DE4137548A1 - Antimicrobial compsn. for antiseptic and disinfectant - contg. acridine dye, chlorhexidine, octenidine, quat. ammonium cpd., iodophor or lactic acid, for skin, mucous membranes and wounds - Google Patents

Abstract

The compsn. contains 0.01-1% of the dye together with chlorhexidine, octenidine, quat. ammonium cpds. iodophores, lactic acid, or lactic acid, and chlorhexidine. The dye is pref. acriflavin and is combined with 0.01-0.5% of chlorhexidine 0.01-0.5% of octenidine, 1-10% of polyvinyl-pyrrolidone -iodine (PVP-iodine) in aq. soln. 1-5% of PVP-iodine in isopropanol/water contg. 40-90 vols. % of alcohol, 0.01-4% of lactic acid, or 0.01-4% of lactic acid and 0.01-0.5% of chlorohexidine. USE/ADVANTAGE - The additives have a synergistic effect, and relatively low concns. of the components have a high antimicrobial action, reducing the toxicological effect. A combination of acriflavin, lactic acid and chlorohexidine has an improved effect against viruses e.g. hepatitis B and herpes simplex-virus.

Description

The invention relates to an antimicrobial drug combination based on acridine dyes for antiseptics and disinfection of the skin, mucous membrane and wound.

Acriflavin - an acridine dye - is preferred for Oral cavity antiseptic in an application concentration of general 0.3% applied. Achieved in the immediate effect it's not quite the effectiveness of chlorhexidine, it is for that superior to chlorhexidine in its retentive effect. (Chandler, A .; Böttcher, I .; Böttcher, U .; Niesler, M .; Neumann, K .; Weuffen, W .: Antiseptic effectiveness of selected anti septics for prophylactic oral irrigation. In: Knoll, K.H. (Ed.) - Applied hygiene in ZMK clinic and practice, Report Dental Hygiene Congress Marburg 1990. pp. 211-217). Acriflavin can also be used on other biotopes for antiseptics are used, e.g. B. on wounds or in the genital area.

However, the discoloration is an undesirable property  limited the application. From this point of view, a Redu Application concentration is desirable.

Acridines also promote the elimination of R plasmids. Chlorhexidine is a bis-guanidine derivative with strong bacteria ricidal properties and good adhesion to the Skin. The quickly effective, little toxic substance has except for instrument and hand disinfection for contraception infections during urological procedures (catheterization tion, cystoscopy, etc.). She is also at Infek used in the mouth and throat. (E. Mutschler Drug effects, textbook of pharmacology and toxicology logie, 1991). However, the concentration of chlorhexi din when used in medical practice quite high what is to be assessed disadvantageously for toxicological reasons. In AS 20 60 439 is a preferred application concentration of 0.5-0.75%. Relatively high concentrations also when using PVP-iodine (iodine complexes with polyvinyl pyrrolidone) applied, so that it is particularly when applied on mucous membranes or on large wound areas mixing side effects may occur as a result of absorption. A general reduction in the application concentration of Antimicrobial agents can in turn reduce their effectiveness and spectrum of effects impair, so that the use of known individual active ingredients and their combinations only one Brings improvement if despite a reduction in users concentration a synergistic increase in effectiveness is achieved.  

The object of the invention is therefore an antimicrobial Active ingredient combination based on acridine dye Antiseptic and disinfection of skin, mucous membrane and wound with relatively low application concentration of the components with high antimicrobial effectiveness to create that too is user-friendly and compatible.

Surprisingly, it was found that the task with a antimicrobial combination of active ingredients based on Acridine dyes can be solved by this is characterized in that the acridine dyes in a Concentration from 0.01 to 1% are combined with Chlorhexidine, octenidine, quaternary ammonium compounds, Iodophores, lactic acid or with lactic acid and chlorhexidine. According to the invention, acri is used in particular as acridine dye flavin used. These agents unexpectedly show combinations have a synergistic effect, so that despite the Reducing the application concentration the antimicrobial Effectiveness is greater than the sum of the antimicrobial Efficacies of the individual active ingredients. The reduction of Concentration of use leads to lower toxicity logical load, at the same time the use of at least two antimicrobial agents spectrum.

The advantageous combinations mentioned below Variants with Acriflavin are characterized by a special high synergistic effect from:

• - 0.01 to 1% acriflavin and 0.01 to 0.5% chlorhexidine.
• - 0.01 to 1% acriflavin and 0.01 to 0.5% octenidine.  
• - 0.01 to 1% acriflavin and 1 to 10% PVP iodine in aqueous solution.
• - 0.01 to 1% acriflavine and 1 to 5% PVP iodine in alcoholic solution, the alcoholic solution being a n- or iso-propanol / water mixture with an alcohol content is between 40 and 90% by volume.
• - 0.01 to 1% acriflavin and 0.01 to 4% lactic acid.
• - 0.01 to 1% acriflavin and 0.01 to 4% lactic acid and 0.01 to 0.5% chlorhexidine.

A triple combination consisting of acriflavin, lactic acid and Chlorhexidine exists, also has a clear improved antimicrobial activity against various Viruses such as hepatitis B virus and herpes simplex virus.

