RU2703735C1 - Pharmaceutical composition containing dhmeq or its analogues - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention refers to medicine and pharmacology and concerns developing and producing medicinal agents including DHMEQ or its analogues which can be used for treating and/or preventing oncological, autoimmune or inflammatory diseases. Invention also refers to medicinal preparations containing the above medicinal agents in a liquid, soft or solid dosage form.

EFFECT: medicinal agents according to the invention are characterized by high efficacy and low toxicity, besides, the specified medicinal agents according to the invention have high stability and bioavailability.

7 cl, 4 dwg, 2 ex, 2 tbl

Description

Technical field

The invention relates to the field of medicine and pharmacology, and relates to the development and production of drugs, including DHMEQ, which can be used for the treatment and / or prevention of cancer, autoimmune or inflammatory diseases.

State of the art

The transcription factor NF-κB is a universal transcription factor that regulates many vital processes in the cell, such as inflammation, immune response and proliferation; it is involved in the carcinogenesis of a number of malignant neoplasms. An upregulation of NF-kB causes inflammation, autoimmune diseases, and the development of viral infections and cancer.

EP1219596 discloses a group of compounds based on the antibiotic epoxycuinomycin C, in particular the compound dehydroxymethylepoxyquinomycin (DHMEQ), which has anti-tumor and anti-inflammatory activities. DHMEQ is a unique NF-kB inhibitor that acts at two levels of nuclear translocation. DHMEQ inhibits both canonical and noncanonical activation pathways of NF-kB. WO2006060819A2 discloses the use of DHMEQ as a sensitizing agent for therapy (e.g., chemotherapy, hormone therapy, radiation therapy, and immunotherapy) directed against both therapeutically resistant and therapeutically sensitive tumor cells. It is also known from this document the use of DHMEQ and structurally similar compounds separately, or in combination with chemotherapy, hormone therapy, radiation therapy and immunotherapeutic agents, for the treatment of oncological diseases, both drug and immunotherapeutically sensitive, and drug immunotherapeutically resistant.

However, there is a problem with the creation of dosage forms of DHMEQ and its analogues with high stability and bioavailability, since DHMEQ has low solubility in the aquatic environment and is also rapidly inactivated in the blood, thereby diminishing the therapeutic effect. DHMEQ is soluble in organic solvents, for example, DMSO, but such a solution has limitations in terms of industrial applicability due to the short shelf life, which leads to the need to prepare solutions almost before administration. Based on the foregoing, the problem of developing a medicinal product based on DHMEQ and its analogues, which have acceptable stability, bioavailability, are suitable for use in the treatment of various diseases and have industrial applicability, remains.

Most drugs reach the consumer in a ready-to-use form or as a so-called drug. Under the finished drug is meant a complex consisting of the drug itself and excipients in the form of a specific form or state of aggregation. Very often, the dosage form determines not only the ease of use of the drug, but also other characteristics of the effectiveness of the drug, such as bioavailability, duration of action, etc.

The styrene copolymer with maleic anhydride is widely used in the oil industry as a sand-bearing fracturing fluid. The copolymer is also commonly used in industry, construction, etc. There is only very limited information about its use as a component for the preparation of cosmetic and pharmaceutical compositions [US8623414]. A method of producing a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) is known from document RU2135187.

Thus, the priority is the creation of a new drug based on DHMEQ or its analogues, and the search for ways to increase the stability of DHMEQ or its analogues for use in the pharmaceutical industry.

Disclosure of invention

The objective of the invention is to develop and obtain a new non-toxic effective drug based on DHEMQ or its analogues, characterized by high stability and bioavailability, for the treatment and / or prevention of cancer, autoimmune or inflammatory diseases.

The technical result of this invention is the development and creation of a new effective non-toxic drug, including DHMEQ or its analogues and the target additive, for the treatment and / or prevention of cancer, autoimmune or inflammatory diseases, which has high stability and bioavailability.

The specified technical result is achieved through the development and creation of a medicinal product containing at least one compound of the formula 1:

формула 1,

Formula 1,

WhereR _one independently selected and represents a hydrogen atom or -C_2-4-alkyl, -OH,

R ₂ is independently selected and is a group selected from (A), (B), (C), (D), (E), (F) or (G):

where R ₃ is independently selected and is —C _1-4 alkyl;

R _four independently selected and represents -C_1-4alkyl;

or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, and a target additive, characterized in that the target additive contains a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA).

