WO2023224519A1 - Novel crystalline form of n,n'-bis-[2-(1н-imidazol-4-yl)ethyl]propanediamide and pharmaceutical use thereof - Google Patents

Abstract

The invention relates to the field of medicine, pharmacology and the chemical and pharmaceutical industry, and more particularly to a novel crystalline form of N,N'-bis-[2-(1Н-imidazol-4-yl)ethyl]propanediamide and to a pharmaceutical composition and a dosage form containing same, which can be used for the treatment and/or prophylaxis of mucosal inflammation of the upper respiratory tract.

Description

NEW CRYSTAL FORM of \.\ '-B11( -|2-( 111-11М11DAZO.1- 4-YL)ETHYL]PROPANDIAMIDE AND ITS PHARMACEUTICAL APPLICATION

Technical field

The invention relates to the fields of medicine, pharmacology and the chemical-pharmaceutical industry, namely to a new crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, containing its pharmaceutical compositions and dosage form, which can find application for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract.

State of the art

Mucosal inflammation syndrome is one of the most common pathologies of the upper respiratory tract, usually related to infectious, vasomotor, allergic and other types of rhinitis. In general, with rhinitis, swelling of the mucous membrane and hypertrophy of the walls of blood vessels develop, which makes breathing difficult and negatively affects the patient’s quality of life (S.E. ILINSKY and M.G. MIKHAILOV, Diagnosis and treatment of chronic inflammatory diseases of the nasopharynx in adults, RUSSIAN RHINOLOGY, 2010, T.18, 3, pp.43-44).

Diagnosis of forms of rhinitis is carried out based on the patient’s complaints and clinical picture. In some cases, differential diagnosis requires laboratory tests and CT scans of the paranasal sinuses. Once the allergen is identified, treatment may be limited to stopping contact with it. In case of severe manifestations in the form of nasal congestion, itching in the nose, sneezing and mucus running down the back wall of the pharynx, adequate pharmacotherapy should be individually selected for the patient (A. L. GUSEV A and M. L. DERBENEV Rhinitis: differential diagnosis and principles of treatment, MEDICAL ADVICE, 2020, 16, pp.102-108).

Decisive importance in the treatment of rhinitis still belongs to the timely use of symptomatic agents aimed at suppressing the mechanisms of development of clinical manifestations and alleviating the course of the disease (A.V. GUROV, Swelling of the mucous membrane of the upper respiratory tract. How to deal with it?, RMJ, 2009, T .17, 19, pp.1254-1258). For symptomatic therapy, vasoconstrictor drugs, anticholinergic drugs, cromones, local and systemic antihistamines, leukotriene receptor blockers, topical and systemic glucocorticosteroids, sorbents, pre- and probiotics.

The closest analogues of the invention in question, used for the symptomatic treatment of rhinitis, are bisamides of formula (I) and a specific representative of bisamides, compound A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide of formula (II), which were first disclosed in patents RU2665688C2 and RU2725881C2. The compounds were reacted with metal salts as chelators. The authors showed the possibility of using bisamides of formula (I) for the treatment and/or prevention of diseases associated with metal-dependent free radical oxidation reactions, for example, iron excess anemia, atherosclerosis, porphyria tarda, poisoning with transition metal salts, etc.

A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

Bisamides of formula (I) of formula (II)

A,A'-Bis[2-(1H-imidazol-4-yl)ethyl]propanediamide can be obtained by the reaction of dimethyl malonate with histamine in a polar organic solvent at a temperature of 85-120°C (RU2679636C1).

In patent RU2685277C1, new properties of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide were studied in detail. The compound has been shown to be effective in suppressing the activity of the third type histamine receptor, in the treatment of allergic diseases (such as year-round and persistent allergic rhinitis) and other diseases associated with excessive stimulation of the third type histamine receptor.

One of the key tasks of the modern pharmaceutical industry is the development of dosage forms with an increased rate of development of the therapeutic effect, which is necessary to prevent the onset of severe consequences. This is more true for symptomatic medications. It should also be noted that the drug and pharmaceutical compositions must be able to be stored for significant periods time, without showing a significant change in the physicochemical properties of the active component.

Information about forms of A,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide that have an increased rate of development of the therapeutic effect has not been identified in the scientific and technical literature. It follows from this that the potential of the compound has not yet been revealed or fully explored.

Thus, the technical problem that has not been solved is the insufficient stability, therapeutic efficacy and pharmacokinetic parameters (rate of development of the therapeutic effect and bioavailability) of dosage forms of A,L/'-bis-[2-(1H-imidazol-4-yl )ethyl]propanediamide.

Disclosure of the invention

Technical result

The objective of the present invention is to develop a storage-stable and non-hygroscopic new form of A,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, which has an optimal set of physicochemical and pharmacokinetic parameters.

The inventors unexpectedly discovered that a new crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, previously unknown in the prior art, has reduced hygroscopicity and increased stability while maintaining good solubility. In addition, the pharmaceutical composition containing the specified new crystalline form has improved compressibility with good flow properties without noticeable electrostatic phenomena. The new crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide also has improved bioavailability, which, in particular, is reflected in the rapid development of the therapeutic effect. These properties are also true for pharmaceutical compositions and medicinal products containing the new crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide.

The technical results to be achieved by the present invention are as follows: - increasing the short-term stability during storage of the form D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide and pharmaceutical compositions and dosage forms containing it;

- increasing the long-term stability of the D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide form and pharmaceutical compositions and dosage forms containing it;

- reducing hygroscopicity while maintaining sufficient solubility of the L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide form;

- improving compressibility while maintaining good flowability without noticeable electrostatic phenomena of a pharmaceutical composition and dosage form containing the form L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide;

- increasing the therapeutic effectiveness of the form D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide and pharmaceutical compositions and dosage forms containing it;

- improving bioavailability, in particular, manifested in an increased rate of development of the therapeutic effect and improved pharmacokinetic parameters of the form L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and pharmaceutical compositions and medicinal products containing it forms;

- effective antipyretic and analgesic effect in the treatment of inflammation of the mucous membrane of the upper respiratory tract;

- expanding the arsenal of drugs for the treatment and/or prevention of rhinitis, pharyngitis, sinusitis and other inflammations of the mucous membrane of the upper respiratory tract.

Stability refers to the ability of the form of a substance, pharmaceutical composition and drug to maintain chemical, physical, microbiological and biopharmaceutical properties within certain limits over a selected period.

Hygroscopicity refers to the ability of a substance to absorb water vapor (moisture) from the air. The degree and intensity of absorption of water vapor depend on the chemical composition of the substance, the form of the substance and the content of water vapor in the air. Compressibility refers to the ability of powder particles to cohere under pressure to form a stable solid dosage form. The flowability of a dosage form characterizes the ability of a powder to uniformly fill a given form.

Therapeutic efficacy refers to the ability of a drug to provide a pharmacological effect. The therapeutic effectiveness of any particular drug can be determined by assessing the response of the patient or animal after administration of the drug; in this case, a drug with high therapeutic efficacy will provide greater relief of symptoms and/or their disappearance than a drug with low therapeutic efficacy.

Different crystalline and amorphous forms of a particular active substance may have different properties, such as dissolution profile, melting point, stability, hygroscopicity, particle shape, density, bioavailability, electrification, compressibility, flowability, etc. These properties must be taken into account in the manufacture of medicines. In particular, strong electrification and low compressibility do not allow obtaining a dosage form such as a tablet. Drug compounds must be able to dissolve well and be stored for long periods of time without exhibiting significant changes in physicochemical properties, for example, not becoming waterlogged, which can lead to both a change in the chemical composition of the drug and to loosening and disintegration of the dosage form, for example , pills.

