RU2737086C2 - Liquid dosage form for treating and preventing influenza and arvi - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: group of inventions refers to chemical-pharmaceutical industry and medicine and concerns a new liquid dosage form for oral administration for treatment and prevention of influenza and ARVI. Liquid dosage form contains 2-(imidazol-4-yl)ethanamide of pentane dihydroxy-1,5 acid or its pharmaceutically acceptable salt, 1-[2-(1H-imidazol-4-yl)ethyl]piperidine-2,6-dione or a pharmaceutically acceptable salt thereof in effective amounts and pharmaceutically acceptable excipients, wherein the pH of the liquid dosage form ranges from 3 to 8. Also disclosed is a method for treating and/or preventing influenza and ARVI and using a liquid dosage form for treating and/or preventing influenza and ARVI.

EFFECT: group of inventions provides a stable liquid form of 2-(imidazol-4-yl)ethanamide pentane-dioic-1,5 acid for treating and preventing influenza and ARVI.

17 cl, 33 tbl, 6 ex

Description

The invention relates to the chemical-pharmaceutical industry and medicine and concerns a new liquid dosage form for the treatment and prevention of influenza and acute respiratory viral infections, containing 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid in an effective amount and excipients.

Acute respiratory viral infections (ARVI) are a group of infectious diseases of viral etiology, characterized by damage to the respiratory tract, mainly in the upper sections, and by a common clinical symptoms. The advances achieved by medicine in the field of infectious pathology have contributed to the development and improvement of methods for the prevention and treatment of diseases, but ARVI continues to remain a serious public health problem for most countries of the world due to the extremely high incidence rate, usually of the nature of seasonal epidemics.

In Russia, 30-40 million cases of infectious diseases are annually recorded, in the structure of which 70% (in some years 90%) are influenza and acute infections of the respiratory tract of viral and unspecified etiology [Selkova E.P. Prevention and treatment of acute respiratory viral infections. The use of amiksin. A guide for doctors. M., 2004]. The reasons for such a high incidence are considered to be the overcrowding of the population in large cities, poor ecology, high mobility of the population, incomplete vaccination coverage, low hygienic culture of people, malnutrition [Zharkova N.Ye. Symptomatic treatment of ARVI: the future belongs to the combined drugs. Rus. honey. zhurn., 2007, 22: 1636].

ARVI occupies one of the leading positions in terms of the appealability of medical help for children and adults, temporary disability, the amount of drugs consumed during the period of illness. The high incidence of ARVI is associated with significant economic losses, primarily due to the indirect costs associated with disability. Children, the elderly, persons with concomitant diseases (various immunodeficiency states, diseases of the lungs, cardiovascular system, liver, kidneys, diabetes mellitus, etc.) are most susceptible to seasonal morbidity.

ARVI - polyetiologic diseases. Currently, more than 200 pathogens are known, however, rhinoviruses (30-50%) and influenza viruses (5-15%) are predominant, causing a high outbreak in the autumn-winter period, much less often diseases are caused by adenoviruses, parainfluenza viruses, respiratory syncytial virus [Selkova E.P. Prevention and treatment of acute respiratory viral infections. The use of amiksin. A guide for doctors. M., 2004].

Influenza A and B viruses are of the greatest epidemic importance, causing annual epidemics, the economic losses from which amount to billions of US dollars. In Russia, the annual total economic damage from influenza is estimated by experts at 40 billion rubles. Every year around the world 250-500 thousand people die from influenza. Numerous studies have shown a consistent relationship between influenza and acute myocardial infarction [Kuznetsova O.Yu., Pleshanova Zh.V. The place of modern combined drugs in the treatment of acute respiratory viral infections in outpatient practice. Consilium medicum, 2012, 3: 74-83].

The mortality rate from some forms of influenza, even with high-tech treatments, is over 50%. In this case, the disease is characterized, as a rule, by an acute onset and severe course: high (40 ° C and more) temperature and prolonged fever with symptoms of intoxication - headache, insomnia, pain in muscles and joints, meningeal symptoms. One of the unfavorable currents is the lightning-fast form, i.e. rapid development of hemorrhagic toxic pulmonary edema and death from respiratory and cardiovascular failure [Int. J. Tuberc. Lung Dis. // 2007 - V.11. - N7. - P.710-721].

In some cases, viral infection predisposes to the development of complications, the most frequent of which are otitis media (most often in children), sinusitis (in adults), exacerbation of chronic bronchitis / COPD or bronchial asthma.

ARVI of non-influenza etiology is more often characterized by a lighter short course. This is due to the fact that rhinoviruses mainly affect the epithelium of the upper respiratory tract, while influenza viruses have a tropism for the epithelium of the lower respiratory tract and can cause the development of acute tracheobronchitis and bronchiolitis. Pneumonia is a rare complication of rhinovirus infection, but it develops in 5-30% of patients with influenza A and 10% of patients with influenza B [Zaitsev A.A. Areas of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17 (23): 1525].

Vaccination remains the most effective way to control seasonal influenza morbidity so far. There is no vaccine effective against rhinovirus infection. Influenza vaccines, depending on the manufacturing technology, are divided into two classes: live and inactivated. Live vaccines are administered intranasally, the traditional route of administration for inactivated vaccines is subcutaneous or intramuscular injection. Despite the promising non-invasive route of administration and the low cost of live vaccines, their use is limited due to their high reactogenicity (the development of symptoms of infection - headache, fever, malaise), allergenicity, and a number of contraindications (age over 50 years, acute diseases, diseases internal organs, immunosuppression and others). In this regard, inactivated vaccines are recommended for mass prevention of influenza. The most important requirement for the vaccines used is the compliance of the antigenic composition with the influenza virus strains, relevant in this epidemiological season [Zaitsev A.A. Areas of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17 (23): 1525].

