EA043247B1 - METHOD FOR OBTAINING MEDICINE FOR PARENTERAL USE - Google Patents

Description

Technical field

The invention relates to the pharmaceutical industry and medicine, relates to a method for producing a drug for parenteral use containing 1-deoxy-1-N[methyl-(2-acridon-9-on-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 diseases of infectious origin.

Prior Art

Connection 1-deoxy-1-N-[methyl-(2-acridon-9-on-10-ul-acetate)]ammonium-D-glucitol is known as a biologically active substance with immunomodulatory action (patent EA 000382). The biological activity of the known compound makes it possible to use it in the treatment of a wide range of human and animal diseases: treatment of thyroiditis (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 immunodeficiencies (RF patent 2364396, RF 2 320293), choreoretinitis (RF patent 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), a utologous cells (RF patent 2325934), burns (RF patent 2166960), staphylococcal infection (RF patent 2441656).

Known homeopathic drug based on N-methylglucamine 9-oxoacridinyl10-acetate when diluted in saline to concentrations of 10' ²⁹ -10' ² mg/ml used for the prevention and treatment of influenza, SARS, hepatitis B and C (RF patent 2281097) , which indicates a 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 drug for parenteral use, containing as an active substance 1-deoxy-1-N-[methyl-(2-acridon-9-on-10-yl-acetate)]ammonium-D-glucitol (patent EA 002462). The preparation additionally contains N-methylglucamine as a stabilizer in the following ratio of components, wt.%: 8.5-25.0, N-methylglucamine - 0.05-1.00, water for injection - up to 100%.

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

The method of obtaining this drug consists in dissolving 1-deoxy-1-N-[methyl-(2-acridon9-one-10-yl-acetate)]ammonium-D-glucitol in water, adding a stabilizer, filtering through a sterilizing filter, bottling in sterile ampoules of 1, 2, and 5 ml and sealed. Further, the resulting ampoules are subjected to thermal sterilization by autoclaving at a temperature of 120°C for 30 minutes.

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

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

However, later it was 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 amount 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 0.5 to 1.0 wt.% occurs spontaneous and difficult to predict precipitation of acridone - the deacetylation product of 1-deoxy-1N-[methyl-(2-acridone-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 standards described in modern international requirements (ICH Q3B (R2) Impurities in new drag products, June 2006).

In a known quantitative range, N-methylglucamine acts as a co-lubilizer and pH regulator during the production and storage of the drug, thereby providing 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 its sterilization. Subsequently, during the storage of the drug under the influence of various external factors (light, temperature jumps and vibration during transportation and storage), as well as when interacting with glass components of the inner surface of the ampoules, micelles are destroyed and these compounds precipitate, which 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 amount of additional impurities - decomposition products of 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 has unacceptable performance and does not meet modern requirements (ICH Q3B (R2) Impurities in new drag products, June 2006).

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

Currently, the most widely used terminal sterilization method in the industrial production of pharmaceuticals is thermal sterilization with saturated pressurized water vapor (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 (EMA 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container, March 6, 2019).

In practice, there are often drugs that contain thermolabile drugs 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 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 radiation. In the application RU 2006142783, sterilization is carried out in the processing of pulsed high-voltage discharges that generate sterilizing UV radiation, and in the application RU 2000130091 a method for electrochemical sterilization of liquids with chemically active particles is proposed. In patent RU 2366347, the proposed method of sterilization is carried out in a cavitation reactor, through which, during the process, the sterilized liquid heated to a predetermined temperature circulates in a closed cycle. 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 pressure of saturated water vapor at this temperature. The method allows to spend acoustic energy in smaller quantities, as well as to reduce the temperature of thermal sterilization.

Currently, combinations of thermal and physical sterilization modes are also used to sterilize unstable aqueous solutions, for example, in patent RU 2238108, heating is carried out by exposure to a microwave electromagnetic field, and sterilization is carried out by an EHF electromagnetic field. Application RU 2003115619 proposes 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 provide a high guarantee of the absence of microbial contamination of the medicinal product, when preparing it, it is often necessary to add various water-soluble antimicrobial preservatives permitted by international pharmacopoeias to the solution: , 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 allows you to sterilize heat-labile 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.

For example, CN 102552950B 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, glycerol, creatinine, sodium caprylate, nicotinamide, or combinations thereof.

