RU2739247C1 - Method of producing a medicinal preparation for parenteral application - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: present invention relates to a method for preparing a medicinal agent for parenteral use, containing as active substance 1-deoxy-1-N-[methyl-(2-acridone-9-on-10-yl-acetate)]-ammonium-D-glucitol, by dissolving the active substance in water for injections, stirring, filtering the solution through a sterilizing filter, dispensing it into sterile containers, characterized by that N-methylglucamine in an amount of not more than 0.05 wt% is added to the solution as an auxiliary component, stirred until complete dissolution of components at temperature of 55-60°C, then obtained solution is cooled to temperature of 22-25°C, and after the stage of filtration and dispensing, it is subjected to thermal sterilization at temperature of 121°C for 8-15 minutes.

EFFECT: technical result of the present invention is the development of an optimum method for preparing a medicinal preparation for parenteral use containing as active component 1-deoxy-1-N-[-methyl-(2-acridone-9-on-10-yl-acetate)]-ammonium-D-glucitol, which will reduce the amount of impurities in the finished medicinal product and increase its shelf life.

1 cl, 7 tbl, 27 ex

Description

Technology area

The invention relates to the chemical-pharmaceutical industry and medicine, concerns a method for producing a medicinal product for parenteral use, containing 1-deoxy-1-N - [- methyl- (2-acridone-9-one-10-yl-acetate)] - ammonium -D-glucitol and has antiviral, antimicrobial, antifungal, antiparasitic, radioprotective and immunomodulatory effects. The drug is used to treat a wide range of infectious diseases.

Prior art

The compound 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol is known as a biologically active substance with an immunomodulatory effect (patent EA 000382) ... The biological activity of the known compound allows it to be used in the treatment of a wide range of diseases in humans and animals: the treatment of therioiditis (RF patent 2306932), oral candidiasis (RF patent 2642053), recurrent vaginal candidiasis (RF patent 2309761), influenza (RF patent 2281097), viral hepatitis in children (RF patent 2154478), arthritis (RF patent 2417091, RF 2169563), purulent-destructive lesions of the mucous membranes and skin (RF patent 2414221, RF 2361626, RF 2295348), onychomycosis (RF patent 2391100), siloadenitis (RF patent 2413507), brucellosis (RF patent 2423143), tuberculosis (RF patent 2296996) viral infections (RF patent 2281097, RF 2526253, RF 2538083, RF 2228756, RF 2459629), secondary immunodeficiency (RF patent 2364396, RF 2320293), choreoretinitis patent (RF patent RF 2275933), odontogenic maxillary sinusitis (RF patent 2460528), hyperplastic laryngitis (RF patent 2214249), tonsillitis (RF patent 2357732), psoriasis and neurodermatitis (RF patent 2292215), squamous cell carcinoma (RF patent 2332277), autologous cell transplantation (RF patent 2325934), burns (RF patent 2166960), staphylococcal infection (RF patent 2441656).

Known homeopathic drug based on N-methylglucamine 9-oxoacridinyl-10-acetate when diluted in saline to concentrations of 10 ^-29 -10 ^-2 mg / ml used for the prevention and treatment of influenza, ARVI, hepatitis B and C (RF patent 2281097), which indicates the high pharmacological activity of the compound even in homeopathic doses and the need to obtain stable solutions for parenteral administration of various concentrations of the active substance.

Known medicinal product for parenteral use, containing as an active substance 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol (patent EA 002462) ... The drug additionally contains as a stabilizer - N-methylglucamine with the following ratio of components, wt. %: 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol - 8.5-25.0, N-methylglucamine - 0, 05-1.00, water for injection - up to 100%.

According to the invention, the photostability and thermal stability of the dosage form are increased during production and storage due to the use of a stabilizer.

A method of obtaining this D-glucitol in water, adding a stabilizer, filtering through a sterilizing filter, filling in sterile ampoules with a volume of 1, 2, and 5 ml and sealing. Next, the resulting ampoules are subjected to thermal sterilization by autoclaving at a temperature of 120 ° C for 30 minutes.

This method is selected as a prototype of the claimed invention.

One of the problems, which is solved in the invention according to the patent EA 002462, is a decrease in the intensity of precipitation during storage of the precipitate insoluble in water N-methylacridone due to the high content of N-methylglucamine from 0.5 to 1.0 wt. %.

However, it was later found that in the prototype with a known sterilization mode of 120 ° C for 30 minutes and a range of stabilizer content, there is an additional increase in the level of single unidentified impurities and the sum of unidentified impurities due to the interaction of the stabilizer with the active component.

In addition, when the content of N-methylglucamine in an amount of from 0.5 to 1.0 mass. % there is a spontaneous and difficult to predict precipitation of acridone, a deacetylation product of 1-deoxy-1-N- [methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol in an alkaline medium during sterilization and storage. In this regard, the level of unidentified impurities in the finished medicinal product manufactured according to the prototype exceeded the norms described in the current international requirements (ICH Q3B (R2) "Impurities in new drug products", June 2006).

