RU2662099C1 - Pharmaceutical compositions for inhalations containing nitroproston - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to the chemical-pharmaceutical industry and is a process for the preparation of a pharmaceutical composition and the pharmaceutical composition itself for the treatment of inflammatory and / or obstructive airways diseases selected from the group consisting of bronchial asthma and obstructive bronchitis, characterized in that it is an inhalation solution comprising 1',3'-dinitroglycerol ester of 11(S),15(S)-dihydroxy-9-keto-5Z,13E-prostodienoic acid, polysorbate 80, benzalkonium chloride in a ratio of 1:2:1 and a pharmaceutically acceptable solvent that is an isotonic sodium chloride solution.

EFFECT: present composition has a physico-chemical stability, is resistant to microbial contamination and includes a minimum amount of auxiliary ingredients.

7 cl, 6 tbl, 4 ex

Description

The present invention relates to medicine and experimental biology, and describes pharmaceutical compositions for inhalation containing an active pharmacological component with a pronounced bronchodilating effect based on 1,3-dinitroglycerin ester of prostaglandin E2 (nitroprone), which can be used in the treatment of bronchial asthma and obstructive bronchitis by inhalation using a nebulizer. The present invention also describes methods for preparing pharmaceutical compositions for inhalation.

State of the art

Asthma and other bronchial obstructive diseases are among the top five pathologies leading to the highest mortality of patients. According to estimates, by 2020, these diseases will come in third place in the number of deaths. Asthma is a chronic inflammatory disease of the respiratory tract, accompanied by bronchial hyperreactivity, which leads to frequent episodes of respiratory failure, asthma attacks and coughing. Chronic bronchial obstructive diseases are characterized by a partial blockade of the respiratory system, which is not completely relieved by drugs. Shortness of breath often progresses and is accompanied by an excessive inflammatory reaction of the lungs to foreign particles or harmful gases (such as cigarette smoke) or allergens.

Therapy for stopping or preventing asthma attacks caused by bronchospasm currently includes the use of beta-agonists, anticholinergics and glucocorticoids. However, about half of patients with asthma, especially with a long history of using bronchodilator drugs, have a deficiency or absence of a bronchodilator effect after inhalation with the indicated drugs. The solution to the problem of expanding the arsenal of bronchodilators is the use of alternative pharmacological targets. Such a target for therapeutic use is the fourth type of prostaglandin receptor (EP4). The pharmacological agent for activating this receptor is prostaglandin 1,3-dinitroglycerin ester N2 - nitroprostone. It is known in the art to use nitroprostone as a bronchodilator in the form of a solution in physiological saline ( Bezuglov VV, Serkov IV A bronchodilator based on prostaglandin. RU 2500397 Nitroproston is a hydrophobic substance and is practically insoluble in water. in the patent of the Russian Federation No. 2500397, the use of nitroprone as a solution in physiological solution consists in pre-mixing an alcohol solution of nitroprone with an isotonic sodium chloride solution, provided that the concentration of ethyl alcohol in the finished form does not exceed 1%, which leads to the formation of an emulsion. it can be used only immediately after preparation.In addition, in this case, the exact dosage of the drug is difficult due to the heterogeneity of the emulsion and partial sorption of nitrop Ostonov on the walls of the vessel used for preparing the dosage form, and the parts of the nebulizer in contact with the solution.

Disclosure of invention

The objective of the invention is the development of pharmaceutical compositions of nitroprone suitable for use in medicine as a bronchodilator delivered in the form of an aerosol using a nebulizer.

The solution to this problem is carried out by creating a pharmaceutical composition for the treatment of inflammatory and / or obstructive diseases of the respiratory tract, selected from the group including bronchial asthma and obstructive bronchitis, characterized in that it is a solution for inhalation, including 1 ', 3'-dinitroglycerin ether 11 (S), 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid (1,3-dinitroglycerin ester of prostaglandin E2, nitroprostone), polysorbate 80, benzalkonium chloride in a ratio of 1: 2: 1 and pharmaceutically acceptable solvent.

In particular embodiments, the pharmaceutically acceptable solvent is an isotonic sodium chloride solution (0.9% sodium chloride solution, physiological saline).

In some embodiments of the invention, the pharmaceutical composition is a composition having the following composition per 1 ml of solution:

Nitroproston - 10-250 mcg

Polysorbate 80 - 20-500 mcg

Benzalkonium chloride - 10-250 mcg

Sodium Chloride - 0.9 mg

Water for injection - up to 1 ml.