In particular embodiments of the invention, the medicament is characterized in that the compound of formula 1 is DHMEQ.

In private embodiments of the invention, the drug is characterized in that the target additive further comprises water.

In private embodiments of the invention, the drug is characterized by the following ratio of components, wt.%:

DHMEQ 0.1-1.2 Styrene copolymer with maleic anhydride, Ammonia Modified (CCMA) 0.2-2.0 Purified water Up to 100.0

In private embodiments of the invention, the drug is characterized by the following ratio of components, wt.%:

DHMEQ 0.1-0.2 Styrene copolymer with maleic anhydride, Ammonia Modified (CCMA) 0.2-0.5 Purified water Up to 100.0

In private embodiments of the invention, the drug is characterized by the following ratio of components, wt.%:

DHMEQ 0.102 Styrene copolymer with maleic anhydride, Ammonia Modified (CCMA) 0.2 Purified water Up to 100.0

In particular embodiments of the invention, the medicament of the invention is intended for the treatment of cancer, autoimmune or inflammatory diseases.

The invention also provides a drug, which is the drug described above, made in liquid dosage form.

In private embodiments of the invention, the drug is characterized in that the liquid dosage form is selected from the group: solution, suspension, emulsion, mucus, liniment, liquid patch, drug syrup.

In particular embodiments of the invention, the medicament is characterized in that the solution is an injection.

The invention also includes a drug, which is the drug described above, made in soft dosage form.

In private embodiments of the invention, the drug is characterized in that the soft dosage form is selected from the group: ointment, suppository, patch, pill.

The invention also includes a drug, which is the drug described above, made in solid dosage form.

In private embodiments of the invention, the medicament is characterized in that the solid dosage form is selected from the group: tablet, dragee, granule, powder, capsule, spansula, medicinal pencil, drug film.

In particular embodiments of the invention, the medicament of the invention is intended for the treatment of cancer, autoimmune or inflammatory diseases.

The invention also includes the preparation of a medicament according to the invention. In particular embodiments of the invention, the medicament of the invention (injection composition) is prepared by incorporating the milled DHMEQ as a suspension into the inventive composition.

The invention also relates to a method for the treatment and / or prevention of cancer, autoimmune or inflammatory diseases in a subject, namely in mammals, including humans.

Detailed Disclosure of Invention

Definition and terms

For a better understanding of the present invention, the following are some of the terms used in the present description of the invention.

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”.

The terms “treatment” , “therapy” encompass the treatment of pathological conditions in a subject, preferably a person, and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.

The term "prevention" , "prevention" covers the elimination of risk factors, as well as the prophylactic treatment of subclinical stages of the disease in a subject, preferably a person, aimed at reducing the likelihood of clinical stages of the disease. Subjects for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increase in the risk of clinical stages of the disease compared with the general population. Preventive therapy refers to a) primary prevention and b) secondary prevention. Primary prophylaxis is defined as prophylactic treatment in patients (subjects) whose clinical stage of the disease has not yet begun. Secondary prophylaxis is the prevention of the repeated onset of the same or similar clinical condition of the disease.

The term "risk reduction" covers therapy that reduces the incidence of the clinical stage of the disease. Examples of reducing the risk of disease are primary and secondary disease prevention.

The term “subject” encompasses all types of mammals, preferably humans.

The term “DHMEQ” as used herein means a dehydroxymethyepoxyquinomycin compound having the structural formula:

.

.

The term copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) in this document means the product of the copolymerization of styrene with maleic anhydride, modified with ammonia, the structural formula of which is:

,

,

where n means the number of monomer units in the SSMA molecule and represents 3 ÷ 15.

The copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) is a white powder. The appearance of a 2% solution of SSMA in water is a clear or slightly turbid liquid - gel. Soluble in water - swells, soluble in glycerin, alcohol. 2% styrene-maleic anhydride copolymer gel modified with ammonia (CCMA) has a pronounced antiviral effect (RU2135187).

As used herein, “formulation of 100.0 injection solution” is understood to mean 100 g of injection solution.

The term "stock solution" as used herein means a pre-prepared, usually concentrated solution, which is then diluted for use.