In a known quantitative range, N-methylglucamine acts as a solubilizer and pH regulator during the production and storage of the drug, thereby exerting a stabilizing effect in solution. However, the solubilizing properties of N-methylglucamine with respect to impurities of acridone and N-methylacridone lead to the formation of quasi-stable micelles from undesirable compounds poorly soluble in water, which are formed at the stage of solution preparation and sterilization. Later, during the storage of the drug under the influence of various external factors (light, temperature fluctuations and vibration during transportation and storage), as well as when interacting with the glass components of the inner surface of the ampoules, micelles are destroyed and these compounds precipitate, which is unacceptable for drugs for parenteral administration.

Moreover, the use of an excess of N-methylglucamine in the concentration range of 0.05-1.0 wt. % leads to a significant alkalization of the solution to pH = 8.5 (1.0% excess of N-methylglucamine) and contributes to the formation of a large number of additional impurities - decomposition products of the glucose derivative N-methylglucamine -toxic compounds from a number of furfurals. In general, especially in the sterilization mode of 120 ° C for 30 minutes, the level of impurities in the medicinal product obtained according to the prototype is unacceptable and does not meet modern requirements (ICH Q3B (R2) "Impurities in new drug products", June 2006) ...

Thus, the development of a method for obtaining a safe and storage-stable dosage form of 1-deoxy-1-N- [methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol in the form of an aqueous solution for intravenous administration is an important technological challenge.

Currently, the most widely used method of terminal sterilization in the industrial production of pharmaceuticals is thermal sterilization with saturated steam under pressure (autoclaving). The parameters of this process are regulated in international pharmacopoeias (State Pharmacopoeia of the Russian Federation 14th edition, European Pharmacopoeia EP 10.0, American Pharmacopoeia USP 40) and guidelines (ЕМА 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container, 6 March 2019).

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

So, in the application RU 2001117337, a variant of radiation sterilization of solutions is proposed, in patent RU 2519841, sterilization by microwave-ultra-high-frequency radiation. In the application RU 2006142783, sterilization is carried out in the treatment of pulsed high-voltage discharges that generate sterilizing UV radiation, and in the application RU 2000130091, a method is proposed for electrochemical sterilization of liquids with reactive particles. In patent RU 2366347, the proposed sterilization method is carried out in a cavitation reactor, through which, during the process, the sterilized liquid heated to a predetermined temperature circulates in a closed loop. In this case, the liquid is exposed to ultrasound, the amplitude of the sound pressure of which is set depending on the pressure and temperature in the reactor, using the value of the saturated water vapor pressure at this temperature. The method allows the consumption of acoustic energy in smaller quantities, and also to reduce the temperature of thermal sterilization.

At present, combinations of thermal and physical sterilization modes are also used to sterilize unstable aqueous solutions, so in patent RU 2238108 heating is carried out by the action of a microwave electromagnetic field, and sterilization is carried out with an EHF electromagnetic field. In the application RU 2003115619, an original combined method of sterilization is proposed by exposure to an electric field and acoustic vibration.

However, since many combined non-standard sterilization methods do not provide a high guarantee of the absence of microbial contamination of the drug, during its preparation, various water-soluble antimicrobial preservatives permitted by international pharmacopoeias are often forced to add to the solution: benzyl alcohol (RU 2209070, RU 210550, RU 2326669, RU 2192855, US 20150126466, UA 26343), benzalkonium chloride (RU 2419417, UA 26343), chlorobutanol (UA 26343), metacresol (RF 2093144), cresol (RU 2020954), phenol (RU 2111012). This combined method makes it possible to sterilize thermolabile drugs under non-standard sterilization regimes, however, it has a very significant drawback - a limitation to medical use, especially in pediatric practice (State Pharmacopoeia of the Russian Federation, 14th edition).

Also, to ensure the possibility of using thermal sterilization of thermolabile injection and infusion solutions, stabilizing agents of various chemical structures are used.

Thus, for example, CN 102552950 B describes a successful method for stabilizing an aqueous solution of adenosine triphosphate with a variety of different Tween 80 compounds, guanidine carbonate, glycine, arginine, propylene glycol, glycerin, creatinine, sodium caprylate, nicotinamide, or combinations thereof.

Patent RU 2529800 shows that the stability of an injectable dosage form of bortezolomib is increased in the presence of highly purified propylene glycol. And in the patent SU 1225573, an increase in the shelf life of a solution of celanide is established, which is achieved by dissolving celanide in 1,2-propylene glycol.

According to patent RU 2260429, the stability of the injection solution of moxifloxacin is achieved by introducing sodium chloride into the solution and in the presence of iron ions.

To stabilize injectable and infusion drugs containing easily oxidizing active substances, complexones are often used: EDTA - ethylenediaminetetraacetic acid, Trilon B (disodium EDTA salt), tetracin-calcium (calcium disodium EDTA salt), which are highly soluble in water and heat-resistant, mechanism the stabilizing action of which is associated with the transfer of heavy metal cations into complex, practically non-dissociable compounds that are inactive with respect to hydroperoxide. These stabilizers are effective especially in cases of using outdated equipment, which is a source of heavy metal contamination of both the starting substances and the finished drug. Hydroquinone, mannitol, glycerin, 8-hydroxyquinoline, etc. have a similar effect. These complexones are indirect antioxidants.