The antimicrobial active ingredient combinations according to the invention are used in aqueous solutions, if necessary Contain alcohol content. The alcohol is added for ver improvement of both the wetting and the solubility of the Active ingredients in long-chain compounds in particular and / or to reduce the viscosity of the active ingredient combination nation. At the same time, the addition of alcohol causes an increased anti microbial effectiveness. In particular, ethanol, Isopro panol or n-propanol used. When using the antimicrobial combination of active substances on a mucous membrane, on a mucosal surface or on a wound the concentration should not be higher than 10% by volume. At normal skin the alcohol concentration can be up to 70% be.  

Depending on the respective application site or the com The active ingredient according to the invention becomes variant variants combination for pH value regulation buffer, for isotonization Electrolytes, to improve wetting agents and wetting if necessary added stability improvers.

The following examples serve for further explanation the invention.

example 1

The synergistic effect of acriflavin through Lactic acid was found in the blocking activation test pointed. The test principle is that one effect is contained in dilution levels in the solid nutrient medium and the combination partner in four different concentrations in punched agar holes of 10 mm in diameter, the sealed on the bottom with an agar drop, pipette in (Weuffen, W .; Mentel, R. (1968): Connections between chemical constitution and anti-germ effect. 22nd communication: Orientative examination of some benzyl isothio cyanate on combination effects with other substances Block activation test. Pharmacy 23, p. 579-582). Pseudomonas aeruginosa was used as the test germ puts. Form on the plates with uninhibited germ growth around the punching holes or take the inhibition zone diameters compared to the control plate without the addition of active ingredient in Agar too, there is an increase in effectiveness. It comes up uncovered plates around the punch holes for germination,  there is an antagonistic interaction. It was repeated attempts.

When evaluating the results, it can be assumed that an increase in the inhibition zone diameter by 2 mm approximately one ver doubling of effectiveness corresponds. This will make it effective of acriflavin by lactic acid in the best case increased approximately 32-fold (Table 1).

Table 1

Bacteriostatic combination effects in the blocking activation test with acriflavine hydrochloride (0.5%) as test substance in the agar

Example 2

According to the methodology in Example 1, the synergistic Increased potency of acriflavin by chlorhexidine showed (Tab. 2), which in the best case about 20 times amounted to.

Table 2

Bacteriostatic combination effects in the blocking activation test with acriflavine hydrochloride (0.5%) as test substance in the agar

Example 3 Inactivation of hepatitis B surface antigen (HBsAg) in the Suspension test methodology

200 ml of a serum pool containing HBsAg from more than 100 HBsAg-positive subjects were treated with 1.8 ml of the test sample Active ingredient solution added and 2, 30, 60, 120 and 240 minutes incubated. The solutions were used for the extensive inactivation diluted 1: 100 after the exposure time. The determinations HBsAg was measured using a radioimmunoassay. (Abbott Diagnostika GmbH, Wiesbaden) according to the regulations of the manufacturer. The evaluation was based on that of Jülich, W.-D .; Kramer, A .; Wiebeck, F. and Weuffen, W. (Disinfec agent test in the germ carrier test with HBsAg as an infection marker for the hepatitis B virus. In: Knoll, H. (ed.) - Applied hospital hygiene, report on the 111th crane kenhaushygiene congress Marburg 1988, vol. 3, pp. 249-257) specified scheme.

Results

The tested individual active ingredients make the immunochemical Reactivity of HBsAg reduced by less than 50%, she must therefore be rated as ineffective in this test system will. In contrast, the combination according to the invention from acriflavin - 0.3%, chlorhexidine acetate - 0.2% and Lactic acid - 2% achieved moderate antiviral activity.  

The combination according to the invention is therefore one Expansion of the range of effects possible.

Table 3

Results of the radioimmunoassay for the determination of HbsAg after inactivation in the suspension test

Claims (8)

1. Antimicrobial combination of active ingredients based on acridine dyes for antiseptics and disinfection of the skin, mucous membrane and wound, characterized in that the acridine dyes are combined with in a concentration of 0.01-1%

• - chlorhexidine
• Octenidine
• - quaternary ammonium compounds
• - iodophores
• - lactic acid
• - or with lactic acid and chlorhexidine.

2. antimicrobial active ingredient combination according to claim 1, characterized, that an acridine dye is acriflavine. 3. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they are 0.01-1% acriflavine and 0.01-0.5% chlorhexidine contains. 4. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they contain 0.1-10 mg / ml acriflavin and 0.01-0.5% Contains octenidine. 5. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they are 0.01-1% acriflavine and 1-10% PVP iodine contains aqueous solution.   6. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they are 0.01-1% acriflavine and 1-5% PVP iodine contains alcoholic solution, the alcoholic solution a n- or iso-propanol / water mixture with one Alcohol content is between 40 and 90% by volume. 7. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they are 0.01-1% acriflavine and 0.01-4% lactic acid contains. 8. antimicrobial active ingredient combination according to claim 1 and 2, characterized, that they are 0.01-1% acriflavine and 0.01-4% lactic acid and contains 0.01-0.5% chlorhexidine.