Crystalline form of N,N'-6uc-[2-( 1 H-imidazol-4-yl)ethyl]propanediamide

This technical problem is being solved, and the specified technical results are achieved thanks to the new crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide.

N,N'-6uc-[2-( 1H-imidazol-4-yl)ethyl] propanediamide

L/,L/'-Bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide can be presented in the form of mesomeric structures. Crystal forms D/,D/'-bis-[2-(1H-imidazole-4- yl )ethyl] propanediamide belong to the present invention regardless of the method of depicting the mesomeric structure. Mesomeric structures include:

For example, L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and D/,D/'-bis-[2-(1H-imidazol-5-yl)ethyl] propanediamide are mesomers. Therefore the concepts "crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide" and "crystalline form of L/,L/'-bis-[2-(1H-imidazol-5 -yl)ethyl]propanediamide" are equivalent concepts.

A mesomer (mesomeric structure) is understood as a structure in the theory of chemical resonance that arises due to the conjugation of multiple bonds and/or lone electron pairs in a molecule. In D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide, a mesomeric effect is possible for two imidazole and two amide groups.

Considering the mesomeric effect, alternative names for Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide according to the present invention are:

гистаминил)малоновая кислота; Bis- 1,3-

histaminyl)malonic acid;

U,U'-Bis-[2-(1H-imidazol-4-yl)ethyl]malonamide; U,U'-Bis-[2-(1H-imidazol-5-yl)ethyl]malonamide; U,U'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide; U,U'-bis-[2-(1H-imidazol-5-yl)ethyl]propanediamide.

The crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention can be characterized by the positions of the peaks in the X-ray powder diffraction pattern obtained using Cu(Kos) radiation, 20 deg: 16.9+0.2, 20.0+0.2 and 21.2+0.2. In a preferred embodiment, the crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention can be characterized by the positions of the peaks in the X-ray powder diffraction pattern obtained using Cu(Kos) radiation, 20 , deg: 16.9+0.2, 19.7+0.2, 20.0+0.2, 21.2+0.2, 22.2+0.2, 23.0+0.2, 23.5+0.2, 26.7+0.2 and 28.8+0.2. In another embodiment, the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention can be characterized by the positions of the peaks in the X-ray powder diffraction pattern obtained using Cu(Kos) radiation, 20 , deg: 10.0+0.2, 16.9+0.2, 19.7+0.2, 20.0+0.2, 21.2+0.2, 22.2+0.2, 23.0+0.2, 23.5+0.2, 26.7+0.2, 28.8+0.2 and 32.3+0.2. In an even more preferred embodiment, the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention can be characterized by the X-ray powder diffraction pattern shown in FIG. 1.

In another embodiment, the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide according to the present invention can be characterized by the crystal lattice system and the parameters of the elementary crystal cells. A crystal cell is a parallelepiped built on the nodes of a crystal lattice, parallel transfers (translations) of which in three dimensions make it possible to construct the entire crystal lattice. The parameters of the crystal lattice are the values of the edges a, b and c) and the values of the angles between them (a, P and y). In a preferred embodiment, the lattice system of the crystalline form of A,L'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention is monoclinic system. A monoclinic crystal is built from parallelepipeds in which a and y = 90°, P 90°. The parameters of the crystal lattice of the monoclinic system are the size of the edges and the value of the indirect angle. In the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide according to the present invention, the edge values are 8.51 + 0.50 A, 4.59 + 0.50 A and 18.00 + 0.50 A (preferably 8.51 + 0.20 A, 4.59+0.20 A and 18.00+0.20 A); and the angle is (degrees): 99.32°+5.00° (preferably 99.32+2.00°). It should be taken into account that the observed parameters of a crystal cell may depend on the measurement temperature. In a preferred embodiment, the fin values are (A, angstroms) 8.51191(18) A, 4.59550(13) A and 18.0085(4) A, and the angle value is (deg) 99.3191(11)° at room temperature (20 to 30° C, preferably 25°C). In another preferred embodiment, the fin values are (A, angstrom): 8.490(4) A, 4.5613(19) A and 17.918(9) A, and the angle (degree) is 99.94(2)° at a temperature of 140 K.

Additionally, the crystal cell and crystal lattice of the solid form can be characterized by the data in FIGS. 2-4.

The term "crystalline form" in the context of the present invention refers to a substance in solid form in which the molecules occupy an ordered position in space and form a crystal lattice. The ordered position of molecules in a crystal lattice is called long-range order. The structure of a certain chemical composition as a result of any physical and chemical influence (mechanical, thermal, pressure, humidity, dissolution in various solvents under different conditions) can greatly change its properties. For the most part, this is caused by a change in the crystal structure or distortion of this structure under the influence of external forces or internal stresses. Some pharmaceutically active substances can form more than one type of crystal structure. Different in crystal structure and properties crystalline forms are called polymorphs. The pharmaceutical substance may also exist in an amorphous phase. The amorphous state of a substance differs from the crystalline state by the lack of order in the mutual arrangement of atoms or molecules in the substance (long-range order in the relative arrangement of molecules), intermolecular distance and higher internal energy.

Powder X-ray diffraction is usually used to study crystalline forms.

The powder X-ray diffractometry method makes it possible to identify even small changes in the state of the atomic lattice of a crystal that are not detected by other methods. X-ray diffraction of polycrystalline samples makes it possible to determine the state of a solid (crystalline, its various forms, amorphous, or combinations thereof). The importance of structural studies is very great. Determining the relationship between the atomic structure and the properties of a substance allows us to establish rational control over technological processes, reveal the reasons for changes in these properties under the influence of one or another factor, and makes it possible to more consciously manage the technological process of creating pharmaceutical substances and change it in the right direction.

The powder X-ray diffraction method is based on the acquisition and subsequent analysis of the diffraction pattern resulting from the diffraction of X-rays on a powder or polycrystalline sample of the material under study. In general, a crystal can be represented as a series of planes onto which an X-ray beam is directed at an angle of 9. Diffracted rays are recorded using a detector or photographic film. To obtain a diffraction pattern from a crystalline powder, the intensities of scattered radiation are measured depending on the angle 29 between the sample and the primary beam. According to the Wulff-Bragg formula nA. = 2dsin9 we can calculate the interplanar distances in the crystal. The data obtained for each substance are strictly individual, so the x-ray diffraction pattern unambiguously characterizes the substance under study (see GPM.1.2.1.1.0011.15 X-ray powder diffractometry). X-ray patterns of crystalline substances give individual, sharply defined narrow lines (clear peaks), and of amorphous substances - a wide blurred maximum (halo). Method for obtaining the crystalline form of C'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

Dimethylmalonate (malonic ester) and histamine or histamine salt can be used as starting materials to obtain the crystalline form. The method for obtaining the crystalline form of D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide includes the following steps:

Stage 1 (optional stage). The interaction of histamine dihydrochloride with a base to form histamine in the form of a free amine;

Stage 2. Interaction of histamine with dimethylmalonate;

Stage 3. Treatment of the product obtained at stage 2 with mineral acid;

Step 4. Alkalinization of the resulting product (or adding a base) until the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide precipitates;

Stage 5 (optional stage). Purification of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide using known methods.

Synthesis scheme:

The following is a detailed description of each stage.

Stage 1. Interaction of histamine dihydrochloride with a base

The reaction of histamine dihydrochloride with a base is carried out to obtain histamine in the form of a free base.