The term “therapeutically effective amount” means an amount of a compound administered or delivered to a patient in which the patient is most likely to exhibit the desired response to treatment (prophylaxis). The exact amount required can vary from subject to subject depending on the type of mammal, age and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

In the case where the compositions (drugs) of the present invention are used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period. The compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Under the " dosage form " in this document refers to the state of the drug, corresponding to the methods of its administration and use and ensuring the achievement of the necessary therapeutic effect.

The term “alkyl” , alone or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the indicated number of carbon atoms (i.e., C _1-4 means from one to four carbon atoms). Examples of alkyls include, in particular, methyl, ethyl, n-propyl, iso-propyl.

The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. Examples of acceptable salts are potassium and sodium phenolates.

Brief Description of the Drawings

Figure 1. Radiograph showing the distribution of the marker (barium sulfate) in the composition of the drug according to the invention in the abdominal cavity of the rat 30 minutes after administration. Marker particles are highlighted in green to improve contrast.

Figure 2. Data on necropsy, drug distribution in the abdominal cavity of the rat 2 hours after administration.

Figure 3. Data necropsy, intact peritoneum of the test animal 14 days after administration of the drug according to the invention.

Figure 4. The survival rates of rats with ovarian tumor in the control and experimental groups:

curve 1 - control group of animals with an ovarian tumor;

curve 2 - a group of animals with an ovarian tumor to which the drug of the invention based on DHMEQ was administered.

Detailed Disclosure of Invention

To create a drug based on the compounds of general formula 1, as described in this invention, in particular based on DHMEQ, suitable for administration, the finished drug must have acceptable bioavailability and stability. It is known that the compounds of general formula 1, in particular the compound DHMEQ, have low solubility and stability in an aqueous medium. It is also known that DMSO is used as a solvent for DHMEQ. However, such solutions have a number of limitations in terms of industrial applicability, due to the short term stability, which leads to the need to prepare solutions almost before administration. To eliminate the above problem, namely, the creation of a drug based on compounds of the general formula 1, in particular DHMEQ, having acceptable stability and bioavailability, and suitable for administration to a subject in need of appropriate treatment, as described in the present invention, a medicament is developed comprising at least one compound of formula 1 or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, and a target additive comprising a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA).

As studies have shown, in the preparation of a medicament according to the invention, the molecules of the compound of general formula 1, in particular DHMEQ, are located between the macromolecules of styrene-maleic anhydride copolymer modified with ammonia (CCMA). Molecules DHMEQ is located in the “carefully” holding cells between the macromolecules of styrene-maleic anhydride copolymer modified with ammonia (CCMA). This is also confirmed by the results of an experiment in which, during the preparation of a medicine according to the invention, preliminary grinding (grinding) in a mortar of a styrene-maleic anhydride copolymer modified with ammonia (CCMA) was carried out, while its macromolecules were changed during mechanical grinding, the bonds were broken, As a result, during swelling, a different viscosity of the solutions of styrene-maleic anhydride copolymer modified with ammonia (CCMA) was observed; the solutions were more liquid. When DHMEQ was added to such solutions, the obtained samples were less stable, since a change in their physicochemical properties was observed.

The target addition of styrene-maleic anhydride copolymer modified with ammonia (CCMA) is not aggressive (i.e., does not affect the active ingredients administered) with respect to compounds of general formula 1, in particular with respect to the DHMEQ molecule, observations were made under the conditions of a refrigerator.

The implementation of the invention

The possibility of an objective manifestation of a technical result when using the invention is confirmed by reliable data given in the examples containing experimental information obtained in the process of conducting research using methods adopted in this field.

It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

DHMEQ pharmaceutical composition of the invention

A method for producing DHMEQ is described, in particular, in document WO2006060819A2.

The method of obtaining a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA), described in particular in document RU2135187.

Example 1. The composition of a 100.0 injection solution: DHMEQ - 0.102 wt.%; SSMA - 0.2 wt.%, Water for injection - the rest is up to 100 wt.%.

