RU2770521C2 - Liquid dosage form for treatment and prevention of flu and arvi - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to chemical and pharmaceutical industry, namely to a liquid dosage form for oral administration for the treatment and/or prevention of flu and/or ARVI. The liquid dosage form for oral administration for the treatment and/or prevention of flu and/or ARVI contains 2-(imidazole-4-yl)ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salt in the effective amount and pharmaceutically acceptable auxiliary substances. In this case, the specified auxiliary substances are selected from a group including a stabilizer, a preservative, a thickener, a sweetener, a flavor and water in following amounts, wt.%: stabilizer 12.6-40.0; preservative 0-5.0; thickener 0-5.0; sweetener 0-50.0; water qs, while pH of the liquid dosage form is from 3 to 8. The liquid dosage form for oral administration for the treatment and/or prevention of flu and/or ARVI contains following substances, g per 100 ml: 2-(imidazole-4-yl)ethanamide of pentanedioic-1,5 acid 0.600; glycerin 20.610; xanthan gum 0.252; maltitol 34.350; sodium methylparahydroxybenzoate 0.177; citric acid monohydrate 0.037; flavor 0.115; purified water up to 100 ml. The use of a liquid dosage form for the treatment and/or prevention of flu and/or ARVI is also described.

EFFECT: above-described liquid form for oral administration for the treatment and/or prevention of flu and/or ARVI has high stability.

20 cl, 33 tbl, 6 ex

Description

The invention relates to the 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)-pentanedioic-1,5 acid ethanamide in an effective amount and excipients.

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

In Russia, 30-40 million cases of infectious diseases are registered annually, 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 amixin. A guide for doctors. M., 2004]. The reasons for such a high incidence are considered to be 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.E. Symptomatic treatment of acute respiratory viral infections: the future belongs to combined drugs. Rus. honey. journal, 2007, 22: 1636].

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

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

Influenza A and B viruses are of the greatest epidemic importance, causing annual epidemics, the economic damage from which amounts to billions of US dollars. In Russia, the annual total economic damage from influenza is estimated by experts at an amount reaching 40 billion rubles. In the world every year, 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].

Mortality from some forms of influenza, even with high-tech treatments, is more than 50%. In this case, the disease is characterized, as a rule, by an acute onset and a severe course: high (40 ° C or more) temperature and prolonged fever with symptoms of intoxication - headache, insomnia, pain in muscles and joints, meningeal symptoms. One of the unfavorable currents is a 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. - N 7. - S. 710-721].

In some cases, viral infection predisposes to the development of complications, the most common 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 milder 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, bronchiolitis. Pneumonia is a rare complication of rhinovirus infection, but develops in 5-30% of patients with influenza A and 10% of patients with influenza B [Zaitsev A.A. Directions 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 to date. 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 of inactivated vaccines is subcutaneously or intramuscularly. Despite the promising non-invasive route of administration and the low cost of live vaccines, their use is limited due to high reactogenicity (development of infection symptoms - headache, fever, malaise), allergenicity and a number of contraindications (age over 50 years, acute diseases, diseases internal organs, immunosuppression, etc.). In this regard, inactivated vaccines are recommended for mass prevention of influenza. The most important requirement for the vaccines used is the correspondence of the antigenic composition to the strains of the influenza virus that is relevant in this epidemiological season [Zaitsev A.A. Directions 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 to influenza viruses, there is no protection against other ARVI pathogens. A promising area of prevention is the use of funds to activate the nonspecific resistance of the organism. At the same time, domestic healthcare is characterized by the frequent use of drugs with a limited evidence base [Zaitsev A.A. Directions 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, eleutherococcus, aralia, etc.) for the prevention of respiratory infections have not been conducted [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. Directions of pharmacotherapy and prevention of acute respiratory viral infections. Rus. Honey. zhurn, 2009, 17(23):1525]: 1) as an addition 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, with 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 who are 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 correspond to the epidemic situation.

