RU2812541C1 - New crystal form of 1-(2-(1h-imidazol-4-yl)ethyl)piperidine-2,6-dione and its pharmaceutical application - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the crystalline form of 1-(2-(1Н-imidazo-4-yl)ethyl)piperidin-2,6-dione characterized by the positions of the peaks in the powder X-ray diffraction pattern 2, 2θ, deg.: 16.3±0.2, 23.8±0.2 и 24.5±0.2. The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione is also characterized by the orthorhombic system of the crystal lattice and the sizes of the edges of the crystal cell,(angstrom): 9.5±0.3, 15.0±0.3 и 15.0±0.3. The invention also relates to a pharmaceutical composition and medicinal product for the treatment and/or prevention of cough, containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione according to the invention in a therapeutically effective amount and at least one pharmaceutically acceptable excipient.

EFFECT: increased stability, decreased hygroscopicity, increased therapeutic effectiveness of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione.

12 cl, 3 dwg, 5 tbl, 6 ex

Description

Field of technology

The invention relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry, namely to a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione containing its pharmaceutical composition and dosage form , which can be used for the treatment and/or prevention of cough.

State of the art

Cough is one of the patient complaints with which patients often seek medical help. Usually the reason is the nature of the cough, which interferes with the patient’s quality of life. It is generally accepted to evaluate cough as a symptom of diseases associated with damage to the human respiratory system. However, during a severe cough, intrathoracic pressure and air flow speed increase, which can lead to a variety of complications. These include, in particular, neurological diseases, for example, depression, headaches, fear of a dangerous disease, etc. (P.V.DICPINIGAITIS et al., Prevalence of depressive symptoms among patients with chronic cough, CHEST, 2006, V.130, N.6, pp.1839-1843, doi:10.1378/chest.130.6.1839).

Therefore, the technical task aimed at finding effective means for the prevention and treatment of cough is an urgent task.

1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (RU2562773C2) is known, for which use for the treatment of viral diseases is disclosed.

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

It is also known to be used for the treatment of eosinophilic diseases (RU2552929C1) and diseases associated with aberrant cytokine activity (WO2019050429A1). A liquid dosage form for oral administration containing 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione is reported (RU2020106386). It is known to use 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione for the treatment of a disorder in patients with steroid resistance, in particular for the symptomatic treatment of asthma, rheumatoid arthritis, systemic lupus erythematosus, gastrointestinal tract and cough (WO2020106191A1). Information on the properties and pharmaceutical use of crystalline forms of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione has not been found in the prior art.

Additionally, it should be noted that an urgent and timely task is also the development of dosage forms that have an increased rate of development of the therapeutic effect to prevent the onset of severe consequences. This is more true for symptomatic drugs.

It should also be noted that one of the disadvantages of many drugs is the lack of stability of the active substance during shelf life. The drug and pharmaceutical compositions must be able to be stored for significant periods of time without showing a significant change in the physicochemical properties of the active component.

A technical problem that has not been solved is the insufficient stability, therapeutic efficacy and pharmacokinetic parameters (rate of development of therapeutic effect and bioavailability) of dosage forms of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6- diona.

Disclosure of the invention

Technical result

The objective of the present invention is to develop a storage-stable, non-hygroscopic new form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, which has an optimal set of physicochemical and pharmacokinetic parameters.

The inventors unexpectedly discovered that a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, previously unknown from the prior art, has reduced hygroscopicity and increased storage stability while maintaining good solubility. In addition, the active pharmaceutical substance containing the specified new crystalline form has improved compressibility with good flow properties without noticeable electrostatic phenomena, while maintaining its therapeutic effectiveness. The new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione 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 a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione.