The main disadvantage of vaccination and specific antiviral prophylaxis is that their action is limited only by influenza viruses, there is no protection against other pathogens of ARVI. A promising direction of prevention is the use of funds to activate the nonspecific resistance of the organism. At the same time, domestic health care is characterized by the frequent use of drugs with a limited evidence base [Zaitsev A.A. Areas of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17 (23): 1525]. Echinacea preparations have a weak interferonogenic effect, and serious studies of various adaptogens (ginseng, Siberian ginseng, aralia, etc.) for the prevention of respiratory infections have not been carried out [Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for the prevention and treatment of the common cold. Cochrane Review, latest version 16 November 1998, In: The Cochrane Library, Oxford].

Treatment and prevention with antiviral drugs is indicated in the following cases [Zaitsev A.A. Areas of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17 (23): 1525]: 1) as an adjunct to late vaccination in risk groups in the first 2 weeks after vaccination (for the period of antibody production); 2) for children who are vaccinated for the first time: taking drugs is indicated within 6 weeks after the first vaccination (the final production of antibodies ends by 2 weeks after the second vaccination); 3) for persons with immunodeficiency who may give an insufficient immune response to vaccination; 4) for persons for whom vaccination is contraindicated (for example, in case of allergic reactions to chicken protein); 5) in the elderly, for whom the effectiveness of vaccination decreases and reaches 50-70%, as an addition to vaccination; 6) for unvaccinated persons in contact with sick relatives and neighbors; 7) when there is a threat of a pandemic; 8) if the antigenic composition of the vaccine used does not match the epidemic situation.

Considering that it is impossible to predict the antigenic structure of the future epidemic (pandemic) influenza A virus, the early design of effective influenza vaccines is difficult; therefore, it is important to have in the arsenal of chemotherapeutic agents for the prevention and treatment of diseases caused by highly pathogenic strains of viruses.

Drugs with a direct effect on the influenza virus (blockers of M2-channels amantadine and rimantadine, and neuraminidase inhibitors oseltamivir and zanamivir) are used for emergency treatment and prevention of influenza.

M2 channel blockers are active against the influenza A virus. In influenza therapy, amantadine and rimantadine, which are antiviral against influenza strains [Am. J. Med. - 1997. - V.102 (ЗA) - N17. - P.55-60], [Watts J. "Asian nations step up action to curb spread of avian influenza" // Lancet. - 2004. - V.363 - N9406. - P.373]. The antiviral drug rimantadine has become widespread in the Russian Federation. It is used for the treatment and prevention of infection caused by influenza A viruses. Its preventive effectiveness during seasonal outbreaks of influenza reaches 70-90% [Kuzin VB, Lovtsova LV, Barsuk AL. Study of the clinical efficacy and tolerability of Antigrippin-Maximum in the treatment of ARVI (influenza). Outpatient Doctor's Handbook, 2010, 1: 3-7]. In addition, according to studies, the use of rimantadine is also characterized by a 25% reduction in the incidence of influenza-like infections [Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet, 2006,367 (9507): 303-13].

Rimantadine showed a pronounced therapeutic effect against the influenza virus of the H3N2 subtype. The mechanism of action on the virus is associated with blocking the function of the viral M2 protein. Inhibition of viral activity occurs at the stages of receptor-mediated endocytosis, decapsidation in the phagolysosome, as well as the assembly and budding of viral particles [Bulletin of the Russian Academy of Medical Sciences // 1993. - N 3. - P.10-15]. However, rimantadine as a representative of the adamantane group has limitations in its use. At high doses, side effects from the central nervous system occur, in particular, the drug can cause seizures. It also has an adverse effect on the liver and kidneys, which makes it unlikely to be used in people with diseases of these organs.

The disadvantage of drugs in this group is the rapidly developing resistance of the virus to them and a number of possible adverse events (nausea, decreased appetite, dizziness, insomnia; among the contraindications - acute liver and kidney disease). In this regard, the use of rimantadine should not be long-term (for prevention, it is recommended to use 50 mg 1 time per day for 10-15 days). It is important that, against the background of other antiviral agents, rimantadine is the most profitable economically.

Currently, the neuraminidase inhibitors of influenza A and B viruses are widely used - oseltamivir phosphate (oseltamivir) and zanamivir (zanamivir), which, by connecting with the hydrophobic site of the active site of influenza virus neuraminidase, block the ability of the latter to cleave sialic acid residues from the surface of the infected cell, thereby suppressing the exit from it of new formed virions.

Neuraminidase inhibitors (oseltamivir, zanamivir) act on influenza A and B viruses. Oseltamivir is available in capsule form. Prophylactic intake is allowed from the age of 12: 75 mg daily 1 time per day for at least 10 days. The drug has a safety profile acceptable for prescription dispensing; the observed undesirable effects (headaches, nausea, diarrhea, etc.) most often do not require its withdrawal. Zanamivir is available only in inhalation form, therefore it is not used for prophylaxis.

The widespread use of neuraminidase inhibitors is limited by their high cost. In addition, in various regions of the world, the growing resistance of influenza viruses to these drugs has been reported [Zaitsev A.A. Areas of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17 (23): 1525].

Currently, there have been cases of resistance to oseltamivir and zanamivir [Menno D. de Jong, Tran Tan Thanh, Truong Huu Khanh et al. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection // N. Engi. J. Med. - 2005. - N353. - P.2667-2572], [Smee D. F., Wong M. H., Bailey K. W., et al. Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and В viruses // Antivir Chem Chemother. - 2006. - V.17, N4. - P.185-192]. This is due to mutations in the neuraminidase gene that make the virus resistant to this class of compounds [Li K.S., Guan Y., Wang J., et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia // Nature. - 2004. - V.430, N6996. - P.209-213], [Hui-Ling Y., Ilyshina N. A., Salomon R. et al. Neuraminidase ingibitor-resistant recombinant A / Vietnam / 1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and vivo // J. Virol. - 2007. - Vol.81. - P.12418-12426; Le Q. M., Kiso M., Someya K. et al. Avian flu: isolation of drug-resistant H5N1 virus // 30 Nature. - 2005. - Vol. 437. - P.1108]. Mutations, according to some reports, occur in about 30% of cases. Neuraminidase inhibitors also have significant CNS side effects.