Thus, patent RU 2362560 describes a drug in the form of a solution for injection, including methylnaltrexone or its salt (a derivative of an opioid antagonist) and a chelating agent EDTA or a derivative thereof. EFFECT: prevention of decomposition of methylnaltrexone or its salt during thermal sterilization and demonstrates stability of methylnaltrexone preparation as a solution during storage for 12 months.

In US patent 8133883 for a composition in an injectable dosage form containing the antibacterial drugs sodium piperacillin and sodium tazobactam, an aminocarboxylic acid, in particular EDTA and its pharmaceutically acceptable salts, is used as a chelating agent to inhibit the formation of solid particles during storage of a solution of the composition, after thawing or reconstitution of the lyophilisate, as well as increasing the compatibility of the composition with aminoglycosides.

For example, patent RU 2284811 describes the use of a combination of stabilizers of Trilon B and alpha hydroxypropionic (lactic) acid to prevent the formation of mechanical impurities in the ciprofloxacin injection solution during the production process, increase storage stability, and improve bioavailability. In patent RU 2205640, the use of Trilon B ensured the stability of the Mexidol solution for 3.5 years without changing the color of the solution.

Often, to stabilize injection solutions, substances are used that destroy hydroperoxides, which, by reducing the rate of branching of oxidation chains, slow down oxidative reactions. These are salts of sulfurous acid, organic sulfur compounds: sodium sulfite (Na ₂ SO ₃ ), sodium metabisulfite (Na ₂ S ₂ O ₃ ), sodium bisulfite (NaHSO ₃ ), unitiol, rongalite, thiourea, methionine, etc.

To stabilize the injection solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate according to patent RU 2635759, a salt selected from the group of sulfite stabilizers of antioxidants is used as a stabilizer: sodium or potassium disulfite (metabisulfite), sodium or potassium sulfite, sodium or potassium hydrosulfite, sodium or potassium thiosulfate, which allows sterilizing the preparation with steam under pressure in an autoclave at a temperature of 100-130 ° C and ensuring the stability of the solution during storage for 5 years.

To stabilize a polyionic infusion solution based on N-methylglucamine sodium succinate (Eurasian patent No. 035241), carboxylic acids from the series: ethanic acid, 2-hydroxybutanedioic acid, 2-hydroxy- 1,2,3-propanetricarboxylic acid, butanedioic, trans-butenedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxypropanoic acid.

According to the invention (EA 029693, RU 2629204), sodium hydroxide, meglumine, TRIS, ethanolamine, diethanolamine, L-arginine are used to stabilize a solution for intravenous administration containing thermally unstable and hydrolytically unstable components nicotinamide, inosine, riboflavin mononucleotide.

A known method of stabilizing (RU 2020941) sodium 10-methylenecarboxylate-9-acridone with methylene blue in order to protect it from exposure to light, however, the patent does not contain data on the thermal stability of such solutions, and methylene blue itself is thermally unstable.

Patent SU 1178447 describes a method for stabilizing aymaline derivatives using polyvinylpyrrolidone with a molecular weight of 11,200. Patent RU 2443432 declares the possibility of using rather poorly water-soluble complexes of tetravalent platinum in an injectable dosage form due to the use of cyclodextrins, which significantly increase their solubility in water without using mixtures with organic solvents.

The authors of the invention RU 2451510 proposed a pharmaceutical composition containing nanoparticles of the drug docetaxel having an average diameter of not more than 200 nm and which is suitable for parenteral administration.

Thus, to solve the problem of stability of aqueous solutions of thermolabile active components during thermal sterilization, stabilizing substances of various chemical nature and mechanism of action are used: antioxidants, chelating agents, surfactants, polymers of various molecular weights, carboxylic acids, amino acids, amino polyols and other compounds.

The effectiveness of the use of a stabilizer depends on its concentration, chemical structure of active components, temperature and time of sterilization, dosage form, and selection of a stabilizer from a number of pharmaceutically acceptable compounds is in most cases an empirical process.

At the same time, it is known that during the production and storage in the finished product, a chemical interaction of active components, packaging materials and excipients occurs with each other and can go in an unpredictable direction with the formation of various undesirable impurities. Such interactions with the formation of impurities of unknown structure can lead not only to side reactions when using the drug, but to a change in its pharmacological activity.

In addition, for compositions containing thermolabile components, the use of standard sterilization regimes leads to degradation of the ingredients with the formation of unacceptable levels of degradation products. On the other hand, low-temperature heat treatment below 110 ° C is not allowed (ЕМА 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container) and for thermolabile drugs only sterilizing filtration and subsequent filling under aseptic conditions are regulated. This method can be used only in case of absolute impossibility of using thermal sterilization.

Thus, the known methods for preparing compositions containing thermolabile components cannot be considered optimal, since during their use a number of problems have been identified that can have a negative effect when using ready-made solutions as a drug.

