Pharmaceutical composition of gramicidin s for treating infectious inflammatory diseases of the oral cavity and throat

Abstract

The invention relates to the field of pharmaceutical chemistry and medicine, and more particularly to a combination, a pharmaceutical composition and a medicament for treating infectious inflammatory diseases of the oral cavity and throat, containing gramicidin S and dyclonine or their pharmaceutically acceptable salts, wherein the active ingredients are present in the following mass ratios: from 50:1 to 1:20 gramicidin S : dyclonine.

Description

[0001] PHARMACEUTICAL COMPOSITION OF GRAMICIDIN C FOR THE TREATMENT OF INFECTIOUS AND INFLAMMATORY DISEASES OF THE ORAL CAVITY AND THROAT

[0002] AREA OF TECHNOLOGY

[0003] The invention relates to the field of pharmaceutical chemistry and medicine and, in particular, to a combination, pharmaceutical composition and medicinal product for the treatment of infectious and inflammatory diseases of the oral cavity and throat, including gramicidin C and dyclonine or their pharmaceutically acceptable salts.

[0004] LEVEL OF TECHNOLOGY

[0005] The most common diseases of social significance include infectious diseases of the oral cavity and pharynx (pharyngitis, glossitis, stomatitis and gingivitis), as well as the upper respiratory tract (adenoiditis, tonsillitis, laryngitis). Despite the significant potential of the means that modern medicine has to combat these diseases, the problem still remains relevant. To a large extent, this is due to both the high incidence rate and the very nature of microorganisms, which are constantly changing and forming resistant strains. The resistance of microorganisms to antibacterial agents is an important problem that determines the correct choice of a particular drug for treating a patient. In the first years after the discovery of penicillin, about 99% of pathogenic staphylococci were sensitive to this antibiotic; in the 1960s, no more than 20-30% of staphylococci remained sensitive to penicillin.Therefore, medical practice requires the constant introduction of new generations of antibiotics.

[0006] At the same time, there is a tendency, along with the search for new pharmacological agents, to make maximum use of the potential of already known agents.

[0007] These agents include gramicidin C, one of the first domestic antibiotics, first obtained by I.F. Gause and M.G. Brazhnikova in 1942.

[0008] Gramicidin belongs to the group of broad-spectrum polypeptide antibiotics, has a bacteriostatic and bactericidal effect on streptococci, staphylococci, pneumococci, causative agents of anaerobic infections and other microorganisms. It is produced by the spore rod Bacillus brevis or Aneurinibacillus migulanus [patent RU 2627182]. A number of antibacterial drugs are known that contain gramicidin C both as the only active ingredient [patent RU 2213558] and in combination with antiseptics, such as cetylpyridinium chloride [patents RU 2633635, RU 2604575], or mucolytics, such as ambroxol [patent RU 2749902].

[0009] A combination drug of gramicidin in the form of lozenges (Registration Certificate No.: LSR-005119 / 08) is known, which is used to treat infectious and inflammatory diseases of the oral cavity and throat: tonsillitis, pharyngitis, tonsillitis, periodontosis, gingivitis and stomatitis.

[0010] The technical problem that was not solved by the analogs considered is the insufficiently wide range of drugs based on gramicidin C. Due to the growing antibiotic resistance, as well as to allow the consumer and the attending physician to choose the most suitable composition for a particular patient, new drugs based on gramicidin C are needed, additionally containing an anesthetic and antiseptic, since the approach to treating each patient must be individual.

[0011] DISCLOSURE OF THE ESSENCE OF THE INVENTION

[0012] Technical result

[0013] The technical results of the present invention are:

[0014] - increasing the antibacterial and anti-inflammatory action of gramicidin C and its compounds;

[0015] - increased rate of dissolution of gramicidin C and its compounds;

[0016] - expansion of the arsenal of means for the treatment of infectious and inflammatory diseases of the oral cavity and throat;

[0017] - improvement of the technological characteristics of pharmaceutical compositions of gramicidin C, for example, flowability and bulk density.

[0018] - increased stability of gramicidin C and its compounds.

[0019] Combination, pharmaceutical composition and medicinal product

[0020] The specified technical results are achieved thanks to a combination, a pharmaceutical composition and a medicinal product for the treatment of infectious and inflammatory diseases of the oral cavity and throat, containing gramicidin C and dyclonine or their pharmaceutically acceptable salts, where the active substances are in the following mass ratios: gramicidin C: dyclonine from 50: 1 to 1: 20.

[0021] Gramicidin C is an antibiotic and is a cyclic decapeptide with the molecular formula C60H92N12O10 and CAS 113-73-5, which is produced by Bacillus brevis.

[0022] Diclonine is a compound 1-(4-butoxyphenyl)-3-piperidin-1-ylpropan-1-one. It has a local anesthetic effect.

[0023] A pharmaceutical composition is understood to be a composition (mixture, composition, etc.) suitable for use in humans or animals, comprising active pharmaceutical substances and excipients. The active pharmaceutical substances in the pharmaceutical composition are gramicidin C or a pharmaceutically acceptable salt thereof as an antibiotic, dyclonine or a pharmaceutically acceptable salt thereof as an anesthetic, and optionally cetylpyridinium chloride or its hydrate as an antiseptic. It will be clear to a person skilled in the art that the pharmaceutical composition of the present invention will also include compositions containing one or more other active pharmaceutical substances.

[0024] A combination is a mixture of two or more active pharmaceutical substances with or without additional excipients.

[0025] A medicinal product or medicinal preparation is understood to mean a substance, combination, or pharmaceutical composition made in the form of a medicinal form.

[0026] "Pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of acids and bases claimed in the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of the compounds or specially prepared. In particular, salts of bases can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” / / J. Pharm. Sci. 1977, 66: 1-19).Preferred salts of gramicidin are gramicidin hydrochloride, preferably gramicidin dihydrochloride. A preferred salt of dyclonine is dyclonine hydrochloride.

[0027] The terms “includes” and “contains” in the context of the present invention mean that the said pharmaceutical compositions (medicines, groups of components, etc.) include the listed components / ingredients, but do not exclude the inclusion of other components / ingredients.

[0028] In one embodiment of the combination, pharmaceutical composition and medicinal product, the active ingredients are in a weight ratio of gramicidin C: dyclonine from 50: 1 to 1: 20, more preferably from 10: 1 to 1: 2, even more preferably from 4: 1 to 1: 1. For example, the active ingredients or their pharmaceutically acceptable salts are in the following weight ratios: gramicidin C: dyclonine 2.25: 1, or gramicidin C: dyclonine hydrochloride 2: 1, or gramicidin C dihydrochloride: dyclonine 2.4: 1, or gramicidin C dihydrochloride: dyclonine hydrochloride 2.13: 1. Other examples of ratios of gramicidin C and dyclonine: 50: 1, 40: 1, 30: 1, 25 : 1, 20 : 1, 15 : 1, 10 : 1, 9 : 1, 8 : 1, 7 : 1, 6 : 1, 5 : 1, 4 : 1, 3 : 1, 2 : 1, 1.5 : 1, 1 : 1, 1 : 1.5, 1 : 2, 1 : 3, 1 : 4, 1 : 5, 1 : 6, 1 : 7, 1 : 8, 1 : 9, 1 : 10, 1 : 15, 1 : 20, as well as all possible ranges between the specified ratios.

