RU2563211C2 - Pharmaceutical composition with analgesic activity in injection form (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition with kappa-opioid agonistic activity, demonstrating an analgesic effect in accordance with the first version contains 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazole dihydrochloride as an active component, and an isotonicity corrigent, selected from salts of organic and inorganic acids, polyols, amino acids, as auxiliary substances. The composition can additionally contain a co-solvent, a corrigent of the solution pH, a cryoprotector, and an antioxidant. In accordance with the second version the pharmaceutical composition contains 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazole dihydrochloride as an active component, and a co-solvent, selected from ethyl alcohol, glycerol, propylene glycol, benzylbenzoate, benzyl alcohol, ethyloleate and fatty oils, including olive oil and peach oil as auxiliary substances. The composition can additionally contain an isotonicity corrigent, a corrigent of the solution pH, a cryoprotector, and an antioxidant.

EFFECT: invention provides the pharmaceutical composition in an injection form with kappa-opioid agonistic activity without narcogenic potential, demonstrating the fast relief of pain syndrome.

12 cl, 5 dwg, 3 tbl, 4 ex

Description

The invention relates to medicine, in particular to pharmacy, and relates to pharmaceutical compositions exhibiting analgesic activity.

Analgesics with high receptor selectivity and minimal morphine-like side effects are known - drugs of a mixed type of action are opioid receptor agonists-antagonists. The pharmacology of these drugs is complex. Synthetic derivatives of phenanthrene (nalbuphine, buprenorphine) and morphinan (butorphanol) are antagonist agonists, opioid analgesics of a mixed type of action with affinity for mu, delta, and kappa subtypes of opioid receptors. Numerous pharmacological studies, ligand-receptor binding studies have led to the conclusion that nalbuphine acts as a κ agonist and partial mu antagonist, buprenorphine partial mu agonist and kappa opioid receptor antagonist, butorphanol partial mu agonist, mu agonist opioid receptors, and also has the properties of a delta antagonist [Redkin AN, Bunyatyan AA, Nasonov EL, Nikoda VV, 2004].

Mixed-action drugs (nalbuphine, buprenorphine and butorphanol) have found limited use as painkillers in practical medicine. The synthesized antagonist agonists, in a number of indicators significantly superior to traditional opiates, retained most of the negative properties and, above all, their narcogenicity, which served as the basis for their inclusion in the lists of psychotropic drugs, the turnover of which in the Russian Federation is limited.

The closest to perform dihydrochloride 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole is a representative of the structural class of substances with a kappa-receptor profile of pharmacological activity, that is, without affecting mu- and delta-opioid receptors, and therefore without narcogenic potential (patent for the invention of the Russian Federation No. 2413512, IPC A61K 31/4188, 2011).

When stopping a strong pain syndrome that occurs as a result of an injury or illness, a quick action of the drug is necessary. The fastest pharmacological effect develops, for example, with the parenteral route of administration, in which the drug enters first into the bloodstream and then into the receptor zone. Most often, injectable solutions are administered parenterally to ensure the rapid release of the drug into the bloodstream.

The objective of the invention is the creation of a pharmaceutical composition with kappa-opioid agonistic activity, ensuring the rapid development of the pharmacological effect with the rapid relief of pain in various types of injuries.

The technical result is a pharmaceutical composition in an injectable dosage form with kappa-opioid agonistic activity, without narcogenic potential, exhibiting an analgesic effect.

The technical result is achieved by a pharmaceutical composition containing, as an active ingredient, 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride, and, as excipients, isotonicity correcting agent providing isotonicity of the injection solution , which is at least one substance selected from the group: salts of organic or inorganic acids (sodium citrate, sodium benzoate, sodium chloride, sodium metabisulfite, sodium bromide, sodium bicarbonate, potassium iodide, potassium x Oridi, calcium chloride, magnesium sulfate, copper sulfate), polyols (glucose, mannitol, sorbitol, lactose, galactose), amino acids (proline, glycine), with the following component ratio, wt.%:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 99.99-0.10 Corrigent of Isotonicity 0.01-99.90

If necessary, the composition may additionally contain a co-solvent, flavoring pH of the solution, cryoprotectant, antioxidant in the following ratio of components, wt.%:

Co-solvent up to 10.00 Corrigent pH solution up to 0.045 Cryoprotectant up to 48.00 Antioxidant up to 2.25

