RU2563238C1 - Antibacterial system for inhibiting growth of pathogenic microflora, composition based thereon, method of preparing composition based on antibacterial system for inhibiting growth of pathogenic microflora - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: antibacterial composition contains silver, stabilisers in the form of polyvinyl-N-pyrrolidone and in the form of a proteinate. The composition is formed as a solid weighed water-soluble form. The silver is pretreated with a proteinate stabiliser, further treated with a polyvinyl-N-pyrrolidone stabiliser and dissolved in water to obtain colloidal silver particles. An antibacterial system is provided, which includes a composition, at least one vessel with a solvent and a flask for preparing a solution of the composition. Another aspect provides a method of producing said system.

EFFECT: use of the group of inventions increases the efficiency of inhibiting growth of pathogenic microflora owing to accurate weighing of the active pharmaceutical substance when preparing a solution of silver proteinate in household conditions while preserving properties of the latter up to the moment when used by the end consumer.

16 cl, 1 tbl, 1 ex

Description

The claimed technical solutions relate to the field of medicine and hygiene and can be used to inhibit the growth of pathogenic microflora of the human body, to increase the effectiveness of the treatment of acute and chronic rhinitis, otitis externa, conjunctivitis, blepharitis, chronic gonorrheic urethitis.

Terms used:

SYSTEM (Greek "sytëma" - a whole made up of parts, a compound) - a set of any elements connected together and considered as a single and functional structural whole (dic.academic.ru> Medical Encyclopedia / http: // dic. academic.ru/dic.nsf/enc_medicine/).

SOLUTION - in medicine - liquid dosage form - a homogeneous transparent mixture of a medicine (solid or liquid) and any liquid (solvent) (Big Encyclopedic Dictionary. 2000 / http://dic.academic.ru/dic.nsf/enc3p/ 251654).

COMPOSITION (from the Latin “componere” - to add, build) - a combination of individual objects into a single whole (Dictionary of foreign words that are part of the Russian language. - Chudinov AN, 1910).

SET - a collection of objects forming something whole (S.I. Ozhegov, N.Yu. Shvedova "Explanatory Dictionary of the Russian Language" /http://ozhegov.info/slovar).

Solvents, individual chemical compounds or mixtures capable of dissolving various substances, i.e. form homogeneous systems of variable composition with them, consisting of two or more components. For liquid - gas and liquid - solid systems, the solvent is considered to be the liquid component.

A technical solution is known - a drug substance under the trade name Silver proteinate - Silver proteinate, which is a brown-yellow or brown light powder, odorless, slightly bitter and slightly astringent taste, containing a colloidal compound of silver oxide, silver nitrate or other silver salt with gelatin, whey albumin, casein or peptone (Radar Drugs Index, http://www.rlsnet.ru/mnn_index_id_1143.htm).

The disadvantages of the known technical solution is that it has weak hygroscopicity and the ability to change when exposed to light. Therefore, it is impossible to buy a finished preparation in the form of a solution based on silver proteinate in a retail pharmacy chain. The drug is made only by prescription on order. A pharmacy prepares a solution of silver proteinate only if its structure includes a production department engaged in the manufacture of medicinal solutions from medicinal raw materials. Independent preparation of a solution of silver proteinate is impossible, because accurate weighing of the active pharmaceutical substance - silver proteinate and compliance with the technology of preparation of the solution is necessary. In the factory, a solution of silver proteinate is unprofitable and impossible due to the short duration of the conservation of aggregate stability of silver ions in aqueous solutions, not exceeding 2-3 weeks.

A technical solution is known - a water-soluble bactericidal composition containing highly dispersed metallic silver stabilized with a protective high molecular weight compound and a method for producing this composition (RF Patent No. 2088234, IPC A61K 31/79, priority 25.11.1994).