Recently, a large number of influenza A virus subtype H5N1 strains have acquired resistance to oseltamivir by replacing one amino acid in neuraminidase (H274Y and N294S) (Hui-Ling Y., Ilyshina NA, Salomon R. et al. Neuraminidase inhibitor-resistant recombinant A / Vietnam / 1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and vivo // J. Virol. - 2007. - Vol. 81. - P. 12418-12426; Le QM, Kiso M., Someya K . et al. Avian flu: isolation of drug-resistant H5N1 virus // Nature. - 2005. - Vol. 437. - P. 1108).

The drugs commonly used against strains of “seasonal” influenza may not work against highly pathogenic strains.

At present, the possibility of using interferon preparations (IFN) for the treatment and prevention of viral infections is widely discussed. It is known that the IFN system is a natural defense system of the body, the main role of which is the inhibition of viral replication. There are three main types of interferons - type I interferons, which include IFN-α, IFN-β, IFN-τ and IFN-ω, type II interferons, which include IFN-γ, and type III interferons, which include IFN- λ. Each of them to one degree or another has antiviral, immunomodulatory, antitumor and antiproliferative effects, but the most pronounced antiviral effect is IFN-α [Ershov FI, Kiselev OI. Interferons and their inducers (from molecules to drugs). M .: GEOTAR-Media, 2005]. Previously, the practice of prophylactic intranasal use of human leukocyte interferon-α (IFN) was widespread. However, the high incidence of adverse events (bloody nasal discharge, flu-like symptoms, drowsiness, allergic reactions, etc.) reduced the value of this method. Now in the arsenal of the doctor there are recombinant forms of IFN, characterized by a good safety profile. The prophylactic efficacy of intranasal IFN has been proven in a number of studies and confirmed by the results of meta-analysis [Jefferson TO, Tyrrell D. Antivirals for the common cold. The Cochrane Database of Systematic Reviews 2005 Issue 3]. The disadvantages of this approach include the side effects of interferons.

Therefore, there is a need to develop new agents and available therapeutic forms for the treatment and prevention of influenza and ARVI.

Known use of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid (glutaryl histamine), which has a pronounced antiviral activity against a wide range of viral pathogens, including influenza virus [RF Patent No. 2141483, 20.11.1999, ].

2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid

It is known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide or its pharmaceutically acceptable salt for the treatment and / or prevention of highly pathogenic infectious diseases such as highly pathogenic influenza A caused by viruses having a pathogenicity index of more than 1.2 , and severe acute respiratory syndrome (SARS) due to type IV coronavirus [EA020283, 10/30/2014].

It is also known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide for the treatment of viral hepatitis C. This agent can also be administered in combination with pegylated interferon and ribavirin. There is also known a pharmaceutical composition of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 for the treatment of viral hepatitis C, which has a pronounced antiviral effect and is effective in the treatment of viral hepatitis C, which can significantly reduce the frequency of side effects of antiviral therapy [RF Patent No. 2496512, 27.10.2013].

It is also known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide or its pharmaceutically acceptable salts for the prevention or treatment of diseases caused by (+) RNA-containing viruses belonging to the enterovirus genus or the flavivirus genus, [WO2014035297 , 29.08.2013].

It is also known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide or its pharmaceutically acceptable salt as an agent for the prevention and / or treatment of diseases associated with a decreased density of interferon receptors by restoring or increasing the density of interferon receptors to overcome resistance to interferon therapy [RF Patent No. 2595862, August 27, 2016, RF Patent No. 2668538, October 1, 2018].

Due to its pronounced antiviral and anti-inflammatory activity, 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid has found wide application in medicine as a means for the treatment and prevention of influenza A and B and other acute respiratory viral infections ( adenovirus infection, parainfluenza, respiratory syncytial infection) and was registered as a drug under the trade name Ingavirin®. The well-known drug Ingavirin® is presented in the form of capsules.

There is also known a pharmaceutical composition of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid in solid dosage form in the form of tablets or capsules, which has viral sotropic and immunogenic activity, characterized in that it includes 2- ( imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, as auxiliary substances of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate [RF Patent No. 2546002, 20.01.2014, WO2015108440, 23.07.2015].

Known structural analogue of Ingavirin®, 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione, as well as its use for the treatment of chronic diseases of the upper respiratory tract, in particular, rhinosinusitis [RF Patent No. RU2562773], which is a frequent complication of acute respiratory viral infection.

1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione

Rhinosinusitis (PC) is an inflammation of the mucous membrane of the nasal cavity and paranasal sinuses (SNP), the problem of which is currently one of the most relevant in otorhinolaryngology (Fokkens WJ, Lund VJ, Mullol J. et al., European Position Paper on Rhinosinusitis and Nasal Polyps, Rhinology, 2007; 45; 20: 1-139). The cause of rhinosinusitis is almost always stagnation of secretions, a block of natural anastomosis of the SNP and a violation of their aeration, when the mechanism of mucociliary clearance suffers, which is an important primary innate mechanism that protects the respiratory tract from the damaging effects of inhaled pollutants, allergens and pathogens.

At the same time, liquid dosage forms of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid or 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6- dione, as well as - their combined use in one dosage form for the treatment and prevention of influenza and ARVI.