The technical result is also achieved by a pharmaceutical composition containing 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride as an active principle, and a co-solvent, which solubilizes the dihydrochloride 9, is an auxiliary substance - (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole in a solvent used for the preparation of injection solutions, which is at least one substance selected from the group: ethyl alcohol, glycerin, propylene glycol, benzylben zoate, benzyl alcohol, fatty oils (olive oil, peach oil), ethyl oleate, in the following ratio, wt.%:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole, 99.99-0.10 Co-solvent 0.01-99.90

If necessary, the composition may additionally contain isotonicity flavoring agent, pH solution flavoring agent, cryoprotectant, antioxidant in the following ratio, wt.%:

Corrigent of Isotonicity up to 48.00 Corrigent pH solution up to 0.045 Cryoprotectant up to 48.00 Antioxidant up to 2.25

As corrigents of the isotonicity of the injection solution, 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride in option 2, as in option 1, at least one substance can be used, selected from the group: salts of organic or inorganic acids (sodium citrate, sodium benzoate, sodium chloride, sodium metabisulfite, sodium bromide, sodium bicarbonate, potassium iodide, potassium chloride, calcium chloride, magnesium sulfate, copper sulfate), polyols (glucose, beckons, sorbitol, lactose, galactose); amino acids (proline, glycine). Excipients that provide isotonicity of the injection solution, allow to obtain an injection solution with an osmotic pressure equal to the osmotic pressure of blood plasma. With parenteral administration of an isotonic solution, damage to tissues lying around the injection site is minimized.

At least one substance selected from the group: inorganic can be used as the pH-correcting solution for the solution of the 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride injection solution acids (hydrochloric acid), organic acids (ascorbic acid, acetic acid, citric acid), salts of organic acids (sodium citrate, sodium acetate).

At least one substance selected from the group: polyols (mannitol, polyols) can be used as cryoprotectants of the injection solution 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride sucrose, lactose), glycerin, dimethyl sulfoxide, polyethylene oxide, cyclodextrins (γ and β-cyclodextrins). The introduction of cryoprotectants into the pharmaceutical compositions of the injectable dosage form 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride allows maintaining the structural integrity of the molecule of the active principle in the preparation of the dosage form.

As an antioxidant of the injection solution, 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride in both variants, at least one excipient selected from the group: inorganic acid salts can be used (sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium sulfoxylate), sulfur-containing excipients (thioglycerol, thiourea, thiosorbitol, cysteine hydrochloride); unitiol, formaldehyde, ascorbic acid, isoascorbic acid, hydroquinone, propyl gallate, lecithin, tocopherols, esters of ascorbic and gallic acids. Antioxidants help to bind free radicals and slow down redox processes.

As co-solvent of the injection solution, 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride in option 1, as in option 2, at least one substance selected can be used from the group: ethyl alcohol, glycerin, propylene glycol, benzyl benzoate, benzyl alcohol, fatty oils (olive oil, peach oil), ethyl oleate. Co-solvents facilitate the solubilization of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride in the solvent used for the preparation of injection solutions.

A method for preparing the composition consists in mixing sterilized components in an injection solvent, for example water. Either ionizing radiation or ultrafiltration is used as a sterilization method. To obtain a lyophilisate, the solution is dried. The lyophilisate composition is a white powder.

The following are examples of a pharmaceutical composition.

Example 1. Obtaining a composition (lyophilisate - composition in the form of a lyophilized powder for injection) containing isotonicity flavor

1a. Into a 1000 ml volumetric flask was added 1.0 g of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride and 53.0 g of mannitol (pyrogen-free for the preparation of injection solutions). Water for injection is poured into the flask to the mark and mixed. The resulting solution is filtered through a filter with a hole diameter of 0.11 μm and simultaneously poured into dark glass bottles, for example, with a volume of 2 ml. Vials are placed in a freeze dryer to obtain a lyophilisate for the preparation of an injection solution. After drying, the bottles are corked with rubber stoppers, aluminum caps for running in and marked.

The content of the active principle (9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride) in one 2 ml vial is 2 mg. The lyophilizate injection solution is prepared extemporaneously. As a solvent for injection, water for injection is used. The concentration of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride after addition of solvent is 1 mg / ml.

The ratio of components in wt.% In the bottle (lyophilisate):

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 1.85 Mannitol (pyrogen-free) (isotonic flavor) 98.15

The mass of the lyophilisate for the preparation of a solution for injection in one bottle is 0.108 g.

1b. The composition was similarly obtained with the ratio in the bottle, wt.%: 0.1 dihydrochloride 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole and 99.90 mannitol.