The technical results to be achieved by the present invention are as follows:

- increasing the storage stability (for 3 years) of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione and the active pharmaceutical substance, pharmaceutical composition and dosage form containing it;

- increasing the long-term (for 10 years) stability of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione and the active pharmaceutical substance, pharmaceutical composition and dosage form containing it;

- reducing hygroscopicity while maintaining sufficient solubility of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione;

- improving compressibility while maintaining good flowability without noticeable electrostatic phenomena of the active pharmaceutical substance, pharmaceutical composition and dosage form containing the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione;

- increasing the therapeutic effectiveness of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione and the active pharmaceutical substance, pharmaceutical composition and dosage form containing it;

- improved bioavailability, increased rate of development of the therapeutic effect of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione and active pharmaceutical substances, pharmaceutical compositions and dosage forms containing it;

- expanding the arsenal of medicines for the treatment and prevention of cough.

Stability refers to the ability of the form of a substance, active pharmaceutical substance, pharmaceutical composition and drug to maintain chemical, physical, microbiological and biopharmaceutical properties within certain limits for 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 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione

The present technical problem is solved, and the specified technical results are achieved thanks to a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione.

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

1-(2-(1H-Imidazol-4-yl)ethyl)piperidine-2,6-dione can be presented in the form of mesomeric structures. Crystalline forms of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione are included in the present invention regardless of the method of depicting the mesomeric structure. Mesomeric structures include:

Mesomers by imidazole group:

For example, 1-(2-(1H-imidazol- 4 -yl)ethyl)piperidine-2,6-dione and 1-(2-(1H-imidazol- 5 -yl)ethyl)piperidine-2,6-dione are mesomers. Therefore, the concepts “crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione” and “crystalline form of 1-(2-(1H-imidazol-5-yl)ethyl)piperidine -2,6-dione" are equivalent concepts. The names “1-(2-(1H-imidazol-4 - yl)ethyl)piperidine-2,6-dione” and “1-[2-(1H-imidazol-4 - yl)ethyl]piperidine-2,6- dione" are also equivalent.

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 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione, a mesomeric effect is possible at the imidazole group.

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by the peak positions in the X-ray powder diffraction pattern obtained using Cu(Kα) radiation, 2θ, deg : 16.3±0.2, 23.8±0.2 and 24.5±0.2. In a preferred embodiment, the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by peak positions in an X-ray powder diffraction pattern obtained using Cu(Kα) radiation, , deg: 16.32±0.2, 23.4±0.2, 23.7±0.2, 23.8±0.2, 24.5±0.2, 26.6±0.2, 27.0±0.2. In another embodiment, the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by the peak positions in an X-ray powder diffraction pattern obtained using Cu(Kα) radiation, 2θ, City: 11.9 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 23.0 ± 0.2, 23.4 ± 0.2, 23.7 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, 26.6 ± 0.2, 27.0 ± 0.2, 28.3 ± 0.2, 35.9 ± 35.9 ± 35.9 ± 35.9 ± 35.9 ± 35.9 ± 0.2 and 47.1±0.2. In an even more preferred embodiment, the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione 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 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention can be characterized by lattice syngony and crystal unit cell parameters. 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 (α, β and γ). In a preferred embodiment, the crystal lattice system of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione according to the present invention is orthorhombic system. In a rhombic crystal, the crystal is built from rectangular parallelepipeds (α, β and γ = 90°). The parameters of the crystal lattice of the rhombic system are the sizes of the edges. In the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to the present invention, the edge values at room temperature (296.15 K) are (in angstroms, ) 9.5±0.3, 15.0±0.3 and 15.0±0.3, and preferably 9.4835, 15.0520 and 14.9745. It should be taken into account that the observed parameters of the crystal cell depend on the measurement temperature.

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. Crystal forms that differ in crystal structure and properties 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 θ. 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 2θ between the sample and the primary beam. Using the Wulff-Bragg formula nλ = 2dsinθ, one 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).

Pharmaceutical composition

The present technical problem is solved, and the specified technical results are also achieved thanks to pharmaceutical compositions for the treatment and/or prevention of cough containing the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 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 includes the active substance - the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 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 can be in any other 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. 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 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione in the pharmaceutical composition is selected from the range from 0.01 to 99.99 wt.%, preferably from 1.00 to 80.00 wt. %, more preferably from 10.00 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.%.

In another preferred embodiment, the pharmaceutical composition includes a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the present invention in an effective amount.

