RU2214281C1 - Preparation for control of intrahospital infection, treatment of medicinal tools and agents of personal hygiene - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention relates to preparation used for control of intrahospital infections, treatment of medicinal tools and agents of personal hygiene. The preparation contains an aqueous solution of copolymer of polyalkyleneguanidine or polyhydroxyalkyleneguanidine, or polyaminoalkyleneguanidine salts. One salt is gluconate, or lactate, or citrate and another is salt of physiologically active organic acid in the ratio of gluconate, or lactate, or citrate and salt of physiologically active organic acid = (3:1)-(9:1). Citric, or sorbic, or acetic, or dehydroacetic, or benzoic, or acridone acetic acid is used physiologically active organic acid. Paper napkins, or cotton tampons, or gauze, or cotton fabric is used as agents for personal hygiene. EFFECT: enhanced fungicide activity, reduced toxicity of preparation. 3 cl, 6 tbl

Description

 The invention relates to medicine and can be used in medical institutions and in everyday life.

 Nosocomial infections are a problem for any medical institution. These are infectious diseases that join the underlying disease due to contact with other patients and the environment of the hospital.

 The most common among nosocomial infections are respiratory viral diseases. Then we should mention staphylococcal and streptococcal infections of the skin and mucous membranes, including fungal parasitic diseases. In the next place in frequency of occurrence are intestinal infections.

 The main role in the prevention of nosocomial infections belongs to the sanitary-hygienic regime in medical institutions. Prevention of nosocomial infections is achieved by a set of measures that eliminate the possibility of contamination of water, food, household and hygiene items used by patients.

 The pre-sterilization treatment of endoscopes in the Russian Federation is carried out according to the instructions of MOH 16 dated 03.09.1990 by imported disinfectants based on sodium persulfate or aldehydes (glutaraldehyde or formaldehyde). The disadvantages of such disinfectants are their instability and the need for a long exposure period.

 It is known to use the drug chlorhexidine for the treatment of hands of medical staff, purulent wounds, sterilization of instruments and the prevention of sexually transmitted diseases (synonyms: hexinone, gibiscrab, dying san, plivesept, fervex, elugel). [Register of Medicinal Products of Russia, 2001 edition, p.937].

 The disadvantage of this drug is its relatively high toxicity, which allows it to be used only topically, as well as allergic properties and inactivity against spores and viruses.

 The closest technical solution to the proposed invention is the drug described in the patent of the Russian Federation 2122865, cl. A 61 L 2/16, 1998, in which 0.5-2% aqueous or 0.5% aqueous-alcoholic solutions of polyhexamethylene guanidine phosphate (PHMG) are used as a disinfectant.

 The disadvantage of this invention are, as in the case of chlorhexidine, comparative toxicity and limitations on physiological activity. So, PHMG phosphate, being an effective antimicrobial drug, has a relatively low activity against pathogenic fungi and molds.

 The technical problem solved by this invention is to increase fungicidal activity and reduce the toxicity of the drug.

R₁ - H₁, алкил, аралкил, алкилсилоксан и др.To solve the technical problem in the drug for combating nosocomial infection, treating medical instruments, patient care products, surrounding items and personal hygiene products, including a PG salt-based antiseptic, a 0.5-5% aqueous solution of a salt copolymer is used as an antiseptic polyacylene guanidine (PAG), or polyoxyalkylene guanidine (PAG), or polyaminoalkylene guanidine (PAG), one of which is gluconate, or lactate, or citrate, and the other with a physiologically active organic acid salt, with against gluconate, or lactate, or citrate salt of physiologically active organic acid (3: 1) - (9: 1), wherein the block copolymer salts polyguanidines formula (PG) has the form

R ₁ - H ₁ , alkyl, aralkyl, alkylsiloxane, etc.

Гл - глюконат, С₆Н₁₂О₇ остаток глюконовой кислоты НОСН₂(СНОН)₄СООН
А - анион органической физиологически активной кислоты, включающей алкил- и арилкарбоновые кислоты, оксикислоты или гетероциклические замещенные органических кислот.

