RU2776367C2 - Drug - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine, namely to an antiseptic drug consisting of an active component and a pharmaceutical diluent. The active component is salt of organic acid of benzyldimethyl[3-myristoylamino-propyl]ammonium in a dehydrated or hydrated form, while organic acid is selected from a group: succinic, maleic, acetic, formic, fumaric, citric, tartaric, malic, malonic, benzoic, lactic and ascorbic acids.

EFFECT: proposed drug has an antiseptic effect, low irritation capability and low degree of absorption to the system blood flow of active substance, which allows for increasing the rate of its usage as a local antimicrobial agent.

15 cl, 1 tbl

Description

The present invention relates to the field of medicine and can be used as an antiseptic drug for the treatment and prevention of infectious and inflammatory diseases.

The synthesis and use of quaternary ammonium salts simultaneously containing an amide group is first described in US Pat.

This patent shows the activity of the resulting product against one standard strain of staphylococcus aureus. The product described by the inventors is a semi-solid at room temperature with a melting point of 54°C (column 3, lines 69-70). However, Example 1 does not provide any other studies confirming the structure of the isolated product. However, studies carried out during the work on the invention, studies on the isolation of a pure suitable drug for medical use show that myristamidopropyldimethylbenzylammonium chloride at room temperature is a crystalline product with a melting point above 90°C.

Thus, it can be assumed that the inventors isolated the mixture of the main product with residual amounts from benzyl chloride and solvent (benzene) and investigated their activity. But the use of such a product for medical purposes is impossible due to the high toxicity of benzyl chloride and benzene. According to line 62, column 3 (example 1), the original myristamidopropyldimethylamine is also a solid, which is also confirmed by our studies. Therefore, the product obtained in example 1 cannot be a mixture of the starting amidoamine and the final compound.

In addition, the presence of residual amounts of the original amidoamine is impossible, because in example 1, benzyl chloride is used in the reaction in a sufficient amount.

It should also be noted that pure myristamidopropyldimethylbenzylammonium chloride does not give a solution with a concentration above 20% in water, and the original myristamidopropyldimethylamine does not dissolve in water at all and precipitates with water from solutions in other solvents. This also confirms that the final product of example 1 cannot contain myristamidopropyldimethylamine impurities, since pages 73-74, column 3, indicate the preparation of clear 25% aqueous solutions.

There are a number of drugs based on benzyldimethyl[3-(myristoylamino)propyl]ammonium chloride in the form of a monohydrate or in a non-hydrated form. These drugs are intended for the treatment and prevention of certain types of diseases RU 2185156, RU 2173142, UA 30143).

The disadvantages of these drugs include their high irritant ability and a high degree of absorption into the systemic circulation of the active substance (high systemic effect).

The present invention is based on the task of developing an active substance based on benzyldimethyl[3-(myristoylamino)propyl]ammonium, which has an antiseptic effect, low irritant ability and a low degree of absorption into the systemic circulation of the active substance, which makes it possible to increase the frequency of its use as a local antimicrobial agent. .

The problem is solved using a drug for the treatment and prevention of infectious and inflammatory diseases, consisting of an active component and a pharmaceutical diluent, while the active component is a benzyldimethyl[3-myristoylamino)propyl]ammonium salt of an organic acid in an anhydrous or hydrated form.

Organic acid refers to organic substances exhibiting acidic properties. The use of organic salts of benzyldimethyl[3-myristoylamino)propyl]ammonium ensures the achievement of a technical result, which consists in reducing the systemic effect of the drug (less absorption into the systemic circulation) and reducing its irritating effect. In addition, this invention expands the range of available drugs.

Preferably, the pharmaceutical diluent is water, or ethyl alcohol, or an isotonic solution, or a mixture thereof.

The content of organic acid benzyldimethyl[3-(myristoylamino)propyl]ammonium salt is preferably 0.01-1.0 wt%.

According to one of the best embodiments of the invention, the active ingredient is a salt of an organic acid selected from the group: succinic, maleic, acetic, formic, fumaric, citric, tartaric, malic, malonic, benzoic, lactic, and ascorbic acids, or is any a mixture of active ingredients, which are salts of an organic acid selected from the group: succinic, maleic, acetic, formic, fumaric, citric, tartaric, malic, malonic, benzoic, lactic, and ascorbic acids.

That is, benzyldimethyl[3-myristoylamino)propyl]ammonium succinate (succinic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium maleate (maleic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium acetate (acetic acid salt) , benzyldimethyl[3-myristoylamino)propyl]ammonium formate (formic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium fumarate (fumaric acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium citrate (citric acid salt), benzyldimethyl [3-myristoylamino)propyl]ammonium tartrate (tartaric acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium malate (malic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium malonate (malonic acid salt), benzyldimethyl[3 -myristoylamino)propyl]ammonium benzoate (benzoic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium lactate (lactic acid salt), benzyldimethyl[3-myristoylamino)propyl]ammonium ascorbate (ascorbic acid salt) or a mixture thereof.

Each of the salts can be used in both anhydrous and hydrated form.

