EA029693B1 - Method for obtaining a stable pharmaceutical composition as an aqueous solution for intravenous administration - Google Patents

Abstract

The invention relates to a chemical and pharmaceutical industry, in particular to a method for the preparation of a stabilized pharmaceutical composition in the form of an aqueous solution which can be used to prepare a drug for intravenous administration containing succinic acid, nicotinamide, inosine and riboflavin mononucleotide as active components and having cytoprotective properties. According to the invention one or more pharmaceutically acceptable components selected from the group consisting of sodium hydroxide, trisoxymethylaminomethane (TRIS), ethanolamine, diethanolamine, sodium carbonate, meglumine are further added to the composition as a stabilizing agent to obtain a stable solution with pH in the range of 6.0 to 8.0, and further thermal sterilisation of the solution is carried out at a temperature from 100°C and exposure time of 8 min to 116°C and exposure time of 2 min.

Description

The invention relates to the pharmaceutical industry, in particular to a method for obtaining a stabilized pharmaceutical composition in the form of an aqueous solution, which can be used to obtain a medicinal product for intravenous administration, containing succinic acid, nicotinamide, inosine and riboflavin mononucleotide and possessing cytoprotective as active components properties. According to the invention, one or more pharmaceutically acceptable components selected from the group comprising sodium hydroxide, trisoxymethylaminomethane (TRIS), ethanolamine, diethanolamine, sodium carbonate, meglumin are added to the composition as a stabilizing agent to obtain a stable solution with a pH value ranging from 6, 0 to 8.0 and additionally carry out thermal sterilization of the solution at a temperature of from 100 ° C and an exposure time of 8 minutes to 116 ° C and an exposure time of 2 minutes.

029693

The invention relates to the pharmaceutical industry, in particular to a method for obtaining a stabilized pharmaceutical composition in the form of an aqueous solution, which can be used to obtain a medicinal product for intravenous administration, containing succinic acid, nicotinamide, inosine and riboflavin mononucleotide and possessing cytoprotective as active components properties.

The development of effective combination drugs for intravenous administration is an important technological task, since the use of highly reactive ingredients in such compositions very often leads to the chemical interaction of the active components with the formation of undesirable, often toxic impurities and decomposition products at all stages of the preparation of the drug.

Upon receipt of sterile solutions of drugs one of the most complex processes leading to the formation of undesirable impurities and reducing the safety of the drug is the process of finishing sterilization, in which there is a complete destruction of all types of microorganisms and their spores.

Currently, the most widely used method of finishing sterilization in the industrial production of drugs is thermal sterilization with saturated steam under pressure (autoclaving). The parameters of this process are regulated in international pharmacopoeias (GF XIII, EP 9.0, I8P 39). Standard sterilization with saturated steam of aqueous solutions of drugs is carried out at a temperature of 120-122 ° C under pressure for 8-15 minutes, depending on the physicochemical properties and other parameters of the object of thermal sterilization.

However, in practice, there are often medications that contain thermolabile medicinal substances that do not allow the use of standard sterilization regimens, and currently industrial technologies are used in combination with other methods of exposure (gamma radiation, ultrasound, etc.), including using chemical sterilization methods.

So, in the application KI 2001117337 the option of radiation sterilization of solutions is proposed, in the patent KI 2519841 the sterilization of microwave microwave radiation. In the application KI 2006142783 sterilization is carried out in the processing of pulsed high-voltage discharges generating sterilizing UV radiation, and in the application KI 2000130091 a method of electrochemical sterilization of liquids with chemically active particles is proposed.

Currently, combinations of thermal and physical sterilization regimes are also used to sterilize unstable aqueous solutions; So. in patent KI 2,238,108, heating is carried out by the action of a microwave electromagnetic field, and sterilization is carried out by an electromagnetic field EHF.

In the application KI 2003115619 proposed an original combined method of sterilization by exposure to an electric field and acoustic vibration.

However, since many combined non-standard sterilization methods do not give a high guarantee of the absence of microbial contamination of a drug, when preparing it, various water-soluble antimicrobial preservatives permitted by international pharmacopoeias are often added: benzyl alcohol (KI 2209070, KI 210550, KI 2326669, KI 2192855, И8 20150126466, IL 26343), benzalkonium chloride (KI 2419417, IA 26343), chlorobutanol (IA 26343), metacresol (RF 2093144), cresol (KI 2020954), phenol (KI 2111012). This combined method allows sterilization of thermolabile drugs with non-standard sterilization modes, but it has a very significant drawback - a restriction to medical use, especially in pediatric practice (GF XIII, CFC. 1.1.0016.15 Sterilization).

It should be noted that parenteral drugs based on succinic acid are widely known in medical practice. In the majority of the described examples, when sterilizing multi-component preparations based on aqueous solutions of succinic acid (patents EA 000879, EA 007865, KI 2536994 and KI 2549448) use the standard pharmacopoeial sterilization regime of 120122 ° С for 8-15 minutes.

It is known that for compositions containing thermolabile components, the use of standard sterilization regimes leads to the degradation of ingredients with the formation of an unacceptable level of decomposition products.

Thus, the determination of the optimal temperature regime for sterilization of multicomponent compositions based on succinic acid, which additionally contain thermolabile ingredients, is the most important task in the development of new drugs.

A method of obtaining a combined preparation containing the composition of succinic acid, inosine, nicotinamide and riboflavin mononucleotide, which is described in the patent EA 001099 and selected as a prototype. The method consists in dissolving the above ingredients in water, filtering through a sterilizing filter, filling it at room temperature into sterile ampoules and sealing it without further applying thermal sterilization of the final product.

This method of obtaining a composition containing hydrolytically unstable inosine and no.

Thinamide, as well as the thermolabile riboflavin mononucleotide, has a significant drawback inherent in filtering sterilization under aseptic conditions, namely, the potentially high probability of contamination by microorganisms when preparing the drug, since sterilizing filtration using a standard 0.22 micron filter creates a reliable barrier for bacteria , but often does not keep spores, viruses and mycoplasmas, which reduces the safety of the solution during use.

In addition, it is obvious that the failure in the prototype from the stage of standard thermal sterilization for 8-15 minutes at 120-122 ° C due to thermal and hydrolytic instability of the ingredients included in the composition.

The objective of the invention is to develop a method of obtaining a stable pharmaceutical composition in the form of an aqueous solution for intravenous administration, allowing to increase its safety when used through the use of thermal sterilization.

The task is solved in that in the method of obtaining a stable pharmaceutical composition in the form of an aqueous solution for intravenous administration, containing as active components succinic acid, inosine, nicotinamide, riboflavin sodium mononucleotide, by dissolving them in water followed by sterilizing filtration, according to the invention in the composition additionally administered as a stabilizing agent one or more pharmaceutically acceptable components selected from the group comprising sodium hydroxide, t isoksimetilaminometan (Tris), ethanolamine, diethanolamine, sodium carbonate, meglumine to obtain a stable solution with a pH ranging from 6.0 to 8.0 in the following ratio, wt.%:

succinic acid 5.00-12.50

inosine 1.00-2.40

Nicotinamide 0.50-1.20

Riboflavin mononucleotide sodium 0.10-0.24

stabilizing agent 3,21-51,30

water up to 100.0%,

and additionally carry out thermal sterilization of the solution at a temperature of from 100 ° C and an exposure time of 8 minutes to 116 ° C and an exposure time of 2 minutes.

In the particular case, the problem is solved by the fact that sodium bicarbonate is additionally introduced into the composition as a stabilizing agent to obtain a stable solution with a pH value in the range of 6.4-7.4, in the following ratio, wt.%:

succinic acid 5.00-12.50 inosine 1.00-2.40 nicotinamide 0.50-1.20 Riboflavin mononucleotide sodium 0.10-0.24 stabilizing agent 3.21-33.06 sodium bicarbonate 0.10-2.90 water up to 100.0%.

In the claimed method for producing a stable pharmaceutical composition, one or more pharmaceutically acceptable components selected from the group are additionally introduced as a stabilizing agent.

This group consists of substances that are pharmaceutically acceptable for a composition containing succinic acid, inosine, nicotinamide, riboflavin sodium mononucleotide sodium as active components, and allows you to save the spectrum of the biological activity of the composition.

In this case, the quantitative content of the stabilizing agent, which is both the individual components listed above, and their various combinations, was chosen empirically to obtain stable aqueous solutions with a pH value in the range from 6.0 to 8.0.

In addition, as a result of the experiments, it was revealed that the addition of sodium bicarbonate to the known composition as a stabilizing agent or in addition to it allows to obtain a stable aqueous solution with a narrower pH range from 6.0 to 7.0 and from 6.4 to 7, 4, which is also a physiologically acceptable pH for intravenous administration of the drug.