[0029] In one embodiment, the combination, pharmaceutical composition and drug of the present invention additionally contain an antiseptic selected from the group consisting of ethanol, isopropanol, chlorhexidine, cetylpyridinium chloride, benzalkonium chloride, cetrimide, hexethidine, benzyldimethylmyristoylaminopropylammonium chloride, tetraethyl ammonium bromide, nitrofural, amylmetacresol, dichlorobenzyl alcohol, ambazone, lysozyme, tyrothricin, benzodiamine. In a preferred embodiment, the combination, pharmaceutical composition and drug of the present invention additionally contain cetylpyridinium chloride or a hydrate, for example, a monohydrate or dihydrate. For example, the combination, pharmaceutical composition and medicinal product of the present invention contain gramicidin C, dyclonine or their pharmaceutically acceptable salts and cetylpyridinium chloride or its hydrate in the following weight ratio of active ingredients gramicidin C: dyclonine hydrochloride: cetylpyridinium chloride 3: 1.5: 1.

[0030] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention include gramicidin C and dyclonine or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where the active substances are contained in the following amounts: gramicidin C 0.01-20.0 wt.%, dyclonine 0.01-10.0 wt.%.

[0031] Solid dosage form

[0032] The combination, pharmaceutical composition and drug of the present invention may include 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 certain dosage form, in particular, in a solid dosage form. In a preferred embodiment, the combination, pharmaceutical composition and drug are a solid dosage form and include one or more pharmaceutically acceptable excipients (auxiliaries), which are selected from the group consisting of a filler, a binder, a lubricant, a disintegrating agent, a glidant, a preservative, a flavor and / or odor corrigent, an acidity regulator and a colorant.

[0033] Examples of solid dosage forms are powders, granules, briquettes, capsules, tablets, dragees, etc. In a preferred embodiment, the composition form of the present invention is a tablet, even more preferably an orodispersible tablet or a rapid-disintegrating tablet, even more preferably a lozenge. In addition, the tablet can be a tablet for solution, a tablet for rinsing, or a tablet for oral solution. A tablet is a solid dosage form, most often obtained by pressing powders or granules containing one or more active substances with or without the addition of excipients. An orodispersible tablet, a rapid-disintegrating tablet, and a lozenge do not require swallowing.

[0034] In the combination, pharmaceutical composition and medicinal product of the present invention in a solid dosage form, gramicidin C or a pharmaceutically acceptable salt thereof, calculated as gramicidin C, is contained in an amount of from 0.01 to 50.0 mg, including all intermediate ranges and values, for example, from 0.5 to 30.0 mg, from 1.0 to 10.0 mg, from 1.0 to 5.0 mg, from 1.5 to 5.0 mg, from 2.0 to 3.5 mg, from 3.0 to 3.5 mg, from 3.0 to 3.4 mg, for example, in an amount of: 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg or 40.0 mg, without limitation to the specified values. In another embodiment, in the combination, pharmaceutical composition and drug of the present invention in a solid dosage form, gramicidin C or its pharmaceutically acceptable salt, calculated as gramicidin C, is contained in an amount of from 0.01 to 20.0 wt.%, including all intermediate ranges and values, for example, from 0.05 to 3.0 wt.%, from 0.1 to 1.0 wt.%, 0.1 to 0.5 wt.%, 0.15 to 0.5 wt.%, 0.2 to 0.35 wt.%, 0.25 to 0.3 wt.%, for example in an amount of: 0.01 wt.%, 0.05 wt.%, 0.1 wt.%, 0.13 wt.%, 0.15 wt.%, 0.2 wt.%, 0.25 wt.%, 0.27 wt.%, 0.3 wt.%, 0.35 wt.%, 0.4 wt.%, 0.45 wt.%, 0.5 wt.%, 1.0 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.% or 4.0 wt.%, not limited to the specified values.

[0035] In the combination, pharmaceutical composition and medicinal product of the present invention in solid dosage form, dyclonine or its pharmaceutically acceptable salt in terms of dyclonine is contained in an amount of from 0.01 to 25 mg, including all intermediate ranges and values, for example, from 0.5 to 15.0 mg, from 0.5 to 5.0 mg, from 0.5 to 3.0 mg, from 1.0 to 2.0 mg, for example, in an amount of: 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, without limitation to the specified values. In another embodiment, in the combination, pharmaceutical composition and drug of the present invention in solid dosage form, dyclonine or its pharmaceutically acceptable salt, calculated as dyclonine, is contained in an amount of from 0.01 to 10.0 wt.%, including all intermediate ranges and values, for example, from 0.02 to 3.0 wt.%, from 0.05 to 1.0 wt.%, from 0.1 to 0.5 wt.%, from 0.1 to 0.2 wt.%, from 0.1 to 0.15 wt.%, for example, in an amount of: 0.01 wt.%, 0.04 wt.%, 0.05 wt.%, 0.08 wt.%, 0.1 wt.%, 0.13 wt.%, 0.15 wt.%, 0.18 wt.%, 0.2 wt.%, 0.25 wt.%, 0.27 wt.%, 0.3 wt.%, 0.35 wt.%, 0.4 wt.%, 0.42 wt.%, 0.45 wt.%, 0.5 wt.%, 1.0 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.% or 4.0 wt.%, without being limited to the specified values.

[0036] The combination, pharmaceutical composition and medicinal product of the present invention in solid dosage form optionally contain cetylpyridinium chloride or its monohydrate in terms of cetylpyridinium chloride in an amount of from 0.01 to 25 mg, including all intermediate ranges and values, for example, from 0.2 to 5.0 mg, from 0.5 to 3.0 mg, from 0.5 to 1.5 mg, for example, in an amount of: 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, without limitation to the specified values. In another embodiment, the combination, pharmaceutical composition and drug of the present invention in solid dosage form optionally contain cetylpyridinium chloride or its monohydrate, calculated as cetylpyridinium chloride, in an amount of from 0.01 to 10.0 wt.%, including all intermediate ranges and values, for example, from 0.02 to 3.0 wt.%, from 0.05 to 1.0 wt.%, from 0.05 to 0.5 wt.%, from 0.05 to 0.2 wt.%, from 0.05 to 0.1 wt.%, for example, in the amount of: 0.01 wt.%, 0.05 wt.%, 0.09 wt.%, 0.1 wt.%, 0.13 wt.%, 0.15 wt.%, 0.18 wt.%, 0.2 wt.%, 0.25 wt.%, 0.27 wt.%, 0.3 wt.%, 0.35 wt.%, 0.4 wt.%, 0.45 wt.%, 0.5 wt.%, 1.0 wt.%,.

[0037] 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, not limited to the specified values.

[0038] The term "filler" or "diluent" means auxiliary substances used to impart a given volume or weight to solid dosage forms. Starch, glucose, sucrose, lactose (milk sugar), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium hydrogen carbonate, white clay (kaolin), gelatin, microcrystalline cellulose (MCC), methylcellulose (MC), ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (H11MC), dextrose, sodium carboxymethylcellulose (Na CMC), calcium carbonate, dibasic calcium phosphate, glycine (aminoacetic acid), dextrin, amylopectin, sorbitol, mannitol, isomalt, pectin or a mixture thereof can be used as fillers. The group is not exhaustive. The filler may be present in the combination, pharmaceutical composition or medicinal product in an amount from 10.0 to 99.0% by weight, including all intermediate ranges, for example, from 50.0 to 99.0 wt.%, from 60.0 to 95.0 wt.%, from 80.0 to 90.0 wt.%, not limited to the specified values.

[0039] The term "binder" means a substance used to achieve the required adhesive force of a solid dosage form. Binders, filling the interparticle space, increase the contact surface of the particles and the cohesive capacity. Examples of such substances are methylcellulose (MC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), polyvinyl alcohol (PVA), alginic acid, sugar syrup, starch paste, etc. The binder can be present in the combination, pharmaceutical composition or drug in an amount of from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 10.0 wt.%, from 0.0 to 8.0 wt.%, from 0.0 to 5.0 wt.%, from 0.0 to 2.0 wt.%, without being limited to the specified values.