1c. Similarly, the composition was obtained with a ratio of components in the bottle, respectively, wt.% 99.99 dihydrochloride 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole and 0.01 mannitol.

Compositions were similarly prepared using at least one substance selected from the group of organic or inorganic acids (sodium citrate, sodium benzoate, sodium chloride, sodium metabisulfite, sodium bromide, sodium bicarbonate, potassium iodide, potassium chloride, calcium as the isotonicity salt salt). chloride, magnesium sulfate, copper sulfate); polyols (glucose, mannitol, sorbitol, lactose, galactose); amino acids (proline, glycine).

Example 2. Obtaining an injection solution of a composition containing a cosolvent and its lyophilisate (composition in the form of a lyophilized powder for injection)

2a. Into a 1000 ml volumetric flask was added 1.0 g of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride and 28.9 ml of propylene glycol (density at 20 ° C - 1 , 0363 g / cm ³ ). The contents of the flask are poured with water for injection to the mark and mixed. The resulting solution was bubbled with argon and filtered through a filter with a hole diameter of 0.11 μm (ultrafiltration) and at the same time it was packaged in a dark glass ampoule for injection with a dispenser. Ampoules are sealed and labeled.

The ratio of components in wt.% In the ampoule:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 0.1 Propylene glycol (cosolvent) 3.0 Water for injection (solvent) 96.9

The volume of the injection solution in one ampoule is 2 ml, the concentration of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride is 1 mg / ml. The introduction of propylene glycol into the injection solution promotes the solubilization of dihydrochloride-2- (4-fluorenyl) 9-morpholinoethylimidazo [1,2-α] benzimidazole.

Preparation of lyophilisate: 1.0 g of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole and 28.9 ml of propylene glycol (density at 20 °) are placed in a 1000 ml volumetric flask C - 1.0363 g / cm ³ ). The contents of the flask are poured with water for injection to the mark and mixed. The resulting solution is filtered through a filter with a hole diameter of 0.11 μm and simultaneously poured into 2 ml dark glass vials. Vials are placed in a freeze dryer to obtain a lyophilisate for the preparation of an injection solution. After drying, the bottles are corked with rubber stoppers, aluminum caps for running in and marked.

The ratio of components in wt.% In the bottle after drying is 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride: propylene glycol (cosolvent) - 3.23: 96.77 wt.%.

2b. Similarly, the composition was obtained with a ratio of components (active principle: propylene glycol), respectively. Wt.% 0.1: 99.90.

2c. Similarly, the composition was obtained at a ratio of components (active principle: propylene glycol), respectively. Wt.% 99,99: 0,01.

Compositions were similarly prepared using, instead of propylene glycol, as a co-solvent, at least one substance selected from the group: ethyl alcohol, glycerin, benzyl benzoate, benzyl alcohol, fatty oils (olive oil, peach oil), ethyl oleate.

Example 3. Obtaining an injection solution of a composition containing pH flavorant and antioxidant, and its lyophilisate

Into a 1000 ml volumetric flask was added 1.0 g of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride, 9.0 g of sodium chloride, 1.0 g of unitiol. The contents of the flask are half-filled with freshly boiled water for injection and shaken until the crystals of the drug substance are completely dissolved, then 1 ml of a 10% solution of hydrochloric acid is poured, mixed. Freshly boiled water for injection is added to the contents of the flask to the mark. The resulting solution was bubbled with argon and filtered through a filter with a hole diameter of 0.11 μm (ultrafiltration) and packaged in a dark glass ampoule for injection using a dispenser. Ampoules are sealed and labeled.

The ratio of components in wt.% In the ampoule:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 0,100 Sodium chloride (isotonicity flavor) 0,900 Hydrochloric acid (pH flavorant) 0.006 Unitiol (antioxidant) 0,100 Water for injection (solvent) 98,894

The volume of injection solution in one bottle is 2 ml, the concentration of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride is 1 mg / ml. The introduction of sodium chloride into the injection solution results in an isotonic injection solution. Hydrochloric acid lowers the pH of the solution, which stabilizes the structure of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride and prevents the formation of impurities. Unitiol is an antioxidant and helps to slow down the oxidation processes of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride during storage.

Preparation of lyophilisate: As described above, the resulting solution is not poured into ampoules, but into 2 ml dark glass bottles. Vials are placed in a freeze dryer to obtain a lyophilisate for the preparation of an injection solution. After drying, the bottles are corked with rubber stoppers, aluminum caps for running in and marked.