The authors of the present invention first established the effect of one or more pharmaceutically acceptable components selected from the group comprising sodium hydroxide, trisoxymethylaminomethane (Tris), ethanolamine, diethanolamine, sodium carbonate, meglumine, and sodium bicarbonate on the stability of an aqueous solution containing such hydrolytically unstable com - 2 029693

ponenty, like nicotinamide and inosine, as well as thermolabile riboflavin mononucleotide, under thermal exposure. The resulting solution has a physiologically acceptable range of pH values and is stable during long-term storage. Thus, the stabilizing agent does not allow the specified active components to decompose under the action of temperature, which made it possible to additionally conduct thermal sterilization of the solution and thereby increase its safety when used as an intravenous solution in medical practice.

The implementation of the proposed method of obtaining a stabilized pharmaceutical composition in the form of an aqueous solution can be illustrated by the examples below.

At the initial stage, to study the factors affecting the stability of the new composition, an aqueous solution containing the active components was studied analogously to the prototype, in wt.%: Succinic acid - 10.0, inosine - 2.0, nicotinamide - 1.0 and riboflavin mononucleotide - 0.2%, water for injection up to 100.0, obtained in example 1.

Example 1. 50.0 l of water for injection, 10.0 kg of succinic acid, 2.0 kg of inosine, 1.0 kg of nicotinamide, 0.2 kg of riboflavin mononucleotide are loaded into the apparatus with a mixer with a capacity of 100 l, mixed until complete dissolution of the components when heated to 40-60 ° C and then the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Studies have shown that the composition of the composition obtained in example 1, is unstable after cooling the solution in ampoules to room temperature precipitated the source of the least soluble ingredient in water - inosine.

To obtain the threshold values of the solubility of the ingredients of the prototype were obtained three model composition with different content of active ingredients while maintaining the molar ratios of active substances (examples 2, 3, 4).

Example 2. In the apparatus with a mixer with a capacity of 100 l load 50.0 l of water for injection, 7.5 kg of succinic acid, 1.5 kg of inosine, 0.75 kg of nicotinamide, 0.15 kg of riboflavin mononucleotide, bring the volume of solution with water for injections up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 750 mg (7.5 wt.%), Inosin 150 mg (1.5 wt.%), Nicotinamide 75 mg (0.75 wt.%), Riboflavin sodium mononucleotide 15 mg (0 , 15 wt.%), Water for injection up to 100.0 wt.%.

Example 3. In the apparatus with a mixer with a capacity of 100 l load 50.0 l of water for injection, 5.0 kg of succinic acid, 1.0 kg of inosine, 0.5 kg of nicotinamide, 0.1 kg of riboflavin mononucleotide, bring the solution volume with water for injections up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 500 mg (5.0 wt.%), Inosin 100 mg (1.0 wt.%), Nicotinamide 50 mg (0.5 wt.%), Riboflavin sodium mononucleotide 10 mg (0 , 1 wt.%), Water for injection up to 100.0 wt.%.

Example 4. A 50 l liter of water for injection, 2.5 kg of succinic acid, 0.5 kg of inosine, 0.25 kg of nicotinamide, 0.05 kg of riboflavin mononucleotide are loaded into an apparatus with a mixer with a capacity of 100 l, and the volume of the solution is adjusted to injections up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 250 mg (2.5 wt.%), Inosin 50 mg (0.5 wt.%), Nicotinamide 25 mg (0.25 wt.%), Riboflavin sodium mononucleotide 5 mg (0 , 05 wt.%), Water for injection up to 100.0 wt.%.

Observation of the samples of the drug showed that inosine precipitate also gradually formed in the solution obtained in example 2, and the compositions obtained in examples 3 and 4 did not form inosine precipitate and were suitable for further study.

The results of the study of the solution obtained in example 3, containing the maximum concentration of active ingredients, which was additionally subjected to thermal sterilization at different temperatures in the range of 100-120 ° C with a standard exposure time of 8 minutes, are given in example 5.

Example 5. A 50 l liter of water for injection, 5.0 kg of succinic acid, 1.0 kg of inosine, 0.5 kg of nicotinamide, 0.1 kg of riboflavin mononucleotide are loaded into an apparatus with a mixer with a capacity of 100 l, and the volume of the solution is adjusted with water for injections up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature range from 100 ± 1 to 121 ± 1 ° C by exposure for 8 minutes. Each 10 ml ampoule contains succinic acid 500 mg (5.0 wt.%), Inosin 100 mg (1.0 wt.%), Nicotinamide 50 mg (0.5 wt.%), Riboflavin mononucleotide 10 mg (0, 1 wt.%), Water for injection up to 100.0 wt.%.

Before and after sterilization, the quantitative content of the active components and the level of impurities formed during the sterilization process and using the HPLC method (Table 1) were determined. The quantitative content of the active components and impurities was determined by HPLC under the following conditions: spectrophotometric detector, wavelength 254 nm, refractometric detector, chromatographic column Reieoteheyeia Riaiu1-Nechu1 250 mm long with an inner diameter of 4.6 mm, filled with a sorbent granulation of 5 μm, or similar ; the eluent flow rate was 0.7 ml / min; the column temperature was 25 ° C; chromatography time 30 min.

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Table 1

Thermal sterilization of the composition

Active ingredients and impurities Sterilization mode / content of active ingredients,% of source and impurities,% Without sterilization 121 ± 1 ° С 110 ± 1 ° С 100 ± 1 ° С succinic acid 100.0 99.5 ± 0.47 100.9 ± 0.50 99.6 ± 0.49 nicotinamide 100.0 90.3 ± 0.51 94.2 ± 0.57 99.5 ± 0.54 Inosine 100.0 68.5 ± 0.54 80.1 ± 0.61 95.6 ± 0.37 Riboflavina mononucleotide 100.0 92.1 ± 1.45 95.4 ± 0.86 98.2 ± 0.54 Hypoxanthin 0.64 ± 0.03 16.4 ± 0.4 7.2 ± 0.1 5.1 ± 0.1 A nicotinic acid 0.1 ± 0.02 11.4 ± 0.3 5.6 ± 0.2 0.18 ± 0.03 Unidentified impurities 0.1 ± 0.03 6.9 ± 0.2 3.5 ± 0.1 2.2 ± 0.1

The composition obtained in example 5 does not maintain the standard mode of thermal sterilization (121 ± 1 ° C, 8 min) - the active components are decomposed with the formation of degradation products: nicotinic acid, hypoxanthine and unidentified impurities. The mode of 100 ± 1 ° C for 8 min also does not provide an acceptable level of impurities in the solution.

Thus, the initial stage of research indicates that the composition obtained in Example 5 is an aqueous solution of chemically active, thermolabile and hydrolysis-prone components, which during thermal sterilization and storage are prone to destruction with the formation of a multitude of unidentifiable impurities that represent the potential danger of using in medical practice. In addition, the resulting solution had an unphysiological pH of 3.15, which also does not allow the use of this solution as a drug for intravenous administration.

An attempt to reduce the risk of contamination by microorganisms under aseptic filling of the medicinal composition and by introducing into the composition of auxiliary components that are chemical preservatives, such as benzyl alcohol, benzalkonium chloride, cresol, propylene glycol in a concentration of 0.5-5.0%, also proved unsuccessful, so how when they were added the crystallization of the mixture of active components from the solution and the color change of the solution occurred, which indicated the chemical interaction of the active components with the auxiliary .

Attempt to sterilize the composition of the prototype with alternative methods of physico-chemical sterilization (radiation, microwave) was also unsuccessful due to the rapid degradation of riboflavin sodium mononucleotide with the formation of colored decomposition products and sludge.

At the next stage, studies were carried out on a model composition with an optimal physiological pH value of 7.3-7.4 corresponding to the pH of human blood suitable for further thermal sterilization, while sodium hydroxide was administered as a stabilizing component (examples 6-11).