To carry out the reaction, prepare a solution of histamine dihydrochloride in any suitable solvent. A suitable solvent may be selected from an alcohol, an ether, a haloalkane, an aromatic hydrocarbon or a nitroalkane. Examples of alcohol are methyl alcohol (methanol), ethyl alcohol (ethanol), isopropyl alcohol (isopropanol), n-butanol, etc. Examples of ethers are diethyl ether (ethoxyethane), tetrahydrofuran (THF), dioxane. Examples of haloalkanes are chloroform, methylene chloride and carbon tetrachloride. Examples of aromatic hydrocarbons are benzene, toluene and xylenes. Examples of nitroalkanes are nitromethane and nitroethane. Preferably, the amount of solvent is selected to ensure complete dissolution of the histamine dihydrochloride. The concentration of the compound can range from 0.01 mol/L (mmol/ml) to 0.5 mol/L (mmol/ml), including intermediate concentrations and concentration ranges, for example, 0.01 mol/L, 0.05 mol/L, 0.1 mol/L, 0.2 mol/l, 0.25 mol/l, 0.3 mol/l, 0.4 mol/l, 0.5 mol/l, from 0.05 mol/l to 0.3 mol/l, from 0.1 mol/l to 0.3 mol/l and from 0.1 mol/ l to 0.2 mol/l.

After the histamine dihydrochloride has dissolved, a suitable base is added to the solution. As a suitable base, for example, sodium hydroxide or potassium hydroxide can be selected. Strong amines such as triethylamine can also be used.

After completion of the neutralization reaction, the resulting amine can be isolated by known methods, for example, extraction followed by removal of solvents. Histamine in the form of a free base can be introduced into the next stage without release. In addition, step 1 can be carried out in conjunction with step 2. For this purpose, step 2 is carried out in the presence of a suitable base, for example in the presence of triethylamine or morpholine.

If histamine free base is used as the starting compound, then step 1 is not necessary.

Stage 2. Interaction of histamine with dimethylmalonate

To carry out the reaction, prepare a solution of histamine in any suitable solvent. A suitable solvent may be selected from an alcohol, an ether, a haloalkane, an aromatic hydrocarbon or a nitroalkane. Examples of alcohol are methyl alcohol (methanol), ethyl alcohol (ethanol), isopropyl alcohol (isopropanol), n-butanol, etc. Examples of ethers are diethyl ether (ethoxyethane), tetrahydrofuran (THF), dioxane. Examples of haloalkanes are chloroform and methylene chloride. Examples of aromatic hydrocarbons are benzene, toluene and xylenes. Examples of nitroalkanes are nitromethane and nitroethane. Preferably, the histamine is dissolved in isopropanol or //-butanol. In another preferred embodiment, the amount of solvent is selected to ensure complete dissolution of the histamine. Histamine concentrations can range from 0.01 mol/L (mmol/ml) to 0.5 mol/L (mmol/ml), including intermediate concentrations and concentration ranges, for example, 0.01 mol/L, 0.05 mol/L, 0.1 mol/L, 0.2 mol/l, 0.25 mol/l, 0.3 mol/l, 0.4 mol/l, 0.5 mol/l, from 0.05 mol/l to 0.3 mol/l, from 0.1 mol/l to 0.3 mol/l and from 0.1 mol/ l to 0.2 mol/l.

After the histamine has dissolved, dimethyl malonate is added to the solution. Preferably, dimethyl malonate and histamine are taken in stoichiometric quantities, that is, in a molar ratio of 1: 2. The molar ratio of dimethyl malonate and histamine can also be from 5:1 to 1:5, more preferably from 1:1 to 1:5, in even more preferably from 1:2 to 1:3. Dimethyl malonate can be added without solvent or in a suitable solvent, for example, ethanol, isopropanol or //-butanol.

Preferably, the reaction is carried out under boiling and stirring.

The reaction time is determined by the amounts of histamine and dimethyl malonate taken and can range from 1 to 48 hours, preferably from 12 to 36 hours. The moment of completion of the reaction can be determined, for example, by thin layer chromatography by the disappearance of the histamine spot.

The reaction product from the reaction mixture can be isolated by known methods, for example, filtration. The product can also be introduced into the next step without intermediate isolation.

Stage 3. Treatment of sediment with mineral acid

The precipitate obtained at stage 2 is treated with an aqueous solution of mineral acid. Such acid can be hydrochloric, sulfuric, phosphoric, nitric and other strong acids, preferably the acid is hydrochloric acid.

The amount of acid is determined based on the amount of dissolved sediment. For more complete dissolution, a small excess of acid can be taken (10-30% of the amount of sediment). The permissible acid concentration is from 0.01 M (mol/l) to 5.00 M (mol/l), more preferably from 0.1 M to 0.2 M. The moment of completion of the reaction can be determined visually upon completion of dissolution of the precipitate.

Stage 4. Alkalinization of the resulting product

A suitable base is added to the solution obtained in step 3. In this case, cloudiness of the solution and/or precipitation in the form of a crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is observed. A suitable base may be an alkali, for example, NaOH and KOH, or Na3CO3 soda.

To accelerate the precipitation of crystals, an auxiliary solvent, for example, an excess of isopropanol, //-butanol or acetone, can be added to the solution.

The reaction is carried out at room temperature or when cooled to 5-15°C. It is recommended to control the pH of the reaction mixture. The moment of completion of the reaction can be determined by the presence of a slightly alkaline medium, for example, by a pH value of 8.0-11.0 of the reaction mixture. In another embodiment, the reaction is completed after the precipitation of crystals has ceased.

The resulting crystals are isolated by known methods, for example, filtration.

Stage 5. Product purification

The precipitate of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide can be further purified by known methods. For example, the precipitate can be washed with organic solvents (hexane, acetone), and then further dried.

Pharmaceutical composition

The present technical problem is solved, and the specified technical results are also achieved thanks to a pharmaceutical composition for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract, containing the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl )ethyl]propanediamide of the present invention and at least one pharmaceutically acceptable excipient. By pharmaceutical composition is meant a composition (mixture, composition, etc.) suitable for use in humans or animals, including an active pharmaceutical substance. The active pharmaceutical substance in the pharmaceutical composition contains the active substance - the crystalline form of A,A'-bis-[2-( 1 H-imidazol-4-yl)ethyl]propanediamide of the present invention. One skilled in the art will understand that the pharmaceutical composition of the present invention will also include compositions containing one or more other active pharmaceutical ingredients.

The terms “includes” and “comprises” in the context of the present invention mean that the specified pharmaceutical compositions (drugs, groups of components, etc.) include the following components/ingredients, but do not exclude the inclusion of other components/ingredients.

Preferably, the pharmaceutical composition is in solid form. Examples of solid dosage forms are powders, granules, briquettes, capsules, tablets, dragees, etc. A person skilled in the art will understand that the pharmaceutical composition of the present invention may have any other form that ensures the preservation of the positive properties of the active pharmaceutical substance or active substance. Most preferably, the solid form is a powder, granule, capsule or tablet. Powder is a solid, undosed dosage form, consisting of solid individual dry particles of varying dispersion, which has the property of flowability. A capsule is a solid dosage or non-dosage dosage form, including a hard (usually gelatinous) shell, inside which is an encapsulate containing one or more active substances with or without the addition of excipients. A granule is a solid dosage form in the form of grains (aggregates of powder particles) of round, cylindrical or irregular shape, containing one or more active ingredients with the addition of excipients. A tablet is a solid dosage form, most often obtained by compressing powders or granules containing one or more active ingredients with or without the addition of excipients.

The quantitative content of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide in the pharmaceutical composition is selected from the range of 0.01 up to 99.99 wt.%, preferably from 1.00 to 80.00 wt.%, more preferably from 5.00 to 60.00 wt.%, for example, 5.00 wt.%, 10.00 wt.%, 15.00 wt.%, 20.00 wt.%, 25.00 wt.%, 30.00 wt.%, 35.00 wt.%, 40.00 wt.%, 45.00 wt.%, 50.00 wt.%, 55.00 wt.%, 60.00 wt.%, from 10.00 wt.% to 20.00 wt.% ; from 20.00 wt.% to 30.00 wt.%; from 30.00 wt.% to 40.00 wt.%; from 40.00 wt.% to 50.00 wt.%; from 50.00 wt.% to 60.00 wt.%, including all intermediate values in increments of 1.00 wt.%. For example, the value 23.00 wt.% is included as one of the values in the range from 20.00 wt.% to 30.00 wt.%.