[0040] The term "lubricant" means auxiliary substances used in the technological process of tablet production at the pressing stage to improve the flowability of granules or powder by reducing friction between particles. The lubricant can be represented by one or more of starch, talc, silicon dioxide, polyethylene oxide (for example, polyethylene oxide-4000), stearic acid, calcium and magnesium stearate, etc. The group is not limited to this list. The lubricant can be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.1 to 30.0 wt.%, including all intermediate ranges, for example, from 0.1 to 20.0 wt.%, from 0.1 to 10.0 wt.%, from 1.0 to 8.0 wt.%, from 1.0 to 5.0 wt.%, without being limited to the specified values.

[0041] 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 tray in which the tablet is formed, used in the technological process of tablet production at the pressing stage. The lubricant may be one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethyleneglycol (with a molecular weight of over 3350), sodium lauryl sulfate, talc, mineral oil, leucine, poloxamer, etc. The group is not limited to this list. The lubricant may be present in the combination, pharmaceutical composition or medicinal product in an amount from 0.1 to 30.0 wt.%, including all intermediate ranges, for example, from 0.1 to 20.0 wt.%, from 0.1 to 10.0 wt.%, from 1.0 to 8.0 wt.%, from 1.0 to 5.0 wt.%, without being limited to the indicated values.

[0042] The term "acidity regulator" means substances that establish or maintain a certain pH value in a product. Acidity regulators include malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, and sorbic acids. The group is not limited to this list. The acidity regulator may be present in a combination, pharmaceutical composition, or medicinal product in an amount from 0.0 to 30.0 wt.%, including all intermediate ranges, for example, from 0.0 to 25.0 wt.%, from 0.1 to 10.0 wt.%, from 0.5 to 5.0 wt.%, from 0.5 to 2.0 wt.%, without being limited to the specified values. The term "disintegrating agent" or "disintegrant" means substances used to improve disintegration or dissolution by ensuring mechanical destruction of tablets in a liquid medium, which is necessary for the fastest release of the active substance.The disintegrating agent may be represented by one or more of microcrystalline cellulose, sodium croscarmellose, crospovidone, sodium starch glycolate, starch, pectin, gelatin, amylopectin, agar-agar, alginic acid, potassium and sodium alginate, silicon dioxide (colloidal), Tween-80, etc. The group is not limited to this list. The disintegrating agent may be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.0 to 30.0 wt.%, including all intermediate ranges, for example, from 0.1 to 20.0 wt.%, from 0.1 to 10.0 wt.%, from 1.0 to 8.0 wt.%, from 1.0 to 5.0 wt.%, without being limited to the specified values.

[0043] Corrigents are used to improve taste (sweetener) and smell (flavoring).

[0044] Sweeteners include, without limitation, maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin and its salts, for example, sodium saccharinate, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame (acesulfame potassium), neotame, lactitol and their pharmaceutically acceptable salts. The group is not limited to this list. The sweetener can be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 10.0 wt.%, from 0.0 to 5.0 wt.%, from 1.0 to 3.0 wt.%, from 1.0 to 2.0 wt.%, without being limited to the specified values.

[0045] Flavorings include, without limitation, raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavorings. The group is not limited to this list. The flavoring may be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 10.0 wt.%, from 0.0 to 5.0 wt.%, from 1.0 to 3.0 wt.%, from 1.0 to 2.0 wt.%, without being limited to the specified values.

[0046] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention comprise gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more excipients selected from the group consisting of a filler, a glidant, a lubricant, an acidity regulator, a disintegrant, a sweetener and a flavoring agent.

[0047] In one embodiment, the combination, pharmaceutical composition and drug of the present invention comprise gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more auxiliary substances selected from the group consisting of a filler, a glidant, a lubricant, an acidity regulator, a disintegrant, a sweetener and a flavoring agent, wherein the filler is selected from the group consisting of isomalt, sorbitol, lactose, mannitol, microcrystalline cellulose; the glidant is selected from the group consisting of talc, silicon dioxide; the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate; the acidity regulator is selected from the group consisting of citric acid, malic acid, lactic acid, tartaric acid;the sweetener is selected from the group including acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group including raspberry, mint, pear, melon flavorings.

[0048] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention contain gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more auxiliary substances selected from the group consisting of the filler isomalt, the lubricants talc and silicon dioxide, the lubricant magnesium stearate, the acidity regulator citric acid, the sweetener acesulfame potassium and the flavoring agent mint.

[0049] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention contain gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-5.0 wt.% and one or more auxiliary substances selected from the group consisting of the filler isomalt, the sliding substances talc and silicon dioxide, the lubricant magnesium stearate, the acidity regulator citric acid, the sweetener acesulfame potassium and the mint flavouring.

[0050] In one embodiment, the combination, pharmaceutical composition and drug of the present invention comprise gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-5.0 wt.% and excipients filler isomalt in an amount of 50.0-95.0 wt.%, sliding agents talc in an amount of 0.25-10.0 wt.% and silicon dioxide in an amount of 0.25-10.0 wt.%, lubricant magnesium stearate in an amount of 0.25-5.0 wt.%, acidity regulator citric acid in an amount of 0.1-15.0 wt.%, sweetener acesulfame potassium in an amount of 0.0-10.0 wt.% and mint flavoring in an amount of 0.0-10.0 wt.%.

[0051] An example of a combination, pharmaceutical composition and drug of the present invention: gramicidin C dihydrochloride 3.2 mg (in terms of gramicidin C 3.0 mg) (0.267 wt.%), dyclonine hydrochloride 1.5 mg (0.13 wt.%), cetylpyridinium chloride monohydrate 1.05 mg (in terms of cetylpyridinium chloride 1.0 mg) (0.09 wt.%), and excipients: colloidal silicon dioxide 5.0 mg (0.417 wt.%), talc 60.0 mg (5.0 wt.%), acesulfame potassium 15.00 mg (1.25 wt.%), flavoring 25.00 mg (2.08 wt.%), anhydrous citric acid 15.60 mg (1.30 wt.%), isomalt 1048.65 mg (87.386 wt.%), magnesium stearate 25.00 mg (2.08 wt.%).

[0052] The amount, composition and form of the pharmaceutically acceptable excipient can be chosen arbitrarily by a specialist in this field, provided that the properties of the active pharmaceutical substances are fully or partially preserved.

[0053] Liquid dosage form The combination, pharmaceutical composition and drug of the present invention may include 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 certain dosage form, in particular, in a liquid dosage form. In a preferred embodiment, the combination, pharmaceutical composition and drug are a liquid dosage form and include one or more pharmaceutically acceptable excipients (auxiliaries) that are selected from the group consisting of a solvent, a stabilizer, a thickener, an emulsifier, a preservative, a taste and / or odor corrigent, an acidity regulator and a colorant.

[0054] In a preferred embodiment, the liquid dosage form is selected from the group comprising a solution (e.g., a gargle solution, a mouthwash solution), a concentrate for preparing a solution, a spray, a syrup, an infusion, a suspension, an emulsion. In a more preferred embodiment, the liquid dosage form is selected from the group comprising a gargle solution, a concentrate for preparing a solution, or a spray. The liquid dosage form can be an aqueous or aqueous-alcoholic solution, for example, an aqueous-ethanol solution, an alcohol concentrate.

