RU2423987C1 - Infusion solution for total blood volume replacement, hydro-electrolytic rebalancing and hematopoiesis process normalisation - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: invention refers to an infusion solution for total blood volume replacement, hydro-electrolytic rebalancing, trace recovery, and hematopoiesis process normalisation. The declared solution contains sodium, potassium, calcium, magnesium, chloride and acetate ions with water, and in addition it contains cobalt, zinc and manganese ions in the following proportions, mmole: Na+ -140; K+ - 4; Ca++ - 2,5; Mg++ - 1; Co++ - 0.0006; Zn++ - 0.022; Mn++ - 0.004; CI- - 111; CH3COO- - 40; and water for injections up to 1 l. ^ EFFECT: solution is balanced in relation to an ionic composition of human blood plasma and effects on erythropoiesis stimulation. ^ 8 tbl, 7 ex

Description

The invention relates to medicine and the pharmaceutical industry, in particular to medicines (medicinal solutions) that contribute to the restoration of the water-electrolyte composition of blood plasma, an infusion solution (IR) to replenish the volume of circulating blood (BCC), restore the water-electrolyte balance and normalize processes hematopoiesis.

Isoosmolar electrolyte solutions are most often used as practical preparations: sodium chloride solution 0.9%, Ringer's solution, Lactasol, Ringer-Locke solution, Plazmalit (USA), Trisol, Quartasol, Chlosol, Ringer's solution-acetate, Darrow's solution, Yonosteril (Germany, "Fresenius"). The ionic composition of these solutions is presented in table 1. These solutions contain the main vital ions that make up blood plasma, such as sodium, potassium, calcium, magnesium, chloride, bicarbonate, acetate, lactate. A deficiency or excess of these ions can lead to serious disorders in the body.

None of the mentioned solutions is completely isoionic with respect to blood plasma, therefore, it cannot have a plasma substituting effect in full.

It is known that in addition to the main electrolytes, the blood plasma also contains trace elements that are divided into irreplaceable (iron, zinc, copper, selenium, manganese, nickel, molybdenum, chromium, cobalt), conditionally irreplaceable and interchangeable,

Essential micronutrients enter the body with food and do not accumulate in the body, therefore, in such critical situations as massive blood loss, burns, dehydration, etc., when eating is impossible in the usual way, the introduction of microelements to the patient is necessary to maintain the blood-forming process.

The closest analogue of the proposed tool is a plasma substitution solution of the company Fresenius AG-Germany - isotonic and isoionic electrolyte solution Yonosteril (prototype) containing ions in a physiologically optimal ratio.

In 1 l of Yonosteril contains, mmol:

Na ⁺ 137.00 K ⁺ 4.00 Ca ⁺⁺ 1.65 Mg ⁺⁺ 1.25 Cl ^- 110.00 CH ₃ COO ^- 36.80

Indication for the use of Yonosteril is extracellular dehydration of various origins, for example, volume loss due to diarrhea, vomiting, fistula, drainage and intestinal obstruction, burns.

Yonosteril is the primary plasma-replacing solution.

The objective of the invention is the expansion of the range of infusion solutions, the development of a drug to replenish the volume of circulating blood, restore water-electrolyte balance and normalize the further own process of hematopoiesis, primarily erythropoiesis.

The problem is solved by creating an infusion solution including ions of sodium, potassium, calcium, magnesium, chloride and acetate in water, characterized in that the composition is balanced with respect to the ionic composition of human blood plasma and additionally contains cobalt, zinc and manganese ions in the following ratio of components, mmol:

Na ⁺ 140.0 K ⁺ 4.0 Ca ⁺⁺ 2.5 Mg ⁺⁺ 1,0 Co ⁺⁺ 0,0006 Zn ⁺⁺ 0,022 Mn ⁺⁺ 0.004 Cl ^- 111.00 CH ₃ COO ^- 40,0 Water for injections up to 1 l

With the same general indications for use, the proposed composition has advantages over Yonosteril in the composition of cations and is preferred, for example, for internal bleeding.

The most important ions for maintaining homeostasis are sodium, potassium, calcium, magnesium, chloride and acetate; the most important trace elements for normalizing your own further hematopoiesis are cobalt, zinc and manganese.

However, the proposed composition of the solution does not reproduce blood plasma, the absence of some irreplaceable, conditionally interchangeable and interchangeable trace elements in it could provoke unexpected reactions of the body in a non-additive manner. The quantitative composition is original, experimentally selected so that its osmolarity does not change the rheological properties of the blood during treatment.