The term "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 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione is contained in a pharmaceutical composition or drug and is used in a specific dosage. The dosage of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione according to the present invention may be in the range of 1 mg to 1000 mg per day, preferably 60 mg to 500 mg . Preferably, in the solid form of the pharmaceutical composition or drug, 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione is present 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 some types of dosage forms, the amount of active substance released from the dosage form per unit 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 selected by one skilled in the art as long as the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione is retained completely or partially.

In a preferred embodiment, the pharmaceutical composition according to the invention includes (wt.%):

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 20.0-30.0% Excipients: Microcrystalline cellulose 30.0-40.0% Sodium starch glycolate 0.0-1.0% Talc 0.0-1.0% Magnesium stearate 0.0-5.0% Lactose anhydrous up to 100%

In a more preferred embodiment, the pharmaceutical composition according to the invention includes (wt.%):

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 22.2% Excipients: Microcrystalline cellulose 36.4% Sodium starch glycolate 0.5% Talc 0.4% Magnesium stearate 1.0% Lactose anhydrous up to 100%

In an even more preferred embodiment, the pharmaceutical composition according to the invention includes:

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 40.00 mg Excipients: Sodium starch glycolate 0.90 mg Microcrystalline cellulose 65.50 mg Lactose anhydrous 71.00 mg Talc 0.80 mg Magnesium stearate 1.80 mg Total: 180.00 mg

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 medicinal product for the treatment and/or prevention of cough containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione or pharmaceutical the 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 a preferred 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: tablets, in particular buccal tablets, effervescent tablets, film-coated tablets, sustained release tablets, regular tablets, controlled release tablets, orally dispersible tablets, lyophilized instant tablets and so on.; capsules such as hard capsules, soft capsules, gelatin capsules and the like; injection powders such as lyophilized injection powders, regular injection powders and the like; solutions, aerosols, sprays, transdermal medicinal products such as patches, granules, suppositories and other dosage forms.

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.

The medicinal product of the present invention may be an active pharmaceutical substance and a pharmaceutical composition comprising a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione. Preferably, the medicinal product also includes at least one pharmaceutically acceptable excipient, however, its presence is not required.

The quantitative content of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione in the drug is selected from the range from 0.01 to 100 wt.%, preferably from 1.00 to 80.00 wt. %, more preferably from 10.00 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.%.

In a preferred embodiment, the medicinal product of the present invention is a tablet and includes a pharmaceutical composition according to the proposed invention (wt.%):

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 20.0-30.0% Excipients: Microcrystalline cellulose 30.0-40.0% Sodium starch glycolate 0.0-1.0% Talc 0.0-1.0% Magnesium stearate 0.0-5.0% Lactose anhydrous up to 100%

as well as film coating.

In a more preferred embodiment, the medicinal product of the present invention is a tablet and includes a pharmaceutical composition according to the proposed invention (wt.%):

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 22.2% Excipients: Microcrystalline cellulose 36.4% Sodium starch glycolate 0.5% Talc 0.4% Magnesium stearate 1.0% Lactose anhydrous up to 100%

as well as dispersed film coating.

In an even more preferred embodiment, the pharmaceutical composition according to the present invention includes

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 40.00 mg Excipients: Sodium starch glycolate 0.90 mg Microcrystalline cellulose 65.50 mg Lactose anhydrous 71.00 mg Talc 0.80 mg Magnesium stearate 1.80 mg Total: 180.00 mg

as well as dispersed film coating Opadry II 85F18422 (white) - 7.20 mg.

The drugs of the present invention can be administered (but not limited to) orally, parenterally, inhalation, subcutaneously, intraperitoneally, topically, rectally. Therapeutic dosage of a medicinal product containing a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione or an active pharmaceutical substance or a pharmaceutical composition of the present invention or a pharmaceutical composition for the treatment of cough , which contains in a therapeutically effective amount the novel crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the present invention, may be adjusted in patients depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, 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 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione and pharmaceutical compositions and medicinal products containing it

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione, the active pharmaceutical substance, the pharmaceutical composition and the drug containing it of the present invention can be used for the treatment of cough.