Patent RU 2529800 shows that the stability of the 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 injection and infusion drugs containing easily oxidized active substances, complexons are often used: EDTA-ethylenediaminetetraacetic acid, Trilon B (EDTA disodium salt), tetracin-calcium (EDTA calcium disodium salt), which are highly soluble in water and heat-resistant, the mechanism of stabilizing the action of which is associated with the conversion of heavy metal cations into complex, practically non-dissociable compounds that are inactive with respect to hydroperoxide. These stabilizers are especially effective when using outdated equipment, which is a source of heavy metal contamination of both the original 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 an injection solution, including methylnaltrexone or its salt (an opioid antagonist derivative) and the chelating agent EDTA or its derivative. EFFECT: invention prevents decomposition of methylnaltrexone or its salt during thermal sterilization and demonstrates the stability of the methylnaltrexone preparation in the form of a solution during storage for 12 months.

In the 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 the composition solution, after it has been thawed or recovery of the lyophilizate, as well as increasing the compatibility of the composition with aminoglycosides.

For example, patent RU 2284811 describes the use of a combination of stabilizers Trilon B and alpha hydroxypropionic (lactic) acid to prevent the formation of mechanical inclusions in the solution for injection of ciprofloxacin 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 makes it possible to sterilize the drug with steam under pressure in an autoclave at a temperature of 100-130 ° C and ensure the stability of the solution during storage for 5 years.

To stabilize the polyionic infusion solution based on N-methylglucamine sodium succinate (Eurasian patent No. 035241) as stabilizers, to reduce the level of formation of its decomposition products - furfurals, carboxylic acids from the series were used: ethanoic acid, 2-hydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, butanedioic, transbutenedioic 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 of nicotinamide, inosine, riboflavin mononucleotide.

There is a known method of stabilization (RU 2020941) of sodium 10-methylenecarboxylate-9-acrydone with methylene blue 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 aymalin derivatives using polyvinylpyrrolidone with a molecular weight of 11,200. mixtures with organic solvents.

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

Thus, to solve the problem of the 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 polyalcohols and other compounds.

The effectiveness of the use of a stabilizer depends on its concentration, the chemical structure of the active components, the temperature and time of sterilization, dosage form, and the 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 in the process of production and storage in the finished product, 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 an unknown structure can lead not only to adverse 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 lead to the degradation of the ingredients with the formation of an unacceptable level of degradation products. On the other hand, low-temperature heat treatment below 110°C is not allowed (EMA 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container) and for heat-labile preparations only sterilizing filtration and subsequent filling under aseptic conditions are regulated. This method can only be used if it is absolutely impossible to use thermal sterilization.

Thus, the known methods for obtaining compositions containing thermolabile components cannot be considered optimal, since their use has revealed a number of problems that can have a negative impact when using ready-made solutions as a drug.

The objective of the present invention is to develop an optimal method for obtaining a drug for parenteral use, containing as an active ingredient 1deoxy-1-N-[-methyl-(2-acridon-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.

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-M-[methyl-(2-acridon-9on-10-yl-acetate)]ammonium-D-glucitol , by dissolving the active substance in water for injection, mixing, 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.% or N- ethylglucamine in an amount of not more than 0.2 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 bottling stage, it is subjected to thermal sterilization at a temperature 121°C, for 815 min.

In the claimed invention, N-ethylglucamine and N-methylglucamine are used as interchangeable chemicals and are alternative features because they have a common essential structural element, have similar properties and have a similar effect on the active substance.

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 the new quantitative range and Nethylglucamine in the established quantitative range, new temperature regimes at the stage of dissolution of the components and after it, the use of thermal sterilization with a reduction in exposure time by more than 2 times .

As experience No. 4 showed, the use of the proposed method with the claimed excipients and temperature conditions significantly affects the reduction in the amount of impurities in the finished product.

The declared amounts of auxiliary components of N-methylglucamine and N-ethylglucamine are due to the fact that at a given content in a solution of 1-deoxy-1-N-[methyl-(2-acridon-9-one-10yl-acetate)]ammonium-D- glucitol in the process of preparing and keeping the solution at a temperature of 5560 ° C, there is no decomposition of the active component and a significant increase in related impurities.

In addition, the low content of N-methylglucamine and N-ethylglucamine in the composition, unlike the prototype, does not have a solubilizing effect on the already formed poorly soluble impurities in water, and in the process of cooling the solution to a temperature of 22-25°C and subsequent filtration, they are 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 min, in combination with the addition of auxiliary components, additionally affects the reduction 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, precipitation of compounds poorly soluble in water does not occur, which makes it possible to establish the shelf life of the finished drug for at least 5 years.