The DHMEQ drug of the invention is prepared as follows:

SSMA was placed in water for injection, mixed and allowed to swell for 60 minutes. The DHMEQ substance is pre-triturated, finely ground, and an SSMA solution is added in an amount of 3% of the total volume of a solution of styrene-maleic anhydride copolymer modified with ammonia (SSMA), triturated to a homogeneous mass, after which the remaining amount of a solution of styrene-maleic anhydride copolymer, modified with ammonia, is added. (SSMA). The resulting composition is thoroughly mixed, packaged in sterile bottles for running in and sterilized by gamma sterilization. The finished pharmaceutical composition, an injectable for intraperitoneal administration, is a thick viscous mass of white with a yellow tint, with finely dispersed inclusions of the substance, evenly distributed in the mass of the solution, density - 1.0 g / cm ³ , pH 6.0. The resulting composition for injection has a viscous consistency.

If necessary, the pharmaceutical composition can be diluted with water for injection or isotonic sodium chloride solution immediately before administration.

Example 2. Composition 100.0 injection composition: DHMEQ - 0.143 mass. %; a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) - 0.2 mass. %; Lutrol F-68 - 0.2 mass. %; cremophor CO-40 - 0.64 wt.%, water for injection - the rest is up to 100 wt.%.

A drug with DHMEQ is prepared as follows:

Lutrol F-68 is dissolved in half the amount of water for injection, mixed, then cremophor CO-40 is dissolved. In the other part of the water for injection, a styrene-maleic anhydride-modified ammonia copolymer (CCMA) is placed, mixed and allowed to swell for 60 minutes. Then, the above solutions are combined into a single solution (A). The substance of the DHMEQ inhibitor is pre-ground, finely ground, and solution (A) is added in an amount of 3% of the total volume of solution (A), ground, then another 3% solution (A) is added, ground to a homogeneous mass, and then the remaining amount of solution is added ( BUT). The resulting composition is thoroughly mixed, packaged in sterile bottles for running in and sterilized by gamma sterilization.

Ready-made injection for intraperitoneal injection is a homogeneous mass in the form of a white gel with a yellow-gray tint, density - 1.0 g / cm ³ , pH - 6.0.

Due to the consistency and physicochemical properties of the composition, the injectable agent is held firmly in the tissues by injection, and the incoming excipients provide an even distribution of finely divided DHMEQ in the injection composition, which is introduced by suspension into the inventive composition; the product is also convenient and hygienic to use.

The study of the medicinal product according to the invention in the conditions in vivo

Evaluation of the applicability of the drug for the chosen route of administration.

To assess the applicability of the drug for intraperitoneal administration, an experiment was conducted to analyze the distribution of the substance in the peritoneal cavity, the effect of the composition of the drug on the mesothelium (adhesions, aseptic peritonitis and abdominal organs with intraperitoneal administration).

The solution was sterilized with gamma radiation. The study used 9 Wistar rats weighing 160–200 g. The animals had all state veterinary certificates, the experiments were carried out in compliance with the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes.

To indicate the distribution of the solution in the peritoneal cavity, barium sulfate particles were introduced into the composition of the drug according to the invention (for example, the composition according to example 1 or 2). According to x-ray of the abdominal organs, the injected composition was distributed evenly across the peritoneal cavity (Fig. 1). Necropsy was also performed 2 hours after administration, which confirmed the uniform distribution of the administered composition in the peritoneal cavity (Fig. 2).

To evaluate the resorption of the drug in the animal’s body, the data of necropsy were studied, carried out before the drug was completely resorbed in the peritoneal cavity, as well as in the intervals according to the phases of adhesiogenesis in case of damage to the peritoneum:

1. Reactive phase (first 12 hours) - clinically and morphologically manifested by signs of shock, damage to the peritoneum is determined.

2. The phase of exudation (1-3 days). The processes of exudation prevail over other processes of inflammation. The permeability of the vascular bed increases, which contributes to the exit into the free abdominal cavity of peritoneal low-differentiated polypotent cells, inflammatory cells and the liquid part of the blood containing fibrinogen.

3. The phase of adhesion (3 days). The loss of fibrin on damaged surfaces, their bonding. Polypotent cells of peritoneal exudate differentiate into fibroblasts that produce collagen.

4. The phase of young adhesions (7-14 days). Loose, insufficient collagen, adhesions are formed. Vascular neoplasm in the commissure and smooth muscle cells migrate into it.

5. The phase of mature adhesions (14-30 days). Dense connective tissue adhesions are formed due to the production and compaction of collagen, reduction of the capillary bed, recalibration of blood vessels.

The following intervals were provided for the elimination of animals from the experiment: 2 hours from the time of administration, 24 hours from the time of administration, 7 days from the time of administration, 14 days from the time of administration.