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

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

M2-channel blockers are active against influenza A virus. In influenza therapy, amantadine and rimantadine, which are antiviral against strains of influenza virus [Am. J. Med. - 1997. - V.102(ZA) - N17. - P.55-60], [Watts J. "Asian nations step up action to curb spread of avian influenza" // Lancet. - 2004. - V.363 - N9406. - P.373]. In the Russian Federation, the antiviral drug rimantadine has become widespread. It is used for the treatment and prevention of infection caused by type A influenza viruses. Its prophylactic efficacy during periods of seasonal influenza outbreaks reaches 70-90% [Kuzin V.B., Lovtsova L.V., Barsuk A.L. Study of the clinical efficacy and tolerability of Antigrippin-Maximum in the treatment of acute respiratory viral infections (flu). Handbook of the polyclinic doctor, 2010, 1: 3-7]. In addition, according to studies, the use of rimantadine is also characterized by a decrease in the incidence of influenza-like infections by 25% [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 H3N2 influenza virus 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 assembly and budding of viral particles [Bulletin of RAMS // 1993. - N 3. - R. 10-15]. However, rimantadine, as a representative of the adamantane group, has limitations in its use. At high doses, there are side effects from the central nervous system, in particular, the drug can cause convulsive phenomena. It also has an adverse effect on the liver, kidneys, which makes it unlikely to be used in people with diseases of these organs.

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

Inhibitors of neuraminidase of influenza A and B viruses, oseltamivir phosphate (oseltamivir) and zanamivir (zanamivir), are currently widely used, which, by combining 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 release of new formed virions from it.

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

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

Currently, there are cases of emergence 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 B 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 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 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 strains of influenza A virus subtype H5N1 have acquired resistance to oseltamivir due to the replacement of one amino acid in neuraminidase (H274Y and N294S) (Hui-Ling Y., Ilyshina N.A., 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 Q.M., Kiso M., Someya K et al. Avian flu: isolation of drug-resistant H5N1 virus // Nature. - 2005. - Vol. 437. - P. 1108).

Drugs commonly used against "seasonal" influenza strains may not be effective against highly pathogenic strains.

Currently, the possibility of using interferon preparations (IFN) for the treatment and prevention of viral infections is being 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 some extent has antiviral, immunomodulatory, antitumor and antiproliferative effects, but IFN-α has the most pronounced antiviral effect [Ershov F.I., Kiselev O.I. 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 frequency of adverse events (bleeding from the nose, flu-like symptoms, drowsiness, allergic reactions, etc.) reduced the value of this method. Recombinant forms of IFN, characterized by a good safety profile, have now appeared in the doctor's arsenal. The prophylactic efficacy of intranasal IFN has been proven in a number of studies and confirmed by the results of a 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 affordable therapeutic forms for the treatment and prevention of influenza and SARS.

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

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

It is known to use 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide or a pharmaceutically acceptable salt thereof 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) caused by type IV coronavirus [EA020283, 10/30/2014].

The use of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide for the treatment of viral hepatitis C is also known. This agent can also be administered in combination with pegylated interferon and ribavirin. Also known is a pharmaceutical composition of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid 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 incidence of side effects of antiviral therapy [RF Patent No. 2496512, October 27, 2013].

It is also known to use 2-(imidazol-4-yl)-ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salts for the prevention or treatment of diseases caused by (+)RNA-containing viruses belonging to the genus Enterovirus or the genus Flavivirus, [WO2014035297 , August 29, 2013].

It is also known to use 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide or a pharmaceutically acceptable salt thereof as a means for the prevention and/or treatment of diseases associated with a reduced 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.

Also known is a pharmaceutical composition of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid in solid dosage form in the form of tablets or capsules with virusotropic and immunogenic activity, characterized in that it includes 2-( imidazol-4-yl)-ethanamide of pentanedioic-1,5 acid, as excipients lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide (Aerosil 300) and calcium stearate [RF Patent No. 2546002, 20.01.2014, WO 2015108440, July 23, 2015].

Known structural analogue of Ingavirin®, 1-[2-(1H-imidazol-4-yl)ethyl]piperidin-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]piperidin-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 W.J., Lund V.J., 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 secretion, blockage of the natural fistulas of the SNP and violation of their aeration, when the mechanism of mucociliary clearance, which is an important primary innate mechanism that protects the airways from the damaging effects of inhaled pollutants, allergens and pathogens, suffers.

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

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 easy to use;

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

But at the same time, there are also disadvantages, the main of which are storage instability 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 repeatedly attempted to create a liquid dosage form of 2-(imidazol-4-yl)-pentanedioic-1,5 acid ethanamide. Although a liquid formulation of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid may have many advantages, including greater patient convenience and ease of dosing, it is a very difficult task to develop such how 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 failed for a long time to develop a sufficiently stable liquid dosage form of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide, acceptable for pharmaceutical use, due to hydrolysis of the active substance at the intramolecular amide bond and the formation of impurities during storage of such a form. The products of hydrolysis are histamine and glutaric acid. As is known from the prior art, free histamine is highly active: it causes spasm of smooth muscles (including bronchial muscles), dilation 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 the surrounding tissues and thickening of the blood. Thus, the presence of this hydrolysis product in a liquid dosage form is highly undesirable. As shown below, the authors succeeded for the first time in developing stable liquid dosage forms of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid by choosing the conditions under which the histamine level in the finished dosage form during storage is controlled to a very low, acceptable for pharmaceutical application level.