The proposed method for obtaining a drug for parenteral use containing 1-deoxy-1-N-[methyl-(2-acridon-9-on-10-ylacetate)]ammonium-D-glucitol as an active substance is optimal compared to prototype method, since it

- 4 043247 reduces the thermal sterilization time by more than half, as well as the use of interchangeable auxiliary components: N-methylglucamine in smaller quantities or Nethylglucamine, which can significantly reduce energy and raw material costs. 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.

The 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 contents of the stabilizer N-me -tilglucamine.

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 formula of the invention of the prototype with several values of the content of the stabilizer from the range of 0.05-1.0 wt.% proposed in the formula.

Prototype sample preparation examples

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)]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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 120°C for 30 minutes.

Example 2

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 (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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 120°C for 30 minutes.

Example 3 A 100 L stirrer apparatus was charged with 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.%) of N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 120°C for 30 minutes.

Received (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.

Samples of preparations were tested for the presence of sediment and mechanical inclusions in reflected light by viewing against 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). The mobile phase was a mixture of 0.05 M potassium dihydrogen phosphate (pH 2.7 to 2.9), acetonitrile for chromatography and methanol for liquid chromatography in a ratio of 65:30:5. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8, 150x3.0 mm, 5 µm or similar (Simadzu LC 20 chromatograph, Japan).

Taking into account the maximum daily dose of the drug 900 mg 1-deoxy-1-M-[methyl-(2-acridon-9-one-10yl-acetate)] ammonium-D-glucitol (2 ampoules of 2 ml of 22.5% solution) , in accordance with world practice (Guideline ICH Q3B (R2) Impurities in new drug products, June 2006, State Pharmacopoeia of the Russian Federation 14 edition), the content of a single unidentified impurity in the drug should be no more than 0.20%, the content of the sum of unidentified impurities should be not >0.50%.

At the indicated dosage of the drug with a content of a single unidentified impurity of more than 0.2%, its identification (establishment of the structure) 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.

- 5 043247

Thus, according to ICH Q3B (R2) Impurities in new drag products, as a criterion for the acceptability of composition stability, 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 not be more than 0.50% throughout the entire shelf life. The presence of sediment and visible mechanical inclusions is not allowed. Samples obtained from the prototype, having an excess in these indicators, were considered not to have passed the test.

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

Table 1

Data on storage stability of the obtained samples according to examples 1-3 using thermal sterilization in the mode of 120°C for 30 min

Level of quality The content of the stabilizer, wt% 0.05 0.5 1.0 Precipitation period, months 36 38 46 The period of accumulation of an unacceptable level of impurities, months > 0.2% of a single unidentified impurity or > 0.5% of the total of unidentified impurities 18 3 0

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

Thus, the production 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.

Experience 2. Study of methods for obtaining a solution of 1-deoxy-1-N-[methyl-(2-acry-don-9-on-10-ylacetate)]ammonium-D-glucitol using various alternative methods and stabilizers.

To stabilize the aqueous solutions of the prototype obtained in examples 1-3 (experiment 1), samples of the preparation were additionally prepared with the addition of various stabilizers in the 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 with ampoules with them in order to displace oxygen from the solution and prevent oxidation processes during storage. The heat sterilization mode was also used at 120°C for 30 min.

All samples of the obtained solutions were placed for accelerated aging at a temperature of 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 once a month, the ampoules were examined for the presence of suspension, sediment, and mechanical inclusions, and the quantitative content of related impurities was determined.

Samples of preparations were tested for the presence of suspension, sediment and mechanical inclusions in reflected light by viewing against 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). The mobile phase was a mixture of 0.05 M potassium dihydrogen phosphate (pH 2.7 to 2.9), acetonitrile for chromatography and methanol for liquid chromatography in a ratio of 65:30:5. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8, 150x3.0 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 accelerated aging conditions, a significant increase (more than 0.5%) in the level of the amount of unidentified impurities. Bubbling solutions with carbon dioxide already at the stage of preparation led to the formation of precipitates.

Addition of such antioxidants, salts of sulfurous acid (sodium sulfite (Na ₂ SO ₃ ) sodium metabisulfite (Na2S2O3), sodium bisulfite (NaHSO3), as well as unithiol, rongalite, thiourea, methionine did not lead to stabilization of the solution of 1-deoxy-1-N-[-methyl-(2-acridon-9-one-10 -yl-acetate)]ammonium-D-glucitol Precipitation and significant growth of related impurities were also observed during accelerated aging.

