DE2426393B2 - Ready-to-use liquid gargle with antimicrobial effectiveness - Google Patents

Description

0.005-0.05% dequalinium chloride,

0.15-0.75% ethoxylated hydrogenated castor oil,

0.1-0.5% propylene glycol ethylene glycol

polyether.and
OJ06- 0.5% sodium lauroyl sarcosinate

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 is additionally 0.05-03% «-Bisabolol contains

The strong antimicrobial effectiveness voi; Dequalinium chloride is used 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

While the therapeutic advantages outweigh the advantages, dequalinium chloride shows some disadvantages on the pharmaceutical side. These include the strongly bitter taste, as well as the instability or compatibility with common auxiliaries, e.g. B. detergents and wetting agents. The latter was discussed in the work by Collier et al. (J. Pharm. Pharmacol. 11, 671, [1959]) examined in detail. Without such auxiliaries, however, dequalinium chloride cannot be used as drugs. If these disadvantages can still be remedied relatively easily in the manufacture of lozenges, they become particularly apparent in the manufacture of liquids. So it is not surprising that liquid preparations with dequalinium chloride as an 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 must be diluted accordingly before use. However, the ready-to-use solution is preferred as the optimal dosage form for therapy of mouth and throat infections alone or with lozenges in combination, by the doctor for use in nebulizers, by the patient as an easy-to-use gargle solution with a constant concentration.
From H, Helwig; Moderne Arzneimittel, Stuttgart (1972), S, 767 wd U98, a liquid drug with antimicrobial activity due to a content of dequalinium chloride is known, 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 Finnish 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 gargle according to the invention is 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.
The inventive gargle with antimicrobial effectiveness and a content of propylene glycol ethylene glycol polyether and sodium lauroyl sarcosinate is used to solve this problem, which is characterized in that it contains 0.005 to 0.05% dequalinium chloride, 0.15 to 0.75% ethoxylated hydrogenated castor oil, Contains 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%.

) 5 According to a preferred embodiment, the gargle contains a K anti-inflammatory component 0.05-03 and preferably 0.1-0.2% «-bisabolol.
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 how investigations

V) have shown that when added to human saliva an inhibition of bacterial growth (hexokinase inhibition), so that in connection with dequalinium chloride there is an additional bacteriostatic effect

Ethoxylated fractions of hydrogenated castor oil are used as the emulsifier, preferably the foaming power is slowed down by the addition of small amounts of physiologically harmless solvents are. 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.

<> i 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

1 dyes can be adjusted, preferably patent blue V ; (EWG-Nr, 13t), like a certificate from Patentblau V Tl (EWGNÄ

Tn (FrÄ

The stability of the erfJntlWgsgemWen .Gurgelroittel was checked by storage at room temperature, at 40 ⁰ C, at 4 ° C, and in the W "* seUcIiroa (24 hours and 40 ° C / 24 hours 4 ° C)

This showed that under all climatic conditions a good stability was given for more than 15 months, (± 3%). :;? .

The antimicrobial 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) did not show any growth either with the undiluted solution or with the 1:10 diluted solution. The same results were obtained with the samples from the climate.

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

The results achieved are comparable to those of known anti-inflammatory drugs. However, since «-Bisabolol its use shows a very high therapeutic index compared to the latter due to its low toxicity 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:

example 1
Gargle solution

0.075 g mouthwash oil

0.200 g ethoxylated hydrogenated castor oil

0.100 g propylene glycol ethylene glycol polyether

0.010 g dequalinium chloride

0.025 g of cyclamate sodium
15,000 grams of pi upylene glycol

0.060 g sodium lauroyl sarcosinate

0.003 g patent blue V
ad 100 ml of water

Example 2
Gargle solution
0.075 g mouthwash oil
0.500 g of ethoxy converted hydrogenated castor oil

0.100g 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:

A clinical test was carried out on 60 patients with the gargle solution according to Example 1 and a commercially available gargle solution which contained 100.0 mg hexetidine and 12.5 mg cetylpyridinium chloride per 100 ml

It should first be pointed out that the content of active ingredients in the previously known gargle solution U2J was 5 mg / 100 ml, while the gargle solution according to the invention contained only 10.0 mg / 100 ml of 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,

J5 hoarseness, difficulty swallowing and phlegm, as well as taste and sensation tested when gargling 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 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.