[0055] In the combination, pharmaceutical composition and drug of the present invention in a liquid dosage form, gramicidin C or a pharmaceutically acceptable salt thereof in terms of gramicidin C is contained in an amount of from 0.01 to 100.0 mg per 1 ml of the liquid dosage form, including all intermediate ranges and values, for example, from 0.01 to 10.0 mg, from 0.01 to 5.0 mg, from 0.1 to 2.0 mg, from 0.1 to 1.0 mg, from 0.1 to 0.5 mg, from 0.2 to 0.3 mg, for example, in an amount of: 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 50.0 mg, without limitation to the specified values. In another embodiment, in the combination, pharmaceutical composition and drug of the present invention in a liquid dosage form, gramicidin C or its pharmaceutically acceptable salt, calculated as gramicidin C, is contained in an amount of from 0.01 to 20.0 wt.%, including all intermediate ranges and values, for example, from 0.01 to 2.0 wt.%, from 0.01 to 0.1 wt.%, from 0.01 to 0.05 wt.%, from 0.02 to 0.03 wt.%, for example in an amount of: 0.01 wt.%, 0.02 wt.%, 0.03 wt.%, 0.04 wt.% 0.05 wt.%, 0.06 wt.%, 0.07 wt.%, 0.08 wt.%, 0.09 wt.%, 0.1 wt.%, 0.15 wt.%, 0.2 wt.%, 0.25 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 2.0 wt.%, 5.0 wt.%, not limited to the specified values.

[0056] In the combination, pharmaceutical composition and drug of the present invention in a liquid dosage form, dyclonine or its pharmaceutically acceptable salt in terms of dyclonine is contained in an amount of from 0.01 to 50.0 mg per 1 ml of the liquid dosage form, including all intermediate ranges and values, for example, from 0.01 to 15.0 mg, from 0.05 to 5.0 mg, from 0.1 to 3.0 mg, from 0.1 to 1.0 mg, from 0.1 to 0.5 mg, from 0.2 to 0.3 mg, for example, in an amount of: 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, without limitation to the specified values. In another embodiment, in the combination, pharmaceutical composition and drug of the present invention in a liquid dosage form, dyclonine or its pharmaceutically acceptable salt in terms of dyclonine are contained in an amount of from 0.01 to 10.0 wt.%, including all intermediate ranges and values, for example, from 0.01 to 3.0 wt.%, including all intermediate ranges and values, for example, from 0.01 to 2.0 wt.%, from 0.01 to 0.1 wt.%, from 0.01 to 0.05 wt.%, from 0.02 to 0.03 wt.%, for example in an amount of: 0.01 wt.%, 0.02 wt.%, 0.03 wt.%, 0.04 wt.% 0.05 wt.%, 0.06 wt.%, 0.07 wt.%, 0.08 wt.%, 0.09 wt.%, 0.1 wt.%, 0.15 wt.%, 0.2 wt.%, 0.25 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 2.0 wt.%, 3.0 wt.%, not limited to the specified values.

[0057] The combination, pharmaceutical composition and medicinal product of the present invention in a liquid dosage form optionally contain cetylpyridinium chloride or its monohydrate in terms of cetylpyridinium chloride in an amount of from 0.01 to 100 mg per 1 ml of the liquid dosage form, including all intermediate ranges and values, for example, from 0.01 to 10.0 mg, from 0.01 to 5.0 mg, from 0.1 to 2.0 mg, from 0.1 to 1.0 mg, from 0.2 to 0.8 mg, from 0.3 to 0.6 mg, for example, in an amount of: 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 50.0 mg, without limitation to the specified values. In another embodiment, the combination, pharmaceutical composition and drug of the present invention in a liquid dosage form optionally contain cetylpyridinium chloride or its monohydrate in terms of cetylpyridinium chloride in an amount of from 0.01 to 10.0 wt.%, including all intermediate ranges and values, for example, from 0.01 to 2.0 wt.%, from 0.01 to 0.1 wt.%, from 0.01 to 0.05 wt.%, from 0.02 to 0.08 wt.%, from 0.03 to 0.06 wt.%, for example in an amount of: 0.01 wt.%, 0.02 wt.%, 0.03 wt.%, 0.04 wt.% 0.05 wt.%, 0.06 wt.%, 0.07 wt.%, 0.08 wt.%, 0.09 wt.%, 0.1 wt.%, 0.15 wt.%, 0.2 wt.%, 0.25 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 2.0 wt.%, 3.0 wt.%, 5.0 wt.%, not limited to the specified values.

[0058] The terms "solvent", "carrier" and "diluent" mean auxiliary substances that allow to bring the product into a state convenient for use, i.e. give it an optimal viscosity. The following can be used as a solvent (carrier, diluent): water (purified), ethanol, isopropanol, polyalcohols, buffer solutions, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). The group is not limited to this list. The solvent (carrier, diluent) can be present in the combination, pharmaceutical composition or medicinal product in an amount of from 5.0 to 99.9 wt.%, including all intermediate ranges, for example, from 50.0 to 99.9 wt.%, from 60.0 to 99.0 wt.%, from 80.0 to 99.0 wt.%, without being limited to the specified values.

[0059] The term "stabilizer" means an auxiliary substance that allows preserving the quality or form of the original pharmaceutical product for a long time. Thickeners are intended to provide a certain viscosity of a liquid dosage form, and emulsifiers - to stabilize emulsions. The group of stabilizers, thickeners and emulsifiers includes, without limitation, alginic acid and its salts, agar, gums, chitosan, fatty acids and their salts, glycerin (glycerol) and its esters, polyoxyethylene (tween 20, tween 40, tween 60, tween 80), polyethylene glycol (PEG 300, PEG 400), propylene glycol, pectin, methylcellulose, carboxymethylcellulose. The group is not limited to this list. The stabilizer (emulsifier, thickener) may be present in the combination, pharmaceutical composition or medicinal product in an amount from 0.0 to 40.0 wt.%, including all intermediate ranges, for example, from 0.01 to 30.0 wt.%, from 5.0 to 25.0 wt.%, from 10.0 to 20.0 wt.%, not limited to the specified values.

[0060] Preservatives are substances that ensure the death or inhibition of the development of harmful microorganisms in a product. Preservatives include, without limitation, benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens (methylparaben, ethylparaben, propylparaben), alkylpyridinium, benzethonium and their pharmaceutically acceptable salts. The group is not limited to this list. A preservative may be present in a combination, pharmaceutical composition or medicinal product in an amount from 0.0 to 10.0 wt.%, including all intermediate ranges, for example, from 0.0 to 5.0 wt.%, from 0.05 to 3.0 wt.%, from 0.1 to 1.0 wt.%, without being limited to the specified values.

[0061] The term "acidity regulator" means substances that establish or maintain a certain pH value in a product. Acidity regulators include malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, phosphoric, aspartic, glutaric, glutamic, sorbic acids and their sodium, ammonium, potassium, calcium, magnesium salts, such as sodium citrate, potassium citrate, calcium citrate, magnesium citrate, sodium tartrate, potassium tartrate, sodium potassium tartrate, sodium phosphate, potassium phosphate, ammonium phosphate. The group is not limited to this list. The acidity regulator may be present in the combination, pharmaceutical composition or medicinal product in an amount from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 15.0 wt.%, from 0.1 to 10.0 wt.%, from 0.5 to 5.0 wt.%, from 0.5 to 2.0 wt.%, without being limited to the indicated values.

[0062] Corrigents are used to improve taste (sweetener) and smell (flavoring).