The main element in the formation of adhesions is a gel-like matrix of fibrin. Macroscopically, the matrix is similar to the administered and distributed drug, has a whitish color and is sticky to the touch. But since the fibrin matrix forms only on the 3rd day, necropsy performed after 2 hours eliminates the error in assessing the contents of the peritoneal cavity.

Necropsy data after 7 and 14 days showed complete resorption of the injected composition and intact peritoneum (Fig. 3).

The experimental results showed a uniform distribution of the drug in the peritoneal cavity, the absence of delimited or diffuse peritonitis, including aseptic, the absence of peritoneal adhesions and the damaging effect of the composition of the injection solvent on the mesothelium.

Evaluation of the antitumor effect of the drug

To evaluate the antitumor effect of the drug, in vivo studies of the drugs of the invention were conducted. The study used 100 Wistar female rats weighing 160–200 g. Some of the animals, after quarantine, were used to maintain the tumor strain. The animals had all state-approved veterinary certificates; the experiments were carried out in compliance with the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes.

Tumor strain

In the experiment, an ovarian tumor strain (OA) was used. The tumor was transplanted into female Wistar rats intraperitoneally in the form of a cell suspension of the tumor in a volume of 0.5 ml / rat (1 × 107 cells / ml) obtained from the ascitic contents of the abdominal cavity of the rat tumor carrier.

A study of the antitumor activity of a drug of the invention based on DHMEQ in Wistar female rats with an ascites ovarian ascites tumor.

After a two-week quarantine, the animals received inoculation from the cattery were inoculated with ascites OA, after which the animals were randomized to the experimental and control groups using the corresponding table of generated random numbers in the MSExcel 2010 program. The day of the OU inoculation was considered the zero day of the experiment. On the first day after inoculation, intraperitoneal administration was started.

The control group consisted of 50 animals with an ovarian tumor. The experimental group consisted of 50 animals that were administered daily for 14 days with the drug of the invention at a dose of the active substance (DHMEQ) of 14.2 mg / kg.

The survival curves of rats in the experimental and control groups are presented in figure 4.

Thus, the drug of the invention, comprising DHMEQ and the target supplement, reliably demonstrated pronounced antitumor activity.

The study of the organoleptic properties and stability of the drug according to the invention

Studies of the drug according to the invention were carried out, in particular, the drug of the following composition was investigated - 100.0 injection solution: DHMEQ - 0.102 mass. %; a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) - 0.2 mass. %, water for injection - the rest is up to 100 wt.% (dosage form).

Several solutions with different concentrations of DHMEQ were prepared:

1. 0 mg / ml - control (composition of a 100.0 injection solution: a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) - 0.2 wt.%, Water for injection - the rest is up to 100 wt.%);

2. 0.21 mg / ml (composition of a 100.0 injection solution: DHMEQ - 0.021 wt.%; A copolymer of styrene with maleic anhydride modified with ammonia (CCMA) - 0.2 wt.%, Water for injection - the rest is up to 100 mass .%);

3. 1.02 mg / ml (composition of a 100.0 injection solution: DHMEQ - 0.102 wt.%; A copolymer of styrene with maleic anhydride, modified with ammonia (CCMA) - 0.2 wt.%, Water for injection - the rest is up to 100 mass .%);

4. 2.05 mg / ml (composition of a 100.0 injection solution: DHMEQ - 0.205 wt.%; A copolymer of styrene with maleic anhydride modified with ammonia (CCMA) - 0.2 wt.%, Water for injection - the rest is up to 100 wt. .%).

Accordingly, per 100 ml of stock solution of the dosage form will require from 21 to 205 mg of DHMEQ.

The results of monitoring the prepared preparations during storage (refrigerator compartment at a temperature of + 5 ° C) are presented in tables 1 and 2 below.