In some embodiments of the invention, the pH of the pharmaceutical composition is 6.2-7.4.

In some particular embodiments of the invention, the pharmaceutical composition further comprises a buffer mixture to maintain a pH of 6.2-7.4.

In some particular embodiments of the invention, the buffer mixture in the pharmaceutical composition consists of a mixture of disodium phosphate and citric acid, or citric acid and sodium hydroxide, or citric acid and sodium citrate, mainly disodium phosphate and citric acid, in some embodiments, in a final concentration of 1 - 100 millimoles per 1 liter of pharmaceutical composition.

The problem is also solved by obtaining the pharmaceutical composition according to the invention, the method comprising mixing solutions of nitroprone and polysorbate 80 in ethanol, removing ethanol in vacuum, adding a solution of benzalkonium chloride and then adding a pharmaceutically acceptable solvent.

In private embodiments of the invention, the amount of alcoholic solutions of nitroprone and polysorbate 80 is chosen so that the ratio of nitroprone and polysorbate 80 is 1: 2.

The solution to this problem is also carried out in the use of the pharmaceutical composition according to the invention for the treatment of inflammatory and / or obstructive diseases of the respiratory tract, selected from the group including bronchial asthma and chronic obstructive pulmonary disease, as well as other inflammatory conditions accompanied by shortness of breath, and in the method of treating these diseases by administering pharmaceutical compositions to patients in the form of aerosols by inhalation, including intranasally, for example using ulayzera inhaler or manual, or any other method that provides an aerosol formation.

When carrying out the invention, the following technical results are achieved:

- developed a pharmaceutical composition of nitroprone, suitable for use in medicine as a bronchodilator delivered in the form of an aerosol using a nebulizer, namely, a composition consisting of:

- a true solution of highly hydrophobic nitroprostone in the concentration range from 10 to 250 μg in 1 ml of isotonic sodium chloride solution, suitable for use in a nebulizer,

- possessing physical and chemical stability,

- resistant to microbial contamination,

- including a minimum amount of auxiliary ingredients.

Terms and Definitions

Unless otherwise specified, all technical and scientific terms used in this document have the same meaning that is generally accepted in the field to which the invention belongs, and can be understood by a specialist with appropriate skills.

In the description of the present invention, the terms “includes” and “including” are interpreted as meaning “includes, inter alia,”. These terms are not intended to be construed as “consists of only”.

"Nebulizer solution" refers to a solution that is dispersible as an aerosol and is a form of aerosol. Inside the nebulizer, a liquid or solution is sprayed onto the ultrafine particles using a method known in the art, including but not limited to compressed air, ultrasound, or a vibrating nozzle.

“Inhalation” is a method of administering a drug by inhaling vapors formed by a finely divided mixture of a drug and water.

“Pharmaceutically acceptable ingredients” are substances that do not have a toxic effect in the indicated doses and do not alter the nature and effectiveness of the active pharmaceutical ingredient.

A “mixture” is the joint inclusion of two or more substances without the formation of chemical bonds, and the physical properties of each of the components remain unchanged.

“Composition” - any association of two or more constituent components.

“Excipients” - any substances (with the exception of the active ingredients) that are part of the medicinal product to give it the necessary properties.

"Active pharmaceutical ingredient" - any substance that is intended for use in the manufacture of a medicinal product, is responsible for the pharmacological effect and in the manufacture of a medicinal product becomes its active ingredient.

"Solubilizers (surfactants)" - chemicals that are soluble in water and capable of forming associations with hydrophobic compounds, contributing to their solubility in aqueous solutions.

“Buffer mixture” - a mixture of substances that provides a certain stable concentration of hydrogen ions (pH) in aqueous solutions.

Detailed description of the invention.

Pharmaceutical compositions for inhalation via nebulizers are typically aqueous solutions of the active pharmaceutical ingredient with the addition of certain amounts of excipients and should not contain more than 1% ethyl alcohol, since ethyl alcohol is irritating to the mucous membranes of the respiratory tract.

There are two variants of pharmaceutical compositions for inhalation using a nebulizer used in asthma: sterile solutions for single-use containers and non-sterile solutions for repeated use containing an antimicrobial ingredient. Typically, such pharmaceutical compositions do not require additional dilution before inhalation.