Example 6. A 50 l liter of water for injection, 5 kg of succinic acid, 1.0 kg of inosine, 0.5 kg of nicotinamide, 0.1 kg of riboflavin mononucleotide and sodium hydroxide, 3.40 kg, are loaded into an apparatus with a mixer with a capacity of 100 l. complete dissolution of the components and establishing the pH of a solution of 7.3-7.4 and then bring the volume of solution to 100 liters of water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Example 7. A 50 l liter of water for injection, 7.5 kg of succinic acid, 1.5 kg of inosine, 0.75 kg of nicotinamide, 0.15 kg of riboflavin mononucleotide and sodium hydroxide 8.51 are loaded into the apparatus with a mixer with a capacity of 100 l. kg to completely dissolve the components and establish a pH of 7.3-7.4 and then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Example 8. A 50 l liter of water for injection, 10 kg of succinic acid, 2.0 kg of inosine, 1.0 kg of nicotinamide, 0.2 kg of riboflavin mononucleotide and sodium hydroxide 6.81 kg are loaded into an apparatus with a mixer with a capacity of 100 l. complete dissolution of the components and establish a pH of 7.3-7.4 and then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Example 9. In the apparatus with a mixer with a capacity of 100 l load 50.0 l of water for injection, 12.5 kg of succinic acid, 2.5 kg of inosine, 1.25 kg of nicotinamide, 0.25 kg of riboflavin mononucleotide and sodium

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hydroxide 8.52 kg until complete dissolution of the components and the establishment of a pH of 7.3-7.4 and then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Example 10. A 50 l liter of water for injection, 15 kg of succinic acid, 3.0 kg of inosine, 1.5 kg of nicotinamide, 0.3 kg of riboflavin mononucleotide and sodium hydroxide 10.22 kg are loaded into an apparatus with a mixer with a capacity of 100 l. and establishing a pH of 7.3-7.4 and then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed.

Example 11. In the apparatus with a mixer with a capacity of 100 l load 50.0 l of water for injection, 20 kg of succinic acid, 4.0 kg of inosine, 2.0 kg of nicotinamide, 0.4 kg of riboflavin mononucleotide and sodium hydroxide 13.62 kg to complete dissolution of the components and establish a pH of 7.3-7.4 and then bring the volume of the solution with water for injection to 100 liters. In the resulting composition it was not possible to achieve complete dissolution of the components - the solution was a yellow homogeneous suspension.

Evaluation of the effectiveness of using sodium hydroxide as a solubilizer of the obtained solutions was carried out for 10 days after filling into ampoules (Table 2), analyzing visually 100 ampoules for the presence of a change in the state of aggregation (precipitation) and a change in the color of the solution. The obtained samples were stored in a KVR 240 Vshbeg climatic chamber at 25 ° C.

table 2

The results of monitoring the compositions containing as a solubilizer sodium hydroxide in examples 6-11

The concentration of the composition according to the content of succinic acid, g / l Description of the solution during preparation The results of the visual analysis of ampoules for 10 days at 25 ° C 5.0 (Example 6) Clear yellow solution No precipitation and no change in original color 7.5 (Example7) Clear yellow solution No precipitation and no change in original color 10.0 (Example8) Clear yellow solution No precipitation and no change in original color 12.5 (Example 9) Clear yellow solution No precipitation and no change in original color 15.0 (Example 10) Clear yellow solution During storage precipitation of 12.0 wt. % ampoules and slight change colors 20.0 (Example 11) does not dissolve Not explored

Experiments have shown that adding sodium hydroxide to a composition similar to the prototype (succinic acid 10.0 wt.%, Inosine 1.0 wt.%, Nicotinamide 0.5 wt.% And riboflavin mononucleotide 0.2 wt.%, Water to 100.0 wt.%), Allowed to completely dissolve the active ingredients (example 8). Aqueous solutions of the composition with the concentration of the active components in 1.25 and 1.5 times more (examples 9 and 10) and two times less (example 6) were also successfully solubilized. The composition with the content of active components two times more than in the prototype (Example 11) failed to solubilize sodium with hydroxide to a true solution.

Since the influence of medium acidity and sterilization temperature of multicomponent aqueous solutions is largely determined by a combination of empirical factors, for further research we determined the limits of the content of active components corresponding to the prototype: succinic acid 5.0–12.5, inosine 1.0–2.5, nicotinamide 0.5-1.25, riboflavin mononucleotide 0.1-0.25 wt.%, which gives, after adding a stabilizing agent sodium hydroxide, a stable true solution for 10 days after filling into ampoules before carrying out the process of thermal th sterilization.

Further, in order to determine pH ranges ensuring the stability of solutions potentially suitable for subsequent thermal sterilization, model solutions No. 1, No. 2 and No. 3 were prepared with different amounts of sodium hydroxide to simulate pharmaceutically acceptable pH values of the solution in the range of 5.4-8, 4 (examples 12, 13, 14). The obtained solutions in ampoules were placed for 3 days in a climatic chamber Wbegirp at a temperature of 60 ± 2 ° С for stress testing and then visually evaluated the condition of the solutions. The results are presented in table. 3

Example 12. (Model solution No. 1). In the apparatus with a stirrer with a capacity of 100 liters load 50.0 liters in 5 029693

dyes for injection, 5.0 kg of succinic acid, 0.5 kg of nicotinamide, 1.0 kg of inosine, 0.1 kg of riboflavin mononucleotide and sodium hydroxide to ensure a pH in the range from 5.4 to 8.4, dilute the solution with water for injection up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 500 mg (5.0 wt.%), Inosin 100 mg (1.0 wt.%), Nicotinamide 50 mg (0.5 wt.%), Riboflavin mononucleotide 10 mg (0, 1 wt.%), Sodium hydroxide from 2.80 to 3.49 wt.%, Water for injection to 100.0 wt.%.

Example 13. (Model solution No. 2). 50.0 l of water for injection, 10.0 kg of succinic acid, 0.5 kg of nicotinamide, 1.0 kg of inosine, 0.1 kg of riboflavin mononucleotide and sodium hydroxide are loaded into the apparatus with a mixer with a capacity of 100 l to ensure a pH in the range of 5.4 to 8.4, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosine 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide from 5.60 to 6.98 wt.%, Water for injection to 100.0 wt.%.

Example 14. (Model solution No. 3). 50.0 liters of water for injection, 12.5 kg of succinic acid, 1.25 kg of nicotinamide, 2.5 kg of inosine, 0.25 kg of riboflavin mononucleotide and sodium hydroxide are charged to the apparatus with a mixer with a capacity of 100 l to ensure a pH in the range from 5.4 to 8.4, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Each 10 ml ampoule contains succinic acid 1250 mg (12.5 wt.%), Inosin 250 mg (1.25 wt.%), Nicotinamide 125 mg (1.25 wt.%), Riboflavin mononucleotide 25 mg (0, 25 wt.%), Sodium hydroxide from 7.01 to 8.72 wt.%, Water for injection to 100.0 wt.%.

Studies have shown the effect of pH on the stability of model solutions (MR) during stress tests. In vials with solutions with a pH below 6.0, precipitation was observed during the first three days of observation, which indicates chemical instability and the formation of water-insoluble impurities. Ampoules with solutions with a pH of 8.0 and higher showed a change in color from yellow to dark brown, which indicates the occurrence of processes of destruction of the active components and further chemical interactions with the formation of potentially dangerous unidentified impurities in the preparation.

Table 3

The influence of the pH of the compositions on the stability at 60 ± 2 ° C (stress testing)

Composition No. Sodium hydroxide content, g / l PH Solution stability MP1 34.89 8.4 Unstable MP2 69.72 8.4 Unstable MRZ 87.23 8.4 Unstable MP1 34.72 8.2 Unstable MP2 69.45 8.2 Unstable MRZ 86,81 8.2 Unstable MP1 34.54 8.0 Stable MP2 69.09 8.0 Stable MRZ 86.36 8.0 Stable

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MP1 34.09 7.4 Stable MP2 68.18 7.4 Stable MRZ 85.22 7.4 Stable MP1 33.84 7.0 Stable MP2 67.67 7.0 Stable MRZ 84,59 7.0 Stable MP1 33.46 6,6 Stable MP2 66.94 6,6 Stable MRZ 83.67 6,6 Stable MP1 32.06 6.0 Stable MP2 64.13 6.0 Stable MRZ 80.17 6.0 Stable MP1 31.11 5.8 Unstable MP2 62.23 5.8 Unstable MRZ 77.78 5.8 Unstable MP1 28.02 5.4 Unstable MP2 56.03 5.4 Unstable MRZ 70.08 5.4 Unstable

Thus, the obtained data show the predominant influence of pH on the stability of model solutions and the absence of dependence on the concentrations of active components in the studied intervals, which indicates the key effect of hydrolysis processes on the stability of the composition, and not the chemical interaction between the components in the investigated pH range from 6.0 to 8.0.

For further study of the stability of the compositions after a stress study, we selected model solution No. 2 (Example 13) containing succinic acid (10.0 wt.%), Inosine (2.0 wt.%), Nicotinamide (1.0 wt.%) , riboflavin sodium mononucleotide (0.2 wt.%) and sodium hydroxide in the range of 6.41-6.91 wt.%, until complete dissolution of the components and the establishment of a pH in the range from 6.0 to 8.0.