It has been shown for the first time that an infusion solution can affect the stimulation of erythropoiesis.

Example 1. Preparation of an infusion solution.

The solution is prepared in water for injection by the mass-volume method. Water for injection is poured into a volumetric flask in the amount of ¾ volume. Then suspended components are loaded, mixing thoroughly until all substances are completely dissolved, and the solution volume is adjusted to the mark with water for injection. All components are readily soluble. The pH of the solution does not require special adjustments. An example of loading is presented in table 2.

In laboratory conditions, experimental batches of solutions were prepared with a volume of not more than 1 liter, 7-fold filtration was carried out through the same paper filter, and then through a Millipor sterilizing filter with a pore diameter of 0.22 μm.

In industrial conditions, a three-stage cascade filtration of IR is carried out: clarifying, preliminary, sterilizing.

Vials from MTO glass were used as packaging. A package made of a polymer film (PVC or PP) was not used to avoid sorption of trace amounts of trace elements. Corked with rubber stoppers and crimped with aluminum caps, the bottles were sterilized with saturated steam: temperature 121 ° C, pressure 0.11 MPa, exposure time 15 min. The analysis of the drug before and after sterilization was carried out according to the indicators adopted for all infusion solutions: description, transparency, lack of mechanical inclusions, pH, density, sterility, pyrogen test, quantitative ion content. The results are presented in table.3.

The test of the claimed solution for sterility was carried out in the laboratory of the Center for Quality Control of Medicines of SPHFA by membrane filtration using thioglycolic medium and Saburo medium. In all experimental batches, a solution of the growth of microorganisms was not observed, which indicates the sterility of the drug and the reliability of the selected sterilization mode.

Example 2. Test solution for pyrogenicity.

The test for pyrogenicity of the solution was carried out in accordance with GP XII (OFS 42-0061-07. P.125) on a group of three rabbits with an initial temperature of 38.5 ° C - 39.5 ° C.

Before the experiment, each rabbit was measured twice with an interval of 30 minutes, the temperature. Differences in temperature readings in the same animal did not exceed 0.2 ° C. The result of the last measurement was taken as the initial temperature.

The infusion solution was injected into the ear vein of a rabbit at the rate of 0.2 ml per 1 kg of animal body weight. Before administration, the solution was heated to 37 ± 2 ° C. The entire volume was injected over 2 minutes.

Temperature measurements after intravenous administration were carried out with an interval of not more than 30 minutes for three hours.

Evaluation of pyrogenicity test results

Rabbit number Weight, kg t _beg., ° C t _con., ° C Δt, ° C ΣΔt, ° C one 2.5 38.5 38.7 0.2 2 2.7 38.7 39.0 0.3 0.6 3 3.0 38.6 38.7 0.1 t _start - temperature of the rabbit before the introduction of the solution, ° C; t _con . - temperature of the rabbit after the introduction of the solution, ° C; Δt is the change in temperature of the rabbit after the introduction of the solution, ° C; ΣΔt is the total value of changes in the temperature of the rabbits after the introduction of the solution, ° C.

Individual temperature deviations did not exceed 0.5 ° C, and the total temperature deviation was less than 1.2 ° C; therefore, the solution is pyrogen-free.

Example 3. Test for abnormal toxicity of the solution.

Abnormal toxicity was determined in mice by the express method of Prozorovsky. When the mice were intravenously injected into the tail vein, the males failed to establish a lethal dose, since even with the introduction of the maximum permissible dose of 0.5 ml, none of the experimental animals died. With an intraperitoneal injection of the maximum permissible dose of 1 ml, all animals also remained alive. It can be concluded that the infusion solution does not have abnormal toxicity.

Study of the pharmacological action of the solution.

The study of the pharmacological action of the solution was carried out on sexually mature white outbred male rats. In the experiment used 30 rats with an initial body weight of 140-160 g at the age of 14-16 weeks to the beginning of the experiment. Animals were randomly (using a random number table) divided into 3 experimental groups of 10 rats without deviations in appearance and deviations in mass of no more than 10% of the average value.

The experimental blood loss was simulated according to the following scheme: twice from animals of the tail vein, blood was taken twice, with a total volume of 4-5 ml, which corresponds to 30-40% of the circulating blood volume. After blood loss was completed, dosed jet injection of infusion solutions into the tail vein began once a day: the 1st group, the control group, was left without compensation, the 2nd group was injected with the Yonosteril solution in the tail vein, and the claimed solution in the 3rd group. The volume of injected solutions per day was at least 50% of the amount of blood loss. The solutions were administered for 10 days. The condition of the animals was evaluated by the following parameters:

- body mass;

- peripheral blood counts;

- the number of ions in the blood plasma;

- indicators of the electrocardiogram.