The ratio of components in the bottle after drying in wt.%:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 9.04 Sodium chloride (isotonicity flavor) 81.37 Hydrochloric acid (pH flavorant) 0.542 Unitiol (antioxidant) 9.04

Similarly, the composition is obtained at a ratio of components in the vial after drying in wt.%:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 7.50 Sodium chloride (isotonicity flavor) 90.17 Hydrochloric acid (pH flavorant) 0,045 Unitiol (antioxidant) 2.25

Compositions were similarly prepared using, instead of sodium chloride, at least one substance selected from the group: salts of organic or inorganic acids (sodium citrate, sodium benzoate, sodium chloride, sodium metabisulfite, sodium bromide, sodium bicarbonate, potassium iodide, potassium instead of sodium chloride) chloride, calcium chloride, magnesium sulfate, copper sulfate); polyols (glucose, mannitol, sorbitol, lactose, galactose); amino acids (proline, glycine).

Compositions were similarly prepared using, instead of hydrochloric acid, at least one substance selected from the group instead of hydrochloric acid as a pH flavoring agent: organic acids (ascorbic acid, acetic acid, citric acid), organic acid salt (sodium citrate, sodium acetate).

Compositions were similarly prepared using, instead of unitiol, as an antioxidant, at least one excipient selected from the group: salts of inorganic and organic acids (sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium sulfoxylate); sulfur-containing auxiliary substance (thioglycerol, thiourea, thiosorbitol, cysteine hydrochloride); formaldehyde; ascorbic acid; isoascorbic acid; hydroquinone; propyl gallate; lecithin; tocopherols; esters of ascorbic and gallic acids.

Example 4. Obtaining a lyophilizate composition containing a cryoprotectant

In a 1000 ml volumetric flask, 1.0 g of 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride and 0.5 g of hydroxypropylated β-cyclodextrin (1: 1 molar ratio of components), pour water for injection to the mark. The resulting solution is left for several days, then filtered through a filter with a hole diameter of 0.11 μm and at the same time Packed in 2 ml dark glass bottles. The bottles are subjected to freeze drying to a moisture value in the lyophilisate not exceeding 1%. Then, 0.106 g of mannitol is added to each vial. The bottles are corked (with rubber stoppers and aluminum caps for running in) and marked.

The ratio of components in wt.% In the bottle after drying:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 1.83 GP-β-cyclodextrin (cryoprotectant) 0.92 Mannitol (isotonic flavor) 97.25

The mass of the contents of one bottle is 0.109 g. The solution is prepared extemporaneously before use. β-cyclodextrin is a steric stabilizer of the 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride molecule and contributes to its stability in solution due to the formation of an inclusion complex.

Similarly, the composition was obtained at a ratio of components in wt.% In a bottle after drying:

9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 1.83 GP-β-cyclodextrin (cryoprotectant) 48.00 Mannitol (isotonic flavor) 50.17

Compositions were similarly prepared using, instead of GP-β-cyclodextrin, as a cryoprotectant, at least one substance selected from the group: polyols (mannitol, sucrose, lactose); glycerol; dimethyl sulfoxide; polyethylene oxide; cyclodextrins (γ-cyclodextrin).

Pharmacokinetic properties of the compound in injectable dosage form

Methods for the study of the pharmacokinetic properties of the compound

In the process of studying the pharmacokinetic properties of the compound, a physicochemical method was used to determine the concentration of the test substance in the biomaterial — high performance liquid chromatography. The experiments were carried out on chinchilla rabbits weighing 2-2.5 kg. The substance and dosage form was administered intravenously and subcutaneously. Twelve hours before the experiments, animals lost access to food without limiting water intake.

Quantification of the studied compound was carried out using high performance liquid chromatography on a Shimadzu computerized system (Japan) with a UV detector at λ = 205 nm on a SUPELCOSIL LC-18 analytical column (5 μm; 100 mm × 4.6 mm). The mobile phase included acetonitrile (J.T. Baker, USA) and a buffer system consisting of monosubstituted potassium phosphate 50 mM pH = 5.0. in the ratio 1: 1 [Smirnova L.A., Raschenko A.I. Ryabukha A.F., Kuznetsov K.A., Suchkov E.A. // Quantitative determination of the compound RU-1205 in biological samples / Volgograd Journal of Medical Scientific Research, 2/2012. - S. 15-17].