However, since nitroprostone is practically insoluble in water, it is practically impossible to obtain a true solution of this substance in water from dry matter. It is known from the prior art that pharmacologically acceptable ingredients can be used as excipients for preparing solutions: cosolvents (for example, ethyl alcohol, propylene glycol); solubilizers (for example, polysorbate 20, polysorbate 80), the addition of which to a hydrophobic substance helps to transfer them to the aqueous phase.

Since, as already mentioned, the use of ethyl alcohol as a solvent does not contribute to the preparation of true solutions (the emulsions formed are heterogeneous and unstable and can be used only immediately after preparation), attempts have been made to create a pharmaceutical composition based on other cosolvents and / or solubilizers. Based on theoretical assumptions (taking into account the chemical properties of nitroprone, namely, its instability in an acidic and alkaline environment), and also as a result of numerous experiments, it was found that the most suitable substance for creating true nitroprone solutions are nonionic solubilizers, for example, fatty esters acids with polyoxyethylene sorbitan (polysorbates). These solubilizers are a mixture of copolymerization products of the partial esters of sorbitol and its anhydrides with 20, 5 or 4 moles of ethylene oxide per 1 mol of sorbitol or its anhydride. Most widely used in the pharmaceutical industry are polysorbates containing 20 parts of hydroxyethylene. In particular, they are used to prepare aqueous solutions of fat-soluble vitamins and many hydrophobic compounds. Polysorbates are typically used at a concentration of 1-15% (Handbook of Pharmaceutical Excipients. Sixth Edition. Ed. RC Rowe, PJ Sheskey, ME Quinn, Pharmaceutical Press, RPS Publishing, London-Washington, 2009, P. 549-553). Unexpectedly It was found that the addition of benzalkonium chloride antimicrobial agent to the composition of nitroprone with polysorbate 80 not only contributes to the production of the most stable and transparent nitroprone solutions that meet all the requirements for physical and chemical stability and resistance to microbial contamination, but reduces the amount of polysorbate used RBAP to minimum values (0,002-0,008 nitroprostona% at a concentration in the final solution 10 ug / ml). This effect is not observed when other antimicrobial agents, as well as other solubilizers and / or cosolvents, are added to the composition instead of benzalkonium chloride. These values are significantly lower than the known concentrations of the prior art for the use of polysorbate 80 (see, for example, Process for increasing the water solubility of lipophilic therapeutic substances - GB758550). The optimal ratio of the components of the aqueous solution of the pharmaceutical composition nitroprostone: polysorbate 80: benzalkonium chloride is a ratio of approximately (i.e., without significant deviation from these values) 1: 2: 1, more preferably exactly 1: 2: 1. It is this ratio that facilitates the preparation of the most stable true nitroprone solutions.

The composition of the composition may also include other pharmaceutically acceptable ingredients, for example, but not limited to, such as solutions of inorganic compounds used to bring the pH of the solution to the optimum value, as well as such as ionic compounds that form buffer mixtures that help maintain the pH of the solution in preset values. Such pharmaceutically acceptable ingredients may include, for example, 0.1 N. sodium hydroxide solution or 0.1 n. hydrochloric acid solution, which are introduced into the finished composition in an amount sufficient to achieve the desired pH value (usually in the amount of 10-30 μl per 20-100 ml of solution); as well as buffer mixtures consisting, for example, of a mixture of disodium phosphate and citric acid, or citric acid and sodium hydroxide, or citric acid and sodium citrate, well known in the art, which are introduced into the composition in an amount necessary to maintain the pH in the required range (usually at a final concentration of 1 to 100 millimoles per 1 liter of pharmaceutical composition. The optimal pH of the solution for inhalation is 6.2-7.4, more preferably 6.2-7.0.

The compositions of the invention are prepared by sequentially mixing pharmacologically acceptable ingredients previously dissolved in pharmacologically acceptable solvents (e.g., ethanol, water, isotonic solution).

An important point in obtaining the compositions according to the invention is the sequence of mixing the ingredients. According to the invention, it is first necessary to mix the alcohol solutions of nitroprone and polysorbate 80 and remove the alcohol, which leads to the formation of a homogeneous mixture of these two components. Then, a solution of benzalkonium chloride in isotonic solution is added to this mixture and stirred until an emulsion is formed, and only after that is diluted with isotonic sodium chloride solution. If you change the sequence of adding a solution of benzalkonium and sodium chloride, the solution remains cloudy at this ratio nitroproston-polysorbate 80 (1: 2). It was through technology that such low concentrations of excipients were achieved.