Inspection was carried out throughout the experiment once a day in the morning and was weighed before modeling blood loss, and then on the 1st, 5th and 10th day after the start of drug administration.

Example 4. The effect of IR on the dynamics of body weight.

Dynamics of body weight is one of the integral indicators of the state of animals. Data on the effect of the administration of IR to animals after experimental blood loss on restoration of body weight are presented in Table 4.

Example 5. The effect of IR on the restoration of peripheral blood counts.

The definition of the clinical picture in acute blood loss includes an assessment of the hematocrit, hemoglobin content, and the number of red blood cells.

The effect of the introduction of the infusion solution on the restoration of peripheral blood parameters after blood loss in rats is presented in table 5.

Example 6. The effect on the ionic composition of the blood.

The amount of ions in the blood plasma was determined in animals before the start of the experiment, as well as 5 days and 10 days after blood loss. The initial values of the number of plasma ions were within the physiological norm. The results are presented in table.6.

Example 7. The effect of the introduction of infusion solutions on the cardiovascular system of rats after blood loss.

Monitoring the state of the cardiovascular system during blood loss allows not only to assess the general condition of animals, but also to identify emerging electrolyte and other disorders.

Tachycardia is an uneconomic mode of the heart. The increase in heart rate in acute blood loss is a cause for concern and indicates an uncompensated deficiency of BCC, ongoing vascular spasm and insufficient infusion therapy. Therefore, a change in heart rate (HR) in acute blood loss is an important clinical sign. Its greatest value is manifested during dynamic observation, then this indicator reflects the clinic and the result of treatment. When simulating blood loss, heart rate in experimental animals was measured immediately after blood sampling and 2 hours after the introduction of infusion solutions, as well as on the 5th day after the start of the experiment. The size of the R, S teeth, and the QRS, QRST, and ST intervals were also evaluated. Table 7 presents the results of an ECG study.

Thus, the dynamics of the indicators of peripheral blood, the content of calcium, magnesium, potassium, sodium and chloride ions indicates that in the group of animals that were administered the claimed infusion solution, deviations from normal parameters either did not develop or were fully compensated by 5-e-10- e day after blood loss. 2 hours after the start of blood loss compensation, most of the electrocardiogram parameters are restored and arrhythmias disappear.

The advantages of the proposed infusion solution over the prototype are presented in summary table 8.

Table 1 Comparative ionic composition of isosmolar electrolyte solutions with blood plasma Solutions Na ⁺ K ⁺ Ca ²⁺ Mg ²⁺ Cl ^- HCO ₃ ^- Acetate Lactate Theoretical osmolarity, mOmol / l Blood plasma 135-145 3,5-5,5 2.25-2.63 0.6-1.1 95-110 20-25 20-80 0.63-2.44 280-290 Sodium Chloride Solution 0.9% 154 154 308 Ringer 147 four 2 153 306 Lactasol 140 four 1,5 one 115 3,5 thirty 295 Ringer Locke 140 2.6 2 143 2 295 Plazmalit (USA) 140 5 1,5 98 295 Trisol 133 13 98 48 292 Quartasol 124 twenty 101 12 31 288 Hlosol 120 23 104 39 286 Ringer's Acetate 135 four 2 one 108 34 284 Darrow 102 36,2 138.9 278 Jonosteril (Germany-Fresenius) 137 four 1.65 1.25 110 36.8 291

table 2 Recommended component loading order Name of components GF XI Solubility (P.92) Amount, g / l Dissolution time, min Cobalt Acetate 4-Aq Easily soluble 0.00015 0.5-1 Manganese Acetate 4-Aqueous Easily soluble 0,00098 0.5-1 Zinc Acetate 2-Aqueous Easily soluble 0.00480 0.5-1 Magnesium chloride 6-water Easily soluble 0,20330 1-3 Calcium chloride Easily soluble 0.28000 1-3 Potassium chloride Easily soluble 0.29800 1-3 Sodium Acetate Easily soluble 3.78000 1-3 Sodium chloride Very soluble 5.85000 2-4