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione, the active pharmaceutical substance containing it, the pharmaceutical composition of the present invention can be used for the manufacture of the drug of the present invention.

The cough for the treatment and/or prevention of which the present invention is aimed may refer to a dry cough, refractory cough, chronic cough of unknown etiology, cough due to diseases of the respiratory tract caused by bronchial asthma, COPD, idiopathic pulmonary fibrosis, lung cancer. Preferably, the cough that the present invention is intended to treat and/or prevent is a dry cough.

In another embodiment, the cough that the present invention is intended to treat and/or prevent may be a cough caused by viral infections. Preferably, the cough may be caused by an acute respiratory viral infection (ARVI). Acute respiratory viral infections refer to infectious diseases that affect the mucous membranes of the upper respiratory tract.

In one embodiment of the present invention, the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione in the pharmaceutical composition or medicinal product of the present invention is administered in an amount of from 5 mg to 200 mg per day, for example, from 5 to 20 mg 1-3 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 a preferred embodiment of the present invention, treatment of cough involves symptomatic treatment, that is, treatment aimed at eliminating the symptom of cough, regardless of the etiopathogenesis of other possible diseases.

Brief description of drawings

Figure 1 - Powder X-ray diffraction pattern of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the present invention;

Figure 2 - Powder X-ray diffraction pattern of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione of the present invention and its comparison with the calculated one. The blue curve is the experiment, the red one is the calculation, the gray one is the difference between them;

Figure 3 - General view of the 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione molecule in the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine -2,6-dione of the present invention. The structure was established according to X-ray diffraction analysis (XRD).

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 to, by the following examples, which illustrate the present invention.

Example 1. Preparation of a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was prepared according to the following procedure.

A sample of 3.0 g of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was ground in a porcelain mortar for 1-2 minutes. After this, the resulting powder was dissolved with stirring in 20 ml of heptane heated to 75°C. Next, the mixture was placed in the refrigerator and kept at a temperature of +5°C for 24 hours. The precipitated crystals were filtered and dried under reduced pressure (100 mmHg) until the mass of the crystals ceased to decrease with further drying. 2.7 g (90%) of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was obtained in the form of a white crystalline powder.

The powder X-ray diffraction pattern of the resulting crystalline form was recorded on a Bruker D8 Advance diffractometer equipped with a slit system for monochromatization and focusing ([CuKα]=1.5418 ), as well as a position-sensitive LynxEye detector, in the angular range of 4-60° with a step of 0.02° along the 2θ angle using reflection geometry.

Figure 1 shows the X-ray powder diffraction pattern of the resulting crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione. Table 1 lists the positions of the 2θ angles and their relative intensities.

Table 1. Angles (2θ, deg) ± 0.2 and their relative intensities (I, %) of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione

Interplanar distance (d), α Angle 2θ, ° Relative intensity, % 7.45 11.9 7 7.00 12.6 3 6.67 13.3 1 5.83 15.2 9 5.44 16.3 64 4.72 18.8 4 4.22 21.0 2 4.14 21.5 3 3.85 23.1 6 3.79 23.4 12 3.75 23.7 100 3.74 23.8 77 3.63 24.5 67 3.52 25.3 2 3.47 25.7 2 3.39 26.3 2 3.35 26.6 eleven 3.30 27.0 21 3.16 28.3 8 3.02 29.6 3 2.99 29.8 4 2.88 31.0 2 2.85 31.3 3 2.77 32.3 3 2.73 32.7 2 2.66 33.6 2 2.65 33.8 2 2.62 34.1 2 2.50 35.9 5 2.50 36.0 4 2.47 36.4 2 2.40 37.5 2 2.39 37.7 2 2.29 39.2 1 2.25 39.9 2 2.23 40.4 2 2.18 41.3 1 2.08 43.5 2 2.02 44.8 2 1.93 47.1 5 1.92 47.2 3 1.86 48.9 2 1.83 49.9 3 1.82 50.1 4 1.79 51.1 2 1.68 54.7 2