Thus, the task of creating a multi-dose pharmaceutical composition for inhalation based on nitroprone is achieved by combining in certain proportions nitroprone, a solubilizer (polysorbate 80), an antimicrobial ingredient (benzalkonium chloride), in addition, other pharmaceutically acceptable ingredients, and water for injection. Such a composition has a pharmacological effect similar to that of pure nitroprone in an equivalent concentration, and can be used in the treatment of inflammatory and / or obstructive respiratory diseases selected from the group including bronchial asthma and obstructive bronchitis by inhaling the vapors of the pharmacological composition of the invention obtained by ultra-small dispersed atomization in a nebulizer. The recommended dose (1 - 2 ml of the pharmaceutical composition) should be diluted with saline to a final volume of 3-4 ml and used completely with a nebulizer inhalation or intranasal.

The following examples are provided to illustrate the present invention and should not be construed as in any way limiting the scope of the invention.

Example 1

At the first stage, nitroprostone compositions were obtained using ethanol and propylene glycol as cosolvents. Physicochemical analysis of the obtained compositions showed, however, that such compositions do not meet the criterion of "transparency" up to a concentration of propylene glycol of 15%. The research results are shown in table 1.

Table 1.

Song Number Nitroproston, a solution in 96% ethanol, ml Propylene glycol, ml Water ml Transparency one one one Up to 100 ml Turbid solution 2 one 10 Opalescence 3 one fifteen Weak opalescence

In a further embodiment, the effect of polysorbate 80 (Tween 80) on the solubilization of the substance of nitroproton was studied. Polysorbate 80 is widely used to obtain solutions of hydrophobic compounds and is part of many inhalation solutions used in medicine. It was shown that the use of 3-3.5% polysorbate 80 with water for injection makes it possible to obtain a stable solution of nitroprone with a basic substance content of 0.1 mg / ml when observed for 10 days (see Table 2).

Table 2.

Song Number Nitroproston, a solution in 96% ethanol, ml Propylene glycol, ml Polysorbate 80, ml Water ml Transparency four one - 3 Up to 100 ml Transparent 5 one - 3,5 Transparent 6 one 10 2,5 Transparent 7 one 9 2,5 Transparent 8 one 8 2,5 Transparent 9 one 8 2 Transparent

For this composition, the optimal composition of the dosage form was as follows:

10 mg / ml nitroprostone solution in 95% ethanol 1.0 ml polysorbate 80 2.0 ml propylene glycol 8.0 ml water for injections up to 100 ml

The resulting solution, however, did not meet the stability criteria. In addition, the lack of proper osmolarity in combination with the presence of alcohols can cause respiratory irritation, so sodium chloride was added to the composition in the amount necessary to obtain a 0.9% solution (see Table 3).

Table 3.

Song Number Nitroproston solution in 96% ethanol, ml Propylene glycol, ml Polysor Bat 80, ml Isotonic sodium chloride solution in water, ml Transparency 10 one 8 2 Up to 100 ml Opalescence eleven one 10 2,5 Opalescence 12 one 10 3 Transparent

For this composition, the optimal composition of the dosage form was as follows:

10 mg / ml nitroprostone solution in 95% ethanol 1 ml propylene glycol 10.0 ml polysorbate 80 3.0 ml sodium chloride 0.009 g water for injections up to 100 ml

The resulting composition was stable and contained nitroprone in the required amount, which was confirmed by quantitative analysis methods. However, this composition contains 1% ethyl alcohol and also propylene glycol, which may have an undesirable effect on the respiratory tract of patients with bronchial asthma.

To achieve a technical result, it was necessary to reduce the amount of polysorbate 80 and abandon the use of propylene glycol and ethyl alcohol in a final concentration of more than 0.2%.

An unexpected solution to this problem was the inclusion of benzalkonium chloride in the composition. It turned out that when using polysorbate 80 in a ratio of 1: 1 with nitroprone, the solution does not become transparent and the desired result is achieved only starting with the ratio of nitroprone-polysorbate 80 1: 2 (see Table 4).

Table 4.