Gl - gluconate, C ₆ H ₁₂ O ₇ residue of gluconic acid, HCH ₂ (CHOH) ₄ COOH
A is the anion of an organic physiologically active acid, including alkyl and aryl carboxylic acids, hydroxy acids or heterocyclic substituted organic acids.

n is 4-50;
x = n / 10-n / 3
As a physiologically active organic acid, citric, or sorbic, or acetic, or dehydrate, or benzoic, or acridonoacetic acids are used.

 As a means of personal hygiene use paper towels, or cotton swabs, or gauze, or cotton cloth.

 From the presented general formula of the preparation of the present invention, it can be seen that they can be considered as copolymers of polyguanidine salts (PG), the structural units of which differ only in the nature of the counterion (anion). Moreover, one of these anions is usually gluconic acid, which is an important metabolic product in living organisms, and in our case it acts as a disinfectant detoxifier.

 To enhance fungicidal activity, as the second anion in the copolymers of the present invention, anions of one or another physiologically active organic acid are used, for example citric, lactic, sorbic, formic, benzoic, acridonoacetic and others, which are used as drugs or preserving additives in food products. Moreover, the variation of the physiologically active acid allows, within certain limits, to vary the properties of the obtained preparation.

 Since the polymer matrix itself, the cationic polyelectrolyte of PG, has the maximum physiological activity (antimicrobial) in the copolymers of PG salts of the present invention, the introduction of a physiologically active anion of an organic acid selected from this group represents an additional way of enhancing the biocidal properties of the drug (mainly fungicidal) and giving it a unique a wide range of biocidal actions, including microbes, viruses, pathogenic fungi and yeast, including spore-forming microorganisms.

 The used method of detoxifying the disinfectant by pairing the cationic biocide of PG with gluconic or other physiologically active organic acid: formic, lactic, citric, acetic, and amino acids plays a certain role in this. It is known that the first stage in the metabolism of various GH salts in the body is their conversion to gluconate.

 Historically, the first studied class of biocidal GHGs were polyalkylene guanidines (PAT), in particular polyhexamethylene guanidine (PHMG). However, polyoxyalkylene guanidines (PAAG) and polyaminoalkylene guanidines (PAAG), as well as various hydrophobic PGs obtained by copolymerization with monofunctional physiologically active amines, for example, benzylamine, higher alkylamines, and alkylamines .

 A distinctive feature of the polymer biocides of the present invention is the extremely prolonged antimicrobial (and fungicidal effect) associated with the formation of a thin polymer film on the surface of the products processed by them, which retains antiseptic properties for a very long time. POAG is also characterized by a specific effect previously established for polyalkylene oxides, which consists in their absorption by subcutaneous fat and long-term preservation together with the corresponding biocidal effect. The noted circumstance is especially valuable when using the developed means for disinfecting the hands of medical personnel.

 The use of a 0.5-5% aqueous solution of a copolymer of PG salts as an antiseptic is optimal and identified as a result of numerous experiments. If the concentration of the aqueous solution is less than 0.5%, then reliable disinfection will not be ensured. When using a concentration of more than 5%, processing is more expensive.

 A sequence of chemical operations has been developed leading to the production of low-toxic and highly effective preparations of copolymers of salts of organic acids based on available GHG chlorides. First, a PG base is obtained from PG chloride by the action of sodium hydroxide in an aqueous solution. Then, by the action of the Na-salt of a physiologically active organic acid in alcohol or water, a PG-base copolymer with a salt of this acid is obtained. In this case, PG-chloride groups, which are essentially unreformed in the first process, are used, and the process is facilitated by the precipitation of the second reaction product, sodium chloride, which is practically insoluble in alcohol, or by peeling a solution of NaCl in water from the polymer. After separating the NaCl precipitate or its solution and removing the alcohol, the required amount of calcium gluconate (the most affordable salt of unstable gluconic acid) is introduced into the obtained polymer mass in the form of a hot 15-20% aqueous solution and calcium is precipitated as its insoluble phosphate by adding an equimolar amount of phosphoric acid. After a special exposure, the precipitate of calcium phosphate is filtered off and the solution of the obtained copolymer of gluconate PG with citrate (acetate, lactate, sorbate, dehydroacetate, etc.) is evaporated.