The objective of the present invention is to develop an optimal method for producing a medicinal product for parenteral use, containing as an active component 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium D-glucitol, which will reduce the amount of impurities in the finished drug and increase its shelf life.

The problem is solved by the fact that, in the method of obtaining a medicinal product for parenteral use, containing as an active substance 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium- D-glucitol, by dissolving the active substance in water for injection, stirring, filtering the solution through a sterilizing filter, pouring it into sterile containers, according to the invention, N-methylglucamine is added to the solution as an auxiliary component in an amount of not more than 0.05 wt. %, stirred until the components are completely dissolved at a temperature of 55-60 ° C, then the resulting solution is cooled to a temperature of 22-25 ° C, and after the stage of filtration and filling, it is subjected to thermal sterilization at a temperature of 121 ° C for 8-15 minutes.

In a particular case, the task is solved by adding N-ethylglucamine to the solution as an auxiliary component in an amount of not more than 0.2 wt%.

The differences between the proposed method and the prototype method are:

- the use of pharmaceutically acceptable auxiliary components from the group of hydroxyamino compounds, in particular: N-methylglucamine in a new quantitative range and N-ethylglucamine in an established quantitative range,

- new temperature regimes at the stage of components dissolution and after it,

- the use of thermal sterilization while reducing the exposure time by more than 2 times.

Experience No. 4 has shown that the use of the proposed method with the claimed excipients and temperature conditions significantly affects the reduction of the amount of impurities in the finished product.

The claimed amounts of auxiliary components N-methylglucamine and N-ethylglucamine are due to the fact that, given their content in a solution of 1-deoxy-1-N- [methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium -D-glucitol in the process of preparation and exposure of the solution at a temperature of 55-60 ° C does not decompose the active component and a significant increase in related impurities.

In addition, the low content of N-methylglucamine and N-ethylglucamine in the composition, in contrast to the prototype, does not have a solubilizing effect on already formed impurities that are poorly soluble in water and during the cooling of the solution to a temperature of 22-25 ° C and with subsequent filtration, they removed without getting into the finished dosage form of the drug.

The use of thermal sterilization of the solution obtained by the above method, while reducing the exposure time at 121 ° C for 8-15 minutes, in combination with the addition of auxiliary components, additionally affects the decrease in the level of impurities.

In this regard, during long-term storage of the medicinal product obtained according to the claimed method, due to the low content of quasi-stable micelles in the solution, no precipitate of compounds poorly soluble in water occurs, which makes it possible to establish the shelf life of the finished product at least 5 years.

The proposed method for producing a medicinal product for parenteral use containing 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol as an active substance is optimal in comparison with the prototype method, since it reduces the time of thermal sterilization by more than half, as well as the use of interchangeable auxiliary components: N-methylglucamine in smaller amounts or N-ethylglucamine, which can significantly reduce the cost of energy and raw materials. At the same time, a decrease in the level of impurities in the drug during its production and storage was achieved, as well as an increase in the shelf life of the drug during storage up to 5 years.

Various options for obtaining a medicinal product according to the claimed method are presented in examples 15-27.

Brief description of the invention

Experience 1. Study of the effect of thermal sterilization on the stability of an aqueous solution of -deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, obtained according to the prototype, with different the content of the stabilizer N-methylglucamine

To study the effect of thermal sterilization on the stability of an aqueous solution of the prototype, samples of the preparation were prepared according to the claims of the prototype with several values of the stabilizer content from the range of 0.05-1.0 mass. % suggested in the formula.

Examples of sample preparation according to the prototype:

Example 1. 70.0 L of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) is loaded into an apparatus with a stirrer with a capacity of 100 l ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 1.00 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 120 ° C for 30 minutes.

Example 2. In an apparatus with a stirrer with a capacity of 100 liters, 70.0 liters of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.50 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 120 ° C for 30 minutes.

Example 3. In an apparatus with a stirrer with a capacity of 100 liters, 70.0 liters of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.050 kg (0.050 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 120 ° C for 30 minutes.

The obtained (examples 1-3) samples of the drug were stored in a climatic chamber (Binder KBF 240) at a temperature of 30 ° C for 5 years (60 months). To assess the quality of the samples during storage, the ampoules were examined once a month for the presence of suspension, sediment and mechanical inclusions, and the quantitative content of related impurities was determined once every 3 months.

Testing of samples of preparations for the presence of sediment and mechanical inclusions was carried out in reflected light by viewing against a background of a black and white matte screen with an illumination intensity of about 3000-3500 lux.

The content of acridone, N-methylacridone and unidentified related impurities was determined by high-performance liquid chromatography (State Pharmacopoeia of the Russian Federation, 14th edition). A mixture of 0.05 M potassium dihydrogen phosphate solution (pH from 2.7 to 2.9), acetonitrile for chromatography, and methanol for liquid chromatography in a ratio of 65: 30: 5 was used as the mobile phase. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8,150 × 3.0 mm, 5 μm or similar (Simadzu LC 20 chromatograph, Japan).