The series of ampoules obtained in example 13 were subjected to thermal sterilization with water vapor under pressure in the temperature range from 100 ± 2 to 121 ± 1 ° С with various time exposures from 2 to 8 min (Table 4). The stability of the compositions after temperature exposure was studied in conditions of accelerated aging in the climate chamber Wthe KWT 240 for 6 months, at a temperature of 40 ± 1 ° С.

The quantitative content of components and impurities was determined by HPLC under the following conditions: a spectrophotometric detector, a wavelength of 254 nm, a refractometric detector, a chromatographic column; the eluent flow rate was 0.7 ml / min; the column temperature was 25 ° C; Chromatography time is 30 minutes.

The conditions for carrying out the thermal sterilization of the samples of the composition were considered acceptable (1SCN3B 1CRIPE8 ϊπ ne \ u bgad rgobie18) for a safe drug for intravenous administration, if after 6 months the concentration of the active ingredients of the active components was not less than 95.0 wt.% not identified impurities did not exceed 2.0 wt.%.

The combined experimental data for the selection of the optimal parameters of thermal sterilization of model solution No. 2 are presented in Table. four.

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Table 4

The results of the experiment on the choice of the optimal parameters of thermal sterilization of model solution No. 2

No of experience pH Temperature and time of sterilization of model solution No. 3 ° C / min 121 + 1/8 121 + 1/2 116 + 2/2 112 + 2/4 108 + 2/6 104 + 2/8 100 + 2/8 E 8.0 - - + + + + + 2 7,8 - - + + + + + 3 7,6 - - + + + + + four. 7.4 - + + four- + + + five. 7.2 - + + + + + + 6 7.0 - - + + + + + 7 6.8 - - + + + + + eight. 6,6 - - + + + + + 9. 6.4 - - + + + + + ten. 6.2 - - + + + + + eleven. 6.0 - - + + + + +

Note:

+ the drug is stable when stored for 6 months,

- the drug is not stable when stored for 6 months.

Analysis of the samples (Table 4) showed that practically at all temperature regimes of sterilization of more than 116 ± 2 ° С, precipitation, formation of a greenish suspension and a significant increase in the amount of hypoxanthine are observed during storage. The sterilization mode at a temperature of 121 ± 1 ° C and an exposure time of 2 minutes allows to obtain stable compositions, but only in a narrow pH range from 7.2 to 7.4, which is extremely inconvenient, since in industrial production it is difficult to obtain solutions with pH close to the equivalence point. Temperatures below 116 ° C make it possible to obtain compositions stable for 6 months in a wide range of pH from 6.0 to 8.0.

Thus, in the course of the research, the optimal amount of the stabilizing agent and the parameters of thermal sterilization of model composition No. 2 containing succinic acid (10.0 wt.%), Inosine (2.0 wt.%), Nicotinamide (1.0 wt.% ), riboflavin mononucleotide sodium (0.2 wt.%) and sodium hydroxide in the range of 6.41-69.1 wt.% until complete dissolution of the components and establishing a pH in the range from 6.0 to 8.0 with thermal sterilization at temperature from 100 ± 2 ° С to 116 ± 2 ° С and exposure from 8 to 2 minutes.

Considering the established parameters of the sterilization process, further evaluation was made of the possibility of using the composition as stabilizers of various pharmaceutically acceptable components from the selected group: sodium bicarbonate (EP 9.0, 01/2017: 0195, p. 3585), sodium carbonate (EP 9 , 0, 01/2017: 0773, p. 3570), sodium hydroxide (EP 9.0, 01/2017: 0677, p. 3836), Tris (EP 9.0, 01/2017: 1053, p. 3885) , ethanolamine (Napochook o £ rkagschasei11 ex1ppl as of 2010, p, 450 450; i8P39-LR), diethanolamine (Napbiok about £ rkagschasei11 pc, 138; and 8p39-Lr, meglyumine (inc), meglyumine (inc), meglyumin (inc), meglyumin, rs1p1epgz 2010, p 228; p.2992), b-arginine (EP 9.0, 01/2017: 080 6, p. 753) and their various combinations.

For this purpose, solutions (examples 15-20) were prepared with different content of solubilizers in the previously established pH range of 6.0-8.0, the process of thermal sterilization was carried out in boundary and intermediate values in the temperature range of 100 and 116 ° C and the corresponding optimal time Exposure from 8 to 2 min and further studied the stability of the compositions during long-term storage at a temperature of 30 ° C in the climatic chamber VTbeg KVE 240 for two years.

The shelf life of the composition was established using the HPLC method: if at the time point of observation the concentration of active components was not less than 95.0 wt.% Of the initial value, the content of unidentified impurities did not exceed 2.0 wt.% And the preparation remained sterile.

Considering that inosine readily undergoes hydrolysis to a poorly soluble hypoxanthine, first of all, we proposed sodium bicarbonate as a mild stabilizing agent (examples 15 and 16).

Example 15 (sodium bicarbonate: series 15-100, 15-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 0.5 kg of nicotinamide, 1.0 kg of inosine, 0.1 kg of riboflavin mononucleotide and 13.76 kg of sodium bicarbonate are loaded into the apparatus with a mixer with a capacity of 100 l. dissolving the components and establishing a pH of 6.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution

- 8 029693

filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into vials with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium bicarbonate 1376 mg (13.76 wt.%), Water for injection to 100.0 wt.%.

Example 16 (sodium bicarbonate: series 16-100, 16-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 0.5 kg of nicotinamide, 1.0 kg of inosine, 0.1 kg of riboflavin mononucleotide and 17.15 kg of sodium bicarbonate are loaded into the apparatus with a mixer with a capacity of 100 l. dissolving the components and establishing a pH of 7.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium bicarbonate 1715 mg (17.15 wt.%), Water for injection to 100.0 wt.%.

However, the process of preparation of the preparation according to examples 15 and 16 occurred with intensive foaming of the solution when introducing bicarbonate into sodium solution, especially at the initial stage of the dissolution process as a result of carbon dioxide evolution. This fact significantly increases the preparation time of the drug and does not allow to reach physiological pH values of 7.3-7.4 of the solution. An attempt to increase the amount of sodium bicarbonate more than 17.1 wt.% (Example 16) did not lead to a further pH shift above 7.0, in addition, precipitation of the components of the composition was observed due to the excess of their solubility limits.

More alkaline solutions of the composition are preferred for clinical use, since one of the main syndromes in the treatment of diseases of the developed composition is a decrease in blood pH (acidemia). The inventive method of obtaining compositions by addition to the composition as a stabilizing agent of one of the pharmaceutically acceptable components selected from the group including sodium hydroxide, trisoxymethylaminomethane (Tris), ethanolamine, diethanolamine, sodium carbonate, meglumin is illustrated by examples 17-30.

The use of a sodium carbonate stabilizer instead of sodium bicarbonate makes it possible to achieve physiological pH values (examples 17 and 18), while the technological process of preparation was also accompanied by abundant release of carbon dioxide and foaming.

Example 17 (sodium carbonate: series 17-100, 17-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 11.22 kg are loaded into the apparatus with a mixer with a capacity of 100 l. dissolving the components and establishing a pH of 6.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each series of 10 ml ampoules contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0 , 2 wt.%), Sodium carbonate (11.66 wt.%), Water for injection to 100.0 wt.%.

Example 18 (sodium carbonate: series 18-100, 18-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 18.46 kg to complete are loaded into the apparatus with a mixer with a capacity of 100 l. dissolving the components and establishing a pH of 8.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each series of 10 ml ampoules contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0 , 2 wt.%), Sodium carbonate (18.46 wt.%), Water for injection to 100.0 wt.%.

Example 19 (sodium hydroxide: series 19-100, 19-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 6.41 kg are mixed into a device with a mixer with a capacity of 100 l. complete dissolution of the components and establish a pH of 6.0 and then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each series of 10 ml ampoules contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0 , 2 wt.%), Sodium hydroxide 641 mg (6.41 wt.%), Water for injection to 100.0 wt.%.

- 9 029693

Example 20 (sodium hydroxide: series 20-100, 20-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, 6.91 kg of sodium hydroxide are loaded into the apparatus with a mixer with a capacity of 100 l. dissolving the components and establishing a pH of 8.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 691 mg (6.91 wt.%), Water for injection to 100.0 wt.%.

Example 21 (Tris: series 21-100, 21-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 19.61 kg are loaded into the apparatus with a mixer with a capacity of 100 l to complete dissolution components and establish a pH of 6.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1961 mg (19.61 wt.%), Water for injection to 100.0 wt.%.