Liquid dosage forms, including syrups, make up a significant part of the range of pharmacies. Their widespread use is due to a number of advantages over other dosage forms:

in their composition, it is possible to reduce the irritating effect of certain medicinal substances;

this dosage form is simple and convenient to use;

With the use of liquid dosage forms, it is possible to mask the unpleasant taste and odor of medicinal substances, as well as the possibility of accurate dosing in a wide range of doses, which is especially important in children's practice.

But, at the same time, there are drawbacks, the main of which are instability during storage and susceptibility to microbiological contamination, as well as the fact that not all biologically active substances are effective in such a dosage form.

Previously, the authors have repeatedly attempted to create a liquid dosage form of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid. Despite the fact that a liquid dosage form of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid can have a large number of advantages, including greater convenience for patients and ease of dosage, the task of its creation is very difficult, since as in solution, in contrast to solid dosage forms, chemical reactions of the active substance with the solvent occur, and the reactions of the active substance and excipients occur much faster. Despite all efforts, the authors for a long time failed to develop a sufficiently stable liquid dosage form of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid, acceptable for pharmaceutical use, due to hydrolysis of the active substance at the intramolecular amide bond and the formation of impurities in the process of storing this form. The hydrolysis products are histamine and glutaric acid. As is known from the prior art, free histamine is highly active: it causes spasm of smooth muscles (including the muscles of the bronchi), expansion of capillaries and a decrease in blood pressure; stagnation of blood in the capillaries and an increase in the permeability of their walls; causes swelling of surrounding tissues and blood thickening. Thus, the presence of this hydrolysis product in a liquid dosage form is highly undesirable. As shown below, the authors for the first time managed to develop stable liquid dosage forms of pentanedioic acid 2- (imidazol-4-yl) -ethanamide, choosing the conditions under which the histamine level in the finished dosage form during storage is controlled at a very low, acceptable for pharmaceutical level applications.

We have surprisingly found that the stability of the liquid dosage form of pentanedioic-1,5 acid 2- (imidazol-4-yl) -ethanamide and the suppression of the formation of undesirable impurities as a result of hydrolysis can be achieved by controlling the pH of the liquid dosage form within a certain range. At the same time, while maintaining the pH in this range, it is not only possible to maintain the level of histamine at a very low level, but the formation of other impurities in quantities exceeding the regulatory limits on the level of impurities in finished dosage forms does not occur.

We also unexpectedly found that the level of histamine in the liquid dosage form of 2- (imidazol-4-yl) -ethanamide pentanedioic-1,5 acid can be controlled at an acceptably very low level when some amounts of 1- [2- ( 1H-imidazol-4-yl) ethyl] piperidine-2,6-dione.

Without wishing to be bound by any theory, the authors suggest that 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione in solution can react with the 2- (imidazole- 4-yl) -ethanamide of pentanedioic-1,5 acid with histamine to form a non-toxic pharmaceutically acceptable compound of the formula:

Thus, the object of the present invention is to create a new stable and suitable for pharmaceutical use dosage form of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, providing high antiviral activity, optimal rate of onset of therapeutic effect and increased ease of use , as well as expanding the arsenal of drugs with antiviral action.

The problem is solved, and the result is achieved by creating a stable liquid dosage form for oral administration for the treatment and prevention of influenza and acute respiratory viral infections, containing 2- (imidazol-4-yl) ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salt in an effective amount and auxiliary substances.

More preferred is a liquid dosage form, characterized in that the pH of the liquid dosage form is 3-8, more preferably 4-8, even more preferably 5-8, even more preferably 5-7, even more preferably 6-7 even more preferably 6.3-6.7, most preferably 6.5.

The task is being solved, and the result is also achieved by creating a new liquid dosage form for oral administration for the treatment and prevention of influenza and ARVI, containing 2- (imidazol-4-yl) ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salt in an effective amount, and also 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof, and auxiliary substances.

More preferred is a liquid dosage form, characterized in that the mass ratio of pentanedioic acid 2- (imidazol-4-yl) ethanamide or a pharmaceutically acceptable salt thereof to 1- [2- (1H-imidazol-4-yl) ethyl ] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof ranges from 10000: 1 to 1: 2, preferably from 10000: 1 to 20: 1, even more preferably from 10000: 1 to 200: 1, even more preferably , from 10000: 1 to 2000: 1, even more preferably from 10000: 1 to 1000: 1.

More preferred is a liquid dosage form, characterized in that 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is contained in an amount of not more than 50 wt% of the content 2- (imidazol-4-yl) pentanedioic-1,5 acid ethanamide, preferably not more than 10 wt%, even more preferably not more than 5 wt%, even more preferably not more than 1 wt%, even more preferably not more than 0.2 wt%, even more preferably 0.1-0.01 wt%.

More preferred is a liquid dosage form, characterized in that it additionally contains an acid.

The acid can be an organic or inorganic acid. The inorganic acid can be selected from the group consisting of hydrochloric, phosphoric and sulfuric.

More preferred is a liquid dosage form wherein the acid is an organic acid.

More preferred is a liquid dosage form, characterized in that the organic acid is selected from the group consisting of malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids.

More preferred is a liquid dosage form, characterized in that the auxiliary substances are selected from a stabilizer, a preservative, a thickener, a sweetener, a flavoring agent and water.

More preferred is a liquid dosage form characterized in that the stabilizer is gums, chitosan, fatty acids and their salts, glycerin, propylene glycol and tragacanth.

More preferred is a liquid dosage form, characterized in that the preservative is selected from the group consisting of benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts.

More preferred is a liquid dosage form, characterized in that the thickener is selected from the group consisting of gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose, and pharmaceutically acceptable salts thereof.

More preferred is a liquid dosage form, characterized in that the sweetener is selected from the group consisting of maltitol, isomalt, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts.

More preferred is a liquid dosage form wherein the flavor is a raspberry, strawberry, orange, berry, apricot, pear, melon, mango, lemonade, or plum flavor, both dry and liquid.

