RU2180222C2 - Antibacterial agent - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention relates to development of agents with the broad spectrum of an antibacterial effect. Invention proposes an antibacterial agent as a powder-like and tableted form containing a powder-like complex of one or a mixture of two and more quaternary ammonium compounds, or their complex with powder-like organic, inorganic or polymeric compounds evolving oxygen at dissolving; or a mixture of quaternary ammonium compounds with metal salts or complexes of metals with urea and accessory substances additionally. The proposed agent shows high bactericidal activity, resistance in prolonged storage, absence of irritable effect on respiratory ways and shows activity against the broad spectrum of gram-positive and gram-negative microorganisms, viruses and fungi. EFFECT: improved properties, enhanced activity of agent. 12 cl, 3 tbl

Description

 The invention relates to medicine and relates to the creation of compositions with a wide spectrum of antimicrobial activity.

 Quaternary ammonium compounds (QAC) are known to have a wide spectrum of antimicrobial activity.

 In particular, it is known that alkyldimethylbenzylammonium chloride (Catamine AB benzalkonium chloride) in low concentrations inhibit the growth of gram-positive, gram-negative bacteria and fungi (E.A. Rudzit et al., Antibiotics, 26, 11, pp. 847-851, 1981).

 Organic and inorganic peroxide compounds, including hydrogen peroxide, in turn, also have a wide spectrum of antimicrobial activity (US Patents 4320116; 2429971; 2266835; 2836533; 4404191; 4477438; 4518585 and others).

 Patents have been patented that combine peroxide compounds with quaternary ammonium compounds; it is contemplated that the new formulations should have higher antimicrobial activity than the starting components (US Patents 2,917,428; 2,436,673; 4,324,784; French Patent 2,663,852).

 The closest in technical essence and the achieved result is a product manufactured under the name of PVC (Russia TU 2386-019-13164401-95 according to Russian patent 1587725, BI 35, 1989), consisting of a mixture of hydrogen peroxide and Catamine AB (50% aqueous Alkyldimethylbenzylammonium chloride solution, Russia, TU 9392-003-48-182528-99).

 Despite the high bactericidal activity, this agent has a number of significant drawbacks: safety and inconvenience in work - the formulation is based on the use of concentrated aqueous solutions of hydrogen peroxide and often causes burns to personnel regardless of the use of protective equipment; instability during storage - within 12 months the content of hydrogen peroxide in the mixture is reduced by 40% from the original. Causes irritation of the respiratory tract of personnel. During prolonged storage and transportation oxygen is released, which leads to an increase in pressure in the containers. Strongly corrodes tools during processing.

 The technical task of the present invention is to remedy these disadvantages and expand the scope.

Powdered or tableted antimicrobial formulations are provided, including powdered antimicrobial formulations consisting of a mixture of powdered complexes of quaternary ammonium compounds and:
powdered compounds releasing active oxygen when dissolved in water or other media,
water-soluble powder forms of metal salts M ²⁺ , M ³⁺ .

 To solve this problem, a powder complex of one or a mixture of two or more Quaternary ammonium compounds (HOURs) with urea, thiourea and other complexing compounds of organic, inorganic, polymer origin was obtained.

 Solutions of the obtained HOUR complexes in water or other liquid media exhibit high bactericidal activity. The activity of solutions of a mixture of two or more complexes of quaternary ammonium compounds is higher than the activity of a solution of complex one (HOUR).

By mixing powdery complexes of one or a mixture of two or more HOURs with powdery compounds releasing active oxygen (when dissolved in water or other media) or with water-soluble complexes or metal salts, new powdery compositions are obtained whose solutions in water or other media exhibit high antimicrobial activity. Compositions have been prepared that combine powdery complexes of quaternary ammonium compounds with: a) powdery sources of active oxygen, such as a complex of hydrogen peroxide with urea (carbamide peroxyhydrate or hydroperite) or polyvinylpyrrolidone, sodium perborate, potassium peroxyhydrate fluoride, potassium peroxycarbonate, sodium monoperoxide sulfate, sodium peroparbonate sulfate, , sodium peryrophosphate, monoperoxyphthalate of magnesium hexahydrate, ammonium persulfate, benzoyl peroxide, calcium, zinc and other peroxides ue inorganic compounds and organic origin that produce active oxygen in water or other media; b) with salts and metal complexes, such as, for example, complexes of AlCl ₃ or Zn (OH) ₂ with urea, etc.

