includes obtaining a solution of the drug by dissolving the following components of the drug in pre-prepared and purified water for injection: sorbitol, sodium lactate, sodium chloride, potassium chloride, magnesium chl oride or magnesium chloride hexahydrate, calcium gluconate, with the following ratio of components, wt%:

sorbitol - 5.0-7.0;

sodium lactate in terms of dry matter - 1.6-2.2;

sodium chloride - 0.5-0.7;

potassium chloride - 0.025-0.035;

magnesium chloride or magnesium chloride hexahydrate

in terms of dry matter - 0.006-0.016;

calcium gluconate - 0.015-0.025;

water for injection - the rest,

the method includes the following steps:

a) water for injection with a temperature of 80-95 ° C is collected in the reactor in a volume of not more than 70% of the calculated amount;

b) load calcium gluconate into the reactor, mix, cool the solution to 40-45 ° C;

c) load sodium chloride into the reactor, mix;

d) load into the reactor magnesium chloride or magnesium chloride hexahydrate, mix;

e) load potassium chloride into the reactor, stir;

f) load sorbitol into the reactor, mix;

g) load sodium lactate into the reactor, mix;

h) bring the volume of the solution to 100% with water for injection, cool the solution to 20-25 ° C, stir;

i) circulate the solution for at least 30 minutes;

j) keep the solution under stirring for at least 1 hour to stabilize;

l) filter the solution in three stages;

l) pack the drug solution into vials;

m) sterilize the vials with the drug solution.

In this case, the method at stage l) the first stage of filtration is carried out through a Sartopure® PP3 polypropylene depth pre-filter with a pore size of 1.2 μm.

The method in step l) the second stage of filtration is carried out through a Sartobran® P filter with a pore size of 0.45 μm.

In this case, the method in stage l) the third stage of filtration is carried out through a Sartobran® P filter with a pore size of 0.2 μm.

The above and other objects, features, advantages, as well as the technical significance of the present invention will be better understood from the following detailed description of the invention.

CARRYING OUT THE INVENTION

The claimed complex preparation has a rheological, anti-shock, detoxification, and alkalizing effect and stimulates intestinal peristalsis. The main pharmacologically active substances of the drug are sorbitol and sodium lactate. In the liver, sorbitol is first converted to fructose, which is later converted to glucose, and then to glycogen. Part of the sorbitol is used for urgent energy needs, while the other part is stored as glycogen. Isotonic sorbitol solution has a disaggregating effect and thus improves microcirculation and tissue perfusion. The disaggregation effect of this drug is of great importance in the pathogenetic therapy of patients with chronic renal failure.

Unlike bicarbonate solution, correction of metabolic acidosis with sodium lactate occurs more slowly as it is included in the metabolism, there are no sharp fluctuations in pH. The effect of sodium lactate appears 20-30 minutes after administration.

Sodium chloride has a rehydrating effect. Replenishes the deficiency of sodium and chlorine ions in various pathological conditions.

Potassium chloride restores the water-electrolyte balance. It has a negative chrono- and batmotropic effect, in high doses - negative ino-, dromotropic and moderate diuretic effects. Participates in the process of conducting nerve impulses. Increases the content of acetylcholine and stimulates the sympathetic division of the autonomic nervous system. Improves the contraction of skeletal muscles in muscular dystrophy, myasthenia gravis.

Calcium gluconate eliminates the deficiency of calcium ions. Calcium ions are necessary for the processes of transmission of nerve impulses, contraction of skeletal and smooth muscles, myocardial activity, bone formation, blood coagulation. Reduces the permeability of cells and the vascular wall, prevents the development of inflammatory reactions, increases the body's resistance to infections and can significantly enhance phagocytosis. Unlike calcium chloride, it does not increase the amount of chlorine introduced and does not irritate tissues when it enters the subcutaneous tissue.