Table 3 The quality indicators of the claimed funds before and after sterilization Quality indicators for the FSF project Before sterilization After sterilization Transparency Transparent Transparent pH 7.36 ± 0.10 7.38 ± 0.10 Density, g / ml 1,100 ± 0,001 1,101 ± 0,001 Osmolarity (cryometric), mOsmol / l 292 ± 2 293 ± 2 Quantitative content, mmol / l Sodium 138 ± 0.1 138.2 ± 0.1 Potassium 3.8 ± 0.01 3.85 ± 0.01 Magnesium 0.9 ± 0.01 0.92 ± 0.01 Calcium 2.2 ± 0.01 2.25 ± 0.01 Chloride 109 ± 0.1 109.3 ± 0.1 Acetate 38.2 ± 0.1 38.25 ± 0.1 Cobalt 0.0005 ± 0.0001 0.0005 ± 0.0001 Zinc 0.0219 ± 0.0001 0.0219 ± 0.0001 Manganese 0.0039 ± 0.0001 0.0039 ± 0.0001

Table 4 The effect of infusion solutions on the restoration of body weight of rats after blood loss No., group The initial mass, g Weight 5 days after blood loss, g Recovery mass to the original,% Weight 10 days after blood loss, g Recovery mass to the original,% 1. Control 190 ± 10 164 ± 17 -13.7 162 ± 19 -14.7 2. Jonosteril 190 ± 4 160 ± 8 -15.8 180 ± 8 -5.3 3. The claimed 198 ± 10 190 ± 10 -4.0 206 ± 13 * +4.0 Note: * - differences from control are statistically significant; italics — differences from group 2 are statistically significant.

Table 5 The effect of the introduction of an infusion solution on the restoration of peripheral blood counts Group Red blood cells, 10 ¹² Hemoglobin, g / l Hematocrit% SIT, pg ICSU,% MCV, μm ³ Original, up to a bloodstream. 5.5 ± 0.8 125 ± 1.8 39.0 ± 0.4 22.7 ± 0.4 32.0 ± 1.0 70.4 ± 2.3 after 5 days The control 3.4 ± 0.5 * 118.6 ± 12.3 45.9 ± 2.9 * 28.2 ± 2.5 * 27.3 ± 0.4 * 137.9 ± 5.6 * Yonosteril 4.1 ± 0.3 * 126.4 ± 9.4 41.8 ± 2.6 30.7 ± 3.1 * 30.1 ± 3.3 101.9 ± 0.9 * The inventive tool 4.7 ± 1.1 128.5 ± 8.3 43.1 ± 1.9 * 27.2 ± 0.8 * 29.7 ± 4.3 91.7 ± 1.7 * after 10 days The control 3.9 ± 0.3 * 127.2 ± 8.1 46.9 ± 2.9 * 32.6 ± 2.7 * 27.1 ± 0.4 * 116.7 ± 9.3 * Yonosteril 4.9 ± 0.9 135.3 ± 16.8 43.9 ± 2.9 27.5 ± 1.9 * 30.7 ± 0.6 89.8 ± 8.2 * The inventive tool 5.8 ± 0.9 133.3 ± 11.9 44.9 ± 5.5 22.9 ± 1.3 29.6 ± 1.6 * 76.7 ± 2.1 * Note: * - differences from the source data are statistically significant; highlighted in bold - differences from indicators in the control group are statistically significant; italics — differences from the indicators in the comparison drug group are statistically significant, p≤0.05.

Table 6 The effect of infusion solutions on the basic ionic composition of the blood. Group number Sodium, mmol / L Potassium, mmol / L Calcium, mol / L Magnesium, mmol / L Chlorides, mmol / L Physiological norm (literature data) 144-157 5.11-5.27 2.35-2.67 - 103-114 Source 151.3 ± 1.6 4.7 ± 0.2 2.31 ± 0.19 0.83 ± 0.03 100.1 ± 2.5 after 5 days 1. Control 155.2 ± 0.8 * 4.9 ± 0.3 2.01 ± 0.18 0.87 ± 0.05 94.0 ± 0.8 * 2. Jonosteril 156.0 ± 2.2 * 4.4 ± 0.4 2.27 ± 0.12 1.01 ± 0.08 * 98.0 ± 1.2 3. The claimed sr 156.5 ± 0.5 * 4.8 ± 0.3 2.03 ± 0.12 0.92 ± 0.05 * 100.5 ± 0.8 after 10 days 1. Control 157.0 ± 1.7 * 5.3 ± 0.2 * 2.10 ± 0.27 0.87 ± 0.06 101.0 ± 3.1 2. Jonosteril 154.6 ± 1.3 * 5.2 ± 0.2 * 2.18 ± 0.12 1.00 ± 0.03 * 97.8 ± 1.0 3. The claimed sr 155.0 ± 0.8 * 4.9 ± 0.1 2.37 ± 0.07 0.80 ± 0.03 99.4 ± 1.1 Note: * - differences from the source data are statistically significant, p≤0.05; highlighted in bold - differences from indicators in the control group are statistically significant, p≤0.05; italics — differences from the indicators in group 2 are statistically significant, p≤0.05.