Taking into account the maximum daily dose of the drug 900 mg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol (2 ampoules of 2 ml 22, 5% solution), in accordance with world practice (ICH Q3B (R2) "Impurities in new drug products", June 2006, State Pharmacopoeia of the Russian Federation 14th edition), the content of a single unidentified impurity in the preparation should be no more than 0.20%, the content of the sum of unidentified impurities should not be ≥0.50%.

At the specified dosage of the drug, with a single unidentified impurity content of more than 0.2%, its identification (structure establishment) and qualification (study of its toxicological safety, carcinogenicity, mutagenicity, teratogenicity) are required, which significantly complicates, increases the cost and slows down the process of drug development and the presence of such a level impurities are potentially unsafe for patients, especially with a long course of use.

Thus, according to ICH Q3B (R2) "Impurities in new drug products" as a criterion for the acceptability of the stability of the composition, it is accepted that the content of a single unidentified impurity in the preparation with the claimed method of preparation should be no more than 0.20%, and the content of the sum of unidentified impurities should be no more than 0.50% throughout the entire shelf life. The presence of sediment and visible mechanical inclusions is not allowed. Samples obtained according to the prototype, having an excess of these indicators, were considered to have failed the tests.

Data on the stability of the prototype during long-term storage of the obtained samples for examples 1-3 are presented in table 1.

The data presented in table 1 indicate the impossibility of using the sterilization mode in the 120 ° C mode for 30 minutes and the declared stabilizer N-methylglucamine in the range indicated in the prototype, since, in addition to precipitation after 36 months of storage (the content of N-methylglucamine is 0.05 mass%), there is also a critically significant accumulation of single unidentified impurities of more than 0.20% and the sum of unidentified impurities ≥0.50% with a stabilizer content in the preparation of 0.05 wt. % after 18 months, with a content of 0.5 wt. % after 3 months, and when its content is 1.0 wt. % critical impurity formation is formed immediately after sterilization. Significant amounts of acridone were also found in the samples obtained according to examples 2 and 3 with a content of N-methylglucamine of 0.5% and 1.0%.

Thus, the preparation method described in the prototype does not allow for the stability of the drug during storage within the framework of modern requirements for the quality of drugs and requires significant changes.

Experiment 2. Study of methods of obtaining a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol using various alternative methods and stabilizers

To stabilize the aqueous solutions of the prototype obtained according to examples 1-3 (experiment 1), samples of the preparation were additionally prepared with the addition of various stabilizers in amounts recommended in pharmaceutical practice, as well as using the method of bubbling the solution with inert gases (nitrogen, helium) and filling the air space in ampoules with them in order to displace oxygen from the solution and prevent oxidation processes during storage. Heat sterilization mode was also used at 120 ° C for 30 min.

All samples of the obtained solutions were put on accelerated aging at 40 ° C in climatic equipment (Binder KBF 240) for 6 months. To assess the quality of the samples immediately after their receipt and during storage, the ampoules were examined once a month for the presence of suspended matter, sediment and mechanical inclusions, and the quantitative content of related impurities was determined.

Samples of preparations were tested for the presence of suspended matter, sediment and mechanical impurities in reflected light by viewing against a background of a black and white matte screen with an illumination intensity of about 3000-3500 lux.

The content of related impurities was determined by high performance liquid chromatography (State Pharmacopoeia of the Russian Federation, 14th edition). A mixture of 0.05 M potassium dihydrogen phosphate solution (pH from 2.7 to 2.9), acetonitrile for chromatography, and methanol for liquid chromatography in a ratio of 65: 30: 5 was used as the mobile phase. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8,150 × 3.0 mm, 5 μm or similar (Simadzu LC 20 chromatograph, Japan).

The use of inert gases did not give positive results on the stability of a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, since under conditions of accelerated aging in the samples, a significant increase (more than 0.5%) of the level of the sum of unidentified impurities was observed. The bubbling of solutions with carbon dioxide already at the stage of preparation led to the formation of precipitates.

Addition of such antioxidants, sulfurous acid salts (sodium sulfite (Na2SO3), sodium metabisulfite (Na2S2O3), sodium bisulfite (NaHSO3), as well as unithiol, rongalite, thiourea, methionine did not stabilize the solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-on-10-yl -acetate)] - ammonium-D-glucitol Precipitation and a significant increase in related impurities with accelerated aging were also observed.

The addition of chelating agents, ethylenediaminetetraacetic acid and its various salts, led to the formation of even more related impurities 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D -glucitol during storage.

These experiments indicate that the degradation of a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol does not follow the redox pathway, but the used equipment and starting substances do not introduce significant contamination with a high redox potential.

To stabilize the solution based on 1-deoxy-1-N - [- methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol, carboxylic acids from the series: ethanoic acid, 2 -hydroxybutanedioic acid, 2-hydroxy-1,2,3-propane tricarboxylic acid, butanedioic, trans-butenedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxypropanoic acid, but this also did not lead to a positive result.

The use of such amino acids as proline, glycine, threonine, glutamine significantly increased the level of related impurities immediately after the sterilization stage, and when the stabilizer arginine was added to the solution of 1-deoxy-1-N - [- methyl- (2-acridone-9-one-10 -yl-acetate)] - ammonium-D-glucitol unexpectedly formed a precipitate even at the stage of its preparation. It was found that the precipitate was acridone acetate, insoluble in water, arginine.