In the powder X-ray diffraction pattern of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, the following intense peaks (maxima) were observed at diffraction angles 2θ (±0.2°): 11.9, 12.6, 15.2, 16.3, 18.8, 21.5, 23.1, 23.4, 23.7, 23.8, 24.5, 26.6, 27.0, 28.3, 29.6, 29.8, 31.3, 32.3, 35.9, 36.0, 47.1, 47. 2. The characteristic peaks were: 16.3, 23.4, 23.7, 23.8, 24.5, 26.6, 27.0. The most intense peaks were: 16.3, 23.8 and 24.5.

The crystal structure of the resulting phase was determined using single-crystal X-ray diffraction and full-profile refinement of the powder diffraction data array (“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 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione and their comparison with the calculated ones is shown in Figure 2. The blue curve is the experiment, the red one is the calculation, the gray one is the difference between them. The parameters of the crystal cell are determined in Table 2.

Table 2. Parameters of the crystal structure of the form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione

Cell Options a(A) 9.4834634 b(A) 15.0470263 c(A) 14.9774650

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was also studied by X-ray diffraction (XRD). The molecule crystallized in the orthorhombic system, space group Pbca. All measurements were carried out at a temperature of 100K using MoKα radiation (λ = 0.71073). A general view of the molecule is shown in Figure 3. Bond lengths and angle values are presented in Tables 3 and 4. Crystallographic information for C ₁₀ H ₁₃ N ₃ O ₂ ( M = 207.23 g/mol): orthorhombic system, space group Pbca (no. 61), a = 9.4516(2) , b = 14.7605(3) , c = 14.7686(3) , V = 2060.37(7) ³ , Z = 8, T = 100 K, μ(MoKα) = 0.096 mm ^-1 , Dcalc = 1.336 g/cm ³ , 28937 reflections collected (5.516° ≤ 2Θ ≤ 61.102°), of which 3149 reflections ( R _int = 0.0410, R _sigma = 0.0229) were used for further calculations.

Table 3. Calculated interatomic distances (bond lengths)

Atom Atom Length/ Atom Atom Length/ O1 C1 1.2171(10) N3 C10 1.3775(11) O2 C5 1.2150(11) C1 C2 1.5023(11) N1 C1 1.3985(11) C2 C3 1.5198(12) N1 C5 1.3999(10) C3 C4 1.5159(12) N1 C6 1.4745(10) C4 C5 1.5056(12) N2 C8 1.3852(11) C6 C7 1.5265(12) N2 C9 1.3241(11) C7 C8 1.4934(12) N3 C9 1.3447(11) C8 C10 1.3700(12)

Table 4. Calculated angles

Atom Atom Atom Angle/° Atom Atom Atom Angle/° C1 N1 C5 124.33(7) O2 C5 N1 119.50(8) C1 N1 C6 118.68(7) O2 C5 C4 122.50(8) C5 N1 C6 117.00(7) N1 C5 C4 117.99(7) C9 N2 C8 105.47(7) N1 C6 C7 110.59(7) C9 N3 C10 106.99(7) C8 C7 C6 113.27(7) O1 C1 N1 120.31(8) N2 C8 C7 121.48(8) O1 C1 C2 122.56(8) C10 C8 N2 109.16(7) N1 C1 C2 117.13(7) C10 C8 C7 129.33(8) C1 C2 C3 111.94(7) N2 C9 N3 112.01(8) C4 C3 C2 108.60(7) C8 C10 N3 106.36(7) C5 C4 C3 113.46(7)

The values of the cell edges obtained in the study of a single crystal differ by 1-3% from those calculated on the basis of powder X-ray diffraction data. This is due to the fact that the study of the single crystal was carried out at a temperature of 100 K, and the study of the powder phase at room temperature.

The resulting crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was used to obtain the active pharmaceutical ingredient (API) through an additional drying step (CO ₂ flow drying, spray drying method, drying under vacuum, etc.) to constant weight. The output was a fine white powder. The finished pharmaceutical substance was placed in a hermetically sealed bottle.