The inventors surprisingly found that the stability of the liquid formulation of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid and the suppression of the formation of undesirable impurities by hydrolysis can be achieved by controlling the pH of the liquid formulation within a certain range. At the same time, while maintaining pH in this range, it is not only possible to maintain the level of histamine at a very low level, but also there is no formation of other impurities in quantities exceeding the regulatory limits on the level of impurities in finished dosage forms.

We have also unexpectedly found that the histamine level in a liquid formulation of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid can be controlled to an acceptable very low level when some amounts of 1-[2-( 1H-imidazol-4-yl)ethyl]piperidin-2,6-dione.

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

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

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 SARS, 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 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 SARS, containing 2-(imidazol-4-yl)ethanamide of pentanedioic-1,5 acid or its pharmaceutically acceptable salt in an effective amount, as well as 1-[2-(1H-imidazol-4-yl)ethyl]piperidin-2,6-dione or a pharmaceutically acceptable salt thereof, and excipients.

More preferred is a liquid dosage form, characterized in that the weight ratio of 2-(imidazol-4-yl)ethanamide pentanedioic-1,5 acid or its pharmaceutically acceptable salt to 1-[2-(1H-imidazol-4-yl)ethyl ]piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is 10,000:1 to 1:2, preferably 10,000:1 to 20:1, even more preferably 10,000:1 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]piperidin-2,6-dione or its pharmaceutically acceptable salt is contained in an amount of not more than 50 wt.% of the content 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.%.

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

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

More preferred is a liquid dosage form, characterized in that 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 excipients are selected from a stabilizer, preservative, thickener, sweetener, flavor 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 their pharmaceutically acceptable salts.

More preferred is a liquid dosage form wherein the sweetener is selected from the group consisting of maltitol, isomaltitol, 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 characterized in that the flavor is raspberry, strawberry, orange, berry, apricot, pear, melon, mango, lemonade or plum flavor in both dry and liquid form.

More preferred is a liquid dosage form, characterized in that the concentration of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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:

liquid maltitol 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 SARS, according to which the liquid dosage form of the present invention is administered orally to the subject.

The subject of the present invention is also the use of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide in the form of a liquid dosage form for the treatment or prevention of influenza and SARS.

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

"Drug (preparation)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of ready-made 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, diagnosis, anesthesia, contraception , cosmetology and more.

"Pharmaceutical composition" means a composition comprising 2-(imidazol-4-yl)-ethanamide of pentanedioic-1,5 acid 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 agents such as preservatives, stabilizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, the choice and proportion of which depends on nature and route of administration and dosage. Protection against the action of microorganisms can be provided with 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 and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of stabilizers are gums (eg xanthan, gellan, konjac), fatty acids and their salts, pectin and tragacanth. Examples of preservatives are benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, parabens, alkyl pyridinium, benzethonium and their pharmaceutically acceptable salts. Examples of thickeners are glycerol, alginic acid, gum arabic, glucose, sucrose, fructose, agar-agar, methylcellulose and their pharmaceutically acceptable salts. Examples of sweeteners are maltitol, isomaltitol, sucralose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. Examples of distributing agents are starch, alginic acid and its salts. A pharmaceutical composition for oral, topical administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration, as a mixture with conventional pharmaceutical carriers. Suitable unit administration forms include oral forms such as oral solutions or suspensions, syrups, sublingual, buccal and topical forms of administration.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and/or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the active substance of 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, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with traditional pharmaceutical carriers. The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, for example, in oral forms, disintegrators, solvents, diluents, stabilizers, suspending agents, flavoring agents, antiseptic agents are used.

A "pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds or obtained specially. In particular, base salts can be prepared specifically from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates, 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 specifically prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metal 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 salts of the declared acids can be obtained, amines and amino acids are selected that have sufficient basicity to form a stable salt and are suitable for medical use (in particular, they must 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. As amino acids, the basic amino acids lysine, ornithine and arginine can be used.