A known technical solution is a water-soluble silver-containing bactericidal composition and a method for its preparation (RF Patent No. 2128047, IPC A61K 31/79, priority 21.06.1995). The water-soluble silver-containing bactericidal composition contains highly dispersed metallic silver and polyvinyl-N-pyrrolidone. The composition is obtained by reacting a 2-5% aqueous solution, ethyl alcohol with an aqueous solution of silver nitrate, in the presence of polyvinylpyrrolidone, at 65-75 ° C in the dark in an inert atmosphere, obtaining highly dispersed metal stabilized by polymer. To an aqueous solution of a dispersion of silver with a metal content of 0.01-1.0 wt. % add a 0.05-10.0% aqueous solution of hydrogen peroxide and conduct the reaction until the reaction mixture is completely discolored. After drying, the composition is isolated.

The disadvantages of the known technical solutions is that in the preparation of water-soluble silver-containing bactericidal compositions, a water-soluble silver nitrate salt is used, which when dissolved in water forms ionic silver, which has high reactivity, which causes their increased toxicity, cauterizing and irritating effect on the skin and mucous membranes. In addition, when ingested, silver ions quickly interact with anions of body fluids, proteins and cellular components, inactivate, forming various inactive compounds.

A technical solution is known, taken as a prototype for the claimed antibacterial composition to inhibit the growth of pathogenic microflora, a water-soluble silver-containing bactericidal composition containing highly dispersed surface-oxidized metallic silver with an oxidation state of 32.26-34.45% with respect to ingredients, wt. %: Highly dispersed surface-oxidized metallic silver - 7.46-8.68, polyvinyl-N-pyrrolidone with MM 8 · 10 ³ -35 · 10 ³ - 91.32-92.54 (RF Patent No. 2128047, IPC A61K 31 / 79, А61K 33/38, priority dated June 21, 1995, published March 27, 1999). The known composition is obtained by the interaction of 0.17-10.0% aqueous solutions of polyvinyl-N-pyrrolidone with MM 8 · 10 ³ -35 · 10 ³ containing 2-5% ethanol, with 0.4-5.2% aqueous nitrate solutions silver (AgNO ₃ ).

The disadvantages of the known technical solutions is that in the preparation of water-soluble silver-containing bactericidal compositions, a water-soluble silver nitrate salt is used, which when dissolved in water forms ionic silver, which has high reactivity, which causes their increased toxicity, cauterizing and irritating effect on the skin and mucous membranes. In addition, when ingested, silver ions quickly interact with anions of body fluids, proteins and cellular components, inactivate, forming various inactive compounds.

A technical solution is known - a system related to molded devices for storing chemicals, in particular pharmaceutical dosage forms for drugs that rapidly decompose in water. The molded device contains an open matrix grid for storing chemicals (US Patent 4371516, IPC A61O 1/03, priority dated July 17, 1981).

A technical solution is known - a system and a method for its preparation, intended for the manufacture of aerosols of moisture-sensitive drugs and a pharmaceutical kit for administering an aerosol (US Patent 6161536, IPC A61J 1/00, priority dated 07.10.1998). The kit may also include a graduated atomizer. The drug for use in the kit is formoterol.

A technical solution is known - an inhaled pharmaceutical system containing Formoterol as an active component, consisting of: a bottle containing a sterile liquid carrier suitable for inhalation; the lid of the vessel with a reservoir for a powder mixture containing Formoterol or the corresponding salt in ionized form and one or more excipients soluble in the carrier and suitable for respiratory use (US Patent 6719994, IPC A61K 31/167, priority 02.03.2001).

The disadvantages of the known solutions is that they are intended for aerosol use, cannot create a composition based on an antibacterial system to inhibit the growth of pathogenic microflora, which allows to obtain silver proteinate in dosage form, ensuring the safety of the properties of the latter until use by the end user, as well as to ensure accurate dosage of the active pharmaceutical substance in the preparation of a solution of silver proteinate at home.