Example 2. Storage stability study of a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione

The stability of the active pharmaceutical substance, which is a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione, was assessed by the accelerated aging method in accordance with GPM.1.1.0009.15 Shelf life of medicines, the state pharmacopoeia RF. At elevated temperatures, as a rule, the physicochemical processes occurring in medicines 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.

The expected storage conditions for the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione were 3 years at a temperature not exceeding 25°C.

The shelf life ( С ) at storage temperature ( tхр ) is related to the _experimental shelf life ( СЭ ₎ at _an elevated experimental storage temperature ( tе ) by the Van't Hoff equation:

; ;

where A is the temperature coefficient, which is taken equal to 2.5.

The storage conditions chosen for the accelerated aging experiment were 28 days at 65°C. To conduct the study, a sample of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was left in a climate chamber for 28 days at a temperature of 65°C. Next, an X-ray diffraction pattern of the resulting sample was recorded. There were no additional reflections in the resulting picture, which indicates the purity of the form and the preservation of the crystal structure. Thus, the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione remains stable under the selected storage conditions.

Example 3. Solubility study of a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione

The determination of the solubility of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione 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 1.0 g of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, 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 100 mg of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione and the procedure described above was repeated. The crystalline form has completely dissolved. According to GPM.1.2.1.0005.15, the substance should be classified as easily soluble.

Example 4. Study of the hygroscopicity of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione

The hygroscopicity of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione was assessed according to GPM.1.2.1.0010.15 Loss in weight on drying, State Pharmacopoeia of the Russian Federation.

The crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was placed in a climate chamber at 80% relative humidity and 25°C for 24 hours. Next, a sample of the resulting substance was placed in a bottle brought to a constant weight. Drying was carried out in a desiccator over phosphorus oxide (V) for 12 hours. After this, the bottle was removed from the desiccator, covered with a lid and weighed.

Weight loss upon drying was calculated using the formula:

m ₁ - mass of the bottle with a lid, m ₂ - mass of the substance together with the bottle before drying; m ₃ - mass of the substance with the bottle after drying.

It was found that the weight loss upon drying is 1.24%, which allows the substance to be classified as slightly hygroscopic.

The substance obtained according to the prototype RU2562773С2 was studied in a similar way.

Both dried substances were analyzed by HPLC. In the substance obtained according to the prototype, an impurity of 5-[2-(1H-imidazol-4-yl)ethylamino]-5-oxopentanoic acid (vitaglutam) with a content of less than 0.5 wt.% was detected. In the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, the content of foreign impurities was less than 0.1 wt.%.

Example 5. Preparation of a pharmaceutical composition containing a new crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione

The pharmaceutical substance of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione obtained in Example 1 was used for the preparation of pharmaceutical compositions according to the compositions disclosed in Table 2.

For each formulation, the pharmaceutical substance was mixed with the excipients listed in Table 5, and the final mixture was thoroughly mixed.

Table 5. Formulations of the pharmaceutical compositions of the present invention containing the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione as the active substance

Composition 1 Composition 2 Composition 3 Composition 4 Components wt.% Components wt.% Components wt.% Components wt.% Active substance 22.2 Active substance 20.0 Active substance 30.0 Active substance 25.0 Microcrystalline cellulose 36.4 Microcrystalline cellulose 40.0 Microcrystalline cellulose 30.0 Microcrystalline cellulose 36.5 Lactose anhydrous 39.5 Lactose anhydrous 34.0 Lactose anhydrous 37.0 Lactose anhydrous 36.5 Sodium starch glycolate 0.5 Sodium starch glycolate 1.0 Sodium starch glycolate 2.5 Talc 0.4 Talc 0.5 Talc 1.0 Magnesium stearate 1.0 Magnesium stearate 5.0 Magnesium stearate 1.0 Composition 5 Composition 6 Composition 7 Composition 8 Components wt.% Components wt.% Components wt.% Components wt.% Active substance 2 Active substance 40.0 Active substance 30.0 Active substance 65.0 Microcrystalline cellulose 47.7 Lactose anhydrous 53.0 Mannitol 66.0 Microcrystalline cellulose 29.0 Lactose anhydrous 49.0 Sodium starch glycolate 0.5 Croscarmellose sodium 5.0 Copovidon 2.5 Crospovidone 4.0 Talc 0.4 Colloidal silicon dioxide 1.0 Talc 1.0 Colloidal silicon dioxide 1.0 Magnesium stearate 0.4 Magnesium stearate 1.0 Sodium stearyl fumarate 0.5 Sodium stearyl fumarate 1.0