Example 22 (Tris: series 22-100, 22-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 41.23 kg are fully loaded into the apparatus with a mixer with a capacity of 100 l. components and establish a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 4123 mg (41.23 wt.%), Water for injection up to 100.0 wt.%.

Example 23 (ethanolamine: series 23-100, 23-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, ethanolamine 9.8 kg are loaded into the apparatus with a mixer with a capacity of 100 l to fully dissolve components and establish a pH of 6.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Ethanolamine 980 mg (9.80 wt.%), Water for injection to 100.0 wt.%.

Example 24 (ethanolamine: series 24-100, 24-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, ethanolamine 11.0 kg are loaded into the apparatus with a mixer with a capacity of 100 l to complete dissolution components and establish a pH of 8.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Ethanolamine 1100 mg (11.0 wt.%), Water for injection to 100.0 wt.%.

Example 25 (meglumine: series 25-100, 25-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 34.91 kg are loaded into the apparatus with a mixer with a capacity of 100 l to completely dissolve components and establish a pH of 8.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 3491 mg (34.91 wt.%), Water for injection to 100.0 wt.%.

Example 26 (meglumine: series 26-100, 26-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 31.32 kg are loaded into the apparatus with a mixer with a capacity of 100 l to fully dissolve components and establish a pH of 6.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through sterilis- 10 029693

A filter with a pore diameter of 0.22 μm is poured into 10 ml ampoules and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 3132 mg (31.32 wt.%), Water for injection to 100.0 wt.%.

Example 27 (diethanolamine: series 27-100, 27-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, diethanolamine 20.83 kg are loaded into the apparatus with a mixer with a capacity of 100 l to dissolve components and establish a pH of 8.0, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Diethanolamine 2083 mg (20.83 wt.%), Water for injection to 100.0 wt.%.

Example 28 (diethanolamine: series 28-100, 28-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium diethanolamine 16.89 kg to full dissolving the components and establishing a pH of 6.0, then adjust the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Diethanolamine 1689 mg (16.89 wt.%), Water for injection up to 100.0 wt.%.

Example 29 (L-arginine: series 29-100, 29-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, b-arginine 28.0 kg are loaded into the apparatus with a mixer with a capacity of 100 l. complete dissolution of the components and establish a pH of 6.0, then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), L-arginine 2830 mg (28.3 wt.%), Water for injection up to 100.0 wt.%.

Example 30 (L-arginine: series 30-100, 30-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, b-arginine 33.5 kg are loaded into the apparatus with a mixer with a capacity of 100 l the complete dissolution of the components and the establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), L-arginine 3350 mg (33.50 wt.%), Water for injection up to 100.0 wt.%.

The inventive method of obtaining compositions by the additional introduction as a stabilizing agent of several pharmaceutically acceptable components selected from the group including sodium hydroxide, trisoxymethylaminomethane (Tris), ethanolamine, diethanolamine, sodium carbonate, meglumin, is illustrated in examples 31-91.

Thus, the introduction of two components at the same time is described in examples 31-60, three in examples 61-84, and four in examples 85-91.

Example 31 (sodium hydroxide, Tris: series 31-100, 31-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 5.98 kg and Tris are loaded into the apparatus with a mixer with a capacity of 100 l. 5.54 kg until complete dissolution of the components and establishing a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 598 mg (5.98 wt.%), Tris 554 mg (5.54 wt.%), Water for injection up to 100.0 wt.%.

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Example 32 (sodium hydroxide, Tris: series 32-100, 32-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 1.81 kg and Tris 14.07 kg until complete dissolution of the components and the establishment of a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 181 mg (1.81 wt.%), Tris 1477 mg (14.77 wt.%), Water for injection up to 100.0 wt.%.

Example 33 (sodium hydroxide, Tris: series 33-100, 33-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 3.38 kg and Tris are loaded into the apparatus with a mixer with a capacity of 100 l. 12.93 kg to completely dissolve the components and establish a pH of 7.4, add a volume of solution to 100 liters of water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 883 mg (3.38 wt.%), Tris 1293 mg (12.93 wt.%), Water for injection to 100.0 wt.%.

Example 34 (sodium hydroxide, meglumine: series 34-100, 34-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide of 5.48 kg and meglumin 7.19 kg until complete dissolution of the components and the establishment of a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 548 mg (5.48 wt.%), Meglumine 719 mg (7.19 wt.%), Water for injection up to 100.0 wt.%.

Example 35 (sodium hydroxide, meglumine: series 35-100, 35-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 3.39 kg and meglumin are loaded into the apparatus with a mixer with a capacity of 100 l. 16.54 kg to completely dissolve the components and establish a pH of 7.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 339 mg (3.39 wt.%), Meglumin 1654 mg (16.54 wt.%), Water for injection up to 100.0 wt.%.

Example 36 (sodium hydroxide, meglumine: series 36-100, 36-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide of 1.85 kg and meglumin are loaded into the apparatus with a mixer with a capacity of 100 l. 22.28 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 185 mg (1.85 wt.%), Meglumine 2228 mg (22.28 wt.%), Water for injection to 100.0 wt.%.

Example 37 (sodium hydroxide, ethanolamine: series 37-100, 37-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 5.07 kg and ethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 2.93 kg, until complete dissolution of the components and establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 507 mg (5.07 wt.%), Ethanolamine 293 mg (2.93 wt.%), Water for injection to 100.0 wt.%.

Example 38 (sodium hydroxide, ethanolamine: series 38-100, 38-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosium, 12 029693 are loaded into the apparatus with a mixer with a capacity of 100 l.

0.2 kg of riboflavin mononucleotide, sodium hydroxide 3.35 kg and ethanolamine 5.22 kg to completely dissolve the components and establish a pH of 6.9, bring the volume of solution to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 335 mg (3.35 wt.%), Ethanolamine 522 mg (5.22 wt.%), Water for injection up to 100.0 wt.%.

Example 39 (sodium hydroxide, ethanolamine: series 39-100, 39-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 1.68 kg and ethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 7.23 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 168 mg (1.68 wt.%), Ethanolamine 723 mg (7.23 wt.%), Water for injection to 100.0 wt.%.

Example 40 (sodium hydroxide, b-arginine: series 40-100, 40-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, 4.93 kg of sodium hydroxide and 9 are loaded into the apparatus with a mixer with a capacity of 100 l. , 59 kg of L-arginine until complete dissolution of the components and the establishment of a pH of 8.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 493 mg (4.93 wt.%), L-arginine 959 mg (9.59 wt.%), Water for injection to 100.0 wt.%.

Example 41 (sodium hydroxide, b-arginine: series 41-100, 41-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 3.57 kg and b are loaded into the apparatus with a mixer with a capacity of 100 l. -arginine 14.27 kg to completely dissolve the components and establish a pH of 7.2, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 357 mg (3.57 wt.%), L-arginine 1427 mg (14.27 wt.%), Water for injection to 100.0 wt.%.

Example 42 (sodium hydroxide, b-arginine: series 42-100, 42-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, 1.9 kg of sodium hydroxide and 19 are loaded into the apparatus with a mixer with a capacity of 100 l. , 68 kg of L-arginine to completely dissolve the components and establish a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 190 mg (1.9 wt.%), L-arginine 1968 mg (19.68 wt.%), Water for injection to 100.0 wt.%.

Example 43 (sodium hydroxide, diethanolamine: series 43-100, 43-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 2.50 kg and diethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 13.29 kg, until complete dissolution of the components and establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 250 mg (2.50 wt.%), Diethanolamine 1329 mg (13.29 wt.%), Water for injection to 100.0 wt.%.

Example 44 (sodium hydroxide, diethanolamine: series 44-100, 44-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 3.66 kg and diethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 8.21 kg to half- 13 029693

After dissolving the components and setting the pH to 6.9, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 366 mg (3.66 wt.%), Diethanolamine 821 mg (8.21 wt.%), Water for injection up to 100.0 wt.%.

Example 45 (sodium hydroxide, diethanolamine: series 45-100, 45-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 1.64 kg and diethanolamine 12.56 kg to completely dissolve the components and establish a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 164 mg (1.64 wt.%), Diethanolamine 1256 mg (12.56 wt.%), Water for injection up to 100.0 wt.%.

Example 46 (Tris, meglumine: series 46-100, 46-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 16.40 kg and meglumin 21 are loaded into the apparatus with a mixer with a capacity of 100 l , 03 kg, until complete dissolution of the components and establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1640 mg (16.4 wt.%), Meglumine 2103 mg (21.03 wt.%), Water for injection to 100.0 wt.%.