The term “therapeutically effective amount” means an amount of an active ingredient that (1) treats or prevents a particular disease, condition, or disorder, (2) relieves, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (3) prevents or prevents delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

The term “pharmaceutically acceptable” means that the substance or composition to which the 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 the substance or composition.

The terms "comprising", "comprises" 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 excipients. Depending on the composition and physico-chemical properties of the active and auxiliary substances, the syrup may have opalescence or be a heterogeneous dispersed system (most often a suspension). Additional liquid dosage forms for oral administration may be oral spray solutions.

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)-pentanedioic-1,5 acid ethanamide

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

Obtaining a solution of citric acid

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

Preparation of xanthan gum solution

Glycerin was placed in a production container. Sieved xanthan gum was added in portions to the glycerol using an overhead stirrer without heat while stirring. Stirring was continued with increasing stirrer speed at room temperature from 20 to 45 minutes.

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

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

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

Upon completion of the dissolution of maltitol, 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 the 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 a 20% aqueous solution of citric acid.

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

Filling was carried out in vials. The drug was dosed by volume. The volume of the filling dose was controlled by weight for compliance with the requirements of SP XIII (OFS.1.4.2.0007.15). For this, scales were used. The drug vials were sealed.

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

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

Name Composition per 100 ml filtered syrup Composition 1 Composition 2 Composition 3 g per 100 ml vial g per 100 ml vial g per 100 ml vial 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 influence 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

liquid maltitol 34.35;

glycerin 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 20% aqueous citric acid or 1M aqueous sodium hydroxide with stirring.

The stability of the syrup was evaluated 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 climate chamber under accelerated testing conditions. The content of the active substance was determined by HPLC using standards.

The "accelerated aging" method consists in keeping the tested medicinal product at temperatures and humidity exceeding the temperature and humidity of its storage during circulation. At elevated temperatures, as a rule, the physicochemical processes occurring in medicinal products are accelerated, leading over time to undesirable changes in quality. Thus, at elevated temperatures, the period of time during which the controlled quality indicators of the medicinal product remain within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at storage temperature. This allows you to significantly reduce the time required to establish the 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 a storage temperature that provides any given shelf life.

Shelf life ( C) at storage temperature ( t _xr ) is related to experimental shelf life ( C _e ) at elevated experimental storage temperature ( t _e ) by the following relationship:

,

,

.where the matching coefficient

.

The temperature coefficient of the chemical reaction rate ( A) is taken equal to 2.5. The above 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 coefficient of conformity ( K ) depending on the selected temperature interval ( t _e - t _xp ), equal to 30 ° C, is 15.6. The experimental storage period with the selected shelf life of 3 years is 71 days.

Statistical processing of the results of the study 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 of the new liquid dosage form in the form of a syrup of the present invention remains stable and chemically pure at pH values up to 8.0. By increasing the 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 causes the choice of pH values of the new syrup of the present invention to achieve higher storage stability (see Table 2).

Table 2. Evaluation 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 according to HPLC data in % of the theoretical content in the syrup at various 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 fifty 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 concentrations of the active substance

In accordance with the procedure given in Example 1, similarly received syrups with different compositions of excipients, having different pH and dosage of the active substance.

Examples of compositions of syrups obtained 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 lemonade flavor 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 3.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 pH 5.8 and a concentration of 2-(imidazol-4-yl)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 pentanedioic-1.5 acid 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 lemonade flavor 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)-pentanedioic-1.5 acid ethanamide 17.5 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 7.0 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 7.0 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 7.0 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 6.0 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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)-pentanedioic-1.5 acid ethanamide 6.0 mg/ml

Name Content,
mg/ml Content,
% (mass) 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 obtained compositions of syrups are tested for stability by HPLC. The compositions show high stability.

Example 4. Obtaining syrups of various compositions

In accordance with the procedure given in Example 1, syrups were similarly prepared with different formulations of excipients having a pH in the range of 3-8.

Examples of compositions of syrups obtained according to the present invention are shown in Table 31.

Table 31. Obtaining syrups with different composition of excipients

Name Composition per 100 ml filtered syrup g per 100 ml vial g per 100 ml vial g per 100 ml vial 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 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 adjusted to pH=3, 5, 8 by titration with sodium hydroxide solutions and the appropriate acid with stirring.

All obtained compositions of syrups were tested for stability by HPLC. The formulations show high stability, indicating that the stability of the liquid dosage form of 2-(imidazol-4-yl)-pentanedioic-1,5 acid ethanamide is due mainly 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 surprisingly found that the greatest stability of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid in a liquid dosage form is achieved by bringing the pH of the liquid dosage form to values of 3-8.