When studying the antimicrobial activity of the obtained compositions, it turned out that aqueous solutions of metal salts and HOURs themselves exhibit high antibacterial properties (see table. 1 *). For example, an aqueous solution of AlCl ₃ • 6H ₂ O and Catamine AB (previously patented as a hemostatic agent, RF patent 2142278) turned out to be a highly active antibacterial drug ("Methods of microbiological control of drugs / FC /, issue 2. Article 187 and amendments to her dated 12/28/95).

A method for the single-stage synthesis of a mixture of powdered sources of active oxygen and a quaternary ammonium compound from liquid starting mixtures has been developed. For example, from a mixture of liquid hydrogen peroxide and Catamine AB (an aqueous 50% solution of dimethylalkylbenzylammonium chloride), a powder containing a mixture of carbamide peroxyhydrate and a complex of Catamine AB with urea was obtained when interacting with urea. Or, from an aqueous solution of AlCl ₃ • 6H ₂ O, Catamine AB and urea, a powder containing all the starting components is obtained.

To regulate the operational, physico-chemical and disinfecting properties of the powder mixtures described in this application, auxiliary components were introduced into their composition. These include:
a) carbonates, bicarbonates, halides, sulfates, hydrosulfates and other water-soluble salts of alkali and alkaline earth metals;
b) water-soluble polymers - PVA, PVP, starch, derivatives of cellulose, alginic acid and other synthetic and natural polymers and copolymers;
c) anionic and / or nonionic surfactants, ampholytes, betaines, polyoxyethylated derivatives of higher fatty alcohols, phenols, acids, sorbitan, lanolin, etc., metal salts, surfactants (lauryl sulfate-M, laurylbenzenesulfanate-M, etc.);
d) organic acids and their salts - tartaric, benzoic, oxalic, adipic, citric, malic, salicylic, and others;
e) desiccants, components for regulating the pH of the mixture, corrosion inhibitors, etc .;
f) stabilizers (for example, to stabilize hydrogen peroxide) salts - salts Mg ²⁺ , Sn ²⁺ , Zn ²⁺ , Cd ²⁺ , Al ³⁺ , etc.

 g) dyes, perfumes and other components required by the recipe.

 The ratio of the powder forms of oxygen sources or metal salts to the powder forms of quaternary ammonium compounds is from 9: 1 to 1: 9. The number of auxiliary compounds is from 0 to 76% by weight of the main components.

 The proposed compounds are stable during long-term storage, easily soluble in water, odorless, do not irritate the respiratory tract. Solutions of the compounds in water or other media are stable and have a prolonged effect against a wide range of gram-positive and gram-negative bacteria, viruses, fungi, etc.

 Based on these mixtures, powdered or tablet formulations were created, the aqueous solutions of which can be used to rinse the mouth, brush and whiten the teeth. Powdered salts of quaternary ammonium compounds were added to household bleaches to give them antiseptic properties. They can be used for processing domestic and industrial premises, hotels, cafes, bars, aircraft cabins, road and rail transport, sports facilities and equipment, and other crowded places, honey. equipment, veterinary hospitals, clothes, shoes, etc.

 The following are examples of the preparation of powdered components of new antimicrobial agents and examples of the preparation of various compositions based on them.

 la) Examples of the preparation of powdered complexes of quaternary ammonium compounds with urea, thiourea and other complexing agents.

 Example 1

To 60 g of Catamine AB (50% solution of dimethylalkylbenzylammonium chloride in water) is added 60 g of urea and stirred at a temperature of 55-60 ^o C for 1 hour. A white mass adheres to the walls of the vessel. 400 ml of isopropyl alcohol are added, cooled to 0 ^{° C.} and the precipitate formed is filtered off. Dry the powder in a vacuum of 100 mm sp. Hg. Art. at a temperature of 30-40 ^o C.

 The yield of the powder complex is 62 g (the HOUR content in the complex is 30-32%). Similarly prepared urea complexes with other N-alkyl-NN-dimetilbenzammoniyhloridami such as lauryl, mirisitil-, cetyl, stearyl, diizobutilkrezoksietoksietil-, N-alkanoilaminopropil-, diisobutyl, fenoksietoksietidimetilbenzilammoniybromidy, alkildietilbenzilammoniyhlorid, alkildimetilnaftilmetilammoniyhlorid (tert-oktilfenoksietil) diethylbenzylammonium chloride.