Example 47 (Tris, meglumine: series 47-100, 47-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 10.0 kg and meglumin 17 are loaded into the apparatus with a mixer with a capacity of 100 l. , 72 kg, until complete dissolution of the components and establishment of a pH of 6.8, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1000 mg (10.0 wt.%), Meglumine 1772 mg (17.72 wt.%), Water for injection up to 100.0 wt.%.

Example 48 (Tris, meglumine: series 48-100, 48-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 5.02 kg and meglumin 23 are loaded into the apparatus with a mixer with a capacity of 100 l. , 29 kg until complete dissolution of the components and the establishment of a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 502 mg (5.02 wt.%), Meglumine 2329 mg (23.29 wt.%), Water for injection up to 100.0 wt.%.

Example 49 (meglumine, b-arginine: series 49-100, 49-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 23.53 kg and b arginine 10.92 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 2353 mg (23.53 wt.%), L-arginine 1092 mg (10.92 wt.%), Water for injection up to 100.0 wt.%.

Example 50 (meglumine, b-arginine: series 50-100, 50-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg are loaded into the apparatus with a mixer with a capacity of 100 l.

Riboflavin mononucleotide, meglumine 15.04 kg and L-arginine 17.07 kg to fully dissolve the complex 14 029693

ponentov and establish a pH of 7.5, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1504 mg (15.04 wt.%), L-arginine 1707 mg (17.07 wt.%), Water for injection to 100.0 wt.%.

Example 51 (meglumine, b-arginine: series 51-100, 51-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine, 8.71 kg, and L- are loaded into the apparatus with a mixer with a capacity of 100 l. arginine 20.18 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 871 mg (8.71 wt.%), L-arginine 2018 mg (20.18 wt.%), Water for injection to 100.0 wt.%.

Example 52 (meglumine, ethanolamine: series 52-100, 52-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 20.36 kg and ethanolamine 4 , 59 kg until complete dissolution of the components and the establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 2036 mg (20.36 wt.%), Ethanolamine 459 mg (4.59 wt.%), Water for injection up to 100.0 wt.%.

Example 53 (meglumine, ethanolamine: series 53-100, 53-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 15.72 kg and ethanolamine 5 are loaded into the apparatus with a mixer with a capacity of 100 l. , 46 kg, until complete dissolution of the components and establishment of a pH of 7.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1572 mg (15.72 wt.%), Ethanolamine 546 mg (5.46 wt.%), Water for injection to 100.0 wt.%.

Example 54 (meglumine, ethanolamine: series 54-100, 54-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 6.33 kg and ethanolamine 7 are loaded into the apparatus with a mixer with a capacity of 100 l. , 82 kg until complete dissolution of the components and the establishment of a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 633 mg (6.33 wt.%), Ethanolamine 782 mg (7.82 wt.%), Water for injection up to 100.0 wt.%.

Example 55 (sodium carbonate, sodium hydroxide: series 55-100, 55a-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 4.11 kg and sodium are loaded into the apparatus with a mixer with a capacity of 100 l. hydroxide 4.04 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 411 mg (4.11 wt.%), Sodium hydroxide 404 mg (4.04 wt.%), Water for injection to 100.0 wt.%.

Example 56 (sodium carbonate, sodium hydroxide: series 56-100, 56-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg are loaded into the apparatus with a mixer with a capacity of 100 l.

inosine, 0.2 kg riboflavin mononucleotide, sodium carbonate 8.82 kg and sodium hydroxide 3.25 kg to

the complete dissolution of the components and the establishment of a pH of 7.2, the solution is adjusted with water for injection

- 15 029693

up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosine 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 882 mg (8.82 wt.%), Sodium hydroxide 325 mg (3.25 wt.%), Water for injection up to 100.0 wt.%.

Example 57 (sodium carbonate, sodium hydroxide: series 57-100, 57-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 14.14 kg and sodium are loaded into the apparatus with a mixer with a capacity of 100 l. hydroxide to 1.62 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 1414 mg (14.14 wt.%), Sodium hydroxide 162 mg (1.62 wt.%), Water for injection to 100.0 wt.%.

Example 58 (sodium carbonate, meglumine: series 58-100, 58-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate of 4.86 kg and meglumin are loaded into the apparatus with a mixer with a capacity of 100 l. 17.59 kg to completely dissolve the components and establish a pH of 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 486 mg (4.86 wt.%), Meglumine 1759 mg (17.59 wt.%), Water for injection up to 100.0 wt.%.

Example 59 (sodium carbonate, meglumine: 59d-100, 59d116 series). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 8.71 kg of meglumine are loaded into the apparatus with a mixer with a capacity of 100 l. , 74 kg, until complete dissolution of the components and establishment of a pH of 7.1, bring the volume of the solution with water for injection to 100 l. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 874 mg (8.71 wt.%), Meglumine 1574 mg (15.74 wt.%), Water for injection up to 100.0 wt.%.

Example 60 (sodium carbonate, meglumin: series 60-100, 60-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium carbonate 14.70 kg of meglumine are loaded into the apparatus with a mixer with a capacity of 100 l. , 11 kg, until complete dissolution of the components and establishment of a pH of 8.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium carbonate 1470 mg (14.70 wt.%), Meglumine 711 mg (7.11 wt.%), Water for injection to 100.0 wt.%.

Example 61 (sodium hydroxide, meglumine, Tris: series 61-100, 61-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 2.60 kg and meglumin are loaded into the apparatus with a mixer with a capacity of 100 l. 11.08 kg, Tris 12.59 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 260 mg (2.6 wt.%), Meglumin, 1108 mg (11.08 wt.%), Tris 1259 mg (12.59 wt.%) Water for injection up to 100.0 wt.%

Example 62 (sodium hydroxide, meglumine, Tris: series 62-100, 62-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg are loaded into the apparatus with a mixer with a capacity of 100 l.

inosine, 0.2 kg riboflavin mononucleotide, sodium hydroxide 3.62 kg and meglumine 11.76 kg, Tris 2.60

- 16 029693

kg to completely dissolve the components and establish a pH of 7.1, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 362 mg (3.62 wt.%), Meglumine 1176 mg (11.76 wt.%), Tris 260 mg (2.6 wt.%), Water for injection to 100.0 wt.%

Example 63 (sodium hydroxide, meglumine, Tris: series 63-100, 63-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 1.3 kg, Tris 11.3 kg and meglumine 8.47 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 130 mg (1.3 wt.%), Meglumine 1130 mg (11.3 wt.%), Tris 847 mg (8.47 wt.%), Water for injection to 100.0 wt.%

Example 64 (sodium hydroxide, ethanolamine, Tris: series 64-100, 64-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 3.98 kg and ethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 4.19 kg, Tris 1.80 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 398 mg (3.98 wt.%), Ethanolamine 419 mg (4.19 wt.%), Tris 180 mg (1.80 wt.%) Water for injection up to 100.0 wt. .%.

Example 65 (sodium hydroxide, ethanolamine, Tris: series 65-100, 65-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 3.08 kg and ethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l. 3.48 kg, Tris 4.88 kg to completely dissolve the components and establish a pH of 7.1, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 308 mg (3.08 wt.%), Ethanolamine 348 mg (3.48 wt.%), Tris 488 mg (4.88 wt.%), Water for injection up to 100.0 wt.%

Example 66 (sodium hydroxide, ethanolamine, Tris: series 66-100, 66-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 1.54 kg and ethanolamine are loaded into the apparatus with a mixer with a capacity of 100 l 6.88 kg, Tris 1.13 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of solution to 100 liters of water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosine 200 mg (2.0 wt.%), Nicotinamide 100 1.54 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg ( 0.2 wt.%), Sodium hydroxide 154 mg (1.54 wt.%), Ethanolamine 688 mg (6.88 wt.%), Tris 113 mg (1.13 wt.%), Water for injection to 100 , 0 wt.%.

Example 67 (sodium hydroxide, meglumine, b-arginine: series 67-100, 67-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 4.37, meglumine 7 are loaded into the apparatus with a mixer with a capacity of 100 l. , 63 kg and Larginina 4.90 kg to completely dissolve the components and establish a pH of 8.0, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 437 mg (4.37 wt.%), Meglumine 763 mg (7.63 wt.%), L- 17 029693

arginine 490 mg (4.90 wt.%), water for injection to 100.0 wt.%.