Table 1. Organoleptic properties of DHMEQ in a solvent containing SSMA and water for injection

Study day Structure Homogeneity Notes 1st day - cooking day At a concentration of DHMEQ 0.21 mg / ml + A liquid opaque solution with opalescence of a yellowish tint with visible particles of DHMEQ. The composition is stable. At a concentration of DHMEQ 1.02 mg / ml + Thick opaque solution with opalescence of a yellowish tint with visible DHMEQ particles. The composition is stable. At a concentration of DHMEQ 2.05 mg / ml + Thick opaque solution with opalescence of a yellowish tint with visible DHMEQ particles. The composition is stable. 3rd day of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. 5th day of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. 7th day of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. Day 9 of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. Study day 11 All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. 13th day of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + The uniformity and color of all samples at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved. 15th day of the study All of the above formulations at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml + Properties of all samples described above at a concentration of DHMEQ 0.21 mg / ml; 1.02 mg / ml; 2.05 mg / ml saved.

Table 2. Organoleptic properties of DHMEQ in a solvent (specified concentration of stock solutions) containing SSMA and water for injection

Study day Structure Homogeneity Notes 1st day of the study At a concentration of DHMEQ 1.43 mg / ml + Thick opaque opalescent yellow-green solution with flow property with visible particles of DHMEQ At a concentration of DHMEQ 7.16 mg / ml + A thick, opaque, opalescent, yellow-green solution that has the property of flowing with visible DHMEQ particles. At a concentration of DHMEQ 14.31 mg / ml + A thick, opaque, opalescent, yellow-green solution that has the property of flowing with visible DHMEQ particles. 3rd day of the study. All of the above formulations in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml + The properties of all the samples described above in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml saved. 5th day of the study All of the above formulations in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml + The properties of all the samples described above in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml saved. 7th day of the study All of the above formulations in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml + The properties of all the samples described above in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml saved. Day 9 of the study All of the above formulations in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml + The properties of all the samples described above in concentrations of DHMEQ 1.43 mg / ml; 7.16 mg / ml; 14.31 mg / ml saved. Study day 11 At a concentration of DHMEQ 1.43 mg / ml + Thick opaque opalescent yellow-green solution with flow property with visible particles of DHMEQ 13th day of the study At a concentration of DHMEQ 7.16 mg / ml + Thick opaque opalescent yellow-green solution with flow property with visible particles of DHMEQ 15th day of the study At a concentration of DHMEQ 14.31 mg / ml - A drug with signs of stratification of the system. Thick. The flow properties are retained. After vigorous agitation, uniformity is restored. 13th day of the study At a concentration of DHMEQ 1.43 mg / ml + Thick opaque opalescent yellow-green solution with flow property with visible particles of DHMEQ 35th day of the study At a concentration of DHMEQ 7.16 mg / ml + Thick opaque opalescent yellow-green solution with flow property with visible particles of DHMEQ

The data of the experiments, presented in tables 1 and 2, indicate the stability of the composition of the drugs according to the invention during storage in different concentration ranges, with the suspension introduction of DHMEQ in the finished composition of the injection solvent containing a copolymer of styrene with maleic anhydride modified with ammonia (CCMA) and water for injection.

Although the invention has been described with reference to the disclosed embodiments, it should 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 (17)

1. A medicament containing at least one compound of formula 1 or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount:

                                 Formula 1 where R ₁ is independently selected and represents a hydrogen atom or C _2-4 alkyl, —OH, R ₂ is independently selected and represents a group selected from (A), (B), (C), (D), (E), (F) or (G):

where R ₃ is independently selected and is —C _1-4 alkyl; R ₄ is independently selected and is —C _1-4 alkyl; and a target additive, characterized in that the target additive contains a copolymer of styrene with maleic anhydride, modified with ammonia (CCMA). 2. The drug according to claim 1, characterized in that the compound of formula 1 is dehydroxymethylepoxyquinomycin (DHMEQ). 3. The drug according to claim 2, characterized in that the target additive further comprises purified water in the following ratio of components, wt. %: DHMEQ 0.1-1.2 SSMA 0.2-2.0 Purified water Up to 100.0 4. The drug according to p. 3, characterized in that it is a solution for injection. 5. The drug according to p. 2, characterized in that the target additive further comprises lutrol F-68, cremophor CO-40 and water for injection in the following ratio of components, wt. %: DHMEQ 0.143 SSMA 0.2 Loutrol F-68 0.2 Cremophor SO-40 0.64, Water for injections Up to 100.0 6. The drug according to claim 5, characterized in that it is a gel for intraperitoneal administration. 7. The drug according to any one of paragraphs. 1-6, characterized in that it is intended for the treatment of cancer, autoimmune or inflammatory diseases.

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