- 6 043247

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

These experiments indicate that the degradation of a solution of 1-deoxy-1-N-[methyl-(2-acridon9-one-10-yl-acetate)]ammonium-D-glucitol does not proceed along the redox pathway, but rather the equipment used and the initial substances do not introduce significant pollution with a high redox potential.

To stabilize the solution based on 1-deoxy-1-N-[methyl-(2-acridon-9-one-10-ylacetate)]ammonium-D-glucitol, carboxylic acids were used from the series: ethanoic acid, 2hydroxybutanedioic acid, 2- hydroxy-1,2,3-propanetricarboxylic acid, butanedioic, transbutenedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxypropanoic acid, however, 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-acridon-9-one-10- yl-acetate)]ammonium-D-glucitol unexpectedly formed a precipitate even at the stage of its preparation. It has been established that acridone acetate, which is insoluble in water, arginine, precipitates.

The use of lysine and histidine as stabilizers of a solution of 1-deoxy-1-M-[methyl-(2acridon-9-one-10-yl-acetate)]ammonium-O-glucitol during sterilization at 120°C for 30 min, vice versa showed effectiveness, 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-one-10-yl-acetate)]ammonium-D-glucitol.

Also, the effect of compounds from the series trisoxymethylaminomethane (TRIS), ethanolamine, diethanolamine, N-ethylglucamine, octanoyl-N-Metylglucamine on the effect on the stability of a solution 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 added to a solution of 1-deoxy-1-N-[methyl-(2-acridon-9-one-10yl-acetate)]ammonium-D-glucitol, formed an emulsion and its use as a stabilizer for solution for intravenous administration 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 growth dynamics of impurities at their content in an amount of 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 with N-ethylglucamine at a concentration of 0.2 wt.%, but the level of related impurities at 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-on-10yl-acetate)]ammonium-D-glucitol with inert gases and adding various types of stabilizers from a number of antioxidants to the solution , chelating agents, surfactants, polymers of various molecular weights, carboxylic acids, amino acids, amino polyalcohols, and others using a sterilization mode at 120°C for 30 min did not lead to an increase in thermal stability and storage stability of 1-deoxy-1-N-[- methyl-(2-acridon-9-one-10-yl-acetate)]ammonium-D-glucitol. In all samples, with the use of the stabilizers described above, precipitation was observed during storage 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 formed compounds and detailed study their toxico-pharmacological characteristics (qualifications).

In the precipitates formed during storage, acridone and N-methyl-lacridone were identified, and in solutions a large amount of unidentified impurities that absorb well in the ultraviolet spectrum of radiation. In this regard, studies have been conducted on the impact of alternative sterilization regimens.

Experience 3.

Stability study of 1-deoxy-1-N-[methyl-(2-acridon-9-one-10-yl-aietate)]ammonium-D-glucitol solution using alternative sterilization modes.

Often, for thermolabile drugs (proteins, amino acids, lipopolysaccharides, etc.), only an aseptic manufacturing process can be used. But since 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 if it is clearly impossible to use 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), a sterilization temperature of at least 110°C is allowed. In this regard, studies of the influence of the sterilization mode of 121°C for 8-15 minutes and low sterilization temperatures of 110 and 115°C were also carried out, taking into account the calculation of the sterilization time, which guarantees thermal sterilization equivalent at a temperature of 121°C. Calculations in accordance with EMA 366428/2018 Guideline on the sterilization of the medicinal product, active substance, excipient and primary container showed that the following modes can be used for guaranteed sterilization of the test samples: 115°C 60 min and 110°C 189 min.

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

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 121°C for 8 minutes.

Example 5

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.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 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)]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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 121°C for 8 minutes.

Example 7

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, 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.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 121°C for 15 minutes.

Example 9

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 121°C for 15 minutes.

Example 10

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 115°C for 60 minutes.

Example 11

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 until a volume of 100 liters is obtained. The resulting solution is filtered through a sterilizing filter of the type

Pall with a pore diameter of 0.22 microns and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 115°C for 60 minutes.

Example 12.

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 115°C for 60 minutes.

Example 13

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 110°C for 189 minutes.