 At the stage of administration of the physiologically active acid, a mixture of Na salts of two acids, for example citric and dehydroacetic, citric and lactic, etc., can be used. In this case, the product of the reaction transformations according to the developed scheme will be the terpolymer of GH gluconate and its two salts with different physiologically active acids, for example, citrate and PG dehydroacetates.

 Example 1. Specific preparation: a copolymer of citrate with PHMG formate.

 We take a portion of 465 g of PHMG hydrochloride, dissolve in 300 ml of water, filter and add with stirring a solution of 145 g of citrate and 41.5 g of sodium formate in 200 ml of water. Separate 500 ml of the lower layer, which is a solution of 150 g of NaCl in water. The polymer (upper) layer is dehydrated to obtain a solid copolymer of citrate with PHMG formate.

Example 2. Specific preparation: a copolymer of gluconate and formate PHMG. A portion of 45 g of the base of PHMG was dissolved in 100 ml of alcohol, and 50 ml of a solution of sodium formate prepared from 3.5 g of formic acid and 2.8 g of NaOH were added to the resulting solution. Decanted a solution of a copolymer of a base of PHMG with formate PHMG from NaCl precipitate. 300 ml of an aqueous gluconate solution was prepared by dissolving 50 g of gluconate powder in water, and the resulting solution was mixed with a solution of a base copolymer of PHMG with formate PHMG. To precipitate calcium, 13 ml of concentrated H ₃ PO _{4 was} added and a solution of a copolymer of gluconate and PHMG formate was filtered off from a precipitate of calcium phosphate. The filtrate was dehydrated and the resulting copolymer was analyzed for antimicrobial activity.

 The resulting copolymers of salts (see table 1) are usually solid, glassy, odorless polymers from light yellow to orange, readily soluble in water and aqueous alcohol.

 The practical use of the invention is illustrated by the following examples.

 Hand treatment of the surgeon. The tests were carried out at the Institute of Transplantology and Artificial Organs. (L.I. Arefieva, N.I. Gabrielyan).

Currently, several methods of disinfecting the hands of surgeons are used:
- washing twice with soap, followed by lubrication of the nails with iodine;
- washing with a solution of potassium permanganate, leading to intense staining of the skin;
- double treatment of hands with 60% isopropyl alcohol;
- finally, treatment for 3-5 minutes with a 0.5% alcohol solution or 0.5-1% aqueous solution of chlorhexidine or phosphopag (fogucide).

 A prerequisite for successful disinfection of the surgeon's hands is a reduction of at least 5 logarithms of concentration as a result of such treatment of microbial contamination.

 To evaluate the effectiveness of the treatment with the developed drugs against standard test cultures, first we conducted comparative in vitro experiments (see Table 2), and then experiments close to the practice of use, in which the effect of the developed drugs was tested on microorganisms in the environment surrounding the patient in medical institution, and belonging to the class of nosocomial infection (table. 3).

 From the above table. 2 and 3 of the data, it can be concluded that for the disinfecting treatment of the surgeon's hands, 3 ml of a 0.5-1% solution of PG copolymers can be used, for example, 2, 4, 5, 9, 13, rubbing them for 1 min before drying. The subsequent flushing for 1 min with saline solution and flushing analysis showed the absence of any microflora in it both for specially contaminated (E. Coli) hands and for hands with natural microflora.

 From the table. 3, in addition, it is seen that hand disinfection with formate / citrate = 3: 1 (Example 12 (Table 1)) is more effective than PHMG phosphate according to RF patent 2122865.

 From the table. 2 shows that before treatment with PG salt, the main microflora surrounding the patient is staphylococcus (48.1%) with a predominance of hemolytic staphylococcus (Staphylococcus haemolyticus - 44.4%) and gram-positive bacilli (40.7%) with a predominance of spore forms (33.3 %).

 After treatment after 48 hours of cultivation, 6 isolates were isolated, among which there was one single living culture of Enterococci (Enterococcus faecalis)).