More preferred is a liquid dosage form, characterized in that the concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid is from 1 to 50 mg / ml, preferably from 5 to 30 mg / ml, from 5 up to 25 mg / ml, 5 to 10 mg / ml, even more preferably 6 mg / ml.

More preferred is a liquid dosage form, characterized in that the excipients are contained in an amount, g:

maltitol liquid 20.0-50.0;

glycerin 0.0-40.0;

citric acid 0.01-1.0;

xanthan gum 0.1-5.0;

sodium methyl parahydroxybenzoate 0.1-5.0;

purified water up to 100 ml.

The subject of the present invention is also a method for the treatment or prevention of influenza and ARVI, according to which the subject is administered a liquid dosage form according to the present invention orally.

The subject of the present invention is also the use of pentanedioic acid 2- (imidazol-4-yl) -ethanamide in the form of a liquid dosage form for the treatment or prevention of influenza and ARVI.

The following are definitions of terms that are used in the description of the present invention.

"Medicinal product (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of finished forms intended for the restoration, correction or change of physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnostics, anesthesia, contraception , cosmetology and other things.

"Pharmaceutical composition" means a composition comprising pentanedioic acid 2- (imidazol-4-yl) -ethanamide or a pharmaceutically acceptable salt thereof in an effective amount and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, delivery vehicles such as preservatives, stabilizers, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavors, antibacterial agents, fungicides, the choice and ratio of which depends on nature and the route of administration and dosage. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of stabilizers are gums (eg xanthan, gellanic, konjacic), fatty acids and their salts, pectin, and tragacanth. Examples of preservatives are benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, parabens, alkylpyridinium, benzethonium, and pharmaceutically acceptable salts thereof. Examples of thickening agents are glycerin, alginic acid, gum arabic, glucose, sucrose, fructose, agar-agar, methylcellulose, and pharmaceutically acceptable salts thereof. Examples of sweeteners include maltitol, isomalt, sucralose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol, and pharmaceutically acceptable salts thereof. Examples of dispensing agents are starch, alginic acid and salts thereof. A pharmaceutical composition for oral, topical administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with conventional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as oral solutions or suspensions, syrups, sublingual, buccal and topical forms of administration.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients is meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active substance according to the present invention or its pharmaceutically acceptable salt may include other active substances, including those with activity, provided that they do not cause undesirable effects.

If necessary, use the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers. The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field to produce common forms, for example, in oral forms, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents, antiseptic agents are used.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of acids and bases disclosed in the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or they can be specially prepared. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of the salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesites malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates, and the like (For a detailed description of the properties of such salts, see Berge SM, et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which the salts of the claimed acids can be obtained, amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane, and the like. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation. The basic amino acids, lysine, ornithine and arginine, can be used as amino acids.

The term "therapeutically effective amount" means an amount of an active substance that (1) treats or prevents a specific disease, condition or disorder, (2) reduces, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (3) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "pharmaceutically acceptable" means that the substance or composition to which this term is applied must be chemically and / or toxicologically compatible with the other ingredients in the formulation and safe for the person being treated with this substance, or composition.

The terms "containing", "contains" means that the specified combinations, compositions and kits include the listed components, but do not exclude the inclusion of other components.

The term "syrup" in the present invention means any liquid dosage form, solution or elixir intended for oral administration, preferably, but not necessarily, containing a thickener, including active and auxiliary substances. Depending on the composition and physicochemical properties of the active and auxiliary substances, the syrup can have opalescence or be a heterogeneous dispersed system (most often a suspension). Additional liquid dosage forms for oral administration can be solutions for spraying in the mouth.

The following are examples of the invention, which illustrate, but do not cover all possible embodiments of the invention and do not limit the invention.

Example 1. Obtaining a syrup containing 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid.

Powders of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, as well as solid auxiliary substances (sodium methyl parahydroxybenzoate, xanthan gum) were sieved through a sieve with a mesh size of 250 μm. Sifted powders, as well as liquid auxiliary substances (glycerin, liquid maltitol), as well as purified water in accordance with the calculation were weighed on a calibrated verified balance into individual marked containers.

Preparation of citric acid solution

Citric acid monohydrate was sieved through a sieve with a mesh size of 800 μm. Purified water was added to sieved citric acid to prepare a 20.0% aqueous solution of citric acid. The resulting solution was filtered through a 200 μm metal sieve into a clean, individually labeled container.

Preparation of xanthan gum solution

Glycerin was placed in a production vessel. Sifted xanthan gum was added portionwise to the glycerin using an overhead stirrer without heating while stirring. Stirring was continued with increasing stirrer revolutions at room temperature for 20 to 45 minutes.

Then, purified water was loaded into the prepared reactor with a stirrer, the stirring device was turned on, and sieved sodium methyl parahydroxybenzoate was added in portions, visually monitoring its dissolution.

After the end of the dissolution of sodium methyl parahydroxybenzoate from the process vessel, sieved 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid was introduced in portions into the reactor, visually monitoring the dissolution.

After the dissolution of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid was completed, weighed maltitol was added in portions to the reactor.

After the dissolution of maltitol was complete, a solution of xanthan gum was added in portions to the reactor.

Then, a filtered 20% aqueous solution of citric acid was introduced into the reactor. Then, a flavoring agent was added in portions to the reactor.

After adding all the components, the stirrer speed was reduced and the solution was allowed to stand for 1 to 3 hours, during which time the xanthan gum in the syrup was hydrated. The pH of the syrup was adjusted to 6.4 by adding 20% aqueous citric acid solution.

At the end of the holding time of the unfiltered solution, the intermediate product was transferred to the stage of obtaining a filtered solution using a filter with a pore size of not more than 1.2 μm into a sealed production container.