Example 14

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.%) N-methylglucamine and water for injection are added until a volume of 100 liters is obtained. The resulting solution is filtered through a Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 110°C for 189 minutes.

Example 15

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 Pall-type sterilizing filter with a pore diameter of 0.22 μm and poured into sterile 1, 2 and 5 ml ampoules, sealed. The ampoules are sterilized with steam under pressure at 110°C for 189 minutes.

The samples obtained according to examples 4-15 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.

Samples of preparations were tested for the presence of suspension, sediment and mechanical inclusions in reflected light by viewing against 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). The mobile phase was a mixture of 0.05 M potassium dihydrogen phosphate (pH 2.7 to 2.9), acetonitrile for chromatography and methanol for liquid chromatography in a ratio of 65:30:5. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8, 150x3.0 mm, 5 µm or similar (Simadzu LC 20 chromatograph, Japan).

Additionally, the samples were inoculated on thioglycol (control of contamination by fungi) and soy-casein (control of contamination by bacteria) nutrient media for testing for sterility and incubated at a temperature of 30-35 and 20-25°C, respectively.

table 2

Data on storage stability of the obtained samples according to examples 4-6 using thermal sterilization in the mode of 121°C for 8 min

Level of quality The content of the stabilizer, wt% 0.05 0.5 1, oh Precipitation period, months - 32 52 The period of accumulation of an unacceptable level of impurities, months > 0.2% of a single unidentified impurity or > 0.5% of the total of unidentified impurities - 6 3

- sediment is not detected or the level of impurities is acceptable.

- 9 043247

Table 3

Data on storage stability of the obtained samples according to examples 7-9 using thermal sterilization in the mode of 121°C for 15 min

Level of quality The content of the stabilizer, wt% 0.05 0.5 1.0 Precipitation period, months - thirty 48 The period of accumulation of an unacceptable level of impurities, months > 0.2% of a single unidentified impurity or > 0.5% of the total of unidentified impurities - 3 0

- sediment is not detected or the level of impurities is acceptable

Level of quality The content of the stabilizer, wt% 0.05 0.5 1.0 Precipitation period, months 25 42 The period of accumulation of an unacceptable level of impurities, months > 0.2% of a single unidentified impurity or > 0.5% of the total of unidentified impurities - 3 0

Table 5

Data on storage stability of the obtained samples according to examples 13-15 using thermal sterilization in the mode of 110°C 189 min

Level of quality The content of the stabilizer, wt% 0.05 0.5 1, oh Precipitation period, months 12 26 thirty The period of accumulation of an unacceptable level of impurities, months > 0.2% of a single unidentified impurity or > 0.5% of the total of unidentified impurities 3 0 0

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) found that the use of sterilization mode 110°C for 189 min 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 allowable values immediately after sterilization (0.5 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 min and 121°C for 15 min gave an insignificant result only with a minimum stabilizer content of 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 represents a risk of going beyond acceptance criteria (0.2 and 0.5%, respectively) in the industrial production of the drug normalized by ICH Q3B (R2) Impurities in new drag products with possible deviations from the temperature and time regimes of the sterilization process. In this case, all samples obtained according to examples 4-15 passed the test for sterility.

Thus, for the first time it has been experimentally established that the stability of an aqueous solution of 1deoxy-1-N-[methyl-(2-acridon-9-on-10-yl-acetate)]ammonium-D-glucitol to thermal effects during sterilization is critically affected by not so much the temperature as the duration of the sterilization process. A milder temperature regime of 110°C for 189 min showed worse results compared to 115°C for 60 min and 121°C for 8 or 15 min, which confirms that the critical sterilization parameter affecting the degradation of 1-deoxy -1-N-[methyl-(2-acridon9-one-10-yl-acetate)]ammonium-P-glucitol and the formation of related impurities is exactly the time of sterilization.

Sterilization modes of 121°С, 15 min and 121°С, 8 min are preferred for this composition, but do not guarantee a low level of impurities during long-term storage, bordering on the maximum permissible values, which indicates an insufficient safety level of the composition when the stabilizer is contained in the concentration range 0.05-1.0 wt.%. The use of the sterilization mode at 115°C for 60 min is inappropriate due to the significant elongation 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-αcridon-9-one-10yl-acetate)]ammonium-D-glucitol, sterilization modes with a shorter temperature exposure time were studied compared to the prototype 121 °C for 15 min and 121°C for 8 min in combination with the addition of auxiliary components N-methylglucamine and N-ethylglucamine in the amount

- 10 043247 sve 0.5 wt.% or less (Experiment 4).