The quantitative composition of a complex pharmaceutical product is represented by the following ranges of component contents:

Sorbitol - 5.0-7.0 g / 100ml,

Sodium lactate in terms of 100% substance - 1.6-2.2 g / 100ml,

Sodium chloride - 0.5-0.7 g / 100ml,

Potassium chloride - 0.025-0.035 g / 100ml,

Magnesium chloride or magnesium chloride hexahydrate in terms of dry matter - 0.006-0.016 g / 100 ml

Calcium gluconate - 0.015-0.025 g / 100ml,

Water for injection up to 100 ml.

The table below shows examples of formulations of a complex pharmaceutical preparation of the present invention.

P / p No. Composition per 100 ml of water, in g Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 sorbitol 6.0 five 5.6 7.0 6,7 5.3 2 sodium lactate on a dry matter basis 1.9 2.2 2.0 1.7 2.1 1.6 3 sodium chloride 0.6 0.55 0.63 0.5 0.65 0.7 4 potassium chloride 0.03 0.027 0.035 0.025 0.029 0.033 five magnesium chloride
in terms of dry matter 0.015 - 0.008 - 0.010 - magnesium chloride hexahydrate
in terms of dry matter - 0.016 - 0.006 - 0.014 6 calcium gluconate 0.020 0.025 0.021 0.015 0.023 0.018 7 water for injections rest rest rest rest rest rest

The above composition is obtained in the following way.

Water for injection is obtained from purified water in a multi-column distiller. Water for injection is obtained from purified water by distillation. Purified water (obtained by filtering tap water through several filters, as well as driven through reverse osmosis) is pumped into a distiller, where it is heated due to heat transfer of pure steam. The heated water enters from the condenser-heat exchanger into the tube space of the heat exchanger, successively distilling through 6 heat exchangers and constantly heating up due to the fact that sterile steam flows through the same heat exchangers, which is cooled from the incoming purified water. Water from the tube space of the heat exchanger goes down the distillation column. Then it rises to the top of the column, where it heats up, boils due to the heat of the technical steam entering the annular space of the column, and due to the evaporation of water. Purified water, falling into the lower part of the column, begins to boil, the resulting steam partially turns into steam for subsequent conversion into injection water, and partially serves as a heater in the next column. The resulting purified steam enters the shell side of the heat exchanger, condenses and gives off heat to the feed water in the tube space. The vapor obtained in the distillation column enters the shell side of the distillation column. The heat generated during the condensation of steam is transferred to the feed water. Water is distilled sequentially through 6 distillation columns. The initial water and the generated steam in the system move in a countercurrent flow. Due to the temperature difference, heated water boils up with the formation of steam. Water is heated in stages at each distillation stage. At the same time, the distillate is cooled and condensed. The steam obtained in the annular space of the last column is directed to the annular space of the condenser-heat exchanger. The distillate (water for injection) obtained in the column enters the condenser and heat exchanger. From the condenser-heat exchanger, the distillate enters the annular space of the refrigerator, at a temperature of 80-95 ° C it enters the collector (closed tanker) for cooling water for injection. Storage of water for injection occurs with constant circulation by a pump at a temperature of 80-95 ° C, but not more than 24 hours.

Then the water for injection passes through pipelines to the stage of "solution preparation".

The reactor is filled with water for injection in a volume of not more than 70% of the calculated amount. Calcium gluconate is loaded into the reactor, the stirrer is turned on and stirred for about 20 minutes. Then the solution is cooled to 40-45 ° C and sodium chloride is loaded into the reactor, stirred for about 10 minutes. Then loaded into the reactor magnesium chloride or magnesium chloride hexahydrate, stirred for about minutes. Next, potassium chloride is loaded into the reactor, stirred for about 10 minutes. Sorbitol is loaded into the reactor, stirred for about 15-20 minutes. Load sodium lactate into the reactor, mix for about 15 minutes. Bring the volume of the solution with water for injection to the required value, cool the solution to 20-25 ° C. Turn off the stirrer and circulation of the solution. Stir and circulate the solution for about 30 minutes. Leave the solution with stirring for about 1 hour to stabilize. After the exposure, the stirrer and the reactor circulation are turned on.