Example 68 (sodium hydroxide, meglumine, b-arginine: series 68-100, 68-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 3.28 kg of meglumine are loaded into the apparatus with a mixer with a capacity of 100 l. , 16 kg and Larginina 9.82 kg to completely dissolve the components and establish a pH of 7.0, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 328 mg (3.28 wt.%), Meglumine 616 mg (6.16 wt.%), Larginin 982 mg (9.82 wt.%), Water for injection up to 100.0 wt.%

Example 69 (sodium hydroxide, meglumin, b-arginine: series 69-100, 69-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 2.20 kg, meglumin 10.0 kg and Larginina 9.44 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of solution to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 220 mg (2.20 wt.%), Meglumine 1000 mg (10.0 wt.%), Larginin 944 mg (9.44 wt.%), Water for injection to 100.0 wt.%

Example 70 (Tris, meglumine, L-arginine: series 70-100, 70-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 15.8 kg of meglumine 6, are loaded into the apparatus with a mixer with a capacity of 100 l. 33 kg and L-arginine 14.60 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1580 mg (15.8 wt.%), Meglumin (6.33 wt.%), L-arginine 633 mg (14.60 wt.%), Water for injection up to 100.0 wt. .%.

Example 71 (Tris, meglumine, b-arginine: 71-100, 71-116 series). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 11.08 kg, meglumin 10 , 40 kg and L-arginine 5.76 kg to completely dissolve the components and establish a pH of 7.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1108 mg (11.08 wt.%), Meglumine 1040 mg (10.40 wt.%), L-arginine 576 mg (5.76 wt.%), Water for injection up to 100, 0 wt.%.

Example 72 (Tris, meglumine, L-arginine: 72-100, 72-116 series). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 6.11 kg, meglumine 10 are loaded into the apparatus with a mixer with a capacity of 100 l , 20 kg and L-arginine 10.20 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 611 mg (6.11 wt.%), Meglumine 1020 mg (10.20 wt.%), L-arginine 1020 mg (10.20 wt.%), Water for injection up to 100, 0 wt.%.

Example 73 (Tris, meglumine, ethanolamine: series 73-100, 73-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 13.4 kg, meglumine 4 , 98 kg and ethanolamine 5.87 kg to completely dissolve the components and establish a pH of 8.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to thermal

- 18 029693

steam sterilization under pressure in the temperature ranges of 100 or 116 ° C with an exposure of 2 and 8 min, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 134 mg (13.4 wt.%), Meglumine 498 mg (4.98 wt.%), Ethanolamine 587 mg (5.87 wt.%), Water for injection up to 100.0 wt. .%.

Example 74 (Tris, meglumine, ethanolamine: 74-100, 74-116 series). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 10.42 kg, meglumine 8 are loaded into the apparatus with a mixer with a capacity of 100 l. , 90 kg and ethanolamine 2.65 kg to completely dissolve the components and establish a pH of 6.9, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1042 mg (10.42 wt.%), Meglumine 890 mg (8.90 wt.%), Ethanolamine 265 mg (2.65 wt.%), Water for injection to 100.0 wt. .%.

Example 75 (Tris, meglumine, ethanolamine: series 75-100, 75-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 3.96 kg, meglumine 11 are loaded into the apparatus with a mixer with a capacity of 100 l. , 68 kg and ethanolamine 4.16 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 396 mg (3.96 wt.%), Meglumine 1168 mg (11.68 wt.%), Ethanolamine 416 mg (4.16 wt.%), Water for injection to 100.0 wt. .%.

Example 76 (Tris, ethanolamine, L-arginine: series 76-100, 76-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 19.26 kg, ethanolamine 2 , 99 kg and L-arginine 8.78 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1926 mg (19.26 wt.%), Ethanolamine 299 mg (2.99 wt.%), L-arginine 878 mg (8.78 wt.%), Water for injection up to 100, 0 wt.%.

Example 77 (Tris, ethanolamine, b-arginine: series 77-100, 77-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 11.23 kg, ethanolamine 1 , 90 kg and L-arginine 9.10 kg until complete dissolution of the components and the establishment of a pH of 6.9, bring the volume of solution to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 1123 mg (11.23 wt.%), Ethanolamine 190 mg (1.90 wt.%), L-arginine 910 mg (9.10.0 wt.%), Water for injection to 100.0 wt.%.

Example 78 (Tris, ethanolamine, L-arginine: series 78-100, 78-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris 5.62 kg, ethanolamine 6 are loaded into the apparatus with a mixer with a capacity of 100 l , 26 kg and L-arginine 2.08 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 562 mg (5.62 wt.%), Ethanolamine 626 mg (6.26 wt.%), L-arginine 208 mg (2.08 wt.%), Water for injection up to 100, 0 wt.%.

Example 79 (meglumine, ethanolamine, b-arginine: series 79-100, 79-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg are loaded into the apparatus with a mixer with a capacity of 100 l.

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inosine, 0.2 kg of riboflavin mononucleotide, meglumine 19.93 kg, ethanolamine 3.98 kg and L-arginine 2.27 kg until the components are completely dissolved and adjusted to pH 8.0, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1993 mg (19.93 wt.%), Ethanolamine 398 mg (3.98 wt.%), L-arginine 227 mg (2.27 wt.%), Water for injection up to 100, 0 wt.%.

Example 80 (meglumine, ethanolamine, b-arginine: 80-100, 80-116 series). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 16.53 kg, ethanolamine 2 , 58 kg and L-arginine 7.24 kg to completely dissolve the components and establish a pH of 6.7, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1653 mg (16.53 wt.%), Ethanolamine 258 mg (2.58 wt.%), L-arginine 427 mg (7.24 wt.%), Water for injection up to 100, 0 wt.%.

Example 81 (meglumine, ethanolamine, b-arginine: series 81-100, 81-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 7.88 kg, ethanolamine 4 are loaded into the apparatus with a mixer with a capacity of 100 l. , 28 kg and L-arginine 8.71 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 788 mg (7.88 wt.%), Ethanolamine 428 mg (4.28 wt.%), L-arginine 871 mg (8.71 wt.%), Water for injection to 100, 0 wt.%.

Example 82 (meglumine, diethanolamine, Tris: series 82-100, 82-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 19.4 kg, diethanolamine 3 are loaded into the apparatus with a mixer with a capacity of 100 l. , 17 kg and Tris 12.03 kg to completely dissolve the components and establish a pH of 8.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 194 mg (19.4 wt.%), Diethanolamine 317 mg (3.17 wt.%), Tris 1203 mg (12.03 wt.%), Water for injection up to 100.0 wt. .%.

Example 83 (meglumine, diethanolamine, Tris: series 83-100, 83-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 16.3 kg, diethanolamine 6 are loaded into the apparatus with a mixer with a capacity of 100 l. , 97 kg and Tris 2.89 kg to completely dissolve the components and establish a pH of 7.1, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 163 mg (16.3 wt.%), Diethanolamine 697 mg (6.97 wt.%), Tris 289 mg (2.89 wt.%), Water for injection up to 100.0 wt. .%.

Example 84 (meglumine, diethanolamine, Tris: series 84-100, 84-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 6.07 kg, diethanolamine 7 , 18 kg and Tris 7.47 kg to completely dissolve the components and establish a pH of 6.0, the solution volume is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meg- 20 029693

lumin 607 mg (6.07 wt.%), diethanolamine 718 mg (7.18 wt.%), Tris 747 mg (7.47 wt.%), water for injection to 100.0 wt.%.

Example 85 (sodium hydroxide, meglumine, ethanolamine, b-arginine: series 85-100, 85-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 3.39 kg, meglumine are loaded into the apparatus with a mixer with a capacity of 100 l. 10.57 kg, ethanolamine 1.18 kg and L-arginine 3.35 kg until the components are completely dissolved and the pH is adjusted to 8.0, the volume of the solution is adjusted to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature range of 100 or 116 ° C with an exposure of 2 and 8 min, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 339 mg (3.39 wt.%), Meglumine 1057 mg (10.57 wt.%), Ethanolamine 118 mg (1.18 wt.%), L-arginine 335 mg (3 , 35 wt.%), Water for injection up to 100.0 wt.%.

Example 86 (sodium hydroxide, meglumine, ethanolamine, b-arginine: series 86-100, 86-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide, 1.54 kg, meglumin 7.62 kg, ethanolamine 2.62 kg and L-arginine 6.97 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of the solution to 100 liters with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature range of 100 or 116 ° C with an exposure of 2 and 8 min, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 154 mg (1.54 wt.%), Meglumine 762 mg (7.62 wt.%), Ethanolamine 262 mg (2.62 wt.%), L-arginine 697 mg (6 , 97 wt.%), Water for injection to 100.0 wt.%.

Example 87 (sodium hydroxide, meglumine, ethanolamine, Tris: series 87-100, 87-116) / Into an apparatus with a mixer with a capacity of 100 l load 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide , 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 2.62 kg, meglumine 5.70 kg, ethanolamine 4.18 kg and Tris 3.17 kg to completely dissolve the components and establish a pH of 8.0, bring volume of solution with water for injection up to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature range of 100 or 116 ° C with an exposure of 2 and 8 min, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 262 mg (2.62 wt.%), Meglumine 570 mg (5.70 wt.%), Ethanolamine 418 mg (4.18 wt.%), Tris 317 mg (3.17 wt.%), water for injection to 100.0 wt.%.

