DE2426393C3 - Ready-to-use liquid gargle with antimicrobial effectiveness - Google Patents

Description

contains

2. Gargle according to claim 1, characterized in that it also contains 10-20% propylene glycol contains

3. Gargle according to claim 1 or 2, characterized in that it also contains 0.05 - 03% «-Bisabolol contains

The strong antimicrobial effectiveness of dequalinium chloride is in many in-vitro and in vivo studies have been confirmed. In addition to gram-negative and gram-positive bacteria and cocci yeasts, dermatophytes, fungi and trichomonads are also produced with a low concentration of active ingredients captures the special position that dequalinium chloride through its bactericidal and fungicidal intensity of action among the known quaternary ammonium compounds, is supplemented by good tolerance on the integument and mucosa, as well as the absence of germ resistance. Because of these properties Dequaliniumchlorid was preferred for the treatment of bacterial and inflammatory infections of the mouth and Pharynx used.

If the therapeutic advantages outweigh the advantages, dequalinium chloride shows some disadvantages on the pharmaceutical side. Among them are the strongly bitter taste, as well as the instability or incompatibility with usual ones Auxiliaries, e.g. B. detergents and wetting agents. The latter was discussed in the work of Collier et. al. (J. Pharm. Pharmacol. 11, 671, [1959]) examined in detail. Dequalinium chloride can be used without such auxiliary substances not be used as a medicinal product. These disadvantages can still be relatively simple are eliminated in the manufacture of lozenges, so they occur in the manufacture of liquids especially in appearance. So it is not surprising that liquid preparations with dequalinium chloride as Ingredient for the treatment of mouth and throat infections only as a concentrate in mostly non-aqueous Preparations, e.g. B. Solutions in propylene glycol are commercially available, which are diluted accordingly before use Need to become. As an optimal form of administration on its own or combined with lozenges Therapy of mouth and throat infections, however, the ready-to-use solution is preferred by the doctor Application in nebulizers, considered easy by the patient Gargle solution to be handled with constant concentration.

From H. Helwig: Moderne Arzneimittel, Stuttgart (1972), p. 767 and 1198 is a liquid drug with Antimicrobial effectiveness known due to a content of dequalinium chloride, but it is a concentrated solution for the treatment of the skin or spray products for the treatment of the skin or

ίο to oral spray preparations; which, however, is dequalinium acetate contained in non-aqueous solution.

A proposal for a mouthwash is also known from a company publication, which propylene glycol ethylene glycol polyether as surfactant and contains sodium lauroyl sarcosinate However, there is nothing in this proposal testified about the addition of dequalinium chloride

The gargles according to the invention are also in a non-aqueous solution, which is easy to handle and has a constant concentration. The gargle according to the invention should also have a pleasant taste and alleviate a large number of ailments.
To solve this problem, the inventive gargle with antimicrobial activity and a content of propylene glycol ethylene glycol polyether and sodium lauroyl sarcosinate, which is characterized in that it contains 0.005 to 0.05% dequalinium chloride, 0.15 to 0.75% ethoxylated hydrogenated castor oil, 0 in aqueous solution , 1 to 0.5% propylene glycol ethylene glycol polyether, and 0.06 to 0.5% sodium lauroyl sarcosinate.

The dequalinium chloride content is preferably 0.010-0.025%.

According to a preferred embodiment, the gargle contains 0.05-0.3 and preferably 0.1-0.2% c.-bisabolol as the anti-inflammatory component.
According to the invention, the gargle contains a surfactant, namely a propylene glycol ethylene glycol polyether, for example one with an average molar weight of 8750 and a degree of ethoxylation of 159 Mo ethylene oxide, in an amount of 0.1-0.5%. This surfactant has not only been shown to be compatible with dequalinium chloride, but is also well tolerated by the mucous membrane.

The gargle contains sodium lauroyl sarcosinate as a wetting agent in a concentration of 0.06 to 0.5%. Sodium lauroyl sarcosinate itself shows, as studies have shown, when added to human Saliva inhibits bacterial growth (hexokinase inhibition), so that in connection with Dequalinium chloride gives an additional bacteriostatic effect.

• y. ' Ethoxylated fractions of hydrogenated castor oil are used as emulsifiers, the foaming power of which is slowed down, preferably by the addition of small amounts of physiologically harmless solvents. Such products are on the market. That

Bo ethoxylated, hydrogenated castor oil is used in an amount used from 0.15-0.75%.

The preparation according to the invention for cold stabilization preferably also contains 10-20% propylene glycol. Preparations with such an additive are freeze-proof.

bj Natural and synthetic aromas can be used as flavorings, which can mask the inherent taste of the dequalinium chloride.
Water-soluble foodstuffs can be used as colorants

dyes are used, preferably Patent Blue V (EEC No. 131), as well as a mixture of Patent Blue V with tartrazine (EEC No. 102).