In another preferred embodiment, the pharmaceutical composition contains the D1,L1'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide crystalline form of the present invention in an effective amount.

The term "effective amount" ("therapeutically effective amount") in the context of the present invention refers to an amount of a pharmaceutical composition or drug that, when administered to a subject, is sufficient to effect such treatment on the disease, disorder or symptom. The "effective amount" may vary, for example, depending on the form in which the substance is present, the nature of the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject, to be treated, and/or on the weight of the subject to be treated. The appropriate amount in any particular case will be apparent to one skilled in the art or can be determined by standard experimentation.

In a preferred embodiment, the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide is contained in a pharmaceutical composition or medicinal product and is used in a specific dosage. The dosage of the crystalline form of D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention may range from 1 mg to 1000 mg per day, preferably from 60 mg to 500 mg. Preferably, L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is present in the solid form of the pharmaceutical composition or drug in an amount corresponding to the recommended dosage.

The term "dosage" as used herein characterizes the content of one or more active substances in quantitative terms per unit dose, or unit volume, or unit mass in accordance with the dosage form, or for of some types of dosage forms, the amount of active substance released from the dosage form per unit of time.

The pharmaceutical composition of the present invention includes at least one pharmaceutically acceptable excipient, which is a carrier of active substances, providing the required volume/weight and the necessary characteristics of the drug in a particular dosage form. Preferably, the pharmaceutical composition includes a pharmaceutically acceptable excipient that is selected from the group consisting of a filler, a binder, a lubricant, a disintegrant, a glidant, a preservative, a flavoring agent and a coloring agent.

The term "excipient" or "diluent" means excipients used to give solid dosage forms a given volume or weight. Starch, glucose, sucrose, lactose (milk sugar), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, white clay (kaolin), gelatin, microcrystalline cellulose (MCC), methylcellulose (MC), can be used as fillers. sodium salt of carboxymethylcellulose (Na CMC), calcium carbonate, disubstituted calcium phosphate, glycine (aminoacetic acid), dextrin, amylopectin, ultraamylpectin, sorbitol, mannitol, pectin, etc. The group is not limited to this list.

The term “binders” means substances included in the tablet mass to give it the necessary viscosity. Water, ethyl alcohol, starch paste, sugar syrup, solutions of carboxymethylcellulose (CMC), hydroxyethylcellulose (OEC), hydroxypropylmethylcellulose (OPMC) are used as binders; polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, etc. The group is not limited to this list.

The term "glidant" refers to auxiliary substances used in the tablet manufacturing process at the compression stage to improve the flow of granules or powder by reducing friction between particles. The sliding substance can be represented by one or more of starch, talc, polyethylene oxide-4000, stearic acid, calcium and magnesium stearate, etc. The group is not limited to this list. The term “lubricant” or “lubricant” means auxiliary substances that help reduce the friction force between the surface of the tablet and the walls of the punch cuvette in which the tablet is formed, used in the technological process of producing tablets at the pressing stage. The lubricant can be represented by one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol (with a molecular weight greater than 3350), sodium lauryl sulfate, talc, mineral oil, leucine and poloxamer, etc. The group is not limited to this list.

The term "disintegrant" means substances used to improve disintegration or dissolution, providing mechanical destruction of tablets in a liquid medium, which is necessary for the rapid release of the active substance. The baking powder can be one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, starch, pectin, gelatin, amylopectin, ultraamylopectin, agar-agar, alginic acid, potassium and sodium alginate, Tween-80, etc. The group is not limited to this list.

Additional components, flavoring agents, are used to improve taste (sweetener) and smell (flavor). These include, for example, sugar, cocoa, vanillin. Dyes (pigments) are used to improve the appearance of pharmaceutical compositions and dosage forms. Examples of dyes are titanium dioxide, indigo carmine.

The amount, composition and form of the pharmaceutically acceptable excipient can be chosen by one skilled in the art as long as the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is retained completely or partially.

Routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, inhalation, topical, transdermal, sublingual and rectal routes. In a preferred embodiment, the pharmaceutical composition is administered orally or sublingually.

In some embodiments, the pharmaceutical composition of the present invention can be prepared using known conventional methods in the pharmaceutical field. Medicine

The present technical problem is solved, and the specified technical results are also achieved thanks to a drug for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract, containing the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl )ethyl]propanediamide or the pharmaceutical composition of the present invention.

A medicinal product (medicinal product) means an active pharmaceutical substance or pharmaceutical composition in the form of a dosage form suitable for use in humans or animals.

In one embodiment, the present invention relates to a drug in solid dosage form. The dosage forms of the present invention include, but are not limited to: granules, tablets, in particular buccal tablets, effervescent tablets, film-coated tablets, sustained release tablets, regular tablets, controlled release tablets, orally dispersible tablets, lyophilized tablets instant tablets, etc.; capsules such as hard capsules, soft capsules, gelatin capsules and the like.

The tablets, powders, capsules and granules of the present invention can be used for the preparation of solutions, gels, ointments or suspensions, including injection solutions, spray solutions, aerosol solutions. These forms can additionally be added to patches, suppositories, transdermal and topical medications.

A person skilled in the art will understand that the drug of the present invention can be in any form that ensures the preservation of the positive properties of the active pharmaceutical substance. Most preferably, the solid form is a powder, granule, capsule or tablet.

A pharmaceutical composition containing a crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide can also act as a medicinal product of the present invention. Preferably, the drug also includes at least one pharmaceutically acceptable excipient, but its presence is not required. The quantitative content of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide in the drug is selected from the range from 0.01 to 100.00 wt.%, preferably from 1.00 to 80.00 wt. .%, more preferably from 5.00 to 60.00 wt.%, for example, 5.00 wt.%, 10.00 wt.%, 15.00 wt.%, 20.00 wt.%, 25.00 wt.%, 30.00 wt.%, 35.00 wt.% , 40.00 wt.%, 45.00 wt.%, 50.00 wt.%, 55.00 wt.%, 60.00 wt.%, from 10.00 wt.% to 20.00 wt.%; from 20.00 wt.% to 30.00 wt.%; from 30.00 wt.% to 40.00 wt.%; from 40.00 wt.% to 50.00 wt.%; from 50.00 wt.% to 60.00 wt.%, including all intermediate values in increments of 1.00 wt.%. For example, the value 23.00 wt.% is included as one of the values in the range from 20.00 wt.% to 30.00 wt.%.

The drugs of the present invention can be administered (but not limited to) orally, parenterally, inhalation, subcutaneously, intraperitoneally, topically, rectally. The therapeutic dosage of a medicinal product containing a new crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide or an active pharmaceutical substance or a pharmaceutical composition of the present invention may be adjusted depending on on the therapeutic effectiveness and bioavailability of active ingredients, the rate of their metabolism and excretion from the body, as well as depending on the age, gender and stage of the patient’s disease.

Use of the crystalline form of N,N'-6uc-l2-(lH-UMudaio i-4-yl)ethyl]propanediamide and pharmaceutical compositions and medicinal products containing it

The crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, the pharmaceutical composition containing it and the medicinal product of the present invention can be used for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract .

The crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and the pharmaceutical composition containing it of the present invention can be used for the manufacture of the drug of the present invention.

In one embodiment of the present invention, a crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide of the present invention as part of a pharmaceutical composition or medicinal product of the present invention administered in an amount of 1 mg to 1000 mg per day, preferably 10 mg to 400 mg. The indicated dosage can be administered either in one dose or divided into several doses throughout the day, for example, 2, 3 or 4 times a day. The most preferred dosage options may be determined based on the age and/or body weight of the patient, as well as the nature of the symptoms exhibited.