Table 7 The effect of the introduction of infusion solutions on the cardiovascular system of rats after blood loss No., group Heart rate R S QRS QRST ST Source 526 ± 49 0.6 ± 0.10 0.16 ± 0.04 0.018 ± 0.004 0.082 ± 0.004 0.035 ± 0.004 Immediately after blood loss 1. Control 600 ± 25.0 0.42 ± 0.20 0.23 ± 0.04 0.019 ± 0.004 0.066 ± 0.005 * 0.048 ± 0.004 * 2. Jonosteril 534.4 ± 35.8 0.62 ± 0.13 0.4 ± 0.18 * 0.016 ± 0.005 0.074 ± 0.005 0.058 ± 0.010 * 3. The claimed sr 554.4 ± 38.6 0.44 ± 0.09 0.37 ± 0.05 * 0.014 ± 0.005 0.068 ± 0.004 * 0.038 ± 0.022 In 2 hours 1. Control 518.4 ± 22.9 0.40 ± 0.11 0.3 ± 0.09 * 0.018 ± 0.004 0.080 ± 0.006 0.062 ± 0.009 2. Jonosteril 557 ± 29.6 0.37 ± 0.09 * 0.48 ± 0.15 * 0.018 ± 0.005 0.078 ± 0.005 0.058 ± 0.012 * 3. The claimed sr 550 ± 50 0.5 ± 0.1 0.21 ± 0.09 0.018 ± 0.004 0.078 ± 0.004 0.034 ± 0.004 in 5 days 1. Control 570 ± 45 0.7 ± 0.3 0.15 ± 0.05 0.018 ± 0.004 0.074 ± 0.005 0.029 ± 0.005 2. Jonosteril 554 ± 29 0.4 ± 0.1 0.24 ± 0.05 0.016 ± 0.005 0.072 ± 0.004 0.032 ± 0.003 3. The claimed sr 530 ± 27 0.4 ± 0.1 0.16 ± 0.04 0.018 ± 0.004 0.078 ± 0.004 0.035 ± 0.004 Note: * - differences from the source data are statistically significant; bold - differences from control are statistically significant; italics — differences from group 2 are statistically significant; p≤0.05.

Table 8 A summary of the effects of the claimed drug in comparison with the drug Yonosteril ("normal" - initial values) Effect Yonosteril The inventive tool 5 days 10 days 5 days 10 days Blood red blood cell count Below normal Norm Norm Norm Blood hemoglobin Norm Norm Norm Norm Hematocrit Above norm Above norm Above norm Norm SIT Above norm Above norm Above norm Norm ICSU Norm Norm Norm Norm Mcy Above norm Above norm Above norm Above the norm, but less than the comparison drug Calcium Norm Norm Norm Norm Magnesium Above norm Above norm Above norm Norm Potassium Norm Norm Above norm Norm Chlorides Below normal Norm Norm Norm Sodium Above norm Above norm Above norm Above norm ECG indicators 2 hours 5 days 2 hours 5 days Heart rate Above norm Norm Above norm Norm R Below normal Norm Norm Norm S Above norm Norm Norm Norm QRS Norm Norm Norm Norm QRST Norm Norm Norm Norm ST Above norm Norm Norm Norm

Claims (1)

An infusion solution to replenish the volume of circulating blood, restore the water-electrolyte balance and normalize its own blood formation process, including sodium, potassium, calcium, magnesium, chloride and acetate ions in water, characterized in that the composition is balanced with respect to the ionic composition of human blood plasma and additionally contains cobalt, zinc and manganese ions in the following ratio of components, mmol:
Na ⁺ 140.0 K ⁺ 4.0 Sa ⁺⁺ 2,5 Mg ⁺⁺ 1,0 Co ⁺⁺ 0,0006 Zn ⁺⁺ 0,022 Mn ⁺⁺ 0.004 Cl ^- 111.00 CH ₃ COO ^- 40,0 Water for injections Up to 1 liter