Then the solution is filtered in three stages on installations with Sartorius® filters with pore sizes of 1.2 μm, 0.45 μm, then 0.2 μm. Before the start of filtration, open the valves for supplying the solution to the filtration units, for filling into the storage tank, turning on the pump. The pressure on the filtration unit must be adjusted. The pressure on the manometer should be no more than 3 kgf / cm². Turn on the pump. The filtration process is started.

Pre-filtration is carried out through a Sartopure® PP3 polypropylene depth prefilter, the latest development from Sartorius Stedim Biotech to remove particles from liquids. Sartopure® PP3 filter with a pore size of 1.2 µm is characterized by high chemical resistance and an extremely low amount of leachable components. Moreover, the filter exhibits effective particle retention and high overall throughput without reducing the flow rate.

The solution then passes through a Sartobran® P filter with a pore size of 0.45 μm. It is a sterilizing pharmaceutical filter with cellulose acetate membrane.

The last stage of filtration is carried out immediately before filling into vials, the solution passes through a Sartobran® P filter with a pore size of 0.2 μm.

This filtration system provides maximum protection of the drug against the possibility of bacterial endotoxins in the drug solution when it passes through the pipeline from the reactor to the bottle.

After the solution is filtered, it enters the filling and capping line. Then the bottles with the solution are sterilized in a water autoclave at a temperature of 120 ° C ± 1 ° C for 30 minutes (glass bottles) or 105 ° C ± 1 ° C for 40 minutes (plastic bottles).

The production of an improved composition of an infusion solution is carried out by replacing components to reduce possible side effects and improve the method of obtaining a drug for infusion therapy by changing actions that lead to time and energy savings, and also provides a new indication for use - for correcting hyperphosphatemia and reducing vascular impermeability in patients with renal failure.

In accordance with international GMP rules and the requirements of national and international articles "Water for injection" in the section "Storage" it is indicated that water for injection is used freshly prepared or stored at a temperature of 80 ° C to 95 ° C. Freshly prepared water for injection has a temperature of about 80 ° C. The first component that is dissolved in the preparation of the solution is calcium gluconate. Calcium gluconate is slowly soluble in water (1:50 in cold and 1: 5 in boiling). Dissolving it first in hot water reduces the dissolution time; in the process of dissolving and stirring calcium gluconate, water for injection is partially cooled naturally. Accordingly, the next stage of cooling the solution before adding the subsequent components takes less time and requires less consumption of cold water to cool the solution. That allows you to save energy consumption with constant industrial production.

The introduction of this drug complies with the basic principle of clinical pharmacology - maximum efficiency with maximum safety of the drug use, and also allows this production cycle to be carried out with the provision of energy efficiency and energy saving in accordance with the ongoing economic and social reform in the field of energy saving.

The following are the results of clinical trials of the claimed drug in order to assess its effectiveness for the specified new appointment.

Solution for infusion 200 ml with the composition according to the present invention was studied in the framework of complex therapy in patients with intoxication syndrome in chronic renal failure in the pre-dialysis period, in need of lowering the level of urea, creatinine, residual nitrogen and phosphorus in the blood.

There were 50 patients in the group receiving the study drug, and 50 patients in the comparison group receiving basic therapy. The groups are matched for gender, age and diagnosis. The study involved patients on inpatient or outpatient treatment, of both sexes, over the age of 18 years, who gave written informed consent to participate in the study, with a confirmed diagnosis of chronic renal failure (CRF) in the pre-dialysis period, in need of lowering the level of urea, creatinine, residual nitrogen and phosphorus in the blood.