In one embodiment, inflammation of the mucous membrane of the upper respiratory tract is associated with rhinitis, or caused by rhinitis, or is rhinitis. In a more specific embodiment, inflammation of the mucous membrane of the upper respiratory tract is caused by allergic rhinitis, infectious rhinitis (eg, viral or bacterial rhinitis) or vasomotor rhinitis. In another embodiment, rhinitis can be in an acute form (acute rhinitis) or in a chronic form (chronic rhinitis). Rhinitis also includes atrophic, hypertrophic rhinitis, rhinitis caused by the use of vasoconstrictor or hormonal drugs, rhinitis associated with burns and damage to the mucous membrane or nosebleeds, rhinitis, etc.

In another alternative, inflammation of the mucous membrane of the upper respiratory tract is associated with sinusitis (rhinosinusitis), or caused by sinusitis (rhinosinusitis), or is sinusitis (rhinosinusitis). In a more specific embodiment, inflammation of the mucous membrane of the upper respiratory tract is caused by sinusitis (sinusitis of the maxillary sinus), frontal sinusitis (sinusitis of the frontal sinus), ethmoiditis (inflammation of the mucous membrane of the cells of the ethmoid labyrinth) and sphenoiditis (inflammation of the mucous membrane of the sphenoid sinus). Sinusitis can be acute (acute sinusitis) or chronic (chronic sinusitis). Sinusitis also includes traumatic, viral, bacterial, fungal, mixed, and allergic sinusitis.

In another alternative, inflammation of the mucous membrane of the upper respiratory tract is associated with pharyngitis, or caused by pharyngitis, or is pharyngitis. In a more specific embodiment, inflammation of the mucous membrane of the upper respiratory tract is caused by tonsillitis, pharyngotonsillitis or nasopharyngitis. In another embodiment, pharyngitis can be in an acute form (acute pharyngitis) or a chronic form (chronic pharyngitis). Pharyngitis also includes viral, bacterial, fungal, allergic, traumatic, catarrhal, hyperplastic, subatrophic, atrophic, and mixed pharyngitis. The crystalline form of L/,U'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and the pharmaceutical composition and medicinal product of the present invention containing it can be used as analgesics and antipyretics in the treatment of inflammation of the mucous membrane of the upper respiratory tract ways. The analgesic effect of the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is manifested in the removal or reduction of pain that arose during the development of the pathological condition. The antipyretic (antipyretic) effect of the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is manifested in a decrease in body temperature during fever. The crystalline form of U,L/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide and the pharmaceutical composition and medicinal product of the present invention containing it can also be used as analgesics and antipyretics in symptomatic therapy and in the case of absence of inflammation of the mucous membrane of the upper respiratory tract.

Brief description of drawings

Figure 1 - Experimental diffraction pattern of a sample of the crystalline form of L/,L/'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (blue curve) and a theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Blue dashes indicate calculated peak positions. Experimental details are outlined in Example 1;

Figure 2 - Structure of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide in the crystalline form of the present invention, obtained by X-ray diffraction analysis;

Fig.3 - Structure of the unit cell of the crystalline form of D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide of the present invention;

Figure 4 - Packing of molecules in the crystal lattice of the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide of the present invention;

Figure 5 - Efficiency of the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide when administered intragastrically in a model of LPS-induced influx of inflammatory cells into the nose. Dexamethasone was used as a comparison drug.

Designations:

* - significance of the difference (P < 0.05) with intact animals, & - significance of difference (P < 0.05) with control;

Figure 6 - Efficiency of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide when administered intragastrically in a model of subchronic rhinosinusitis in mice. Desloratadine, Loratadine and Dexamethasone were used as comparison drugs.

Designations:

* - significance of the difference (P < 0.05) with intact animals,

& - significance of difference (P < 0.05) with control;

Figure 7 - Efficacy of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide in a model of laryngeal inflammation induced by the application of a formaldehyde solution to rats. Dexamethasone, Paracetamol, Ibuprofen and the combination of Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu) were used as comparison drugs.

Designations:

* - significance of the difference (P < 0.05) with the intact group,

& - significance of difference (P < 0.05) with control;

Figure 8 - Efficacy of crystalline form A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide in a model of febrile reaction in rats. Ibuprofen, Paracetamol, Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu for flu and colds) were used as a comparison drug.

Designations:

* - significance of the difference (P < 0.05) with the intact group,

& - significance of difference (P < 0.05) with control;

Figure 9 - The effect of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide on the number of writhings in 15 minutes on a model of a specific pain reaction using the method of chemical irritation of the peritoneum (test “vinegar writhing” ). Ibuprofen (Nurofen), Paracetamol (Paracetamol) and Ketorolac (Ketorol) were used as a comparison drug.

Designations:

*- significance of difference (P < 0.05) with the intact group,

& - significance of difference (P < 0.05) with control. Unless otherwise specified, all technical and technical terms used in this context have their common meaning in the art.

Carrying out the invention

The present invention is further illustrated, but not limited, by the following examples.

Example 1. Preparation of the crystalline form of , '-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

To a solution of 0.500 g (4.5 mmol) of histamine in 20 ml of isopropanol, 0.360 g (2.25 mmol) of a solution of dimethyl malonate in 10 ml of isopropanol was added dropwise with stirring. The mixture was refluxed with stirring for 20 hours. The precipitate that formed was filtered off and dissolved in a minimum amount of 0.1 M hydrochloric acid. To neutralize the resulting solution, a 10-fold amount of isopropyl alcohol (by volume) was added to it, after which sodium carbonate was slowly added to the mixture (under traction). When the medium reached a slightly alkaline reaction, the product precipitated in the form of colorless crystals. The addition of sodium carbonate was stopped after precipitation was complete. The crystalline precipitate was filtered off and washed with acetone. The product was air dried. Obtained: 0.474 g (73%) of the crystalline form of A,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide.

Next, an X-ray diffraction pattern of the resulting crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide was recorded. All studies were performed on a Bruker D8 Advance X-ray diffractometer ( _CuC copper radiation) with a position-sensitive LynxEye detector, reflection geometry, with rotation. Data collection was carried out using the Bruker DIFFRACplus software package, analysis - using the EVA program and Topas V5.0.

Figure 1 shows an X-ray powder diffraction pattern of the resulting crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide. Table 1 lists the positions of the 29 angles and their relative intensities. Table 1. Intensities and positions of some peaks with a relative intensity greater than 3% for a sample of the crystalline form of D/,/U-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide

Position. Interplanar „ . . l, g l 1 Rel. Mon. [%]

[ 20] distance [A]

9.979 8.86 8.0

10.922 8.09 10.3

16.890 5.25 39.0

19.716 4.50 40.9

20.001 4.44 100.0

21.179 4.19 84.9

22.062 4.03 5.9

22.247 3.99 18.4

23.016 3.86 12.3

23.529 3.78 8.4

24.910 3.57 3.8

25.771 3.45 4.8

26.762 3.33 32.1

27.949 3.19 5.9

28.830 3.09 26.5

31.613 2.83 9.0

32.271 2.77 11.9

34.112 2.63 8.0

The following intense peaks (maxima) were observed at diffraction angles of 20 (± 0.2°): 10.0, 16.9 , 19.7, 20.0, 21.2, 22.2, 23.0, 23.5, 26.7, 28.8 and 32.3. The characteristic peaks were: 16.9, 19.7, 20.0, 21.2, 22.2, 23.0, 23.5, 26.7, 28.8 and 32.3. The most intense highs are: 16.9, 20.0 and 21.2.