Composition Number Nitroprostone lyophilized, mg Benzalkonium chloride, mg Polysorbate 80, mg Isotonic sodium chloride solution in water, ml pH Transparency 13 one one 3 Up to 100 ml 6.4 Transparent fourteen one one 2 6.4 Transparent fifteen one one one 6.4 Opalescence

The optimal composition of this dosage form is shown below:

Nitroprostone 1.0 mg Benzalkonium chloride 1.0 mg Polysorbate 80 2.0 mg Sodium Chloride 0.9% Infusion Sterile Up to 100 ml

The stability of this composition was studied during storage for a year. It is established that such a composition containing a minimum amount of excipients is stable when stored at a temperature of + 2 ° C to + 8 ° C for at least a year. The results of the study are shown in Table 5.

Table 5.

Shelf life, months pH Foreign matter quantitation 6.2 to 7.4 Admixture of prostaglandin A ₂ -dinitro-glycerol ester A ₂ not more than 0.5% From 9.8 to 10.2 μg nitroprone in 1 ml of a solution of the dosage form 0 6.4 0.02 9.9 3 6.4 0,03 9.9 6 6.35 0.05 9.9 9 6.35 0,07 9.9 12 6.3 0.09 9.9

Thus, the technical result - obtaining a stable solution of nitroprone in an isotonic sodium chloride solution containing a minimum amount of excipients - was achieved.

Example 2. Preparation of a solution of nitroprone for inhalation 25 μg / ml

0.875 ml of a 1% solution of nitroprone in medical ethyl alcohol 95% and 3.5 ml of a 0.5% solution of polysorbate 80 in medical ethyl alcohol 95% are placed in a reaction vessel for working under vacuum. The solutions are mixed until the solutions are completely mixed and the solvent is removed in a vacuum of a water-jet pump. 3.5 ml of a 0.25% solution of benzalkonium chloride in isotonic sodium chloride solution is added to the residue. Stir until a homogeneous emulsion is formed and 346.5 ml of isotonic sodium chloride solution is slowly added in portions with stirring. Stirred for 30 minutes until a clear solution of the pharmaceutical composition is formed.

Composition per 1 ml of composition:

Nitroproston - 25 mcg

Polysorbate 80 - 50 mcg

Benzalkonium chloride - 25 mcg

Sodium Chloride - 0.9 mg

Water for injection - up to 1 ml.

Example 3. Preparation of a solution of nitroprone for inhalation 250 μg / ml

In a reaction vessel for working under vacuum, 17.5 ml of a 1% solution of nitroprone in medical ethyl alcohol 95% and 70 ml of a 0.5% solution of polysorbate 80 in medical ethyl alcohol 95% are placed. The solutions are mixed until the solutions are completely mixed and the solvent is removed in a vacuum of a water-jet pump. 70 ml of a 0.25% solution of benzalkonium chloride in an isotonic sodium chloride solution are added to the residue. It is stirred until a homogeneous emulsion is formed and 630 ml of isotonic sodium chloride solution are slowly added in portions. Stirred for 30 minutes until a clear solution of the pharmaceutical composition is formed.

Composition per 1 ml of composition:

Nitroprostone - 250 mcg

Polysorbate 80 - 500 mcg

Benzalkonium chloride - 250 mcg

Sodium Chloride - 0.9 mg

Water for injection - up to 1 ml.

Example 4. The pharmacological activity of the composition of nitroprone obtained in example 3.

The studies were conducted on male rats weighing 200-220 g. For the study, the doses of the composition of the invention 0.85 μg / kg, 2.13 μg / kg, 4.26 μg / kg, which was administered by inhalation, were selected.

To implement the model, rats were immunized with a single intraperitoneal injection of 0.5 ml of a solution containing 100 μg / ml ovalbumin and 100 mg / ml aluminum hydroxide (adjuvant). On the 29th, 30th and 31st day of the experiment, a bronchospastic reaction was provoked by inhalation of an ovalbumin solution in increasing concentrations of 0.1, 0.3 and 0.5%. On day 32, bronchospastic reaction was assessed. The exposure time was recorded (the time from the start of ovalbumin inhalation to the onset of the acute phase of bronchospasm), the duration of the acute and subacute phases, and the duration of the restored respiration (from the moment of breathing recovery to the end of registration).