Patients of the main group (30 people) were prescribed the solution for infusion of 200 ml, 200 ml, according to the present invention, once a day, intravenously, by drop, for 10 days against the background of basic therapy (low-protein diet, antihypertensive drugs, correctors of renal anemia).

Patients 30 people, who made up the comparison group, received only basic therapy for 10 days (low-protein diet, antihypertensive drugs, correctors of renal anemia).

At the same time, other drugs with a similar hypoazotemic effect were excluded. We used the drugs of the underlying disease necessary for treatment and other drugs compatible with the drug, as well as the necessary physiotherapeutic methods of treatment.

The patients were hospitalized at the TMA clinic in the nephrology department. In all patients, the diagnosis was clinically verified and laboratory confirmed.

The study included 60 patients with chronic renal failure of various etiologies, including 31 (52%) men and 29 (48%) women.

The experimental group consisted of patients aged 18 and more, aged 19 to 73 years. The average age of the patients was 50.8 ± 3.3 years. Of these, 13 women (43.3%) and 17 men (56.7%).

In the comparison group with such diagnoses and the corresponding age at the age of 20 to 74 years. The average age of the patients was 47.7 ± 2.9 years. Of these, 16 women (53.3%) and 14 men (46.7%).

In 38 patients, chronic pyelonephritis was the cause of CRF, and in 22 - chronic glomerulonephritis. CPI I Art. ascertained in 31 patients, II Art. - at 23, III Art. - at 6. Patients were admitted to the hospital in connection with the progression of renal failure. Evaluation of the effectiveness and safety of treatment was based on monitoring the general condition of patients, the clinical course of the disease, and laboratory parameters.

Before the start of the study, all patients underwent a preliminary examination, including physical examination, objective examination, registration of the patient's subjective complaints; clinical analyzes: general blood test, general urine analysis; biochemical analyzes: total protein, urea, creatinine, K +, Na + blood phosphorus, GFR, ALT, AST, bilirubin; instrumental studies: ultrasound of the kidneys.

Table 1

Description of patients included in the study:

Index Experienced group Control group Total Number of patients thirty thirty 60 Average age, years (M ± m) 50.8 ± 3.3 47.7 ± 2.9 Women 13 (43.3%) 16 (53.3%) 29 (48%) Men 17 (56.7%). 14 (46.7%). 31 (52%)

In addition, patients of all groups received antihypertensive drugs (enap at a dose of 5–10 mg / day), enterosorbents (enterosgel), and iron preparations. The volume of therapy in the examined groups did not differ significantly. All patients complained of headache, weakness, fatigue, decreased appetite, thirst, in 2 patients with chronic renal failure, stage III. periodically there was vomiting, itching of the skin, 8 patients complained of nausea. An objective study revealed pallor of the skin in 18 patients, dry skin in 4 patients, peripheral edema in 3 patients. The assessment of the subjective state was carried out by patients on a 3-point scale: symptoms are significantly expressed (3 points), moderately expressed (2 points), slightly expressed (1 point), absent (0 points). The diary was filled in every day in the morning, the condition for the past day was assessed. The general condition was assessed as unsatisfactory (3 points), moderate (2 points), satisfactory (1 point), good (0 points).

The analysis of the data obtained (Table 2) indicates a positive assessment of the dynamics of their condition by patients in all groups. The most pronounced symptoms of reducing intoxication in the group of patients who received the claimed pharmaceutical preparation according to the present invention, compared with the indicators of patients of group II, who received glucose infusion.

table 2

Subjective symptoms I group II group Before treatment
M ± m After treatment
M ± m Before treatment
M ± m After treatment
M ± m Headache 2.2 ± 0.07 1.6 ± 0.06 2.1 ± 0.09 1.8 ± 0.07 Nausea 1.6 ± 0.06 0.8 ± 0.03 1.5 ± 0.03 1.2 ± 0.03 Itchy skin 1.3 ± 0.05 0.4 ± 0.02 1.2 ± 0.06 0.6 ± 0.04 Decreased appetite 2.5 ± 0.08 1.4 ± 0.06 2.4 ± 0.08 1.5 ± 0.07 Thirst 1.9 ± 0.09 0.9 ± 0.07 2.0 ± 0.09 1.1 ± 0.06 General state 2.6 ± 0.08 1.2 ± 0.08 2.5 ± 0.06 1.6 ± 0.03

In 45 patients arterial hypertension (AH) was recorded: I degree (mild) - in 14 examined; II degree (moderate) - in 18 patients; III degree (high) - in 13 patients.