Filling was carried out into vials. The drug was dosed by volume. The filling dose volume was monitored by weight for compliance with the requirements of the State Pharmacopoeia XIII (OFS.1.4.2.0007.15). A balance was used for this. The vials with the drug were sealed.

According to this technique, the compositions shown in Table 1 were obtained.

Table 1. Obtaining syrups containing 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid as an active substance

Name Composition for 100 ml of filtered syrup Composition 1 Composition 2 Composition 3 g per bottle 100 ml g per bottle 100 ml g per bottle 100 ml 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 0.10 0.600 5.0 Glycerol 39,60 20,610 12.60 Xanthan gum 4.950 0.252 0.155 Sodium methyl parahydroxybenzoate 0.105 0.177 4.775 Maltitol liquid 21.50 34,350 49.50 Citric acid monohydrate 0.955 0.037 0.010 Flavoring - 0.115 - Purified water up to 100 ml up to 100 ml up to 100 ml

Example 2. Study of the effect of the pH of the syrup on the stability of the finished dosage form during storage.

Similarly to Example 1, syrups of the following composition were additionally obtained, g:

2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 0.6

maltitol liquid 34.35;

glycerol 20.61;

xanthan gum 0.252;

sodium methyl parahydroxybenzoate 0.177;

purified water up to 100 ml.

The pH of the syrup was adjusted to pH = 3, 5, 8 and 9 by adding a 20% aqueous citric acid solution or 1 M aqueous sodium hydroxide solution with stirring.

The stability of the syrup was assessed by the content of the active substance 2- (imidazol-4-yl) -ethanamide pentanedioic-1,5 acid at 4 different pH values by the accelerated aging method.

All samples were stored in glass or plastic vials in a climatic chamber under accelerated test conditions. The active substance content was determined by HPLC using standards.

The "accelerated aging" method consists in keeping the tested medicinal product at temperatures and humidity higher than the temperature and humidity of its storage during circulation. At elevated temperatures, as a rule, physical and chemical processes occurring in drugs are accelerated, leading over time to undesirable changes in quality. Thus, at an elevated temperature, the period of time during which the controlled quality parameters of the medicinal product remain within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at the storage temperature. This can significantly reduce the time required to establish an expiration date.

According to the results obtained in the process of "accelerated aging" of the drug, it is also possible to solve the inverse problem, i.e. set the storage temperature to a specified shelf life.

The shelf life ( C) at storage temperature ( t _xp ) is associated with the experimental shelf life ( C _E ) at an elevated experimental storage temperature ( t _e ) by the following relationship:

,

,

.where the match factor

...

The temperature coefficient of the rate of chemical reaction ( A) is assumed to be 2.5. The given dependence is based on the Van't Hoff rule about a 2-4-fold increase in the rates of chemical reactions with an increase in temperature by 10 ° C.

In accordance with OFS.1.1.0009.15, the value of the conformity coefficient ( K ), depending on the selected temperature range ( t _e - t _xp ), equal to 30 ° C, is 15.6. The experimental storage period for a selected shelf life of 3 years is 71 days.

Statistical processing of the research results is carried out using the statistical package SPSS Statistics 19.0.

It was found that after 71 days of storage under the conditions of the accelerated aging method, the new liquid dosage form in the form of a syrup according to the present invention remains stable and chemically pure at pH values up to 8.0. With an increase in pH, the syrup remains chemically pure for less than 10 days, then the content of the active substance decreases significantly and the content of impurities increases, which determines the choice of the pH values of the new syrup according to the present invention to achieve higher stability during storage (see Table 2).

Table 2. Assessment of the stability of the obtained dosage forms by the accelerated aging method.

storage time at ( t _e - t _xp ) = 30 ° С, day The amount of active substance found by HPLC data in% of the theoretical content in the syrup at different pH values 3.0 5.0 6.4 * 8.0 9.0 0 100 100 100 100 100 ten 99.5 99.9 100 99.5 91.9 20 99.4 99.5 99.7 99.3 86.5 thirty 99.2 99.2 99.4 99.0 81.1 40 98.5 98.7 99.0 98.4 77.8 50 98.0 98.2 98.7 97.9 71.2 60 97.5 97.8 98.3 97.3 65.7 71 96.4 97.0 97.9 96.5 60.0

* composition 1 from Example 1

Example 3. Obtaining syrups with different pH and active substance concentrations.

In accordance with the procedure described in Example 1, syrups with different compositions of excipients, having different pH and dosage of the active substance, were obtained in a similar way.

Examples of syrup formulations prepared according to the present invention are shown in Tables 3-30.

Table 3. Obtaining a syrup with a pH of 4.0 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 282.40 24,000 Maltitol liquid 412.20 36,000 Citric acid monohydrate 3.00 0.257 Sodium methyl parahydroxybenzoate 1.78 0.153 Purified water up to 100 ml up to 100%

Table 4. Obtaining a syrup with a pH of 3.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid 1.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 282.40 24,000 Maltitol liquid 412.20 36,000 Citric acid monohydrate 1.22 0.210 Sodium methyl parahydroxybenzoate 1.78 0.153 Purified water up to 100 ml up to 100%

Table 5. Obtaining a syrup with a pH of 5.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid 1.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 282.40 24,000 Maltitol liquid 412.20 36,000 Citric acid monohydrate 0.176 0.030 Sodium methyl parahydroxybenzoate 1.78 0.153 Purified water up to 100 ml up to 100%

Table 6. Obtaining a syrup with a pH of 7.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 282.40 24,000 Maltitol liquid 412.20 36,000 Sodium hydroxide 1 M solution 0.077 0.007 Sodium methyl parahydroxybenzoate 1.78 0.153 Purified water up to 100 ml up to 100%

Table 7. Obtaining a syrup with a pH of 5.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 282.40 24,000 Maltitol liquid 412.20 36,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 1.20 0.103 Strawberry flavor 1.54 0.132 Purified water up to 100 ml up to 100%