The use of lysine and histidine as stabilizers of a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol during sterilization at 120 ° C in for 30 minutes, on the contrary, showed efficiency, but only a slight tendency to slow down the formation of the level of related impurities during storage.

The use of surfactants, polymers and polyalcohols (tween 80, polyvinylpyrrolidones, polyethylene glycols, polyvinyl alcohols of various molecular weights, triacetin, glycerin, propylene glycol) did not give a positive result in reducing the level of related impurities in a solution of 1-deoxy-1-N - [- methyl - (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol.

The effect of trisoxymethylaminomethane (TRIS), ethanolamine, diethanolamine, N-ethylglucamine, octanoyl-N-Methylglucamine on the effect of 1-deoxy-1-N - [- methyl- (2-acridone- 9-on-10-yl-acetate)] - ammonium-D-glucitol in the production method with a sterilization mode of 120 ° C for 30 min.

Octanoyl-N-methylglucamine, when 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol was added to the solution, formed an emulsion and its use as a stabilizer for intravenous solution was not possible. The use of such hydroxyamino compounds trisoxymethylaminomethane (TRIS), ethanolamine, diethanolamine during sterilization at 120 ° C for 30 min showed a slight decrease in the dynamics of impurity growth when their content was 0.5%; however, during storage, the level of impurities remained unacceptably high and did not meet the requirements recommended by ICH Q3B (R2) "Impurities in new drug products", June 2006. The most significant effect was found when using N-ethylglucamine at a concentration of 0.2 wt. %, however, the level of related impurities by 6 months of accelerated aging was about 0.5%.

Thus, the use of bubbling a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol with inert gases and the addition to the solution of various types of stabilizers from a number of antioxidants, surfactant chelating agents, polymers of various molecular weights, carboxylic acids, amino acids, amino poly alcohols and others using the sterilization mode at 120 ° C for 30 minutes did not lead to an increase in thermal stability and storage stability of 1-deoxy-1-N- [α-methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol. In all samples, with the use of the stabilizers described above, during storage, precipitation was observed and a significant increase in the level of single and total unidentified impurities above the recommended ICH Q3B (R2) "Impurities in new drag products", June 2006 values and requiring identification of the resulting compounds and detailed studying their toxic and pharmacological characteristics (qualifications).

Acridone and N-methylacridone were identified in the precipitates formed during storage, and in solutions a large amount of unidentified impurities that absorb well in the ultraviolet spectrum of radiation. In this regard, studies were conducted on the effect of alternative sterilization regimens.

Experiment 3. Study of the stability of a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) 1-ammonium-D-glucitol using alternative sterilization modes

Often for thermolabile drugs (proteins, amino acids, lipopolysaccharides, etc.), it is possible to use only an aseptic production process. But since the aseptic filling of the drug without final thermal sterilization poses a high risk of possible microbial contamination in the production process and its use is allowed only in the case of an unambiguous impossibility of using thermal sterilization, attempts were made to sterilize the prototype in alternative modes recommended in world practice. In accordance with modern requirements (EMA 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container), the use of a sterilization temperature of at least 110 ° C is allowed. In this regard, studies were also carried out on the effect of the sterilization mode at 121 ° C for 8-15 minutes and low sterilization temperatures of 110 ° C and 115 ° C, taking into account the calculation of the sterilization time, which guarantees thermal sterilization equivalent at a temperature of 121 ° C. Calculations in accordance with the EMA 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container showed that for guaranteed sterilization of the test samples, it is possible to use the following modes: 115 ° C for 60 minutes and 110 ° C for 189 minutes.

To study the effect of these sterilization modes, samples of the composition were prepared according to the prototype, but with alternative sterilization modes (Examples 4-15):

Example 4. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 1.00 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at a temperature of 121 ° C for 8 minutes.

Example 5. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.50 kg (0.50 wt.%) of N-methylglucamine and water for injection are added to obtain a volume of 100 liters. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at a temperature of 121 ° C for 8 minutes.

Example 6. 70.0 L of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) is loaded into an apparatus with a stirrer with a capacity of 100 l ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.050 kg (0.050 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at a temperature of 121 ° C for 8 minutes.

Example 7. In an apparatus with a stirrer with a capacity of 100 liters, 70.0 liters of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 1.00 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. The ampoules are sterilized with steam under pressure at 121 ° C for 15 minutes.

Example 8. 70.0 L of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.50 kg (0.50 wt.%) of N-methylglucamine and water for injection are added to obtain a volume of 100 liters. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. The ampoules are sterilized with steam under pressure at 121 ° C for 15 minutes.

Example 9. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.050 kg (0.050 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. The ampoules are sterilized with steam under pressure at 121 ° C for 15 minutes.

Example 10. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 1.00 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 115 ° C for 60 minutes.

Example 11. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.50 kg (0.50 wt.%) of N-methylglucamine and water for injection are added to obtain a volume of 100 liters. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 115 ° C for 60 minutes.