A technical solution is known - a pharmaceutical kit for producing liquid agents that can be administered to humans in the form of aerosols for the diagnosis, prophylaxis, or treatment of human diseases (Application WO / 2003/035030, IPC A61K 9/08, priority dated October 24, 2002). The kit of the invention contains an active component and a volume with a sterile aqueous solution capable of dispersing or dissolving the solid composition to form a liquid composition, which may be of an aerosol type.

The disadvantages of the known technical solutions is that in the preparation of water-soluble silver-containing bactericidal compositions, a water-soluble silver nitrate salt is used, which when dissolved in water forms ionic silver, which has high reactivity, which causes their increased toxicity, cauterizing and irritating effect on the skin and mucous membranes. In addition, when ingested, silver ions quickly interact with anions of body fluids, proteins and cellular components, inactivate, forming various inactive compounds.

The objective of the proposed technical solution is to develop an antibacterial composition for inhibiting the growth of pathogenic microflora, an antibacterial system comprising an antibacterial composition for inhibiting the growth of pathogenic microflora, and a method for producing an antibacterial system comprising an antibacterial composition for inhibiting the growth of pathogenic microflora, allowing to obtain silver proteinate in a dosage form, providing preservation of the properties of the latter until the end user uses it m, as well as to ensure accurate dosing of active pharmaceutical ingredient in the preparation of silver proteinate solution under conditions of home use.

The problem is solved in that the antibacterial composition for suppressing the growth of pathogenic microflora, containing silver and a stabilizer in the form of polyvinyl-N-pyrrolidone, additionally contains a stabilizer in the form of proteinate, formed in the form of a solid dosage form, soluble in water, in which silver is made with a pre-treated stabilizer proteinate, additionally treated with stabilizer polyvinyl-N-pyrrolidone, and soluble in water to obtain colloidal particles of silver. In this case, the proteinate serves as a silver stabilizer, polyvinyl-N-pyrrolidone serves as a stabilizer of silver protein, the molecular weight of polyvinyl-N-pyrrolidone

(8-35) × 10 ³ - 91.5-92.5 g / mol. When dissolved in water, the solid dosage form contains from 7.0 to 9.0% silver and is made in the form of a tablet, which can be in the form of a geometric figure used for the production of medicines or hygiene products, for example, in the form of a tablet, in the form of a cylinder, in the form of a dragee, in the form of a ball.

An antibacterial system comprising an antibacterial composition for suppressing the growth of pathogenic microflora as an active component, at least one vessel with a solvent additionally contains a vial for preparing a solution of the antibacterial composition, the solvent being purified water, the antibacterial composition containing silver and a stabilizer in the form of polyvinyl-N -pyrrolidone, a stabilizer in the form of a proteinate, is formed in the form of a solid, water-soluble dosage form in which silver is produced flaxed with pre-treated stabilizer proteinate, additionally treated with stabilizer polyvinyl-N-pyrrolidone, and soluble in water to produce colloidal silver particles, while the active component is sealed. The vessel with the aqueous solution is made either in the form of a dropper tube, or in the form of a polymer ampoule, or in the form of a glass ampoule, the bottle is made with the volume necessary and sufficient to prepare a solution of the composition with a concentration of 1% to 5% when one active component is dissolved in the volume of solvent contained in the same container with the solvent, the sealed package is made in the form of a contour package, which can be either aluminum foil, or polymer-coated paper, or a combined material consisting of aluminum foil and polyvinyl chloride film, or of a combined material consisting of polymer coated paper and aluminum foil.