Example 5 Preparation of a syrup containing 2-(imidazol-4-yl)-ethanamide of pentanedioic-1,5 acid and 1-[2-(1H-imidazol-4-yl)ethyl]piperidin-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 similarly to the procedure 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 2-(imidazol-4-yl)-ethanamide of pentanedioic-1,5 acid and 1-[2-(1H-imidazol-4-yl)ethyl]piperidine-2,6-dione

Name Composition per 100 ml filtered syrup Composition 4 Composition 5 Composition 6 Composition 7 g per 100 ml vial g per 100 ml vial g per 100 ml vial g per 100 ml vial 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide 0.10 0.600 5.0 0.600 1-[2-(1H-imidazol-4-yl)ethyl]piperidin-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 parahydroxybenzoate 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. Study 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, in storage

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

2-(imidazol-4-yl)-ethanamide of pentanedioic-1.5 acid 0.600;

1-[2-(1H-imidazol-4-yl)ethyl]piperidin-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 adjusted to pH=3; 5; 6; eight; and 9 by adding 20% citric acid aqueous solution or 1M sodium hydroxide aqueous solution with stirring.

The stability of the syrup was evaluated by the content of histamine admixture 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 )=30ºС, day The amount of histamine detected by HPLC in mole % 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 fifty 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 has been found that when stored under accelerated aging conditions in a liquid dosage form of the present invention containing 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide and 1-[2-(1H-imidazol-4-yl) ethyl]piperidine-2,6-dione, histamine levels can be maintained at a relatively low tolerable level even at alkaline pH.

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

Claims (30)

1. Liquid dosage form for oral administration for the treatment and/or prevention of influenza and/or 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 pharmaceutically acceptable excipients where these excipients are selected from the group consisting of a stabilizer, preservative, thickener, sweetener, flavor and water in the following amounts, wt. %: stabilizer 12.6-40.0 preservative 0-5.0 thickener 0-5.0 sweetener 0-50.0 water qs while the pH of the liquid dosage form is from 3 to 8. 2. Dosage form according to claim 1, additionally containing a pH modifier. 3. The dosage form of claim 2, wherein the pH modifier is a pharmaceutically acceptable acid. 4. The dosage form of claim 3, wherein the acid is a pharmaceutically acceptable organic acid. 5. Dosage form according to claim 4, where the organic acid is selected from the group including malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. 6. The dosage form according to claim 5, wherein the organic acid is citric acid. 7. The dosage form of claim. 1, where the stabilizer is selected from the group including gums, chitosan, fatty acids and their pharmaceutically acceptable salts, glycerin, propylene glycol and tragacanth. 8. Dosage form according to claim 7, where the stabilizer is glycerol. 9. The dosage form of claim 1, wherein the preservative is selected from the group consisting of benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkylpyridinium, benzethonium, and pharmaceutically acceptable salts thereof. 10. Dosage form according to claim 9, where the preservative is sodium methyl parahydroxybenzoate. 11. The dosage form of claim. 1, where the thickener is selected from the group including gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and their pharmaceutically acceptable salts. 12. Dosage form according to claim 11, where the thickener is xanthan gum. 13. The dosage form according to claim 1, where the sweetener is selected from the group including maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. 14. The dosage form of claim 13, wherein the sweetener is liquid maltitol. 15. Dosage form according to claim 1, additionally containing a flavoring agent. 16. The dosage form of claim 15 wherein the flavor is raspberry, strawberry, orange, berry, apricot, pear, melon, mango, lemonade, or plum flavor. 17. Dosage form according to claim 1, characterized in that the concentration of 2-(imidazol-4-yl)-pentanedioic-1,5-ethanamide is from 1 to 50 mg/ml. 18. Dosage form according to claim 2, containing: maltitol liquid, glycerol, citric acid, xanthan gum, sodium methyl parahydroxybenzoate, fragrance, and purified water. 19. Liquid dosage form for oral administration for the treatment and / or prevention of influenza and / or SARS, containing the following substances, g per 100 ml: 2-(imidazol-4-yl)ethanamide of pentanedioic-1,5 acid 0.600 Glycerol 20.610 xanthan gum 0.252 Maltitol 34.350 Sodium methyl parahydroxybenzoate 0.177 Citric acid monohydrate 0.037 flavoring 0.115 Purified water up to 100 ml 20. The use of a liquid dosage form according to any one of paragraphs. 1-19 for the treatment and/or prevention of influenza and/or SARS.