[0063] Sweeteners include, without limitation, maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin and its salts, for example, sodium saccharinate, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame (acesulfame potassium), neotame, lactitol and their pharmaceutically acceptable salts. The group is not limited to this list. The sweetener can be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 10.0 wt.%, from 0.0 to 5.0 wt.%, from 1.0 to 3.0 wt.%, from 1.0 to 2.0 wt.%, without being limited to the specified values.

[0064] Flavorings include, without limitation, raspberry, strawberry, apricot, mint, pear, melon, mango, lemonade or plum flavorings. The group is not limited to this list. The flavoring may be present in the combination, pharmaceutical composition or medicinal product in an amount of from 0.0 to 20.0 wt.%, including all intermediate ranges, for example, from 0.0 to 10.0 wt.%, from 0.0 to 5.0 wt.%, from 1.0 to 3.0 wt.%, from 1.0 to 2.0 wt.%, without being limited to the specified values.

[0065] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention comprise gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more excipients selected from the group consisting of a solvent, a stabilizer, a thickener, an emulsifier, a preservative, an acidity regulator, a flavoring agent and a sweetener.

[0066] In one embodiment, the combination, pharmaceutical composition and drug of the present invention comprise gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more auxiliary substances selected from the group consisting of a solvent, a stabilizer, a thickener, an emulsifier, a preservative, an acidity regulator, a flavoring agent and a sweetener, wherein the solvent is selected from the group consisting of water and ethanol; the stabilizer, thickener and emulsifier are selected from the group consisting of glycerol, propylene glycol, polyethylene glycol, polysorbate (tween 80), sodium alginate, methylcellulose, carboxymethylcellulose; the preservative is selected from the group consisting of methylparaben (methyl parahydroxybenzoate) and propylparaben (propyl parahydroxybenzoate); the acidity regulator is selected from the group including citric acid and sodium citrate;the sweetener is selected from the group including acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group including raspberry, mint, pear, melon flavorings.

[0067] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention contain gramicidin C or gramicidin C dihydrochloride, dyclonine or dyclonine hydrochloride, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate and one or more auxiliary substances selected from the group consisting of solvents water and ethanol; stabilizers (thickeners, emulsifiers) glycerol, propylene glycol, polysorbate 80 (tween 80), PEG 300; preservatives methylparaben and propylparaben, acidity regulators citric acid and sodium citrate, mint flavoring and sweetener sucralose.

[0068] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention contain gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, optionally cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-10.0 wt.% and one or more auxiliary substances selected from the group consisting of solvents water and ethanol; stabilizers (thickeners, emulsifiers) glycerol, propylene glycol, polysorbate 80 (tween 80), PEG 300; preservatives methylparaben and propylparaben, acidity regulators citric acid and sodium citrate, mint flavoring and sweetener sucralose.

[0069] In one embodiment, the combination, pharmaceutical composition and medicinal product of the present invention comprise gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-10.0 wt.% and excipients selected from the group consisting of ethanol solvent in an amount of 1.0-30.0 wt.%; stabilizers (thickeners, emulsifiers) glycerol in an amount of 0.01-30.0 wt.%, propylene glycol in an amount of 0.01-5.0 wt.%, polysorbate 80 (tween 80) in an amount of 0.01-5.0 wt.%, PEG 300 in an amount of 0.01-5.0 wt.%; preservatives methylparaben in an amount of 0.001-3.0 wt.% and propylparaben in an amount of 0.001-3.0 wt.%, acidity regulators citric acid in an amount of 0.001-3.0 wt.% and sodium citrate in an amount of 0.001-3.0 wt.%, mint flavoring in an amount of 0.001-3.0 wt.% and sweetener sucralose in an amount of 0.001-3.0 wt.%, the rest is water.

[0070] An example of a combination, pharmaceutical composition and drug of the present invention: gramicidin C 0.30 mg (0.03 wt.%) dyclonine hydrochloride 0.15 mg (0.015 wt.%) cetylpyridinium chloride 0.50 mg (0.05 wt.%) glycerol 166 mg (16.6 wt.%) ethanol 96% 95 mg (9.5 wt.%) mint flavor 4.1 mg (0.41 wt.%) polysorbate 802.0 mg (0.2 wt.%) sucralose 1.0 mg (0.1 wt.%) methylparaben 0.92 mg (0.092 wt.%) propylparaben 0.10 mg (0.01 wt.%) citric acid monohydrate 0.29 mg (0.29 wt.%) sodium citrate 0.11 mg (0.011 wt.%)

[0071] Water purified to 1 ml (the rest).

[0072] The amount, composition and form of the pharmaceutically acceptable excipient can be chosen arbitrarily by a specialist in this field, provided that the properties of the active pharmaceutical substances are fully or partially preserved.

[0073] Pharmaceutical use

[0074] The combination, pharmaceutical composition and medicinal product of the present invention are intended for the treatment of infectious and inflammatory diseases of the oral cavity and / or throat. Infectious and inflammatory diseases of the oral cavity and / or throat include, in particular, angina, pharyngitis, glossitis, tonsillitis, periodontitis, gingivitis, stomatitis, laryngitis, adenoiditis.

[0075] The said combination, pharmaceutical composition and medicinal product are intended for local application. Local application means irrigation or spraying of the combination, pharmaceutical composition and medicinal product on the mucous membrane of the oral cavity and throat, rinsing, resorption or dispersion in the oral cavity.

[0076] The combination, pharmaceutical composition and medicinal product are used in the treatment of infectious and inflammatory diseases of the oral cavity and / or throat in a certain dosage. The term "dosage" used herein characterizes the content of one or more active substances in quantitative terms per 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.

[0077] The dosage of gramicidin C according to the present invention may be in the range of 1 mg to 50 mg per day, preferably 1 mg to 20 mg, even more preferably 3 to 12 mg per day. The dosage of dyclonine hydrochloride may be in the range of 0.5 to 25 mg per day, preferably 1 mg to 10 mg, even more preferably 1 to 5 mg per day.

[0078] Routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, topical and sublingual. In a preferred embodiment, the pharmaceutical composition is administered orally or sublingually.

[0079] In some embodiments, the pharmaceutical composition of the present invention can be prepared using known conventional methods in the pharmaceutical field.

[0080] Implementation of the invention

[0081] The present invention is further illustrated, but not limited, by the following examples.

[0082] Example 1. Getting a combination

[0083] To obtain the combination of the present invention, gramicidin C, dyclonine and cetylpyridinium chloride are mixed in the required quantities. Examples of the obtained combinations are given in Table 1.

[0084] Table 1. Combinations of the present invention

[0085] Example 2. Obtaining a pharmaceutical composition and a medicinal product in the form of a solid dosage form

[0086] To prepare a pharmaceutical composition in the form of a lozenge, each component of the drug is preliminarily sifted manually or using a vibrating sieve. The calculated amount of filler, sweetener, flavor corrigent, dyclonine hydrochloride, cetylpyridinium chloride, sliding agent, acidity regulator is loaded into the mixer, mixed, the calculated amount of lubricant is added and mixed. The tablets are manufactured on a rotary tablet press. The resulting tablets are dust-free and transferred to the packaging stage. The finished tablets can be packed in blisters, and the blisters - in cardboard packs. Examples of the resulting pharmaceutical compositions and drugs in solid form are given in Table 2.

[0087] Table 2. Pharmaceutical compositions of the present invention

[0088] Table 2 continued.

[0089] The detailed composition of the pharmaceutical composition of the present invention is presented in Table 3. Table 3. Example of the pharmaceutical composition of the present invention

[0090] Example 3. Obtaining a pharmaceutical composition and a medicinal product in the form of a liquid dosage form The production tank was filled with water, ethanol 96% and Tween 80 were added.