A method for producing an antibacterial system, comprising an antibacterial composition for suppressing the growth of pathogenic microflora, comprising the steps of: a) preparing system components, including at least one hermetically sealed vessel, which comprises purified water containing at least one active component, which is made in the form of an antibacterial composition, containing silver, a stabilizer in the form of polyvinyl-N-pyrrolidone, a stabilizer in the form of a proteinate, c) the formation of an antibacterial composition in the form of a solid dosage a water-soluble form in which silver is made with a pre-treated stabilizer proteinate, an additionally treated stabilizer polyvinyl-N-pyrrolidone, and soluble in water to obtain colloidal particles of silver, while the active component is placed in a sealed package containing at least one packaging element, a bottle for dilution of one active component in water contained in one vessel; c) the use of a container made with the possibility of placing in it at least one sealed package with at least one active component, at least one hermetically sealed container with a solvent, at least one bottle, instructions for use. The protein serves as a silver stabilizer, and polyvinyl-N-pyrrolidone serves as a silver protein stabilizer. The molecular weight of polyvinyl-N-pyrrolidone is (8-35) × 10 ³ - 91.5-92.5 g / mol. The solid dosage form when dissolving water contains from 7.0 to 9.0% silver and is made in the form of a tablet, which can be made in the form of a geometric figure used for the production of medicines or hygiene products, for example in the form of a cylinder, or in the form of a ball.

The technical effect achieved by the claimed technical solutions consists in the possibility of obtaining silver proteinate in a dosage form that ensures the preservation of the properties of the latter until it is used by the end user, in the ability to ensure accurate dosing of the active pharmaceutical substance in the preparation of a solution of silver proteinate at home, in the expansion of the means of this destination.

The essence of the claimed technical solutions is explained as follows.

The unique properties of silver ions are an effective antibacterial effect. Doctors of various specialties, including otorhinolaryngology in the treatment of purulent rhinitis of a bacterial nature, sinusitis (including sinusitis), pharyngitis, adenoiditis, eustachitis, otitis media, etc. ready to use solutions based on silver, so they give a quick positive effect.

Along with the instability of an aqueous solution of silver proteinate, in the manufacture of an active pharmaceutical substance of silver proteinate, the quality of active silver ions is used to pass into a bound state: silver binds to a protein substrate, which is then dried. A colloidal solution is obtained from an active pharmaceutical substance by dissolving it in purified water. Dissociating from protein complexes into water, silver ions pass into an active state, due to which they easily penetrate the bacterial cell and disrupt its vital processes.

According to the principle of pharmacological action, the drug is no less unique: in a low percentage concentration, the colloidal suspension has a bacteriostatic effect, in a higher - bactericidal. Its antiseptic properties are universal: drops destroy the entire bacterial and fungal flora. Therefore, the use of a solution of the antibacterial composition does not cause dysbiosis, which is especially important in modern conditions of the pharmaceutical market oversaturation with synthetic antibiotics.

Obtaining an antibacterial composition is as follows.

- The substance of silver proteinate is mixed with polyvinyl-N-pyrrolidone (with MM (8-35) 10 ³ );

- The resulting mass is moistened with 95% ethyl alcohol, at the rate of 0.05 kg of alcohol per 1 kg of silver proteinate substance;

- The resulting mixture is dried;

- Next, granulation of the mixture is carried out through a sieve with a hole diameter of 1.0 mm

Then, tabletting is carried out by pressing method with preliminary wet granulation (IA Muravyov. Drug technology. Volume I. M.: “Medicine”, 1980, 394 p.). An antibacterial composition is formed in the form of a solid, water-soluble dosage form. When dissolved in water, the solid dosage form contains from 7.0 to 9.0% silver and is made in the form of a tablet, which can be in the form of a geometric figure used for the production of medicines or hygiene products, for example, in the form of a tablet, in the form of a cylinder, in the form of dragees, in the form of a ball.

An antibacterial system comprising an antibacterial composition for inhibiting the growth of pathogenic microflora as an active component is prepared as follows.

- The resulting antibacterial composition is packaged in a contour package, which can be either aluminum foil or polymer coated paper, or a combined material consisting of aluminum foil and a PVC film, or a combined material consisting of polymer coated paper and foil aluminum.

- Production of the required amount of purified water. The purified water is poured into at least one vessel with a solvent, which can be made, for example, in the form of a tube dropper, either in the form of a polymer ampoule, or in the form of a glass ampoule.