Example 12. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.050 kg (0.050 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized with steam under pressure at 115 ° C for 60 minutes.

Example 13. In an apparatus with a stirrer with a capacity of 100 liters, 70.0 liters of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 1.00 kg (1.00 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized by steam under pressure at 110 ° C for 189 minutes.

Example 14. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.50 kg (0.50 wt.%) of N-methylglucamine and water for injection are added to obtain a volume of 100 liters. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized by steam under pressure at 110 ° C for 189 minutes.

Example 15. Into an apparatus with a stirrer with a capacity of 100 l load 70.0 l of water for injection, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate) ] -ammonium-D-glucitol, the resulting mixture is stirred until the components are completely dissolved, then 0.050 kg (0.050 wt.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing Pall filter with a pore diameter of 0.22 µm and poured into sterile ampoules with a volume of 1, 2 and 5 ml, sealed. Ampoules are sterilized by steam under pressure at 110 ° C for 189 minutes.

Obtained in examples 4-15 samples were stored in a climatic chamber (Binder KBF 240) at a temperature of 30 ° C for 5 years (60 months). To assess the quality of the samples during storage, the ampoules were examined once a month for the presence of suspension, sediment and mechanical inclusions, and the quantitative content of related impurities was determined once every 3 months.

Testing samples of preparations for the presence of suspension, sediment and mechanical impurities was carried out in reflected light by viewing against a background of a black and white matte screen with an illumination intensity of about 3000-3500 lux.

The content of acridone, N-methylacridone, and unidentified related impurities was determined by high performance liquid chromatography (State Pharmacopoeia of the Russian Federation, 14th edition). A mixture of 0.05 M potassium dihydrogen phosphate solution (pH from 2.7 to 2.9), acetonitrile for chromatography, and methanol for liquid chromatography in a ratio of 65: 30: 5 was used as the mobile phase. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8, 150 × 3.0 mm, 5 μm or similar (Simadzu LC 20 chromatograph, Japan).

Additionally, samples were inoculated on thioglycolic (control of fungal contamination) and soybean casein (control of bacterial contamination) culture media for testing for sterility and incubated at 30-35 and 20-25 ° C, respectively.

When studying the stability during sterilization and storage of samples of solutions of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol obtained according to examples 4-15 (Table 2-5) it was found that the use of the sterilization mode of 110 ° C for 189 minutes did not give a positive result in the entire range of concentrations of the stabilizer declared in the prototype, since the level of single unidentified impurities exceeded the permissible values immediately after sterilization (0.5 wt.% and 1.0 wt.% stabilizer) or after 3 months of storage (0.05 wt.% stabilizer), and the use of modes 115 ° C for 60 min, 121 ° C for 8 minutes and 121 ° C in within 15 minutes gave an insignificant result only with a minimum content of the stabilizer - 0.05 wt. %, the content of single unidentified impurities by the end of the storage period (60 months) was about 0.15%, and the amount of unidentified impurities was about 0.45%, which poses a risk of going beyond the acceptance criteria (0.2% and 0.5%, respectively ) during industrial production of the drug, standardized by ICH Q3B (R2) "Impurities in new drug products" with possible deviations from the temperature and time regimes of the sterilization process. In this case, all samples obtained in examples 4-15 passed the sterility test.

Thus, it was experimentally established for the first time that the stability of an aqueous solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol to thermal effects during sterilization is not so much the temperature as the duration of the sterilization process. The milder temperature regime of 110 ° C for 189 minutes showed worse results compared to 115 ° C for 60 minutes and 121 ° C for 8 or 15 minutes, which confirms that the critical sterilization parameter influencing the destruction of 1-deoxy -lN - [- methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol and the formation of related impurities is precisely the time of sterilization.

Sterilization modes 121 ° C, 15 min and 121 ° C, 8 min are preferred for this composition, but they do not guarantee a low level of impurities during long-term storage, bordering the maximum permissible values, which indicates an insufficient level of safety of the composition when the stabilizer is contained in the concentration range 0.05 -1.0 mass. %. The use of a sterilization regime at 115 ° C for 60 minutes is impractical due to a significant lengthening of the technological process and increased energy consumption at the sterilization stage.

As a possible option for stabilizing a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, sterilization regimes with a shorter temperature exposure were studied. compared with the prototype 121 ° C for 15 minutes and 121 ° C for 8 minutes in combination with the addition of auxiliary components N-methylglucamine and N-ethylglucamine in an amount of 0.5 wt. % and less (Experience 4).

Experience 4. Study of the effect of modes of sterilization of solutions of the prototype at temperatures of 121 ° C for 8 and 15 minutes in combination with the addition of auxiliary components N-methylglucamine and N-ethylglucamine in an amount of 0.5 wt. % and less

Prepared solutions of 1-deoxy-1-N - [- methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol with different content of auxiliary components in a wide range of concentrations, according to examples 16- 27 and subjected to thermal sterilization at 121 ° C for 8 minutes and 121 ° C for 15 minutes. Ampoules with the compositions were placed in climatic equipment (Binder KBF 240) to study the stability during long-term storage at a temperature of 30 ° C for 5 years (60 months). To assess the quality of the samples during storage at observation points 0, 6, 12, 24, 36, 48, 60, an analysis was carried out for the presence of suspended matter, sediment and mechanical inclusions, and the quantitative content of related impurities was determined.