Studies have shown that in the experimental group before treatment, the value of systolic blood pressure (SBP) was 153.3 ± 4.2 mm Hg. and the value of diastolic blood pressure (DBP) was 90 ± 1.9 mm Hg, respectively. As can be seen from the data presented in Table 3, arriving on the 10th day of treatment, in group I the SBP value was 136.7 ± 2.9 mm Hg. and DBP 83.7 ± 1.3 mm Hg. respectively.

In the control group, the mean SBP was also equal to 145.3 ± 4.0 mm Hg before treatment, and DBP was 88.0 ± 2.3 mm Hg, respectively. As can be seen from Table 3, in group II who received basic therapy, after treatment the mean SBP was 138.3 ± 4.0 mm Hg and DBP 84.2 ± 1.9 mm Hg, respectively.

Thus, the most pronounced tendency towards normalization of blood pressure was recorded in the group of patients receiving the claimed pharmaceutical preparation according to the present invention. In all groups of patients, an increase in daily diuresis was noted, which was also most pronounced in group I: in group I, diuresis before treatment was 1.1 ± 0.3 l / day, respectively. and 1.7 ± 0.2 l / day; in group II - 1.2 ± 0.3 l / day. and 1.4 l / day.

The dynamics of the pulse against the background of treatment of the examined patients did not differ significantly (statistically significantly). If in the experimental group the mean value of the pulse was equal to 81.8 ± 1.7 before treatment, and after treatment it was equal to 76.8 ± 1.0.

The dynamics of the pulse in the control group: the pulse was 81.0 ± 1.2, and after treatment it was 79.0 ± 0.9, respectively.

Table 3

Basic indicators I group II group Before treatment
M ± m After treatment
M ± m Before treatment
M ± m After treatment
M ± m Blood pressure, mm Hg
Systolic
Diastolic 153.3 ± 4.2
90 ± 1.9 136.7 ± 2.9
83.7 ± 1.3 145.3 ± 4.0
88.0 ± 2.3 138.3 ± 4.0
84.2 ± 1.9 Pulse / heart rate 81.8 ± 1.7 76.8 ± 1.0 81.0 ± 1.2 79.0 ± 0.9

Along with the indicators of blood pressure, heart rate, the patients examined by us, the results of some laboratory studies, in particular clinical analyzes, were analyzed: a general blood test, a general urine test; biochemical analyzes: total protein, urea, creatinine, K +, Na +, blood phosphorus, GFR, ALT, AST, bilirubin; instrumental studies: ultrasound of the kidneys.

As can be seen from the presented data (table 4), in the group receiving the pharmaceutical preparation according to the present invention, and in the group of patients receiving basic therapy, it does not significantly affect the level of hemoglobin, leukocytes and the content of erythrocytes in the blood. In both groups, in the dynamics of treatment, there was almost the same ESR values of the blood, which varied within the limits of physiological fluctuations.

There are also no significant fluctuations in bilirubin, aminotransferases in the blood, which indicates the safety of drugs, the absence of negative hepatotropic effects.