Table 8. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Apricot flavor 0.92 0.079 Purified water up to 100 ml up to 100%

Table 9. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Melon flavor 0.58 0.050 Purified water up to 100 ml up to 100%

Table 10. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Purified water up to 100 ml up to 100%

Table 11. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 12. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Pear flavor 1.16 0.099 Purified water up to 100 ml up to 100%

Table 13. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid 1.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Flavor lemonade 0.12 0.010 Purified water up to 100 ml up to 100%

Table 14. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Maltitol liquid 286.25 25,000 Purified water up to 100 ml up to 100%

Table 15. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 3.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 3.50 0.300 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Mango flavor 0.30 0.026 Purified water up to 100 ml up to 100%

Table 16. Obtaining a syrup with a pH of 5.0 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.60 0.137 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 17. Obtaining a syrup with a pH of 5.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 18. Obtaining a syrup with a pH of 6.0 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.00 0.086 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 19. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Apricot flavor 0.94 0.081 Purified water up to 100 ml up to 100%

Table 20. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Strawberry flavor 0.58 0.050 Purified water up to 100 ml up to 100%

Table 21. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Xanthan gum 2.52 0.220 Purified water up to 100 ml up to 100%

Table 22. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 23. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Pear flavor 1.16 0.100 Purified water up to 100 ml up to 100%

Table 24. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Flavor lemonade 0.24 0.021 Purified water up to 100 ml up to 100%

Table 25. Obtaining a syrup with a pH of 5.8 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid of 17.5 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 17.50 1,500 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.103 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Raspberry flavor 0.24 0.021 Purified water up to 100 ml up to 100%

Table 26. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 7.0 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 7.00 0.600 Glycerol 326.20 28,000 Maltitol liquid 286.25 25,000 Citric acid monohydrate 1.20 0.105 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.52 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 27. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 7.0 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 7.00 0.600 Glycerol 209.70 18,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 1.20 0.105 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.56 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 28. Obtaining a syrup with a pH of 6.5 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1.5 acid 7.0 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 7.00 0.600 Maltitol liquid 458,00 40,000 Citric acid monohydrate 1.20 0.105 Sodium methyl parahydroxybenzoate 1.78 0.153 Xanthan gum 2.56 0.220 Plum flavor 0.64 0.055 Purified water up to 100 ml up to 100%

Table 29. Obtaining a syrup with a pH of 6.4 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid 6.0 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 6.00 0.524 Glycerol 206.10 18,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 0.374 0.033 Sodium methyl parahydroxybenzoate 1.78 0.155 Xanthan gum 2.52 0.220 Raspberry flavor 1.145 0.100 Purified water up to 100 ml up to 100%

Table 30. Obtaining a syrup with a pH of 6.4 and a concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1.5 acid 6.0 mg / ml.

Name Content,
mg / ml Content,
% (mass.) 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 6.00 0.524 Glycerol 206.10 18,000 Maltitol liquid 343.50 30,000 Citric acid monohydrate 0.374 0.033 Sodium methyl parahydroxybenzoate 1.78 0.155 Xanthan gum 2.56 0.220 Plum flavor 0.76 0.060 Purified water up to 100 ml up to 100%

All syrup formulations obtained were tested for stability by HPLC. The formulations show high stability.

Example 4. Obtaining syrups of various compositions.

In accordance with the procedure described in Example 1, syrups with various compositions of auxiliary substances having a pH in the range of 3-8 were obtained in a similar way.

Examples of syrup formulations prepared according to the present invention are shown in Table 31.

Table 31. Obtaining syrups with different composition of auxiliary substances.

Name Composition for 100 ml of filtered syrup g per bottle 100 ml g per bottle 100 ml g per bottle 100 ml 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 0.600 0.600 0.600 Glycerol - 20.65 - Glucose - - 22.75 Agar agar 0.305 - - Gellan gum - 0.295 - Stearic acid 0.485 - - Tragacanth - - 0.374 Sodium methyl parahydroxybenzoate - 0.180 - Benzyl alcohol - - 0.192 Benzoic acid 0.125 - - Maltitol 35.72 34.35 - Lactitol - - 31.54 Citric acid - - 0.042 Malic acid 0.055 - - Acetic acid - 0.031 - Purified water up to 100 ml up to 100 ml up to 100 ml Total: 114.5 114.5 114.5

The pH of each syrup was brought to pH = 3, 5, 8 by titration with sodium hydroxide solutions and the corresponding acid with stirring.

All obtained syrup compositions were tested for stability by HPLC. The formulations show high stability, which indicates that the stability of the liquid dosage form of 2- (imidazol-4-yl) -ethanamide pentanedioic-1,5 acid is mainly due to the pH value, and not to the composition of specific excipients, which varied greatly by chemical nature for the compositions shown in Table 3.

Thus, it was unexpectedly found that the greatest stability of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid in a liquid dosage form is achieved when the pH of the liquid dosage form is adjusted to values of 3-8.

Example 5. Obtaining a syrup containing 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione.

Compositions of syrups containing together 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione were obtained in a similar manner from Example 1, with the difference that after the stage of dissolution of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, the calculated amount of sifted 1- [2- (1H-imidazol-4-yl) ethyl ] piperidine-2,6-dione, visually monitoring the dissolution of the latter (see Table 32).

Table 32. Compositions of syrups containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione.