Experience 4.

The study of the influence of modes of sterilization solutions of the prototype at temperatures of 121°C for 8 and 15 min in combination with the addition of auxiliary components of N-methylglucamine and Nethylglucamine in the amount of 0.5 wt.% or less.

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

Samples of preparations were tested for the presence of suspension, sediment and mechanical inclusions in reflected light by viewing against 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 solution of potassium dihydrogen phosphate (pH from 2.7 to 2.9), acetonitrile for chromatography and methanol for liquid chromatography in a ratio of 65:30:5. The detection wavelength is 254 nm. Chromatographic column Zorbax SB-C8, 150x3.0 mm, 5 µm or similar (Simadzu LC 20 chromatograph, Japan).

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

Example 16

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-Dglucitol and add 0.50 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 17.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-Dglucitol and add 0.20 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 18.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-D-glucitol and add 0.05 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 19.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-D-glucitol and add 0.03 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 20.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridone-9-ov -10-yl-acetate)]ammonium-Dglucitol and add 0.02 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 21.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-D-glucitol and add 0.01 wt.% N-methylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 22.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-Dglucitol and add 0.50 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 23.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-Dglucitol and add 0.20 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 24.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-Dglucitol and add 0.05 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 25.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-D-glucitol and add 0.03 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 26.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[methyl-(2-acridon-9-one -10-yl-acetate)]ammonium-D-glucitol and add 0.02 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

Example 27.

50.0 l of water for injection are loaded into an apparatus with a stirrer with a capacity of 100 l and its temperature is brought to 55-60 ° C, 22.5 kg of 1-deoxy-1-N-[-methyl-(2-acridone-9- he-10-yl-acetate)]ammonium-D-glucitol and add 0.01 wt.% N-ethylglucamine. Next, the volume of the solution is adjusted with water for injection to 100 l and 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 2 or 5 ml ampoules and sealed. The obtained ampoules are subjected to heat sterilization with steam under pressure.

- 12 043247

Table 6

Storage stability data for 1-deoxy-1-N[methyl-(2-acridon-9-one-10-yl-acetate)]ammonium-D-glucitol solution

- the drug is unstable (the presence of a suspension or sediment is observed and / or does not meet the acceptance criteria for the level of a single and the amount of unidentified impurities).

+ the drug is stable (meets the acceptance criteria for the level of a single and the amount of unidentified impurities).

Table 7

Storage stability data for 1-deoxy-1-N[methyl-(2-acridon-9-one-10-yl-acetate)]ammonium-D-glucitol solution

- the drug is unstable (the presence of a suspension or sediment is observed and / or does not meet the acceptance criteria for the level of a single and the amount of unidentified impurities).

+ the drug is stable (meets the acceptance criteria for the level of a single and the amount of unidentified impurities).

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-M-[methyl-(2-acridon-9-on-10-ylacetate)]ammonium-D-glucitol in modes 121 °C for 8 min and 121°C for 15 min 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 the effect on thermal stability and storage stability of an aqueous solution of 1-deoxy-1-N-[methyl-(2-acridon-9-one-10yl-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-O-glucitol in the mode of 121°C within 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-acridon-9-one-10-ylacetate)]ammonium-D-glucitol in accordance with modern requirements (Guideline ICH Q3B (R2) Impurities in new drag products, June 2006). At the same time, the content of auxiliary components is selected empirically to obtain stable aqueous solutions, namely: the content of Nethylglucamine 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 1-deoxy-1-N-[methyl-(2-acridon-9-one-10-yl-acetate)]ammonium-D-glucitol as an active substance, using the sterilization mode 121 °C for 8-15 minutes and the addition of auxiliary components of N-methylglucamine in smaller quantities compared with the prototype and Nethylglucamine, provides a reduction in the time of thermal sterilization by more than half, while achieving a significant reduction in the level of formation of impurities during production and storage, which made it possible to increase the period shelf life of the drug for up to 5 years.

Claims (1)

A method for producing a medicinal product for parenteral use containing 1-deoxy-1-N-[methyl-(2-acridon-9-one-Yu-yl-acetate)]ammonium-O-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.% or N-ethylglucamine in an amount of not more than 0.2 wt.%, stir 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 bottling stage, it is subjected to thermal sterilization at a temperature of 121 ° C in within 8-15 minutes.