Table 4

Basic indicators I group II group Before treatment After treatment Before treatment After treatment General blood analysis Hemoglabin 94.5 ± 2.9 99.2 ± 2.8 98.5 ± 2.7 100.1 ± 2.2 Erythrocytes 3.4 ± 0.1 3.7 ± 0.1 3.5 ± 0.1 3.8 ± 0.1 Leucrocytes 8.3 ± 0.6 7.4 ± 0.4 6.9 ± 0.4 6.4 ± 0.3 ESR 22.8 ± 2.8 15.2 ± 1.7 22.2 ± 2.5 17.0 ± 2.2 VSK, sec
Start
end 213.4 ± 2.5
242.4 ± 2.1 223.1 ± 2.5
252.1 ± 1.4 211.5 ± 2.0
243.1 ± 1.8 217.8 ± 1.5
249.7 ± 1.5 Blood chemistry ALT 23.7 ± 1.7 24.5 ± 1.5 28.8 ± 2.8 33.8 ± 2.1 AST 18.7 ± 1.5 20.6 ± 1.4 22.6 ± 2.3 25.6 ± 2.1 Bilirubin 15.8 ± 0.7 17.2 ± 0.4 15.2 ± 0.7 16.2 ± 0.5

The initial protein content of blood serum in patients with CRF in the pre-dialysis period did not differ significantly. Against the background of therapy with the pharmaceutical preparation according to the present invention, an increase in the content of total serum protein was noted by 4%, in the comparison group by 0.5% (Table 5).

While taking the pharmaceutical preparation according to the present invention in patients with chronic renal failure, a significant decrease in serum creatinine and urea was noted by 21.8% and 15%, in the comparison group by 2.58% and 2.4%, respectively.

Under the conditions of therapy, patients showed a significant decrease in the level of daily protein loss: in the group of patients with chronic renal failure receiving Nephrocizin - by 44.4%, in the group of patients with chronic renal failure receiving basic therapy - by 33.3%.

In patients of the comparison group, the studied parameters (the level of total protein in blood serum, the content of creatinine and urea in the blood, daily proteinuria) did not change significantly over 20 days of observation.

Against the background of therapy with the pharmaceutical preparation according to the present invention, in patients with CRF in the pre-dialysis period, a significant improvement in the indicators of nitrogen and protein metabolism was noted. Thus, the therapeutic effect of the drug, apparently, is maximally realized in conditions of impaired nitrogen metabolism against the background of the predominance of catabolic processes, which is characteristic of chronic renal failure.

For the first time, results were obtained indicating a significant decrease in proteinuria in patients with chronic renal failure while taking the pharmaceutical preparation according to the present invention, perhaps this is due to the cell-protective mechanisms of the clinical activity of this drug, due to the normalization of the redox state of the antioxidant system.

Glomerular filtration rate is one of the most important indicators that determine the functioning of the renal apparatus. If the glomerular filtration rate is significantly lower than normal, this indicates a malfunction of the kidneys, leading to the accumulation of toxic metabolic products in the body.

- if the GFR is 90 ml / min / 1.73 m ² or higher, this indicates that the kidneys are healthy.

- GFR between 60 and 89 ml / min / 1.73 m ^{2 is} characteristic of the second stage of chronic kidney disease (CKD). If the value of this indicator varies in the range from 30 to 59 ml / min / 1.73 m ² , this indicates the third stage of CKD, a decrease in GFR to 15-29 ml / min / 1.73 m ² indicates the fourth stage of CKD.

- If the glomerular filtration rate is less than 15 ml / min / 1.73 m ² , we are talking about terminal chronic kidney disease, that is, the kidneys are not able to perform their functions.

As seen from the presented data (Table 5) before treatment was average GFR of patients of the 1st group of 28.9 ± 3.2 ml / min / 1.73 m ^2, and the second group of average GFR 40.7 ± 4.7 ml / min / 1.73 m ² . In the first group, against the background of the application of the claimed pharmaceutical preparation according to the present invention for 10 days, GFR increased by 42.46% (41.2 ± 4.7 ml / min / 1.73 m ² ), and in the second group in patients who received only basic therapy, GFR decreased by 2.95% (39.5 ± 3.7 ml / min / 1.73 m ² .