Name Composition for 100 ml of filtered syrup Composition 4 Composition 5 Roster 6 Roster 7 g per bottle 100 ml g per bottle 100 ml g per bottle 100 ml g per bottle 100 ml 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid 0.10 0.600 5.0 0.600 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione 0.20 0.012 0.005 0.00018 Glycerol 39.40 20.61 12.60 20,610 Xanthan gum 4.950 0.252 0.155 0.252 Sodium methyl parahydroxy benzoate 0.105 0.177 4.775 0.177 Maltitol liquid 21.50 34,338 49,495 34,350 Citric acid monohydrate 0.955 0.037 0.010 0.037 Flavoring - 0.115 - 0.115 Purified water up to 100 ml up to 100 ml up to 100 ml up to 100 ml

Example 6. Investigation of the effect of the pH of the syrup on the stability of the finished dosage form containing 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine- 2,6-dione, on storage.

Similarly to Example 5, syrups of the following composition were additionally obtained, g:

Pentanedioic acid 2- (imidazol-4-yl) ethanamide 0.600;

1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione 0.012;

maltitol liquid 34.338;

glycerin 20.610;

xanthan gum 0.252;

sodium methyl parahydroxybenzoate 0.177;

purified water up to 100 ml.

in which the pH of the syrup was brought to pH = 3; five; 6; eight; and 9 by adding a 20% aqueous citric acid solution or a 1 M aqueous sodium hydroxide solution with stirring.

The stability of the syrup was assessed by the content of histamine impurity at 5 different pH values by the accelerated aging method according to Example 2. The histamine content was determined by HPLC using a standard solution of histamine dihydrochloride.

Table 33. Evaluation of the level of hydrolysis products in the obtained dosage forms under conditions of accelerated aging.

storage time at ( t _e - t _xp ) = 30 ° C, day Found by HPLC the amount of histamine in molar% of the initial content of glutaryl histamine at various pH values 3.0 5.0 6.0 8.0 9.0 0 0 0 0 0 0 ten 0 0 0 0 0 20 0 0 0 0 0.1 thirty 0 0 0 0.1 0.2 40 0.1 0 0 0.2 0.3 50 0.2 0.1 0 0.3 0.6 60 0,4 0.2 0 0.7 0.9 71 0.5 0.3 0.1 0.9 1.0

It was found that during storage under accelerated aging conditions in a liquid dosage form according to the present invention containing 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione, histamine levels can be maintained at a relatively low acceptable level even at alkaline pH.

The invention can be used in medicine, pharmacology, chemical and pharmaceutical industry.

Claims (19)

1. Liquid dosage form for oral administration for the treatment and prevention of influenza and acute respiratory viral infections, containing 2- (imidazol-4-yl) ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salt, as well as 1- [2- (1H-imidazole -4-yl) ethyl] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof in effective amounts and pharmaceutically acceptable excipients, wherein the pH of the liquid dosage form ranges from 3 to 8. 2. A dosage form according to claim 1, characterized in that the weight ratio of pentanedioic acid 2- (imidazol-4-yl) ethanamide or its pharmaceutically acceptable salt to 1- [2- (1H-imidazol-4-yl ) ethyl] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof ranges from 10,000: 1 to 1: 2, preferably from 10,000: 1 to 20: 1, even more preferably from 10,000: 1 to 200: 1, even more preferably from 10000: 1 to 2000: 1, even more preferably from 10000: 1 to 1000: 1. 3. A dosage form according to claim 1, characterized in that 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is contained in an amount of not more than 50 wt% from the content of 2- (imidazol-4-yl) ethanamide of pentanedioic-1,5 acid, preferably not more than 10 wt.%, even more preferably not more than 5 wt.%, even more preferably not more than 1 wt.%, even more preferably not more than 0.2 wt%, even more preferably 0.1-0.01 wt%. 4. A dosage form according to claim 1, characterized in that it additionally contains a pharmaceutically acceptable acid. 5. A dosage form according to claim 4, wherein the acid is a pharmaceutically acceptable organic acid. 6. A dosage form according to claim 5, characterized in that the organic acid is selected from the group including malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. 7. A dosage form according to claim 1, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of a stabilizer, a preservative, a thickener, a sweetener, a flavoring agent and water. 8. A dosage form according to claim 7, characterized in that the stabilizer is selected from the group consisting of gums, chitosan, fatty acids and their pharmaceutically acceptable salts, glycerol, propylene glycol and tragacanth. 9. A dosage form according to claim 7, characterized in that the preservative is selected from the group consisting of benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkyl pyridinium, benzethonium and their pharmaceutically acceptable salts. 10. A dosage form according to claim 7, wherein the thickener is selected from the group consisting of gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose, and pharmaceutically acceptable salts thereof. 11. A dosage form according to claim 7, characterized in that the sweetener is selected from the group consisting of maltitol, isomalt, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. 12. A dosage form according to claim 7, wherein the flavoring is raspberry, strawberry, orange, berry, apricot, pear, melon, mango, lemonade or plum flavor. 13. A dosage form according to claim 1, characterized in that the concentration of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid is from 1 to 50 mg / ml. 14. A dosage form according to any one of claims 1 to 13, characterized in that the pharmaceutically acceptable excipients are contained in an amount, g: maltitol liquid 20.0-50.0 glycerol 0.0-40.0 citric acid 0.01-1.0 xanthan gum 0.1-5.0 sodium methyl parahydroxybenzoate 0.1-5.0 purified water up to 100 ml 15. A dosage form according to claim 14, characterized in that it contains the following substances, g per 100 ml: Pentanedioic acid imidazolylethanamide 0.600 1- [2- (1H-imidazol-4-yl) ethyl] piperidine-2,6-dione 0.00018 Glycerol 20,610 Xanthan gum 0.252 Maltitol 34,350 Sodium methyl parahydroxybenzoate 0.177 Citric acid monohydrate 0.037 Purified water up to 100 ml 16. A method of treating and / or preventing influenza and ARVI, according to which the subject is orally administered a liquid dosage form according to any one of claims. 1-15. 17. The use of a liquid dosage form for oral administration according to any one of paragraphs. 1-15 for the treatment and / or prevention of influenza and SARS.