 Example 2

60 g of a 50% solution of didecylmethylammonium chloride in water and 60 g of urea are added to 200 ml of isopropyl alcohol, stirred at 55-60 ^o C for 1 hour. The resulting light yellow solution was filtered through a nylon filter, the filtrate was cooled to 0 ^° C and left to stand until a precipitate formed. The precipitate was filtered off and dried in a vacuum of 100 mm Hg. Art. at 30-40 ^o C.

 The yield of the mixture of the complex is 60 g.

 Similarly prepared complex of urea with other quaternary ammonium compounds, such as dialkildietil-, dioktildimetil-, alkiltrimetil-, alkilmetilizohinoliniyhlorid, oktildetsildimetilammoniyhlorid and urea complexes didetsildimetilammoniybromidom, alkiltrimetilammoniybromidom, tsetildietilbenzilammoniybromidom, tetradetsilpiridiniybromidom, cetyl pyridinium bromide, stearilkarboksimetil (trimetilammoniybromidom) and others. Quaternary ammonium compounds with various substituents at the nitrogen atom.

 Example 3

To 200 ml of isopropyl alcohol add 60 g of a 50% solution of a mixture of (1.1) alkyldimethylbenzylammonium chloride and alkyldiethylbenzylammonium chloride and 60 g of urea. Stirred at 55-60 ^o With 1 hour. The resulting solution was filtered through a nylon filter, the filtrate was cooled and left to stand until a precipitate formed. The precipitate was filtered, washed twice with 200 ml of isopropyl alcohol.

 The yield of the mixture of the complex is 60 g.

 Example 4

To 60 g of a 50% solution of alkyl dimethylbenzylammonium chloride (Catamine AB) add 60 g of thiourea and stirred at 55-60 ^o C for 1 hour. White mass falls out. 400 ml of isopropyl alcohol are added, cooled to 0 ^{° C.} , the precipitate is filtered off and dried in vacuum at 30-40 ^° C. Yield 58 g.

 Example 5

In 200 ml of isopropyl alcohol, 30 g of dimethyl didecylammonium bromide and 45 g of polyvinylrirrolidone are dissolved. The mixture is maintained at 35-40 ^o With 6 hours. The precipitate formed is filtered off and dried in vacuo. The output of the complex is 48 g.

 Ib) Preparation of complexes of metal salts with urea.

 Example 6

70 g of urea and 54 g of AlCl ₃ · 6H ₂ O are dissolved in 150 ml of isopropyl alcohol, and stirred for 2 hours at 60 ^° C. Cool, the precipitated white precipitate is filtered off, washed with cold alcohol and dried in vacuum. Urea complexes with other metal salts are similarly prepared.

 IIa) One-step synthesis of a powder mixture of sources of active oxygen and a quaternary ammonium compound.

 Example 7

A) 6 g of Catamine AB (50% aqueous solution of apkyldimethylbenzylammonium chloride) are added to 100 ml of 30% hydrogen peroxide at 20 ^o С and stirred, 90 g of urea is added to the resulting mixture and stirred for 1 hour at 20 ^o С. During this time, the urea is completely dissolved . Over the next hour, crystalline precipitation gradually begins. Stirred for another 1 hour at 30 ^o C, cooled to 0 ^o and added 600 ml of chilled isopropyl alcohol. The precipitate is filtered, washed with another 300 ml of cold isopropyl alcohol. The resulting complex of a mixture of hydrogen peroxide and Catamine AB with urea is dried in a vacuum of 100 mm sp. Hg. Art. Yield 32 g.

B) A mixture is prepared of 100 ml of 38% hydrogen peroxide and 6 g of Catamine AB. 90 g of urea is added to the mixture and stirred for 1 hour at 38-40 ^° C. The liquid mixture is filtered, transferred to crystallizers, cooled to -5 ^° C. The mixture is kept at this temperature for 6 hours. The precipitate formed is isolated by centrifugation and dried in a vacuum oven to a moisture content of not more than 0.1%.

 Similarly, powder mixtures of complexes of hydrogen peroxide and other quaternary ammonium compounds with urea, thiourea, polyvinylpyrrolidone, etc. are prepared.

IIb) One-step synthesis of a powder mixture containing simultaneously Catamine AB, AlCl ₃ and urea.

 Example 8

36 g of urea, 1.5 g of Catamine AB and 27 g of AlCl ₃ · 6H ₂ O are successively dissolved in 70 ml of isopropyl alcohol. The mixture is stirred for 2 hours at 50 ^° C. A white precipitate is formed which is coated with a suspension. Cool for 2 hours at 0 ^{° C.} , add another 50 ml of isopropyl alcohol and filter. The white powder of the complex of urea with AlCl ₃ and Catamine AB is dried in vacuum at 30-40 ^o C.