- Use a bottle to prepare a solution of the composition to inhibit the growth of pathogenic microflora. In this case, the bottle is made with the volume necessary and sufficient for the preparation of a solution of the composition with a concentration of 1-5%, when one active component is dissolved in the volume of the solvent contained in one vessel with the solvent.

A method of obtaining an antibacterial system, including an antibacterial composition for inhibiting the growth of pathogenic microflora, is performed as follows:

- prepare the components of the antibacterial system, including at least one hermetically sealed vessel, which is made as described above.

- form an antibacterial composition to inhibit the growth of pathogenic microflora in the form of a solid dosage of water-soluble form in which silver is made with a pre-treated stabilizer proteinate, additionally treated with a stabilizer polyvinyl-N-pyrrolidone, and dissolved in water to obtain colloidal silver particles, while the active component sealed packaging containing at least one packaging element, a bottle for diluting one active component in water contained in one suck is placed e, by the technology described above.

- Use the container, which is performed with the possibility of placing in it at least one sealed package with at least one active

component, at least one hermetically sealed vessel with a solvent, at least one bottle, instructions for use.

Example 1

The antibacterial activity of the antibacterial composition to suppress the growth of pathogenic microflora was carried out at the Federal State Institution “Scientific Research Institute of Epidemiology and Microbiology named after Honorary Academician N.F. Gamalei »of the Ministry of Health of the Russian Federation.

The object of the study is an antibacterial composition for suppressing the growth of pathogenic microflora, made in the form of a tablet for the preparation of a solution for topical application, 200 mg.

Research methods: microbiological studies in accordance with the Guidelines for the Preclinical Studies of Medicines, Chapter 316, Clause 1.2 and MUK 4.2.1890-04 - by the method of serial dilutions in a liquid nutrient medium - Mueller-Hinton broth.

The bactericidal concentration was determined by plating on Mueller-Hinton agar, chocolate and blood agar.

Determination of the activity of a 2% aqueous solution was carried out by seeding from dilutions of 10 ³ , 10 ⁴ , 10 ⁵ , 10 ⁶ , 10 ⁷ CFU / ml of cultures of strains with the addition of a 2% solution of the composition, incubated at 37 ° C for 18-24 hours.

The results of the study are shown in table 1.

Based on the studies established:

- 2% solution of the studied antibacterial composition has a bactericidal effect on all clinical strains included in the study: S.aureus, S.haemolyticus, S.epidermidis, S.cohnii, S. pneumoniae, S. pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonasas aeruginosa, Neisseria subflava, Burkholderia cenocepacia with a quantitative content of these pathogens 10 ³ , 10 ⁴ , 10 ^s , 10 ⁶ , 10 ⁷ CFU / ml;

- obtained the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the studied antibacterial composition for microorganisms: S.aureus, S.haemolyticus, S.epidermidis, S.cohnii, S. pneumoniae, S.pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Neisseria subflava, Burkholderia cenocepacia.

The advantages of the claimed technical solutions are as follows:

1. An antibacterial composition for suppressing the growth of pathogenic microflora, packaged in a blister pack, retains the consumer properties of the active pharmaceutical ingredient for a shelf life declared by the manufacturer at room temperature, without requiring special storage conditions.

2. The obtained antibacterial system, which includes an antibacterial composition to inhibit the growth of pathogenic microflora as an active component, has a high specific biological activity, the solution destroys the bacterial and fungal flora that causes diseases of the upper respiratory tract.

3. The obtained antibacterial system, including an antibacterial composition to inhibit the growth of pathogenic microflora as an active component, allows you to prepare a solution of silver proteinate at home in a clearly dosed concentration (1-5%), which is prescribed by a doctor in the treatment of diseases of the upper respiratory tract.