The following organic salts of the active component benzyldimethyl[3-myristoylamino)propyl]ammonium were obtained within the framework of the studies of the present invention:

1. benzyldimethyl[3-myristoylamino)propyl]ammonium succinate (succinic acid salt);

2. benzyldimethyl[3-myristoylamino)propyl]ammonium maleate (maleic acid salt);

3. benzyldimethyl[3-myristoylamino)propyl]ammonium acetate (acetic acid salt);

4. benzyldimethyl[3-myristoylamino)propyl]ammonium formate (formic acid salt);

5. benzyldimethyl[3-myristoylamino)propyl]ammonium fumarate (fumaric acid salt)

6. benzyldimethyl[3-myristoylamino)propyl]ammonium citrate (salt of citric acid);

7. benzyldimethyl[3-myristoylamino)propyl]ammonium tartrate (salt of tartaric acid);

8. benzyldimethyl[3-myristoylamino)propyl]ammonium malate (salt of malic acid);

9. benzyldimethyl[3-myristoylamino)propyl]ammonium malonate (salt of malonic acid);

10. benzyldimethyl[3-myristoylamino)propyl]ammonium benzoate (salt of benzoic acid);

11. benzyldimethyl [3-myristoylamino)propyl]ammonium lactate (lactic acid salt);

12. benzyldimethyl[3-myristoylamino)propyl]ammonium ascorbate (salt of ascorbic acid);

13. benzyldimethyl[3-myristoylamino)propyl]ammonium chloride (hydrochloric acid salt).

Sample No. 13 benzyldimethyl[3-myristoylamino)propyl]ammonium chloride corresponds to the prototype, is not included in the scope of the present invention, and is used as a control sample within the framework of the present invention.

On the basis of these samples, aqueous solutions of the drug were prepared with an active component content of 0.01 wt%, 0.5 wt%, and 1 wt%.

The evaluation of the systemic action of the drugs was carried out on experimental animals of two types: 30 male and female mice weighing 23-26 g and 60 male and female rats weighing 140-160 g. The drugs were administered intraperitoneally in a volume of 0.3 ml per 10 g of body weight for mice ( 30 g/kg); 0.5 ml per 100 g body weight for rats (5 g/kg).

The {absorption rate?} of sample 1 was taken as a unit (preparations 13, 26, 39).

The evaluation of the irritating effect was carried out according to the HET-CAM test on the chorion-allantoic membrane of the chick embryo.

The evaluation was carried out on 20 chick embryos, for each sample, white Leggron chickens aged 9-10 days, kept for 7 days in a thermostat t 37.8°C, at a constant relative humidity of 62.5%.

The preparations were tested in 20 repetitions for each preparation. The work was carried out on 20 chick embryos of white hens of the Leggron breed, aged 9-10 days, kept for 7 days in a thermostat at a temperature of 37.8°C, at a constant relative humidity of 62.5%. Before starting work, the egg was fixed on a fixing stand with the blunt end up; the shell was opened in the center of the blunt end, the entire air chamber was freed from the shell, after which the surface of the open air chamber was moistened with isotonic sodium chloride solution (0.89%) at a temperature of 37°C. After that, the egg was placed in a thermostat for 30 minutes, then the solution was aspirated with a micropipette, the moistened hard shell was removed from under the shell, without damaging the chorion-allantoic shell. A preparation heated to 37°C was applied at a dose of 0.3 g and the effect of the substance was observed for 240 seconds.

The results of these studies are shown in Table 1.

Table 1

Using the methods recommended by the World Health Organization (WHO), we studied the antimicrobial effect of drugs in comparison with the prototype against Escherichia coli, Staphylococcus aureus, and Candida albicans. The experiments showed identical efficacy of preparations 1-12 and preparations based on the control sample No. 13 (preparations 13, 26 and 39). An increase in the antimicrobial effect of drugs with a concentration of 0.1% wt. up to 1% wt. showed a natural increase in antimicrobial activity.

Also, the antimicrobial activity of drugs in an isotonic solution and an alcohol-water solution of various concentrations was studied. Within the framework of these studies, results identical to those of water were obtained. Namely, it was found that the use of these organic salts of the active substance shows antimicrobial activity and always provides a lower irritant effect and a lower systemic effect of the drug (less absorption into the systemic circulation).

Claims (15)

1. An antiseptic preparation consisting of an active ingredient and a pharmaceutical diluent, characterized in that the active ingredient is a benzyldimethyl[3-myristoylamino)propyl]ammonium salt of an organic acid in an anhydrous or hydrated form, while the organic acid is selected from the group: succinic, maleic , acetic, formic, fumaric, citric, tartaric, malic, malonic, benzoic, lactic and ascorbic acids. 2. An antiseptic preparation according to claim 1, characterized in that it contains water, or ethyl alcohol, or an isotonic solution, or a mixture thereof and a salt of an organic acid benzyldimethyl[3-(myristoylamino)propyl]ammonium in an amount of 0.01 as a pharmaceutical diluent -1.0% wt. 3. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is any mixture of active ingredients, which are salts of an organic acid selected from the group: succinic, maleic, acetic, formic, fumaric, citric, tartaric, malic, malonic, benzoic, lactic and ascorbic acids. 4. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of succinic acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 5. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of maleic acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 6. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a benzyldimethyl[3-myristoylamino)propyl]ammonium salt of acetic acid in anhydrous or hydrated form. 7. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a formic acid salt of benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 8. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of fumaric acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 9. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of citric acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 10. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a benzyldimethyl[3-myristoylamino)propyl]ammonium salt of tartaric acid in an anhydrous or hydrated form. 11. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of malic acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 12. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of malonic acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 13. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a benzyldimethyl[3-myristoylamino)propyl]ammonium salt of benzoic acid in anhydrous or hydrated form. 14. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a lactic acid salt of benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form. 15. Antiseptic preparation according to any one of paragraphs. 1 or 2, characterized in that the active ingredient is a salt of ascorbic acid benzyldimethyl[3-myristoylamino)propyl]ammonium in anhydrous or hydrated form.