The stability of the gargles according to the invention was determined by storage at room temperature, at 40 ° C, at 4 ° C, as well as in a changing climate (24 hours 40 ° C / 24 Hours 4 ° C)

This showed that under all climatic conditions good stability was given for 15 months. (± 3%).

The antinucrobial activity of the solution according to Example 1 was in vitro in the agar diffusion test and Germ suspension test determined against the following test germs:

Candidia albicans

Staphylococcus aureus

Streptococcus pyogenes (serological group A)

Neisseria flava

Neisseria catarrhalis

Both the freshly prepared solution and batches from the climate test were used for the test, who have already been exposed to different climatic conditions for 3, 6 and 15 months.

The agar diffusion test (10 ⁵ germs / ml) showed with 0.1 ml of the drug solution a very strong inhibitory effect on Candida, Staphylococcus aureus, Streptococcus and Neisseria (inhibitor diameter 2.5 cm). The germ suspension test (10 ⁶ germs / ml) showed no growth either with the undiluted solution or with the 1:10 diluted solution. The same results were obtained with the samples from the climatic test.

The anti-inflammatory effect of bisabolol was determined in vitro on the calf's cornea, the incorporation of radioactive sulfate in the proteochondroitin sulfates and proteokeratan sulfates being determined. It could be shown here that-bisabolol shows a 15% ^{inhibition of the incorporation in a concentration of ίθ ~ 4} M, and a 58% inhibition of ^{10 ~ 3 M.}

The results obtained are comparable to those of known anti-inflammatory drugs. However, since «-Bisabolol shows a very high therapeutic index compared to the latter due to low toxicity, is its use as an additional anti-inflammatory agent in an antimicrobial gargle solution depending on Indication justified

The clinical effectiveness of the gargles according to the invention was tested in blind tests on numerous Proven proven. It was found that within 2-3 days the above named gram-positive and gram-negative germs were no longer detectable, as well as symptoms of inflammation went back quickly.

The gargle according to the invention is explained in more detail in the following examples:

Gargle solution Mouthwash oil example 1 0.075 g ethoxylated hydrogenated castor oil 0.200 g Propylene glycol ethylene glycol polyether 0.100 g Dequalinium chloride 0.010 g Cyclamate sodium 0.025 g Propylene glycol ί 5,000 g Sodium lauroyl sarcosinate 0.060 g Patent blue V 0.003 g water ad 100 ml

Example 2
Gargle solution

0.075 g mouthwash oil

0.500 g ethoxylated hydrogenated castor oil

0.100 g propylene glycol ethylene glycol polyether

0.010 g dequalinium chloride

0.100 g «-Bisabolol

0.080 g sodium lauroyl sarcosinate

0.025 g of cyclamate sodium
15,000 grams of propylene glycol

0.003 g patent blue V,
ad 100 ml of water

With the gargle according to the invention and a recognized commercially available gargle preparation the following comparative tests carried out:

With the gargle solution according to Example 1 and a

commercial gargle solution containing 100.0 mg hexetidine and 124 mg cetylpyridinium chloride per 100 ml a clinical trial was conducted in 60 patients

It should first be noted that the Content of active ingredients in the previously known gargle solution was 112 mg / 100 ml, while in the one according to the invention Gargle solution contained only 10.0 mg / 100 ml of the active ingredient, dequalinium chloride.

Both gargle solutions were used over a period of 6 days at the same dose of 6 χ 5 ml each Administered on the day

In addition to objective parameters (gingivitis, stomatitis, pharyngitis, tonsillitis, lateral cord angina, involvement of the larynx, Periodontal disease, bad breath and bleeding gums) were subjective parameters such as cough, Hoarseness, difficulty swallowing and mucus, as well as taste and sensation when gargling tested and at the beginning, after 24, 36 and 48 hours, as well as after 3, 4, 5 and 6 days with the key figures 0.1, 2 and 3 accordingly not available / easy / medium / strong, rated

In 20 patients, throat and tonsil swabs were used for a comparative assessment of the effect Performing a bacteriological test taken.

The following results were found:

judgement

The taste of the gargle solution according to the invention was rated as "pleasant" by 24 patients

as reported against 22 patients who were treated with the previously known gargle solution. the The gargle solution according to the invention found 26 patients "pleasant" when gargling compared to 23 patients, that gurgled with the previously known solution.

The inspection parameters gingivitis, stomatitis, pharyngitis, tonsillitis, lateral cord angina and involvement of the larynx are roughly the same for the two gargle solutions.
In the case of the parameters cough, hoarseness, 63.7% of the patients who were treated with the gargle solution according to the invention were symptom-free, compared with 30% of the patients who used the previously known gargle solution. In the case of hoarseness, 50% of the patients who were treated with the gargle solution according to the invention were symptom-free, compared with 25% of the patients who used the previously known gargle solution. The parameter swallowing difficulties showed an improvement rate (freedom from symptoms + improvement) of

100% for the gargle solution according to the invention, compared to 85.7% of the previously known gargle solution. Of the The mucilage parameter is roughly the same for both.