The crystal structure of the resulting phase was determined using full-profile refinement of an array of powder diffraction data (“Rietveld method”). The measurements were carried out at room temperature (296.15K). A general view of the diffraction patterns of samples of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide and their comparison with the calculated ones is also shown in Fig. 1. The blue curve is the experiment, the red one is the calculation, the gray one is the difference between them. The crystal cell parameters are determined in Table 2. Table 2. Parameters of the crystal structure of form A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

The crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide was also studied by X-ray diffraction (PC A). X-ray diffraction studies of the compound were carried out on a Bruker APEX II diffractometer (MoKa radiation, graphite monochromator, w-scanning). The structure was deciphered by the direct method and refined by the least squares method in the anisotropic full-matrix approximation using P ² w and is presented in Fig. 2. Hydrogen atoms are calculated geometrically and refined by imposing restrictions on bond lengths and bond angles. Crystallographic information for the CisHisNeCh cell: monoclinic system, space group P2/n, a = 8.490(4) A, b = 4.5613(19) A, c = 17.918(9) A, a = 90°, P = 99.94(2) °, y = 90°, V = 683.5(5) A ³ , Z = 2, T = 140 K. More detailed crystallographic information is presented in Table 3.

Table 3. Crystallographic data of A,A'-bis[2-(1H-imidazol-4-yl)ethyl] propanediamide

The structure of the unit cell and crystal packing is presented in Figs. 3 and 4.

The cell parameters obtained in PC A single crystal differ by 1-3% from those calculated using the Rietveld method. This is due to the fact that the study of the single crystal was carried out at a temperature of 140 K, and the study using full-profile refinement of the powder diffraction data array was carried out at room temperature.

Example 2. Study of long-term stability and hygroscopicity during storage of a new crystalline form of N,N'-6uc-l2-(lH-UMudaio i-4-yl)ethyl]propanediamide

The long-term stability study was conducted under the following conditions:

Time period: 36 months;

Temperature: 25 ± 2°C;

Relative humidity: 60 + 5%;

Sample control was carried out:

1st year: 3rd, 6th, 9th and 12th months (+ 10 days);

2nd year: 6th and 12th months (+ 15 days);

3rd year 12 months (+ 30 days).

Methods for studying the sample: water determination using the Karl-Fischer method (GOST 33593-2015) and high-performance liquid chromatography (HPLC). The measurement results are presented in Table 4.

Table 4. Study of long-term stability and hygroscopicity of a sample of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

Example 3. Study of short-term stability and hygroscopicity during storage of a new crystalline form of N,N'-6uc-l2-(lH-UMudaio i-4-yl)ethyl]propanediamide

The short-term stability study was conducted under the following conditions:

Time period: 6 months;

Temperature: 40 ± 2°C;

Relative humidity: 75±5%;

Sample control was carried out at the 3rd and 6th months (± 10 days).

Methods for studying the sample: water determination using the Karl-Fischer method (GOST 33593-2015) and high-performance liquid chromatography (HPLC). The measurement results are presented in Table 5.

Table 5. Study of short-term stability and hygroscopicity of a sample of the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

Example 4. Preparation of a pharmaceutical composition and medicinal product containing a new crystalline form of N,N'-6uc-l2-(lH-UMudaio i-4-yl)ethyl]propanediamide

The crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide obtained in Example 1 was used for the preparation of pharmaceutical compositions according to the compositions shown in Table 6.

For each composition, the crystalline form of D/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide was mixed with the excipients listed in Table 6, then the final mixture was thoroughly mixed. Table 6. Formulations of the pharmaceutical compositions of the present invention containing the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide as the active substance

The resulting pharmaceutical composition was tableted on a tablet machine consisting of a steel matrix with holes and two chrome-plated rods located one above the other - upper and lower punches of the corresponding diameter. The lower punch fixes the space in the matrix into which the pharmaceutical composition is poured. Next, the upper punch compresses the composition. The upper and lower punches are then removed sequentially from the die, ejecting the tablet. For tableting, the 1st and 2nd compositions of the composition were chosen. The result was tablets containing a crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide as the active substance.

Example 5: Solubility Study

The determination of the solubility of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide was carried out in accordance with GPM.1.2.1.0005.15 Solubility, the State Pharmacopoeia of the Russian Federation. Phosphate buffer with pH 6.8 was used as a model of human saliva.

To 100 mg of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide, 1.0 ml of phosphate buffer was added and the resulting suspension was continuously shaken for 10 minutes at 25°C. The substance did not dissolve completely; the solution was cloudy.

Next, 1.0 ml of phosphate buffer was added to 10 mg of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide and the procedure described was repeated. above procedure. The crystalline form has completely dissolved. A saturated solution was obtained by dissolving 45 mg of the substance in 1 ml of phosphate buffer. According to GPM.1.2.1.0005.15, the substance should be classified as soluble.

This example illustrates the suitability of the crystalline form of N.N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide for the subsequent preparation of liquid dosage forms, for example, solutions for injections, sprays, aerosols, etc.

Example 6. Study of the activity of the crystalline form of N,N'-6uc-[2-(lH-imidazol-4-yl)ethyl]propanediamide in a model of histamine-induced nasal congestion in dogs

The model of histamine-induced nasal congestion in dogs was carried out according to the standard method (R.L. TINIAKOV et al., Canine model of nasal congestion and allergic rhinitis, JOURNAL OF APPLIED PHYSIOLOGY, 2003, V.94, N.5, pp.1821-1828). Beagle dogs were injected into the nasal cavity with a 5% histamine solution in a volume of 250 μl/nostril. Before the administration of histamine and 10 minutes after the administration of histamine, the volume of the nasal cavity of the right and left nostrils was measured using a rhinometer.

In the first experiment, the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide (hereinafter referred to as APS, active pharmaceutical substance) was administered intragastrically once in doses of 1.62 and 5.4 mg/kg over 8 hours before histamine administration. Comparison drugs Desloratadine (Erius) at a dose of 0.12 mg/kg, Ebastine (Kestin) at a dose of 0.27 mg/kg were administered intragastrically in a similar regimen. Experimental information and results are presented in Table 7.

In the second experiment, the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide (hereinafter referred to as APS, active pharmaceutical substance) was administered intragastrically once in doses of 1.62 and 5.4 mg/kg over 30 minutes before histamine administration. Comparison drugs Desloratadine (Erius) at a dose of 0.12 mg/kg, Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu for flu and colds) at a dose of 54 mg/kg were administered intragastrically in a similar regimen. Experimental information and results are presented in Table 8.

The obtained data were checked using the Shapiro-Wilk test for the normality of the distribution of the values obtained during the experiment. In the case of a non-normal distribution to assess intergroup differences 1-way ANOVA (with Dunn's post-analysis) was used. In the case of normal distribution, 1-way ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. Table 7. Activity study in the histamine-induced nasal congestion model in dogs

Table 8. Activity study in the histamine-induced nasal congestion model in dogs.

The data presented in Tables 7 and 8 clearly show that administration of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide significantly increases the volume of the nostrils in a model of histamine-induced nasal congestion in dogs. The effect occurred 35 minutes after administration of the substance and lasted for at least 8 hours. In terms of severity of action, the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide was superior to Desloratadine and Ebastine. In addition, a significant effect was observed within 5-10 minutes after the administration of histamine. The study also demonstrates the rapidly developing and more long-term therapeutic effect when using the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention compared to the prototype RU2685277C1.