Then, a comparative assessment was made of the effectiveness of the copolymer of PG and PHMG phosphate in the treatment of the hands of personnel who voluntarily participated in the experiment (see Table 3). The disinfection of the surgeon's hands from natural microflora, including St. epidermis, St.aureus, Prot.mirabilis, as well as under the conditions of artificial seeding, 1 ml of suspension containing 10 ⁹ test microorganisms E. Coli and Staph.aureus.

 The minimum bacteriostatic concentration of the disinfectant was monitored during the standard disinfection procedure: 2 times rubbing 3 ml of a 0.5% solution of the copolymer of PG salts in water or 50% aqueous alcohol for 1 min until the skin dries.

 The fight against nosocomial infection, the processing of medical instruments and patient care items.

 Studies were conducted under the supervision of the head. Department of Gastroenterology MONIKI prof. G.V. Tsodikova and carried out as follows. To enhance the contact of the drug with the object of disinfection, a 10x10 cm gauze was moistened with 1% formate / citrate = 3: 1 solution (example 16, table 1), slightly squeezed and applied to the disinfected item, pressed tightly to it and left for 10, 15 s to complete the disinfection, then the gauze was removed from the treated surface and after 20 minutes, washouts were taken from this square, which were incubated in the thermostat for 24 hours or 48 hours (Tables 4 and 5).

 After contact with the drug for 10-15 seconds, no contaminated samples were detected when the results were taken into account after 24 hours of cultivation.

 It is known that the microorganisms surrounding patients in a hospital, for example, in the intensive care unit, are gram-positive cocci and rods, gram-negative rods, yeast-like fungi, i.e., the usual causative agents of nosocomial infections.

 From the table. Figure 6 shows that hemolytic staphylococcus and streptococcus have the highest resistance to formate / citrate = 3: 1 (16, Table 1) from the above assortment.

 Disinfection of endoscopes with copolymers of PG salts.

 The work was carried out in the gastroenterological department of MONICA under the guidance of Professor G.V. Tsodikova.

 A copolymer of gluconate with benzoate POAG (poly-4,9-dioxadodenenguanidine) was used. Fiber-optic gastroduodenoscopes were disinfected. After pre-sterilization cleaning, the devices were soaked for 15 min in a 0.5% solution of copolymer 13 (Table 1). The channels of the device were washed with the same solution. Not a single case of contamination of the endoscopes with any microorganisms was observed after such treatment.

 A special study was performed on the absence of infection of endoscopes with the hepatitis virus after treatment with a disinfectant solution of the PG copolymer. Studies have shown sterility of the device against viruses.

Claims (3)

1. A drug for combating nosocomial infections, processing medical instruments, equipment and personal care products, including an antiseptic based on a polyguanidine salt, characterized in that a 0.5-5% aqueous solution of a copolymer of salts of polyalkylene guanidine or polyoxyalkylene guanidine is used as an antiseptic or polyaminoalkylene guanidine, one of which is gluconate, lactate, citrate, and the other is a salt of a physiologically active organic acid, with a ratio of gluconate and salt of a physiologically active acid (3: 1) - (9: 1), while the structural formula of the copolymer of salts of polyalkylene guanidines, or polyoxyalkylene guanidines, or polyaminoalkylene guanidines is

where n = 20-50;
x = n / 10 - n / 3;
R ₁ is H, alkyl, aryl, aralyl, alkylsiloxane;
R ₂ - (CH ₂ ) ₃ O (CH ₂ ) ₄ O (CH ₂ ) ₃ -;

Ch - C ₆ H ₁₂ O ₇ residue of gluconic acid CH ₂ OH- (CHOH) ₄ COOH;
A - citrate, sorbate, benzoate, lactate, formate, dehydroacetate, acridone acetate.  2. The composition according to claim 1, characterized in that as a physiologically active organic acid, citric, or sorbic, or acetic, or dehydrate, or benzoic acid or acridonoacetic acid is used.  3. The composition according to claim 1, characterized in that as personal care products use paper towels, or cotton swabs, or gauze, or a cotton cloth.

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