The bacteriological test showed at the end of therapy 10 patients the following result:

known gargle solution:

4 smears (= 40%) without findings,

6 smears (= 60%) bacterial growth.

The bacterial growth was weak to strong and predominantly limited to greening and haemolytic streptococci, Proteus mirabilis, Staphylococcus aureus and albus, enterococci and E. colL

Gurgell solution according to the invention: 8 smears (= 80%) without findings 2 smears (= 20%) bacterial growth. The bacterial growth was weak and limited itself to! Achromobacter faecalis (1 case), greening streptococci and Staphylococcus albus (1 case).

In summary, therefore, it follows that the gargle solution according to the invention both in the subjective as well as objective parameters a clear superiority of the effect compared to the previously known Gargle solution shows a surprisingly high superiority of the effect of the gargle solution according to the invention can be derived from the bacteriological findings, this also with regard to the concentration of active substances with the gargle solution according to the invention only about '/ u the amount of active ingredient in the previously known gargle solution

Furthermore, the minimal inhibitory concentrations

Tratic-nen determined in different cultures, namely once on the previously mentioned, previously known gargle solution, which contained 11 mg / 100 ml of the active ingredient combination , furthermore with one containing 123 mg / 100 ml of cetylpyridinium chloride

ίο Gargle solution and the gargle solutions according to the invention according to Example 1 and Example 3. The in Example 3 The gargle solution according to the invention described contains, in addition to 25 mg dequalinium chloride, 100 mg bisabolol / 100 ml

The examinations were carried out as follows:

D.S.T. agar (Oxoid) cooled to 55 ° C was poured into the ratios 1:10, 1:20, 1:40, 1:80, 1: 100, 1: 200.1: 400.1: 800 mixed with the various test solutions in order to then cast the corresponding plates.

This agar dilution series was inoculated with the Multipoint Inoculator (Denley). Undiluted 16-hour precultures were used as inoculum for the streptococci, and for all other microorganisms in physiological saline solution diluted 1: 100

16-hour precultures.

After incubation for 24 hours (or 72 hours for Candida), the dilution of the Active substances read as MICs, which clearly show the growth compared to the active substance-free control plate

inhibited.

According to the invention, previously known gargle-gargle solution with Gargle solution Gargle solution gel solution with 12.5 mg / 100 ml

according to example 1 according to example 3 112.5 mg / 100 ml cetyl pyridinium

Wh-kstoffkombin. chloride

Proteus morganii 28175 U Proteus rettgeri 28381 U E. coli 28217 U

Pseudomonas aeruginosa 29468 U KlebsieUa-Group 20428 B Staphylococcus pyogenes 20483 B. Staphylococcus pyogenes 20764 B Staphylococcus pyogenes 20S96 B Staphylococcus pyogenes 21340 B Enterococci 21198 B

Enterococci 28224 U Hemolys. Streptococcus A group

21017 B

Hemolys. Streptococcus A group

21326 B

Hemolys. Streptococcus A group

21327 B

Greening Streptococci 21330 B Greening Streptococci 21731 B Candida 20S08 B Candida 20593 B Candida 20592 B Candida 20614 B

1: 200
1: 200

1: 200
: 40
: 100
: 100
: 100
: 100

< 1 : 10

1: 200
1: 200

1: 100
1: 100
1: 200
1: 200
l: _t 200
1: 200

> 1: 800

> 1: 800

> l: 800
> l: 800

1: 100
1: 100
1: 100
1: 100

< 1 : 10

1:40 1: 100 1: 400 1: 100 1:40 1: 100 1: 400 1: 100 1:40 1: 100 1: 400 1: 100 1:40 1: 100 1: 400 1: 100 1:10 1:40 1: 200 1:80 1:10 1:20 1: 200 1:80 1: 100 1: 100 > 1: 800 1: 100

1: 100

1: 100

1:20

1:20

1:20

1:20

From these results it can be seen that the minimum inhibitory concentration of the invention Gargle solution compared to the previously known, 112.5 mg / 100 ml gargle solution containing the active ingredient combination in vitro has the same effect in the cultures of Proteus, E. coli, Pseudomonas, Klebsiella, of lesser effect in the groups St nphylococcus pyogenes, Enterococci, haemolytic and greening streptococci and superior to the Candida culture.

Compared to the gargle solution containing only cetylpyridinium chloride, there is a high degree of superiority Candida and greening strep.

From the results, however, it can be seen that the gargle solution according to the invention, which is essential contains less active ingredient than the previously known gargle solutions.

Claims (1)

Patent claims: 1. Ready-to-use, liquid gargle with antimicrobial effectiveness and a content of Propylene glycol ethylene ^ glycol polyether and sodium lauroyl sarconsinate, characterized in that it is in aqueous solution 0.005-0.05% dequalinium chloride, 0.15-0.75% ethoxylated hydrogenated castor oil, 0.1-0.5% propylene glycol ethylene glycol polyether, and
0.06-0.5% sodium lauroyl sarcosinate