Example 7 Bioavailability Study

The tablets obtained in example 4 (dosage 2 and 10 mg) were administered intragastrically to dogs for 14 days once a day in doses of 2 mg (1 tablet 2 mg), 6 mg (3 tablets 2 mg) and 20 mg (2 tablets 10 mg) per dog. Blood plasma samples were collected after the 14th administration of the drug at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing and before dosing. Blood from dogs was collected from the lateral vein of the leg in a volume of 0.2 ml into polypropylene tubes containing 20 μl of 5% EDTA. Blood plasma was separated by centrifugation at 10,000 rpm for 10 minutes and stored until analysis at a temperature not exceeding -70°C. HPLC-MS/MS analysis was used to determine the concentration of the active substance. Chromatographic conditions were selected by introducing a solution of the test compound in a mixture of acetonitrile: water (1:1) into the MS/MS detector through an HPLC system to achieve optimal chromatographic parameters. Concentrations of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide in blood plasma were calculated using a calibration curve constructed from the areas of chromatographic peaks of standard samples of the test compound in intact plasma or homogenate of an intact organ sample, normalized to the area of the internal standard. The measurement results are presented in tables 9 and 10.

Table 9. Content of the active substance in the blood plasma of dogs after a single intragastric administration in doses of 2, 6 and 20 mg per dog

Table 10. Content of the active substance in the blood plasma of dogs after 14-fold intragastric administration in doses of 2, 6 and 20 mg per dog

The results of the study show that the bulk of the active substance was excreted within 24 hours, and the maximum content in the blood plasma was observed within 1-2 hours after administration of the drug. Similar studies were carried out with tablets obtained according to the prototype (RU2685277C2). The content of the active substance was assessed 2 hours after a single administration of the drug (2 mg tablet, 2 mg dose). The content of the substance in the blood was 15.2 ± 4.1 ng/ml, which is statistically lower than the concentration achieved when using tablets according to the present invention. Thus, the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and the dosage form containing it demonstrate improved bioavailability in comparison with the prototype.

Example 8. Study of activity in the model of lipopolysaccharide (LPS)-induced influx of inflammatory cells into the nose

Wistar rats were injected into the nasal cavity (both nostrils) with a 0.125 μg/kg LPS solution in a volume of 20 μl/nostril so that the solution did not fall into the nasopharynx. The crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (hereinafter referred to as APS, active pharmaceutical substance) was administered intragastrically once in doses of 1.8, 9, 18 mg/kg immediately before LPS administration . The reference drug Dexamethasone at a dose of 0.6 mg/kg was administered in a similar manner. 4 hours after LPS administration, nasal lavage was collected from the animals, and the number of inflammatory cells in the lavage was determined. The obtained data were checked using the Shapiro-Wilk test for normality of distribution of values obtained during the experiment. In case of non-normal distribution, 1-way ANOVA (with Dunn's post-analysis) was used to assess between-group differences. In the case of normal distribution, 1-way ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. The experimental conditions are presented in Table 11, the measurement results are shown in Fig.5.

Table 11. Conditions for testing activity in the lipopolysaccharide (LPS)-induced nasal inflammatory cell influx model in dogs

The data obtained show that with oral administration of the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, the influx of leukocytes, macrophages and neutrophils into the nasal cavity of the animal is significantly reduced. In terms of the severity of the action, the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide was not inferior to dexamethasone.

Example 9. Study of activity in a mouse model of subchronic rhinosinusitis

The model of subchronic rhinosinusitis in mice was implemented according to standard methods (JSBAE et al., Mouse model of IL-17-dominant rhinitis using polyinosinic-polycytidylic acid, ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH, 2017, V.9, N.6, pp.540 -549). Female balb/c mice were injected into each nostril with 5 μl of saline containing 100 μg of ovalbumin (Sigma, A5503) and 100 μg of Poly (EC) (Sigma, P1530), administration was carried out on days 1, 2, 3, 7 and 14. In the sham group, 5 μl of saline was injected into each nostril. To develop nasal inflammation, from days 15 to 21 inclusive, 5 μl of saline was injected intranasally into each nostril of experimental animals, containing 3% ovalbumin. The crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide (hereinafter referred to as APS, active pharmaceutical substance) was administered intragastrically once in doses of 0.3, 3, 30 mg/kg 1 time per day on days 15-21 simultaneously with intranasal administration of a 3% ovalbumin solution. Comparison drugs Desloratadine (Desloratadine) at a dose of 0.75 mg/kg, Loratadine (Loratadine) at a dose of 1.5 mg/kg, Ebastine (Kestin) at a dose of 3 mg/kg, Dexamethasone (Dexamethasone) at a dose of 1 mg/kg were administered in a similar regimen. 24 hours after the last administration of ovalbumin (day 22), nasal lavage was collected from the animals and the number of inflammatory cells in the lavage was determined. The obtained data were checked using the Shapiro-Wilk test for the normality of the distribution of the values obtained during the experiment. In case of non-normal distribution, 1-way ANOVA (with Dunn's post-analysis) was used to assess between-group differences. In the case of normal distribution, 1-way ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. The experimental conditions are presented in Table 12, the measurement results are shown in Fig.b.

Table 12. Conditions for studying activity in a mouse model of subchronic rhinosinusitis

The data obtained show that in a model of subchronic rhinosinusitis in mice, oral administration of the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide significantly reduces the influx of leukocytes and macrophages into the nasal cavity. According to the severity of the action, the crystalline form A,A'-bis-[2-(1H- imidazol-4-yl)ethyl] propanediamide was not inferior to Dexamethasone, Desloratadine and Loratadine.

Example 10. Study of activity in a model of non-infectious pharyngitis induced by the application of a formalin solution to rats

A model of formalin-induced inflammation of the larynx was implemented according to standard methods (GLVISWANATHA et al., Novel experimental model of non-infectious pharyngitis in rats, JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 2014, V.69, N.2, pp.189-195) . Rats under anesthesia were injected with Evans Blue dye (30 mg/kg) into the external jugular vein through a catheter. 10 minutes after the injection of the dye, applications were made to the surface of the pharyngeal mucosa with a 30% formaldehyde solution (3 times for 5 seconds each). 60 minutes after application of a 30% formaldehyde solution, the animals were euthanized by exsanguination. The head of each rat was perfused with heparinized saline (40 U/ml) to remove intravascular dye. The degree of inflammation was assessed using the dye exudation test. Evans Blue dye from the fabric was extracted into formamide at 55°C for 24 hours. Absorbance was determined spectrophotometrically at 620 nm. The crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide (hereinafter referred to as API, active pharmaceutical substance) in doses of 1.8, 5.4, 9 and 18 mg/kg was administered intragastrically over 1 hour before applying formaldehyde. Comparator drugs Dexamethasone, Paracetamol, Ibuprofen and the combination of drugs Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu for flu and colds) were administered in a similar regimen. The obtained data were checked using the Shapiro-Wilk test for the normality of the distribution of the values obtained during the experiment. In case of non-normal distribution, 1-way ANOVA (with Dunn's post-analysis) was used to assess between-group differences. In the case of normal distribution, 1-way ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. The experimental conditions are presented in Table 13, the measurement results are shown in Fig.7. Table 13. Conditions for studying activity in a model of non-infectious pharyngitis induced by the application of a formalin solution to rats

The results of the study show that the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide has an anti-inflammatory effect and reduces vascular permeability. In terms of the severity of the action, the crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propandiamide was not inferior to Dexamethasone, Paracetamol, Ibuprofen and the combination of drugs Paracetamol + Pheniramine + Phenylephrine + Ascorbic acid.