Table 5

Indicators of proteinuria, protein and nitrogen metabolism in patients within 10 days against the background of the use of the pharmaceutical preparation according to the present invention - solution for infusion 200 ml, (M ± m)

Basic indicators I group II group Before treatment After treatment Before treatment After treatment General urine analysis Density 1008.3 ± 0.7 1012.1 ± 3.3 1010.0 ± 0.8 1008.0 ± 0.7 Protein 0.9 ± 0.2 0.5 ± 0.2 0.9 ± 0.3 0.6 ± 0.1 Leucrocytes 14.1 ± 2.7 8.0 ± 1.4 11.8 ± 2.2 6.7 ± 1.4 Erythrocytes 6.0 ± 2.0 5.2 ± 1.5 6.7 ± 1.9 4.7 ± 1.5 Cylinders 1.1 ± 0.3 1.1 ± 0.3 2.3 ± 0.6 1.6 ± 0.5 Blood chemistry Urea 15.3 ± 1.3 13.0 ± 1.0 12.6 ± 1.2 12.9 ± 0.9 Creatinine 331.9 ± 32.8 259.5 ± 27.2 236.3 ± 23.6 230.2 ± 21.8 Total protein 57.6 ± 3.4 59.9 ± 3.4 59.8 ± 1.7 60.1 ± 1.6 K ⁺ blood mmol / l 4.1 ± 0.1 4.1 ± 0.1 4.1 ± 0.1 4.2 ± 0.1 Na ⁺ blood mmol / l 141.3 ± 0.9 144.6 ± 1.0 139.7 ± 0.9 143.2 ± 1.4 Calcium, mmol / l 3.19 ± 0.10 2.69 ± 0.05 3.17 ± 0.10 3.04 ± 0.08 Phosphorus, mmol / l 2.15 ± 0.09 1.84 ± 0.07 2.10 ± 0.09 2.01 ± 0.09 Calcium * phosphorus, mmol ² / l ² 7.10 ± 0.50 4.84 ± 0.24 7.22 ± 0.50 6.53 ± 0.43 SFK 38.9 ± 3.2 49.2 ± 4.7 38.7 ± 4.7 39.5 ± 3.7

The obtained results show that the patients of the first group in terms of GFR before the use of the claimed pharmaceutical preparation according to the present invention entered the third stage of CKD, and after treatment for GFR moved to the second stage of CKD.

As can be seen from the above data, there was a significant effect of therapy on indicators of urea, creatinine, phosphorus, glomerular filtration rate in group I. Improvement in the indicators of nitrogen-excreting renal function, GFR under conditions of treatment with a pharmaceutical preparation according to the present invention can be associated, first of all, with the detoxification, diuretic effect of this drug, a decrease in the degree of arterial hypertension, which is accompanied by an increase in the function of residual functioning nephrons. Group II also showed positive, but unreliable dynamics. Group I showed a significant decrease in daily proteinuria.

Analysis of the data provided indicates a certain nephroprotective effect of the pharmaceutical preparation according to the present invention, the administration of which was accompanied by a significant decrease in daily proteinuria, creatinine, urea, phosphorus content in the blood, an increase in GFR, and daily urine output. The tendency to normalize blood pressure when prescribing the claimed pharmaceutical preparation according to the present invention in chronic renal failure is explained by their diuretic and nephroprotective effects, detoxification and alkalizing effects, as well as potentiation of the effect of loop diuretics.

It has been shown that the pharmaceutical preparation of the present invention, included in the standard therapy for CKD, helps to reduce the serum concentration of osteoporosis markers and, as part of the standard therapy for CKD, significantly improves calcium-phosphorus metabolism, impaired in patients with CKD due to secondary hyperparathyroidism.