In the control group, inhalation of a resolving dose of ovalbumin to pre-sensitized rats caused a pronounced bronchospastic reaction. The maximum time of inhalation of ovalbumin, according to the technique, was 300 seconds. In this group, it amounted to 182.5 seconds, i.e. the acute phase in most animals occurred before the end of inhalation of ovalbumin. Lateral position in animals (acute phase) was observed on average for 51.9 seconds, after which a subacute phase was observed, which is characterized by deep rapid breathing lasting 225.6 seconds, respectively. And the duration of the restored breathing after the bronchospastic reaction was 140 seconds.

In animals to which the nitroprone composition of the invention was administered at a dose of 0.85 mg / kg, no differences were found from the control group in all indicators.

In animals to which the nitroprone composition of the invention was administered in doses of 2.13 and 4.26 mg / kg, the acute phase occurred later (statistically significant) compared with the control group: the exposure time was 312.5 sec and 295.6 sec, respectively . A statistically significant decrease in the duration of the subacute phase was observed after administration of the nitroprone composition of the invention in doses of 2.13 and 4.26 mg / kg.

A summary of the pharmacological activity of the pharmaceutical composition of nitroprostone for inhalation is shown in Table 6.

Table 6: Evaluation of the bronchoprotective activity of the pharmaceutical composition of nitroprostone for inhalation of 250 μg / ml after a single injection on a model of antigen-induced bronchospasm in rats.

Exposure time, sec The duration of the acute phase, sec The duration of the subacute phase, sec The duration of the restored breath, sec Intact 300 ± 0 0 ± 0 0 ± 0 300 ± 0 The control 182.5 ± 17.4 * 51.9 ± 11.7 * 225.6 ± 32.9 * 140 ± 40.2 * Nitroprostone, 0.85 mg / kg 231.3 ± 30.8 47.5 ± 13.2 * 180 ± 25 * 141.3 ± 27.5 * Nitroprostone, 2.13 mg / kg 312.5 ± 16.8 & 22.5 ± 9 * & 98.8 ± 26.5 * & 166.3 ± 23.8 * Nitroprostone
4.26 mg / kg 295.6 ± 21.9 & 31.3 ± 11.7 * 72.5 ± 58.9 & 200.6 ± 55.3

* - significantly relative to intact animals (p <0.05)

& - significantly relative to control (p <0.05)

The data obtained indicate the presence of bronchoprotective activity in the model of antigen-induced bronchospasm in the pharmaceutical composition of nitroprone 250 μg / ml according to the invention in doses of 2.13 and 4.26 mg / kg

Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications are possible without departing from the gist of the present invention.

Claims (8)

1. A pharmaceutical composition for the treatment of inflammatory and / or obstructive diseases of the respiratory tract, selected from the group including bronchial asthma and obstructive bronchitis, characterized in that it is a solution for inhalation, including 1 ', 3'-dinitroglycerin ether 11 (S) , 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid, polysorbate 80, benzalkonium chloride in a ratio of 1: 2: 1 and a pharmaceutically acceptable solvent, which is an isotonic sodium chloride solution. 2. The pharmaceutical composition according to claim 1, having the following composition per 1 ml of composition: 1 ', 3'-dinitroglycerin ester of 11 (S), 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid 10-250 mcg polysorbate 80 20-500 mcg benzalkonium chloride 10-250 mcg sodium chloride 0.9 mg water for injections up to 1 ml 3. The pharmaceutical composition according to any one of paragraphs. 1, 2, the pH of which is 6.2-7.4. 4. The pharmaceutical composition according to p. 3, which further comprises a buffer mixture, ensuring the maintenance of pH at the level of 6.2-7.4. 5. The pharmaceutical composition according to claim 4, in which the buffer mixture consists of a mixture of disodium phosphate and citric acid, or citric acid and sodium hydroxide, or citric acid and citric acid sodium. 6. A method of obtaining a pharmaceutical composition according to claim 1, comprising mixing solutions of 1 ', 3'-dinitroglycerin ester 11 (S), 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid and polysorbate 80 in ethanol removing ethyl alcohol in vacuo, adding a solution of benzalkonium chloride and then adding a pharmaceutically acceptable solvent, which is an isotonic sodium chloride solution. 7. The method according to p. 6, in which the number of alcohol solutions of 1 ', 3'-dinitroglycerin ether 11 (S), 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid and polysobrate 80 is chosen so that the ratio of 1 ', 3'-dinitroglycerin ester of 11 (S), 15 (S) -dihydroxy-9-keto-5Z, 13E-prostadiene acid and polysobrate 80 was 1: 2.