[0091] After that, the following substances were successively added to it with stirring until completely dissolved: dyclonine hydrochloride, cetylpyridinium chloride, propylene glycol, polyethylene glycol, glycerin, citric acid monohydrate, sodium citrate, sucralose, gramicidin C hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, mint flavoring. The resulting mixture was additionally stirred for an hour until completely homogenized, after which it was filtered, poured into bottles and packaged.

[0092] Examples of the obtained compositions are given in Table 4.

[0093] Table 4. Pharmaceutical compositions of the present invention

[0094] Example 4. Stability study

[0095] The stability of the pharmaceutical composition of the present invention was assessed by the accelerated aging method according to OFS.1.1.0009.15 Shelf life of medicinal products, the State Pharmacopoeia of the Russian Federation. At elevated temperatures, as a rule, the physicochemical processes occurring in medicinal products are accelerated, leading over time to undesirable changes in quality. Thus, at elevated temperatures, the period of time during which the controlled quality indicators of the medicinal product remain within acceptable limits (experimental shelf life) is artificially reduced.

[0096] For this purpose, a 600 mg experimental sample of the composition was placed in aluminum foil for blisters, after which it was transferred to a climate chamber at a temperature of 40±2°C and a relative humidity of 75+5%. The samples were analyzed after 1 month, 3 months, and 6 months.

[0097] The compositions of the samples are presented in Table 5. The compositions were obtained similarly to Example 2. Table 5. Pharmaceutical compositions for determining the technological characteristics of mixtures

[0098] In the HPLC analysis, a mixture of methanol and 0.1% phosphoric acid solution in a volume ratio of 80:20 was used as a solvent. To prepare the test solution, about 0.600 g of powder was placed in a 50 ml volumetric flask, 35 ml of solvent was added, the mixture was shaken vigorously on a shaker for 15 min, then sonicated for 15 min, cooled, the volume of the solution was brought up to the mark with solvent, mixed and filtered through a membrane filter with a pore diameter of 0.45 μm, discarding the first portions of the filtrate.

[0099] To prepare a standard solution of gramicidin C, about 30.0 mg of gramicidin C hydrochloride was placed in a 20 ml measuring flask, dissolved in a solvent, the volume of the solution was brought up to the mark with the same solvent and mixed.

[0100] A buffer solution with pH 2.5 for chromatography was prepared as follows. 6.00 g of lithium perchlorate was placed in a 1000 ml volumetric flask, 900 ml of water for chromatography were added, the mixture was stirred until the salt was completely dissolved, 1.0 ml of concentrated phosphoric acid was added, the mixture was stirred, the pH of the resulting solution was adjusted to 2.5 ± 0.05 using 30% sodium hydroxide solution, the volume of the solution was adjusted to 1000 ml with water for chromatography, the mixture was stirred and filtered through a membrane filter with a pore diameter of 0.45 μm.

[0101] Chromatographic conditions:

[0102] Column "Kinetex® C 18", 2.6 µm; 100 x 4.6 mm from

[0103] Phenomenex,

[0104] Mobile phase A: buffer solution pH 2.5; Mobile phase B: acetonitrile for chromatography;

[0105] Depending on the peak area, the quantitative content of gramicidin C was determined by comparing it with the peak area of ​​a standard gramicidin C solution.

[0106] The results of the study are presented in Table 6.

[0107] Table 6. Stability study of the pharmaceutical composition of the present invention

[0108] The obtained results indicate the stability of the pharmaceutical composition of the present invention over a long period of time.

[0109] Example 5. Technological characteristics of pharmaceutical compositions

[0110] To study flowability and bulk density, 5 compositions were obtained similarly to example 4.

[0111] To determine the bulk density and flowability, 100 g of each composition was prepared. Approximately 100 g of the test sample is carefully added to a dry graduated cylinder with a volume of 250 ml without compaction. The observed (apparent) volume of the uncompacted test sample is determined from the nearest division of the graduated cylinder. The bulk density is calculated in grams per milliliter (g / ml) as the ratio of the mass of the sample to the volume of the uncompacted sample.

[0112] To determine the flowability, a sample of the test material is placed without compaction in a dry funnel with a closed outlet opening of 10 mm in diameter. The outlet opening of the funnel is opened and the time it takes for the entire sample to pass through the opening is determined. Flowability is calculated as the ratio of the sample mass to a unit of time. The measurement results are presented in Table 7.

[0113] Table 7. Bulk density and flowability of pharmaceutical compositions Thus, the pharmaceutical compositions of the present invention 32, 33 and 34 have increased bulk density and flowability, which is an advantage when producing solid dosage forms. The compositions are poured out of the bin faster, and are also dosed into matrices more uniformly and densely.

[0114] Example 6. Study of the rate of dissolution of compositions

[0115] The dissolution rate study was carried out for pharmaceutical compositions 32-36 obtained in Example 4.

[0116] Weighed portions of the compositions weighing 1 g were placed in 10 ml of a water-salt solution of hyposalix, which maximally replicates the pH and other characteristics of saliva. The dissolution of the studied compositions was observed. Samples were taken to measure the content of gramicidin C in dissolved form after 15, 30, 45 minutes.

[0117] The content of gramicidin was determined by HPLC. The method of quantitative determination is presented in Example 4. The measurement results are presented in Table 8.

[0118] Table 8. Dissolution of gramicidin C

[0119] The compositions of the present invention (32, 33 and 34) provide an increased dissolution rate of gramicidin C.

[0120] Example 7. Study of antimicrobial activity

[0121] For in vitro studies of the antimicrobial activity of pharmaceutical compositions 32-36, strains of Staphylococcus aureus ATCC 6538-P and Streptococcus pneumoniae ATCC 6303 were used.

[0122] The study was conducted in two consecutive stages.

[0123] At the first stage of the study, the antibacterial activity of the studied objects was determined by establishing the minimum inhibitory concentration (MIC) by serial dilutions in gramicidin C agar against Staphylococcus aureus and Streptococcus pneumoniae strains using the standard method [MUK 4.2.1890-04 "Determination of the sensitivity of microorganisms to antibacterial drugs". - URL: https: / / docs.cntd.ru / document / 1200038583]. The principle of the method is to sow the studied microorganism strains on Petri dishes with agar containing serial double dilutions of the antibacterial drug (ABD). The results are presented in Table 9.

[0124] Table 9. Antimicrobial activity of composition 32

[0125] Based on the obtained results, the MIC was selected to be 16 μg / ml for the active substance Gramicidin C against Staphylococcus aureus ATCC 6538-P and Streptococcus pneumoniae ATCC 6303.

[0126] At the second stage of the study, a comparison of the antibacterial activity of the studied compositions was carried out using the agar diffusion method in accordance with OFS.1.2.4.0010.18 "Determination of the antimicrobial activity of antibiotics using the agar diffusion method" [State Pharmacopoeia of the Russian Federation. XIV edition. - M .: 2018]. The principle of the method lies in the ability of the test object and the comparison object on dense nutrient media to form zones of inhibition of the growth of the studied microorganism strain.

[0127] During the preparation for the experiment, the optimal seeding concentration of the microorganism was chosen to be 10 4 CFU / ml.

[0128] The studied objects were added to the prepared nutrient medium in the minimum inhibitory concentration.

[0129] Incubation

[0130] To reduce the influence of fluctuations in time between instillation of the solutions used in the experiment, after adding the solutions of the objects under study, the Petri dishes were kept at room temperature for 1 hour. Then the dishes were incubated in a thermostat at a temperature of (36±1)°C for 24 hours under aerobic conditions for Staphylococcus aureus, and for Streptococcus pneumoniae in an atmosphere containing 5% CO2.