Claims (16)

1. An antibacterial composition for inhibiting the growth of pathogenic microflora, containing silver and a stabilizer in the form of polyvinyl-N-pyrrolidone, characterized in that it further comprises a stabilizer in the form of a proteinate, formed in the form of a solid dosage form soluble in water in which silver is pretreated a proteinate stabilizer, additionally treated with a stabilizer polyvinyl-N-pyrrolidone, and soluble in water to obtain colloidal particles of silver. 2. The antibacterial composition according to claim 1, characterized in that the proteinate serves as a silver stabilizer. 3. The antibacterial composition according to claim 1, characterized in that polyvinyl-N-pyrrolidone serves as a stabilizer of silver proteinate. 4. The antibacterial composition according to claim 1, characterized in that the molecular weight of polyvinyl-N-pyrrolidone is (8-35) × 10 ³ - 91.5-92.5 g / mol. 5. The antibacterial composition according to claim 1, characterized in that the solid dosage form when dissolved in water contains from 7.0 to 9.0% silver. 6. The antibacterial composition according to claim 1, characterized in that the solid dosage form is made in the form of a tablet. 7. The antibacterial composition according to claim 6, characterized in that the tablet is made in the form of a geometric figure used for the production of medicines or hygiene products, for example in the form of a tablet, in the form of a cylinder, in the form of a dragee, in the form of a ball. 8. An antibacterial system comprising an antibacterial composition for suppressing the growth of pathogenic microflora as an active component, at least one vessel with a solvent, characterized in that it additionally contains a bottle for preparing a solution of the antibacterial composition, the solvent being purified water, the antibacterial composition contains silver and a stabilizer in the form of polyvinyl-N-pyrrolidone, a stabilizer in the form of a proteinate, is formed as a solid dosage soluble in water rmy, wherein silver formed pretreated stabilizer proteinate further processed stabilizer polyvinyl-N-pyrrolidone, and dissolved in water to give a colloidal silver particles, wherein the active ingredient is placed sealed packaging. 9. The antibacterial system according to claim 8, characterized in that the vessel with the solvent is made either in the form of a tube dropper, or in the form of a polymer ampoule, or in the form of a glass ampoule. 10. The antibacterial system according to claim 8, characterized in that the vial is made with the volume necessary and sufficient to prepare a solution of the composition of a concentration of 1-5%, when one active component is dissolved in the volume of the solvent contained in the same vessel with the solvent. 11. The antibacterial system according to p. 8, characterized in that the sealed package is made in the form of contour packaging. 12. The antibacterial system according to claim 11, characterized in that the contour packaging is made of either aluminum foil or polymer coated paper, or of a combined material consisting of aluminum foil and a polyvinyl chloride film, or of a combined material consisting of paper with polymer coating and aluminum foil. 13. A method of obtaining an antibacterial system, comprising an antibacterial composition for inhibiting the growth of pathogenic microflora, comprising the steps of:
a) the preparation of the components of the system, including at least one hermetically sealed vessel, which is performed containing purified water, at least one active component, which is performed in the form of an antibacterial composition containing silver, a stabilizer in the form of polyvinyl-N-pyrrolidone, a stabilizer in the form of a proteinate,
c) the formation of an antibacterial composition in the form of a solid dosage of a water-soluble form in which silver is made with a pre-treated stabilizer proteinate, an additionally processed stabilizer polyvinyl-N-pyrrolidone, and dissolved in water to obtain colloidal particles of silver, while the active component is sealed. containing at least one packaging element, a bottle for diluting one active component in water contained in one vessel,
c) the use of a container made with the possibility of placing in it at least one sealed package with at least one active component, at least one hermetically sealed container with a solvent, at least one bottle, instructions for use. 14. The method according to p. 13, characterized in that the proteinate serves as a silver stabilizer, and polyvinyl-N-pyrrolidone serves as a silver protein stabilizer. 15. The method according to p. 14, characterized in that the molecular weight of polyvinyl-N-pyrrolidone is (8-35) × 10 ³ - 91.5-92.5 g / mol. 16. The method according to p. 13, characterized in that the solid dosage form when dissolving water contains from 7.0 to 9.0% silver and is made in the form of a tablet, which can be made in the form of a geometric shape used for the production of medicinal or hygienic means, for example in the form of a cylinder, or in the form of a ball.

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