Example 88 (sodium hydroxide, meglumine, ethanolamine, Tris: series 88-100, 88-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 1.54 kg, meglumine are loaded into the apparatus with a mixer with a capacity of 100 l. 7.61 kg, ethanolamine 2.36 kg and Tris 5.45 kg to completely dissolve the components and establish a pH of 6.0, bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature range of 100 or 116 ° C with an exposure of 2 and 8 min, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 154 mg (1.54 wt.%), Meglumine 761 mg (7.61 wt.%), Ethanolamine 236 mg (2.36 wt.%), Tris 545 mg (5.45 wt.%), water for injection to 100.0 wt.%.

Example 89 (meglumine, ethanolamine, diethanolamine, Tris: series 89-100, 89-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 7.45 kg, ethanolamine 3 , 80 kg, diethanolamine 3.98 kg, Tris 9.96 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 745 mg (7.45 wt.%), Ethanolamine 380 mg (3.80 wt.%), Diethanolamine 398 mg (3.98 wt.%), Tris 996 mg (9.96 wt. .%), water for injection to 100.0 wt.%.

Example 90 (meglumine, ethanolamine, diethanolamine, Tris: series 90-100, 90-116). In the apparatus with a mixer - 21 029693

With a capacity of 100 liters, 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumin 10.00 kg, ethanolamine 2.50 kg diethanolamine 2.50 kg, Tris 15.1 kg to completely dissolve the components and establish a pH of 8.0, bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules are subjected to thermal sterilization with water vapor under pressure in the temperature ranges of 100 or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1000 mg (10.0 wt.%), Ethanolamine 250 mg (2.50 wt.%), Diethanolamine 250 mg (2.50 wt.%), Tris 151 mg (15.1 wt. .%), water for injection to 100.0 wt.%.

Example 91 (meglumine, ethanolamine, diethanolamine, Tris: series 91-100, 91-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 16.53 kg, ethanolamine 1 are loaded into the apparatus with a mixer with a capacity of 100 l. , 55 kg, diethanolamine 2.67 kg, Tris 3.07 kg, until the components are completely dissolved and the pH is adjusted to 6.0, the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1653 mg (16.53 wt.%), Ethanolamine 155 mg (1.55 wt.%), Diethanolamine 267 mg (2.67 wt.%), Tris 307 mg (3.07 wt. .%), water for injection to 100.0 wt.%.

Special cases of the implementation of the proposed method are described in examples 92-96. In the study of compositions using pharmacopoeial sodium bicarbonate to obtain physiologically acceptable pH values, it was possible to obtain only in combination with other stabilizers added in equimolar ratio to succinic acid, while the maximum achievable values of pH did not exceed 7.3-7.5 (examples 92 -96). Further addition of sodium bicarbonate resulted in precipitation of the components of the combinations.

Example 92 (sodium hydroxide, sodium bicarbonate: series 92-100, 92-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, sodium hydroxide 6.77 kg, and sodium bicarbonate 2.05 kg to completely dissolve the components and establish a pH of 7.4, then bring the volume of solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Sodium hydroxide 598 mg (5.98 wt.%), Sodium bicarbonate 205 mg (2.05 wt.%), Water for injection up to 100.0 wt.%.

Example 93 (meglumine, sodium bicarbonate: series 93-100, 93-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 33.06 kg and sodium bicarbonate 2.49 kg to completely dissolve the components and establish a pH of 7.3, then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 3306 mg (33.06 wt.%), Sodium bicarbonate 249 mg (2.49 wt.%), Water for injection up to 100.0 wt.%.

Example 94 (Tris, sodium bicarbonate: series 94-100, 94-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 20.52 kg and sodium bicarbonate are loaded into the apparatus with a mixer with a capacity of 100 l. 2.90 kg to completely dissolve the components and establish a pH of 6.7, then bring the volume of solution with water for injection to 100 liters The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 2052 mg (20.52 wt.%), Sodium bicarbonate 290 mg (2.90 wt.%), Water for injection up to 100.0 wt.%.

Example 95 (Tris, sodium bicarbonate: series 95-100, 95-116). 50.0 liters of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, Tris, 20.52 kg and sodium bicarbonate are loaded into the apparatus with a mixer with a capacity of 100 l. 0.10 kg to the full extent - 22 029693

the creations of the components and the establishment of a pH of 6.4, then the volume of the solution is adjusted to 100 l with water for injection. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Tris 2052 mg (20.52 wt.%), Sodium bicarbonate 10 mg (0.10.0 wt.%), Water for injection to 100.0 wt.%.

Example 96 (meglumine, sodium hydroxide, sodium bicarbonate: series 96-100, 96-116). 50.0 l of water for injection, 10.0 kg of succinic acid, 1.0 kg of nicotinamide, 2.0 kg of inosine, 0.2 kg of riboflavin mononucleotide, meglumine 16.53 kg, sodium hydroxide are loaded into the apparatus with a mixer with a capacity of 100 l. 3.39 kg and sodium bicarbonate 2.37 kg to completely dissolve the components and establish a pH of 7.3, then bring the volume of the solution with water for injection to 100 liters. The resulting solution is filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 10 ml and sealed. Next, the resulting series of ampoules is subjected to heat sterilization with water vapor under pressure in the temperature ranges of 100 ° C or 116 ° C with an exposure time of 2 and 8 minutes, respectively. Each 10 ml ampoule contains succinic acid 1000 mg (10.0 wt.%), Inosin 200 mg (2.0 wt.%), Nicotinamide 100 mg (1.0 wt.%), Riboflavin mononucleotide 20 mg (0, 2 wt.%), Meglumine 1653 mg (16.53 wt.%), Sodium hydroxide 339 mg (3.39 wt.%), Bicarbonate 237 mg (2.37 wt.%), Water for injection to 100.0 wt.%

Table 5

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When studying the stability of the compositions (Table 5) with various formulations of stabilizing agents, it was established:

1) the composition obtained in examples 29, 40-42, 49-51, 67-72, 76-81, 85-86, which included L-arginine, could not withstand long-term storage for 2 years at 30 ° C . In samples that contain arginine as a stabilizing agent, a significant amount of unidentified impurities is formed during storage, the presence of which reduces the safety of using parenteral drug, and therefore these compositions cannot be used in medical practice;

2) the possibility of using sodium thidroxide, sodium carbonate, meglumine, Tris, ethanolamine, diethanolamine, sodium bicarbonate, and their various combinations as stabilizing agents for the production of drugs for intravenous administration with physiological pH values and stable during storage for more than 2 years.

Thus, the inventive method allows to obtain a stabilized pharmaceutical composition in the form of an aqueous solution, to prevent the destruction of the active components and significantly reduce the likelihood of contamination by microorganisms in the preparation of the drug, which increases its safety while maintaining therapeutic efficacy.

Claims (2)

CLAIM 1. A method of obtaining a stable pharmaceutical composition in the form of an aqueous solution for intravenous administration containing succinic acid, inosine, nicotinamide, riboflavin sodium mononucleotide sodium as active components, by dissolving them in water followed by sterilizing filtration, characterized in that as a stabilizing agent, one or more pharmaceutically acceptable components selected from the group comprising sodium hydroxide, Tris-oxymethylaminomethane (Tris), ethanol Ying, diethanolamine, sodium carbonate, meglumine, to obtain a stable solution with a pH value in the range from 6.0 to 8.0 in the following ratio of components, wt.%: succinic acid - 5.00-12.50, inosine - 1, 00-2.40, nicotinamide - 0.50-1.20, riboflavin sodium mononucleotide - 0.10-0.24, stabilizing agent - 3.21-51.30, water - up to 100.0%, and additionally carry out thermal sterilization of the solution at a temperature of 100 ° C and an exposure time of 8 minutes to 116 ° C and an exposure time of 2 minutes. 2. A method of obtaining a stable pharmaceutical composition according to claim 1, characterized in that sodium bicarbonate is additionally introduced into the composition to obtain a stable solution with a value of 28 029693 by pH in the range from 6.4 to 7.4 in the following ratio of components, wt.%: succinic acid 5.00-12.50, inosine - 1.00-2.40, nicotinamide - 0.50-1.20 , riboflavin sodium mononucleotide - 0.10-0.24, stabilizing agent - 3.21-33.06, sodium bicarbonate - 0.10-2.90, water - up to 100.0%. ABOUT