[0131] Data Analysis

[0132] On Petri dishes after incubation in a thermostat, the diameters of the growth inhibition zones of Staphylococcus aureus and Streptococcus pneumoniae were measured using a measuring ruler and the activity of the studied objects was calculated in accordance with the article of the OFS 1.1.0014.15 using dispersion analysis.

[0133] The results of measurements of the diameters of the inhibition zones of Staphylococcus aureus ATCC 6538-P and Streptococcus pneumoniae ATCC 6303 are presented in Table 10 and show the inhibitory ability of the studied objects to suppress the growth of microorganisms. Table 10. The arithmetic mean value of the diameters of the inhibition zones, at a dose of 16 μg / ml.

[0134] Analysis of the in vitro experiment results showed statistically significantly more pronounced antibacterial activity of the compositions of the present invention 32-34 compared to compositions 35 and 36.

Claims

Invention formula 1. A combination for the treatment of infectious and inflammatory diseases of the oral cavity and throat, containing gramicidin C and dyclonine or their pharmaceutically acceptable salts, wherein the active substances are in the following mass ratios: gramicidin C: dyclonine from 50: 1 to 1:

20.

2. The combination according to claim 1, characterized in that the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride and the pharmaceutically acceptable salt of dyclonine is dyclonine hydrochloride.

3. The combination according to claim 1, characterized in that the active substances are in a mass ratio of gramicidin C: dyclonine from 10: 1 to 1:

2.

4. The combination according to claim 1, characterized in that the active substances are in a mass ratio of gramicidin C: dyclonine from 4: 1 to 1:

1.

5. The combination according to claim 1, characterized in that the active substances or their pharmaceutically acceptable salts are in the following mass ratios: gramicidin C: dyclonine 2.25: 1, or gramicidin C: dyclonine hydrochloride 2: 1, or gramicidin C dihydrochloride: dyclonine 2.4: 1, or gramicidin C dihydrochloride: dyclonine hydrochloride 2.13:

1.

6. The combination according to claim 1, characterized in that it additionally contains an antiseptic selected from the group consisting of ethanol, isopropanol, chlorhexidine, cetylpyridinium chloride, benzalkonium chloride, cetrimide, hexethidine, benzyldimethylmyristoylaminopropylammonium chloride, tetraethyl ammonium bromide, nitrofural, amylmetacresol, dichlorobenzyl alcohol, ambazone, lysozyme, tyrothricin, benzodiamine.

7. The combination according to i.1, characterized in that said combination additionally contains cetylpyridinium chloride or its hydrate.

8. The combination according to claim 1, characterized in that the said combination contains gramicidin C, dyclonine or their pharmaceutically acceptable salts and cetylpyridinium chloride or its hydrate in the following weight ratio of active ingredients gramicidin C: dyclonine hydrochloride: cetylpyridinium chloride 3: 1.5:

1.

9. The combination according to claim 1, characterized in that the infectious and inflammatory diseases of the oral cavity and throat are selected from the group including tonsillitis, stomatitis, gingivitis, glossitis, pharyngitis, tonsillitis, periodontitis, adenoiditis and laryngitis.

10. A pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and throat, containing gramicidin C and dyclonine or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where the active substances are in the following mass ratios: gramicidin C: dyclonine from 50: 1 to 1:

20.

11. The pharmaceutical composition according to item 10, characterized in that the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride and the pharmaceutically acceptable salt of dyclonine is dyclonine hydrochloride.

12. The pharmaceutical composition according to item 10, characterized in that the active substances are in a mass ratio of gramicidin C: dyclonine from 10: 1 to 1:

2.

13. A pharmaceutical composition according to I.10, characterized in that the active substances are in a mass ratio of gramicidin C: dyclonine from 4:1 to 1:

1.

14. The pharmaceutical composition according to item 10, characterized in that the active substances or their pharmaceutically acceptable salts are in the following mass ratios: gramicidin C: dyclonine 2.25: 1, or gramicidin C: dyclonine hydrochloride 2: 1, or gramicidin C dihydrochloride: dyclonine 2.4: 1, or gramicidin C dihydrochloride: dyclonine hydrochloride 2.13:

1.

15. The pharmaceutical composition according to item 10, characterized in that said composition additionally contains an antiseptic selected from the group consisting of ethanol, isopropanol, chlorhexidine, cetylpyridinium chloride, benzalkonium chloride, cetrimide, hexethidine, benzyldimethylmyristoylaminopropylammonium chloride, tetraethyl ammonium bromide, nitrofural, amylmetacresol, dichlorobenzyl alcohol, ambazone, lysozyme, tyrothricin, benzodiamine.

16. A pharmaceutical composition according to item 10, characterized in that said composition additionally contains cetylpyridinium chloride or its hydrate.

17. A pharmaceutical composition according to item 10, characterized in that said composition is a solid dosage form.

18. A pharmaceutical composition according to item 17, characterized in that the solid dosage form is selected from the group comprising a powder, an orally dispersible tablet, a lozenge tablet, and a tablet for preparing a solution.

19. A pharmaceutical composition according to item 17, characterized in that said composition contains one or more auxiliary substances selected from the group consisting of a filler, a binder, a lubricant, a disintegrating substance, a glidant, a preservative, a sweetener, a flavoring agent, and an acidity regulator.

20. The pharmaceutical composition according to item 19, characterized in that the filler is selected from the group comprising isomalt, sorbitol, lactose, mannitol, microcrystalline cellulose; the glidant is selected from the group comprising talc, silicon dioxide; the lubricant is selected from the group comprising magnesium stearate, calcium stearate, sodium stearyl fumarate; the acidity regulator is selected from the group comprising citric acid, malic acid, lactic acid, tartaric acid; the sweetener is selected from the group comprising acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group comprising raspberry, mint, pear, melon flavorings.

21. The pharmaceutical composition according to item 19, characterized in that said composition contains the filler isomalt, the lubricants talc and silicon dioxide, the lubricant magnesium stearate, the acidity regulator citric acid, the sweetener acesulfame potassium and the flavoring agent mint.

22. A pharmaceutical composition according to item 10, characterized in that said composition is a liquid dosage form.

23. The pharmaceutical composition according to claim 22, characterized in that the liquid dosage form is selected from the group including a rinsing solution, a concentrate for preparing a solution, and a spray.

24. A pharmaceutical composition according to claim 23, characterized in that said composition contains one or more auxiliary substances selected from the group consisting of a solvent, a stabilizer, a thickener, an emulsifier, a preservative, a sweetener, a flavoring agent, and an acidity regulator.

25. The pharmaceutical composition according to claim 24, characterized in that the solvent is selected from the group consisting of water and ethanol; the stabilizer, thickener and emulsifier are selected from the group consisting of glycerol, propylene glycol, polyethylene glycol, polysorbate (tween 80), sodium alginate, methylcellulose, carboxymethylcellulose; the preservative is selected from the group consisting of methylparaben (methyl parahydroxybenzoate) and propylparaben (propyl parahydroxybenzoate); the acidity regulator is selected from the group, including citric acid and sodium citrate; the sweetener is selected from the group including acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group including raspberry, mint, pear, melon flavorings.

26. The pharmaceutical composition according to claim 24, characterized in that said composition contains the solvents water and ethanol; stabilizers (thickeners, emulsifiers) glycerol, propylene glycol, polysorbate 80 (tween 80), PEG 300; preservatives methylparaben and propylparaben, acidity regulators citric acid and sodium citrate, mint flavoring and sweetener sucralose.