 III) Examples of the preparation of powdered antimicrobial compositions from complexes of quaternary ammonium compounds.

Example 9. (wt.%)
Catamine AB complex with urea - 50-100
Auxiliary components - 0-50
Example 10. (wt.%)
Catamine AB complex with urea - 25-50
The complex of dimethyl didecylammonium bromide with urea - 25-50
Auxiliary components - 0-50
IV. Examples of the preparation of powdered antimicrobial compositions based on powdered complexes of quaternary ammonium compounds (QAC) and carbamide peroxyhydrate.

 Example 11

In the mixer for the preparation of powdered compositions are mixed, wt.%:
Urea peroxyhydrate (hydroperite, contains 12-35% hydrogen peroxide) - 10-30
The complex of alkyldimethylbenzylammonium chloride with urea - 3-10
Excipients - 0-50
Example 12

Analogously to example 11 prepare a mixture, wt.%):
Urea peroxyhydrate (hydroperite) - 20-50
Complex of dimethyl didecylammonium bromide with urea - 3-10
Auxiliary components - 0-50
Example 13

Analogously to example 11 prepare a mixture, wt.%:
Urea peroxyhydrate (hydroperite) - 20-50
Alkyldimethacbenzylammonium chloride complex - 10
Alkyldiethylbenzylammonium chloride complex - 10
Auxiliary components - 0-50
Example 14

Analogously to example 11 prepare a mixture, wt.%:
Urea peroxyhydrate (hydroperite) - 10-30
Catamine AB Complex with Urea - 1-10
The complex of didecyldimethylammonium bromide with urea - 1-10
Auxiliary components - 0-50
Example 15

Analogously to example 11 are mixed, wt.%:
Complex of hydrogen peroxide with polyvinylpyrrolidone - 20-50
The complex of dimethylalkylbenzylammonium chloride with urea - 3-10
Auxiliary components - 0-50
V. Examples of the preparation of powdered antimicrobial mixtures and tabletting mixtures based on HOUR complexes and peroxosols.

VI. Example 16 (wt.%):
Sodium Parborate - 40
Catamine AB complex with urea - 6.7
B / w sodium carbonate - 20
Sodium Chloride - 1
Sodium Lauryl Sulfate - 1
Aerosil - 0.3
Oxalic acid - 20
Magnesium Stearate - 1
Sodium Sulfate - 10
Example 17 (wt.%):
Sodium Parborate - 30
Catamine AB Complex with Urea - 3
Sodium Bicarbonate - 30
Sodium Sulfate - 10
Tartaric acid - 20
Starch (maize) - 5
Sodium Chloride - 1
Magnesium Stearate - 1
Example 18 (wt.%):
Sodium percarbonate (12% active oxygen) - 45
Catamine AB Complex with Urea - 4
Sodium Carbonate - 30
Sodium Chloride - 10
Sodium Lauryl Sulfate - 0.3
Tartaric acid - 10
Aerosil - 0.3
Sodium Oleate - 0.4
Example 19. (wt.%):
Potassium persulfate (4.5% active oxygen) - 20
Catamine AB Complex with Urea - 4
Sodium Chloride - 60
Sodium Carbonate - 15
Inhibitor - 0.7
Aerosil - 0.3
Example 20. (wt.%):
Sodium peryrophosphate (9% active oxygen) - 20
Complex of dimethylalkylbenzylammonium chloride with urea - 5
Sodium Sulfate - 50
Sodium Bicarbonate - 20
Alkyl aryl sulfate - 5
VI. Examples of the preparation of antimicrobial compositions based on HOUR and metal salts.

Example 21 (wt.%):
A complex of aluminum chloride with urea - 25-50
Catamine AB Complex with Urea - 1-10
Auxiliary components - Else.

Example 22 (wt.%):
The complex of zinc acetate with urea - 25-50
Catamine AB Complex with Urea - 1-10
Auxiliary components - Else.

Example 23 (liquid composition) (wt.%):
AlCl ₃ • 6H ₂ 0 - 25 g
Catamine AB - 1 g
Water - Up to 100 ml
VII. Examples of antiseptic compositions for the hygienic treatment of the hands of medical personnel, skin, operating and injection fields, etc. are given in table. 2.

 Viii. Examples of the preparation of powdered compositions based on complexes of HOUR and metal peroxides.