Example 11 Activity Study in a Rat Fever Model

The febrile reaction model was implemented according to standard methods (J. TOMAZETTI, et al. Baker yeast-induced fever in young rats: characterization and validation of an animal model for antipyretics screening, JOURNAL OF NEUROSCIENCE METHODS, 2005, V.147, NI, pp. 29-35). Animals without signs of deviations in appearance were selected for the experimental group in such a way that the individual weight value deviated from the average value within the sex by no more than ±20%. Wistar rats were injected subcutaneously with a 20% baker's yeast suspension (12 ml/kg). The crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (hereinafter referred to as APS, active pharmaceutical substance) in doses of 3.6, 5.4, 9, 13.5, 18 mg/kg was administered intragastrically, once 14 hours after introducing yeast. Comparison drugs Ibuprofen (Nurofen) at a dose of 18 mg/kg, Paracetamol (Paracetamol) at a dose of 45 mg/kg, Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu for influenza and colds) at a dose of 2 g/kg was administered intragastrically in a similar manner. Rectal temperature was measured with an electric thermometer before pyrogen administration and 14, 16, 17, 18, 19, 20 and 24 hours after it. The obtained data were checked using the Shapiro-Wilk test for the normality of the distribution of the values obtained during the experiment. In case of non-normal distribution, 1-way ANOVA (with Dunn's post-analysis) was used to assess between-group differences. In the case of normal distribution, 1-way ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. The experimental conditions are presented in Table 14, the measurement results are shown in Fig. 8.

Table 14. Conditions for studying activity in the febrile reaction model in rats

The results of the study show that the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide has an antipyrogenic effect. In terms of the severity of the effect, the crystalline form of U,U'-bis-[2-(1H-imidazol-4-yl)ethyl]propandiamide is superior to the reference drugs Ibuprofen and Paracetamol and is not inferior to the combination drug Paracetamol + Phenylephrine + Pheniramine + Ascorbic acid (TeraFlu for influenza and colds).

Example 12. Study of activity in a model of a specific pain reaction using the method of chemical irritation of the peritoneum (vinegar writhing test)

A model of a specific pain reaction using the method of chemical irritation of the peritoneum (the “vinegar writhing” test) was implemented according to the standard method (M. SOBCZAK et al., Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms, EUROPEAN JOURNAL OF PHARMACOLOGY, 2014, V.736, pp.63-69). The study was conducted on outbred mice, the individual weight of which deviated from the average value within the sex by no more than ±20%. The crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (hereinafter referred to as API, active pharmaceutical substance) was administered to mice once intragastrically. The reference drug Ibuprofen (Nurofen), Paracetamol (Paracetamol) and Ketorolac (Ketorol) were administered intragastrically in a similar manner. After 1 hour, to conduct the “vinegar writhing” test, mice were intraperitoneally injected with 1% acetic acid in a volume of 10 ml per 1 kg of animal weight. The number of writhings (convulsive contractions of the abdominal muscles, accompanied by stretching of the hind limbs and arching of the back) was assessed 15 minutes after the administration of acetic acid. The obtained data were checked using the Shapiro-Wilk test for the normality of the distribution of the values obtained during the experiment. In the case of a non-normal distribution, 1-way ANOVA (with Dunn's post-analysis) was used to assess between-group differences. In case of normal distribution, Lway ANOVA (with Tukey's post-analysis) was used to compare multiple groups. The difference between the results was considered significant at a significance level of P <0.05. The experimental conditions are presented in Table 15, the measurement results are shown in Fig.9.

Table 15. Conditions for studying activity in the “vinegar cramps” test

The results of the study show that the crystalline form of Y,Y'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide significantly reduces the number of pain reactions (writhing) in mice caused by intraperitoneal administration of acetic acid. By The severity of the action of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide is not inferior to Ibuprofen, Paracetamol and Ketorolac.

Claims

Claim 1. Crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, characterized by the peak positions in the powder X-ray diffraction pattern, 29, deg: 16.9+0.2, 20.0+0.2 and 21.2+0.2. 2. Crystal form according to claim 1, characterized by the positions of the peaks in the powder X-ray diffraction pattern obtained using Cu(Ka) radiation, 29, deg: 16.9+0.2, 19.7+0.2, 20.0+0.2, 21.2+0.2, 22.2+0.2, 23.0+0.2, 23.5+0.2, 26.7+0.2, 28.8+0.2 and 32.3+0.2. 3. Crystalline form according to claim 1, characterized by the positions of the peaks in the powder X-ray diffraction pattern obtained using Cu(Ka) radiation, 29, deg: 10.0+0.2, 16.9+0.2, 19.7+0.2, 20.0+0.2, 21.2+0.2, 22.2+0.2, 23.0+0.2, 23.5+0.2, 26.7+0.2, 28.8+0.2 and 32.3+0.2. 4. Crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, characterized by monoclinic system, crystal cell edge values, A (angstrom): 8.51+0.50 A, 4.59+0.50 A and 18.00+0.50 A; and angle (deg): 99.32° +5.00°. 5. Crystalline form according to item 4, characterized by edge values, A (angstrom): 8.51191(18) A, 4.59550(13) A and 18.0085(4) A, and angle value (deg) 99.3191(11)° at room temperature . 6. Crystalline form according to point 4, characterized by edge values, A (angstrom): 8.490(4) A, 4.5613(19) A and 17.918(9) A, and angle (deg) 99.94(2)° at a temperature of 140 TO. 7. A method for obtaining the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide according to any of paragraphs 1-6, including the interaction of histamine with dimethyl malonate and treatment of the resulting product with mineral acid, followed by by alkalizing or adding a base until the crystalline form of A,A'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide precipitates. 8. The method of claim 7, further comprising the step of producing histamine by reacting histamine dihydrochloride with a suitable base. 9. The method according to claim 7, further comprising adding a solvent selected from isopropanol, n-butanol and acetone at the alkalization stage. 10. Pharmaceutical composition for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract, containing a crystalline form ^,^'-bis-[2-(lH-imidazol-4-yl)ethyl]propandiamide according to any one of claims 1 to 6 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient. 11. Pharmaceutical composition according to claim 10, characterized in that inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis. 12. A medicinal product in solid form for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract, containing the crystalline form of L/,L/'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to any of claims 1-6 or the pharmaceutical composition according to claim 10 or 11. 13. The medicinal product according to claim 12, characterized in that the solid form is a powder, granule, capsule or tablet. 14. The medicinal product according to claim 12, characterized in that it includes at least one pharmaceutically acceptable excipient. 15. The drug according to item 12, characterized in that inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis. 16. Use of the crystalline form of D/,D/'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide according to any one of claims 1-6 for the treatment and/or prevention of inflammation of the mucous membrane of the upper respiratory tract. 17. Application according to item 16, characterized in that inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis. 18. Application according to claim 17, characterized in that the rhinitis is selected from allergic rhinitis, infectious rhinitis, vasomotor rhinitis, atrophic rhinitis and hypertrophic rhinitis. 19. Application according to item 16, characterized in that inflammation of the mucous membrane of the upper respiratory tract is caused by sinusitis. 20. Application according to item 19, characterized in that sinusitis is selected from traumatic sinusitis, viral sinusitis, bacterial sinusitis, fungal sinusitis, mixed sinusitis, allergic sinusitis, sinusitis (sinusitis of the maxillary sinus), frontal sinusitis (sinusitis of the frontal sinus), ethmoiditis (inflammation mucous membrane of the cells of the ethmoid labyrinth), sphenoiditis (inflammation of the mucous membrane of the sphenoid sinus). 21. Application according to item 16, characterized in that inflammation of the mucous membrane of the upper respiratory tract is caused by pharyngitis. 22. Application according to item 21, characterized in that pharyngitis is selected from viral pharyngitis, bacterial pharyngitis, fungal pharyngitis, allergic pharyngitis, traumatic pharyngitis, catarrhal pharyngitis, hyperplastic pharyngitis, subatrophic pharyngitis, atrophic pharyngitis, mixed pharyngitis, tonsillitis, pharyngotonsillitis and nasopharyngitis . 23. Use according to any of paragraphs 17-22, characterized in that the specified disease occurs in acute or chronic form. 24. Use according to any one of paragraphs 16-22, in which the crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide has an analgesic and antipyretic effect.