27. A pharmaceutical composition for the treatment of infectious and inflammatory diseases of the oral cavity and throat, containing gramicidin C and dyclonine or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, where the active substances are contained in the following quantities: gramicidin C 0.01-20.0 wt.%, dyclonine 0.01-10.0 wt.%.

28. The pharmaceutical composition according to claim 27, characterized in that the pharmaceutically acceptable salt of gramicidin C is gramicidin C dihydrochloride and the pharmaceutically acceptable salt of dyclonine is dyclonine hydrochloride.

29. The pharmaceutical composition according to claim 27, characterized in that said composition additionally contains an antiseptic selected from the group consisting of ethanol, isopropanol, chlorhexidine, cetylpyridinium chloride, benzalkonium chloride, cetrimide, hexethidine, benzyldimethylmyristoylaminopropylammonium chloride, tetraethyl ammonium bromide, nitrofural, amylmetacresol, dichlorobenzyl alcohol, ambazone, lysozyme, tyrothricin, benzodiamine.

30. A pharmaceutical composition according to paragraph 27, characterized in that said composition additionally contains cetylpyridinium chloride or its hydrate.

31. A pharmaceutical composition according to paragraph 27, characterized in that said composition is a solid dosage form.

32. The pharmaceutical composition according to paragraph 31, characterized in that the solid dosage form is selected from the group including powder, tablet, orodispersible tablet, lozenge tablet and tablet for solution preparation.

33. A pharmaceutical composition according to claim 31, characterized in that said composition contains one or more auxiliary substances selected from the group consisting of a filler, a binder, a lubricant, a disintegrating substance, a glidant, a preservative, a sweetener, a flavoring agent, and an acidity regulator.

34. The pharmaceutical composition according to paragraph 33, characterized in that the filler is selected from the group including isomalt, sorbitol, lactose, mannitol, microcrystalline cellulose; the glidant is selected from the group including talc, silicon dioxide; the lubricant is selected from the group including magnesium stearate, calcium stearate, sodium stearyl fumarate; the acidity regulator is selected from the group including citric acid, malic acid, lactic acid, tartaric acid; the sweetener is selected from the group including acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group including raspberry, mint, pear, melon flavorings.

35. A pharmaceutical composition according to paragraph 33, characterized in that said composition contains the filler isomalt, the lubricants talc and silicon dioxide, the lubricant magnesium stearate, the acidity regulator citric acid, the sweetener acesulfame potassium and the flavoring agent mint.

36. The pharmaceutical composition according to claim 31, characterized in that the said composition contains gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-5.0 wt.% and auxiliary substances filler isomalt in an amount of 50.0-95.0 wt.%, sliding substances talc in an amount of 0.25-10.0 wt.% and silicon dioxide in an amount of 0.25-10.0 wt.%, lubricant magnesium stearate in an amount of 0.25-5.0 wt.%, acidity regulator citric acid in an amount of 0.1-15.0 wt.%, sweetener acesulfame potassium in in an amount of 0.0-10.0 wt.% and mint flavoring in an amount of 0.0-10.0 wt.%.

37. The pharmaceutical composition according to item 36, characterized in that said composition contains gramicidin C dihydrochloride 0.267 wt.%, diclonine hydrochloride 0.13 wt.%, cetylpyridinium chloride 0.09 wt.%, and excipients: isomalt 87.386 wt.%, colloidal silicon dioxide 0.417 wt.%, talc 5.0 wt.%, acesulfame potassium 1.25 wt.%, flavoring 2.08 wt.%, anhydrous citric acid 1.30 wt.%, magnesium stearate 2.08 wt.%.

38. A pharmaceutical composition according to paragraph 27, characterized in that said composition is a liquid dosage form.

39. The pharmaceutical composition according to claim 38, characterized in that the liquid dosage form is selected from the group including a rinsing solution, a concentrate for preparing a solution, and a spray.

40. A pharmaceutical composition according to claim 38, characterized in that said composition contains one or more auxiliary substances selected from the group consisting of a solvent, a stabilizer, a thickener, an emulsifier, a preservative, a sweetener, a flavoring agent, and an acidity regulator.

41. The pharmaceutical composition according to claim 40, characterized in that the solvent is selected from the group consisting of water and ethanol; the stabilizer, thickener and emulsifier are selected from the group consisting of glycerol, propylene glycol, polyethylene glycol, polysorbate (tween 80), sodium alginate, methylcellulose, carboxymethylcellulose; the preservative is selected from the group consisting of methylparaben (methyl parahydroxybenzoate) and propylparaben (propyl parahydroxybenzoate); the acidity regulator is selected from the group consisting of citric acid and sodium citrate; the sweetener is selected from the group consisting of acesulfame potassium, sucralose, aspartame, sucrase, sodium saccharinate; the flavoring is selected from the group consisting of raspberry, mint, pear, melon flavorings.

42. A pharmaceutical composition according to claim 40, characterized in that said composition contains solvents water and ethanol; stabilizers (thickeners, emulsifiers) glycerol, propylene glycol, polysorbate 80 (tween 80), PEG 300; preservatives methylparaben and propylparaben, acidity regulators citric acid and sodium citrate, mint flavoring and sweetener sucralose.

43. The pharmaceutical composition according to claim 38, characterized in that the said composition contains gramicidin C or gramicidin C dihydrochloride in an amount of 0.01-20.0 wt.%, dyclonine or dyclonine hydrochloride in an amount of 0.01-10.0 wt.%, cetylpyridinium chloride or cetylpyridinium chloride monohydrate in an amount of 0.0-10.0 wt.% and auxiliary substances: ethanol solvent in an amount of 1.0-30.0 wt.%; stabilizers (thickeners, emulsifiers) glycerol in an amount of 0.01-30.0 wt.%, propylene glycol in an amount of 0.01-5.0 wt.%, polysorbate 80 (tween 80) in an amount of 0.01-5.0 wt.%, PEG 300 in an amount of 0.01-5.0 wt.%; preservatives methylparaben in an amount of 0.001-3.0 wt.% and propylparaben in an amount of 0.001-3.0 wt.%; acidity regulators citric acid in an amount of 0.001-3.0 wt.% and sodium citrate in an amount of 0.001-3.0 wt.%; mint flavoring in an amount of 0.001-3.0 wt.%; sweetener sucralose in an amount of 0.001-3.0 wt.% and water.

44. The pharmaceutical composition according to claim 43, characterized in that the said composition contains gramicidin C 0.03 wt.%, dyclonine hydrochloride 0.015 wt.%, cetylpyridinium chloride 0.05 wt.%, glycerol 16.6 wt.%, ethanol 96% 9.5 wt.%, mint flavoring 0.41 wt.%, polysorbate 800.2 wt.%, sucralose 0.1 wt.%, methylparaben 0.092 wt.%, propylparaben 0.01 wt.%, citric acid monohydrate 0.29 wt.%, sodium citrate 0.011 wt.%, Purified water is the rest.

45. A medicinal product for the treatment of infectious and inflammatory diseases of the oral cavity and throat, comprising a combination according to any of paragraphs 1-9 or a pharmaceutical composition according to any of paragraphs 10-44.

46. ​​The use of a combination according to any of paragraphs 1-9, a pharmaceutical composition according to any of paragraphs 10-44 and a medicinal product according to paragraph 45 for the treatment of infectious and inflammatory diseases of the oral cavity and throat.

47. The use according to paragraph 46, characterized in that the infectious and inflammatory diseases of the oral cavity and throat are selected from the group including tonsillitis, stomatitis, gingivitis, glossitis, pharyngitis, tonsillitis, periodontitis, adenoiditis and laryngitis.

Images