Example 6. Preparation of a medicinal product containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione

The pharmaceutical composition obtained in example 5 was tableted on a tablet machine consisting of a steel matrix with holes with a diameter of 10 mm and two chrome-plated rods located one above the other - upper and lower punches. 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 first composition of the composition described in example 5 was chosen.

A drug containing the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was obtained in the form of a tablet with a diameter of 10 mm and a height of 3 mm. The tablet was additionally coated with Opadry II.

Composition of the tablet:

Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 40.00 mg Excipients: Sodium starch glycolate 0.90 mg Microcrystalline cellulose 65.50 mg Lactose anhydrous 71.00 mg Talc 0.80 mg Magnesium stearate 1.80 mg Total (without shell): 180.00 mg Dispersed film coating Opadry II 85F18422 (white) 7.20 mg Total (with shell): 187.2 mg

Claims (16)

1. Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, characterized by peak positions in the powder X-ray diffraction pattern, 2θ, deg: 16.3±0.2, 23.8±0.2 and 24.5± 0.2. 2. Crystalline form according to claim 1, characterized by the positions of the peaks in the powder X-ray diffraction pattern obtained using Cu(Kα) radiation, 2θ, deg: 16.3±0.2, 23.4±0.2, 23.7±0.2, 23.8±0.2, 24.5±0.2 , 26.6±0.2, 27.0±0.2. 3. Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione, characterized by the orthorhombic system of the crystal lattice and the sizes of the edges of the crystal cell, (angstrom): 9.5±0.3, 15.0±0.3 and 15.0±0.3. 4. Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to claim 3, characterized by the sizes of the edges of the crystal cell, (angstrom): 9.4835, 15.0520 and 14.9745 at room temperature (296.15 K). 5. Pharmaceutical composition for the treatment and/or prevention of cough, containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidin-2,6-dione according to any one of claims 1-4 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient. 6. Pharmaceutical composition according to claim 5, including (wt.%): Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 20.0-30.0 Excipients: Microcrystalline cellulose 30.0-40.0 Sodium starch glycolate 0.0-1.0 Talc 0.0-1.0 Magnesium stearate 0.0-5.0 Lactose anhydrous up to 100 7. Pharmaceutical composition according to claim 6, including (wt.%): Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 22.2 Excipients: Microcrystalline cellulose 36.4 Sodium starch glycolate 0.5 Talc 0.4 Magnesium stearate 1.0 Lactose anhydrous up to 100 8. Pharmaceutical composition according to claim 5, including: Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 40.00 mg Excipients: Sodium starch glycolate 0.90 mg Microcrystalline cellulose 65.50 mg Lactose anhydrous 71.00 mg Talc 0.80 mg Magnesium stearate 1.80 mg Total: 180.00 mg 9. A medicinal product for the treatment and/or prevention of cough, containing a crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione according to any one of claims 1-4 in a therapeutically effective amount or a pharmaceutical composition according to any one of claims 5-8. 10. The medicine according to claim 9, made in the form of a tablet or capsule. 11. Medicine according to claim 9, including: Crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 40.00 mg Excipients: Sodium starch glycolate 0.90 mg Microcrystalline cellulose 65.50 mg Lactose anhydrous 71.00 mg Talc 0.80 mg Magnesium stearate 1.80 mg Total (without shell): 180.00 mg Dispersed film coating Opadry II 85F18422 (white) 7.20 mg Total (with shell): 187.2 mg 12. Use of the crystalline form of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione according to any of claims 1-4 for the manufacture of a medicinal product according to any of claims 9-11.