π 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 cough and hoarseness, 63.7% of the patients who were treated with the gargle solution according to the invention were symptom-free compared to 30% of the patients who used the previously known gargle solution. In the case of hoarseness, 50% of the patients were treated with the gargle solution according to the invention

ι «were treated, symptom-free, compared to 25% of Patients who used the previously known gargle solution. With the parameter swallowing difficulties one shows Rate of improvement (freedom from symptoms + improvement) of

100% for 4 gargle solutions according to the invention, opposite 85.7% of the previously known gargle solution, The The parameter Yerschleiroung corresponds to both in approximately.

The bacteriological test on 10 patients at the end of therapy gave the following results:

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

Gurgle solution according to the invention:
8 smears (= 80%) without findings
2 smears (= 20%) bacterial growth.
The bacterial growth was weak and limited 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, also with regard to the concentration of the active substance with the gargle solution according to the invention only approx. i / ta the amount of active ingredient in the previously known gargle solution amounts to.

The minimum inhibitory concentrations were still used determined in different cultures, namely once on the previously mentioned, previously known Gargle solution, which contained 112.5 mg / 100 ml of the active ingredient combination, continued with one Containing 12.5 mg / 100 ml of cetylpyridinium chloride

ίο gargle solution and the gargle solutions according to the invention according to Example 1 and Example 3. Contains the gargle solution according to the invention described in Example 3 in addition to 25 mg dequaline rhine 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 with the different test solutions offset in order to then cast corresponding plates.

This agar dilution series was made with the MuIdpoint inoculator (Denley) inoculated Undiluted 16-hour precultures were used as inoculum for the streptococci, for all other microorganisms diluted 1: 100 in physiological saline solution lf> 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 According to the invention Previously known Gur Gargle solution with Gargle solution Gargle solution gel solution with i 2.5 mg / 100 ml according to example I. according to example 3 112.5 mg / 100 ml Cetyl pyridinium Active ingredient combination. chloride

Proteus morganii 28175 U <1:10 Proteus rettgeri 28381 U <1: 10 E. coli 28217 U <1: 10 Pseudomonas aeruginosa 29468 U <1:10 Kleteiella Group 20428 B <1:10 Staphylococcus pyogenes 20483 B. 1:40 Staphylococcus pyogenes 20764 B ϊ: 40 Staphylococcus pyogenes 20596 B. 1:40 Staphylococcus pyogenes 21340 B 1:40 Enteiococci 21198 B 1.10 Enterococci 28224 U 1:10 Hemolys. Streptococcus A group
21017 B 1: 100 Hemolys. Streptococcus A group
21326 B 1: 200 Hemolys. Streptococcus A group
21327 B 1: 200 Greening Streptococci 21330 B 1: 200 Greening Streptococci 21731 B 1:40 Candida 20508 B 1: 100 Candida 20593 B 1: 100 Candida 20592 B 1: 100 Candida 20614 B 1: 100

<1:10

<1:10

1: 100 1: 400 1: 100 1: 400 1: 100 1: 400 1: 100 1: 400 1:40 1: 200 1:20 1: 200 1: 100. > 1: 800 1: 200 > 1: 800 1: 200 > l: 800 1: 100 > 1: 800 1: 100 > l: 800 1: 200 1: 100 1: 200 1: 100 1: 200 1: 100 1: 200 1: 100

: 100: 100 .100: 100: 80

: 80: 100

: 100: 100

: 20: 20: 20: 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 less effect in the groups Staphylococcus pyogenes, enterococci, hemolyzing and greening streptococci and superior to 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)

Claims; l _r Ready, flössi ^ it gargles with antimicrobial activity and a content of Propylenglykoläthylenglykolpolyätber and Natriumlauroylsarconsinat, characterized in that it contains in aqueous solution