Testing samples of preparations for the presence of suspension, sediment and mechanical impurities was carried out in reflected light by viewing against a background of a black and white matte screen with an illumination intensity of about 3000-3500 lux.

The content of acridone, N-methylacridone, and unidentified related impurities was determined by high performance liquid chromatography (State Pharmacopoeia of the Russian Federation, 14th edition). A mixture of 0.05 M potassium dihydrogen phosphate solution (pH from 2.7 to 2.9), acetonitrile for chromatography, and methanol for liquid chromatography in a ratio of 65: 30: 5 was used as the mobile phase. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8,150 × 3.0 mm, 5 μm or similar (Simadzu LC 20 chromatograph, Japan).

The implementation of the proposed method of obtaining a medicinal product for parenteral use, containing as an active substance 1-deoxy-1-N- [methyl- (2-acridon-9-on-10-yl-acetate)] - ammonium-D-glucitol, can be illustrated by examples 16-27.

Example 16. In an apparatus with a stirrer with a capacity of 100 l, 50.0 l of water for injection is charged and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.50 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The resulting ampoules are subjected to thermal sterilization with steam under pressure.

Example 17. Into an apparatus with a stirrer with a capacity of 100 L, 50.0 L of water for injection is charged and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.20 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 18. In an apparatus with a stirrer with a capacity of 100 l, 50.0 l of water for injection is charged and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.05 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 19. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.03 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 20. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.02 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 21. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.01 wt. % N-methylglucamn. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 22. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.50 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 23. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.20 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 24. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.05 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 25. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.03 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 26. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-D-glucitol and add 0.02 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

Example 27. Into an apparatus with a stirrer with a capacity of 100 l load 50.0 l of water for injection and bring its temperature to 55-60 ° C, load 22.5 kg of 1-deoxy-1-N - [- methyl- (2-acridone -9-on-10-yl-acetate)] - ammonium-B-glucitol and add 0.01 wt. % N-ethylglucamine. Next, the volume of the solution is brought to 100 l with water for injection and the exposure is carried out with stirring until the components are completely dissolved. The resulting solution is cooled to a temperature of 22-25 ° C, filtered through a sterilizing filter with a pore diameter of 0.22 μm, poured into ampoules with a volume of 2 or 5 ml and sealed. The ampoules obtained are subjected to thermal sterilization with steam under pressure.

As a result of the studies, it was found for the first time that when using thermal steam sterilization under pressure of a solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D- glucitol in modes 121 ° C for 8 minutes and 121 ° C for 15 minutes and the additional introduction of auxiliary components: N-ethylglucamine in an amount of not more than 0.2 wt. % and N-methylglucamine in an amount of not more than 0.05 wt. %, has a significant effect on the thermal stability and storage stability of an aqueous solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol for 5 years.

Thus, the authors of the present invention obtained the optimal mode of thermal sterilization of an aqueous solution of 1-deoxy-1-N - [- methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol in mode 121 ° С for 8-15 minutes, and the fact of the influence of the declared auxiliary components on the thermal stability of an aqueous solution of 1-deoxy-1-N - [- methyl- (2-acridone-9-one-10-yl-acetate)] -ammonium-D-glucitol in accordance with modern requirements (ICH Guideline Q3B (R2) "Impurities in new drug products", June 2006). In this case, the content of auxiliary components is selected empirically to obtain stable aqueous solutions, namely: the content of N-ethylglucamine in an amount of not more than 0.2 wt. % and N-methylglucamine - in an amount of not more than 0.05 wt. %.

The claimed method for producing a medicinal product for parenteral use, containing as an active substance 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, using sterilization mode 121 ° C for 8-15 minutes and the addition of auxiliary components of N-methylglucamine in smaller amounts compared to the prototype and N-ethylglucamine, provides a reduction in the time of thermal sterilization by more than half, while a significant reduction in the level of impurity formation during production and storage is achieved , which made it possible to increase the shelf life of the drug during storage up to 5 years.

Claims (2)

1. A method of obtaining a medicinal product for parenteral administration containing 1-deoxy-1-N- [methyl- (2-acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol as an active substance, by dissolving the active substance in water for injection, mixing, filtering the solution through a sterilizing filter, pouring it into sterile containers, characterized in that N-methylglucamine is added to the solution as an auxiliary component in an amount of not more than 0.05 wt. %, stirred until the components are completely dissolved at a temperature of 55-60 ° C, then the resulting solution is cooled to a temperature of 22-25 ° C, and after the filtering and filling stage it is subjected to thermal sterilization at a temperature of 121 ° C for 8-15 minutes. 2. The method according to claim 1, characterized in that N-ethylglucamine is added to the solution as an auxiliary component in an amount of not more than 0.2 wt. %.