By the end of the observation period, patients receiving standard therapy showed a decrease in the concentration of some markers, comparable in both groups; as a result, serum concentrations of markers in both groups also remained comparable. In group I, patients who received the pharmaceutical preparation according to the present invention significantly decreased the concentration of osteoporosis markers: calcium, phosphorus and the product of the concentration of calcium and phosphorus. In group II, significant changes in the concentrations of calcium and phosphorus were not observed, although in isolation, calcium and phosphorus in this group also did not change in concentration.

No side effects of the claimed pharmaceutical preparation according to the present invention were observed in the doses used.

Thus, from the results of clinical studies, it is confirmed that:

- a complex infusion preparation according to the claimed invention has a positive effect on the course of chronic renal failure due to detoxification, diuretic effects, and a decrease in the severity of arterial hypertension;

- the use of the infusion preparation according to the present invention in the complex therapy of chronic renal failure is accompanied by a decrease in the content of urea and creatinine in the blood, an increase in the glomerular filtration rate;

- the pharmaceutical preparation of the present invention, included in the standard therapy regimen for CKD, helps to reduce the serum concentration of markers of osteoporosis, in particular, phosphorus-calcium metabolism, and as part of the standard therapy for CKD significantly improves calcium-phosphorus metabolism, impaired in patients with CKD due to secondary hyperparathyroidism and as a result the calcification of blood vessels decreases;

- the complex infusion preparation according to the present invention has a positive effect on vascular permeability and helps to reduce vascular impermeability in patients with renal failure;

- an important property of the preparation according to the present invention is good tolerability; during the observation period, not a single case of side effects and / or allergic reactions was recorded when using the preparation;

- the complex infusion preparation according to the present invention has a certain nephroprotective effect.

As a result, the complex pharmaceutical preparation according to the present invention can be included in the complex therapy of intoxication syndrome in chronic renal failure as an effective, safe and affordable drug.

Claims (23)

1. A method of manufacturing a complex infusion drug, including obtaining a solution of the drug by dissolving the following components of the drug in previously prepared and purified water for injection: sorbitol, sodium lactate, sodium chloride, potassium chloride, magnesium chloride or magnesium chloride hexahydrate, calcium gluconate, in the following ratio components, wt%: sorbitol 5.0-7.0 sodium lactate on a dry matter basis 1.6-2.2 sodium chloride 0.5-0.7 potassium chloride 0.025-0.035 magnesium chloride or magnesium chloride hexahydrate in terms of dry matter 0.006-0.016 calcium gluconate 0.015-0.025 water for injections rest, the method includes the following steps: a) water for injection with a temperature of 80-95 ° C is collected in the reactor in a volume of not more than 70% of the calculated amount; b) load calcium gluconate into the reactor, mix, cool the solution to 40-45 ° C; c) load sodium chloride into the reactor, mix; d) load into the reactor magnesium chloride or magnesium chloride hexahydrate, mix; e) load potassium chloride into the reactor, stir; f) load sorbitol into the reactor, mix; g) load sodium lactate into the reactor, mix; h) bring the volume of the solution to 100% with water for injection, cool the solution to 20-25 ° C, stir; i) circulate the solution for at least 30 minutes; j) keep the solution under stirring for at least 1 hour to stabilize; l) filter the solution in three stages; l) pack the drug solution into vials; m) sterilize the vials with the drug solution. 2. A method according to claim 1, wherein in step k) the first stage of filtration is carried out through a Sartopure® PP3 polypropylene depth pre-filter with a pore size of 1.2 μm. 3. The method according to PP. 1, 2, in which at stage l) the second stage of filtration is carried out through a Sartobran® P filter with a pore size of 0.45 μm. 4. The method according to PP. 1-3, in which in step k) the third stage of filtration is carried out through a Sartobran® P filter with a pore size of 0.2 μm. 5. A complex infusion preparation obtained by the method according to claim 1. 6. The use of a complex infusion drug according to claim 5 to correct hyperphosphatemia and reduce vascular impermeability in patients with renal failure.