Example 29. Therapeutic composition for external use, wt.%:
Zinc Peroxide - 10
Calcium Peroxide - 1
Catamine AB Complex with Urea - 0.2
PEG1500 - 59.8
Propylene glycol - 29
IX. Examples of the preparation of compositions of powders and tablets for rinsing the mouth, brushing and whitening teeth on the basis of complexes of HOURs and peroxosols.

Example 30 (wt.%):
Potassium Monopersulfate - 20
Catamine AB Complex with Urea - 3
Ethylenediaminetetraacetic acid - 1
Sodium Bicarbonate - 20
Sodium Carbonate - 10
Citric Acid - 10
Malic Acid - 10
Sulfamic acid - 3
sodium sulphate o / w - 12
Sodium dodecyl sulfate - 0.5
PEG 4000 - 6
PEG 6000 - 3-5
Protease - 1.5
Fragrance - 3
Dye - 0.01
X. Examples of compositions of household bleaches with antibacterial action based on complexes of HOURs and peroxosols.

Example 31 (wt.%):
Potassium Monopersulfate - 20
Sodium Chloride - 60
Sodium Carbonate - 15
Catamine AB Complex with Urea - 5
A comparative assessment of the antibacterial activity of the obtained compounds (IPC - the minimum inhibitory concentration) are given in table. 3.

Claims (12)

 1. An antimicrobial agent containing a powder complex of one or a mixture of two or more Quaternary ammonium compounds (QAC), as well as excipients selected from the group of water-soluble salts of alkali and alkaline earth metals, water-soluble synthetic and natural polymers and copolymers, anionic and / or nonionic surfactants, organic acids and their salts, desiccants, pH adjusting mixtures, corrosion inhibitor, stabilizer, dye, perfume, and the number of auxiliary components is from 0 to 76% of the weight of the main components.  2. An antimicrobial agent containing a powder complex of one or two HOURs with powdered compounds of organic, inorganic or polymer origin, emitting active oxygen upon dissolution, selected from the group of solid powder complex of hydrogen peroxide, sodium perborate, potassium peroxyhydrate, potassium percarbonate, sodium monopersulfate potassium, potassium peroxomonosulfate, sodium peryrophosphate, monoperoxyphthalate magnesium hexahydrate, ammonium persulfate, benzoyl peroxide, p roksida calcium, zinc peroxide, and auxiliary substances selected from the group of water soluble salts of alkali and alkaline earth metals; water soluble synthetic and natural polymers and copolymer; anionic and / or nonionic surfactants; organic acids and their salts, desiccants, pH adjusting mixtures, corrosion inhibitor, stabilizer, dye, perfume, while the ratio of active oxygen sources and HR is 9: 1-1: 9, and the amount of auxiliary components is from 0 to 76% of the weight of the main components.  3. An antimicrobial agent containing a powder complex of one or a mixture of two or more HOURs with metal salts or a complex of metals with urea, as well as excipients selected from the group of water-soluble salts of alkali and alkaline earth metals; water-soluble synthetic and natural polymers and copolymers, anionic and / or nonionic surfactants, organic acids and their salts, desiccants; mixtures that regulate pH, corrosion inhibitor, stabilizer, dye, perfume, while the amount of auxiliary components is from 0 to 76% by weight of the main components.  4. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it contains carbonates, bicarbonates, halides, sulfates, hydrosulfates as water-soluble salts of alkali and alkaline earth metals.  5. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it contains polyvinyl alcohol, polyvinylpyrrolidone, starch, cellulose derivatives, alginic acid as water-soluble polymers.  6. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it contains ampholytes, betaines, polyoxyethylated derivatives of higher fatty alcohols, phenols, acids, sorbitan, lanolin, metal salts, lauryl sulfate as anionic and nonionic substances M, laurylbenzenesulfanate-M.  7. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it contains tartaric, benzoic, oxalic, adipic, citric, malic, or salicylic acids as organic acids.  8. The antimicrobial agent according to claim 1, or 2, or 3, characterized in that it is made in powder form.  9. The antimicrobial agent according to claim 1, or 2, or 3, characterized in that it is made in tablet form.  10. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it is intended for rinsing the oral cavity, brushing and whitening teeth.  11. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it has a prolonged effect against a wide range of gram-positive and gram-negative bacteria, viruses, fungi.  12. The antimicrobial agent according to claim 1, 2, or 3, characterized in that it is intended for the treatment of premises, vehicles, sports equipment, clothing, shoes.

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