The dependence of peak areas on the concentration of the studied compound was analyzed by regression analysis. Statistical processing of the results was carried out using the computer program Excel [Firsov A.A., Zherdev V.P. et al. // Methodological recommendations for the study of the analgesic activity of drugs / Guidelines for preclinical studies of drugs, ed. V.P. Fisenko. M., 2012. - S. 843-851].

The pharmacokinetic properties of the substance and the injectable dosage form of the compound with a single intravenous administration are shown in Fig. 1. The ordinate shows the content of the compound in the blood of rabbits after intravenous administration of the substance and injection for a dose of 25 mg / kg (injection is made in accordance with example 1A). The abscissa indicates the time since the introduction of the studied substances.

Table 1 presents the pharmacokinetic parameters of the compound in rabbits with intravenous administration of a substance and a solution for injection at a dose of 10 mg / kg.

When conducting a study of the injection for intravenous administration, no differences were found between the pharmacokinetic curves (Fig. 1). The injection solution circulates longer in the blood of rabbits compared with the substance, as evidenced by a statistically significant (p≤0.01) increase in the half-life and average retention time of one drug molecule in the animal's body. Moreover, the relative bioavailability is close to 100% (table. 1). Based on the data presented, it was found that the area under the curve after administration of the dosage form is not significantly inferior to this indicator after administration of the substance (Fig. 2).

The pharmacokinetic properties of the substance and injectable dosage form of the compound with a single subcutaneous injection are presented in Fig. 2, which shows the content of the compound in the blood of rabbits after subcutaneous administration of an injection solution compared with the substance.

The pharmacokinetic parameters of the compound in rabbits with subcutaneous administration of a substance and a solution for injection at a dose of 25 mg / kg are presented in table 2.

Based on a study of the pharmacokinetic properties of the injection for subcutaneous administration, some differences were revealed between the substance and the dosage form (Fig. 2). So, it was found that the area under the curve of the compound in the form of a dosage form is slightly inferior to this indicator of the compound in the form of a substance. The elimination half-life characteristic of the substance of the compound is approximately 30% higher relative to the dosage form. The average retention time, clearance and apparent volume of distribution are statistically significantly different for the substance and dosage form, but the absolute values of these parameters are almost the same. It was revealed that for the injectable dosage form with subcutaneous administration, a high relative bioavailability is characteristic.

ANALGESIC PROPERTIES OF COMPOUNDS IN INJECTION MEDICINAL FORM.

Methods for the study of the analgesic activity of the compound

Hot Plate Test [Kitchen I. Assessment of the hot-plate antinociceptive test in mice. A new method for the statistical treatment of graded data. / Kitchen I, Crowder M. // J Pharmacol Methods. - 1985. Vol. 13, No. 1. - P. 1-7] allows you to evaluate the presence of a central mechanism of analgesic action and is based on behavioral responses controlled by supraspinal structures in response to pain [Voronina TA, Guzevatykh LS // Guidelines for the study of the analgesic activity of drugs / Guidelines for preclinical studies of drugs, ed. V.P. Fisenko. M., 2012. - S. 202]. An experimental study was performed on male mice. The test compound was administered at doses of 1 mg / kg. At various time intervals after administration of the test compound, the animal was placed on a copper plate heated to 55 ° C surrounded by a plastic cylinder. We recorded the latent time of the nociceptive reaction in the form of licking of the hind legs, which appears in animals with the threshold of pain sensitivity [D. le Bars, M. Gozariu. Animal models of nociception / D. le Bars, M. Gozariu, S.W. Cadden. // Pharmacol. Rev. - 2001. Vol. 53 No. 4 - R. 611]. A criterion for the analgesic effect was considered a statistically significant increase in the latent period of the reaction after administration of the substance. Statistical data processing was performed using the Kruskal-Wallis and Mann-Whitney criteria.

Table 3 shows the effect of the compound 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride when administered subcutaneously at a dose of 1 mg / kg on the antinociceptive effects in the Hot Plate test (M ± m) in the form of a substance and an injectable form obtained according to example 1a.

For example 1b, the latent period after 60 minutes is 14.8 ± 1.2 (66.3%), after 120 minutes 18.6 ± 1.4 (109.0%).

For example 1c, the latent period after 60 minutes is 14.1 ± 0.9 (58.4%), after 120 minutes 18.0 ± 1.2 (102.2%).

For example 2b, the latent period after 60 minutes is 14.7 ± 1.4 (65.2%), after 120 minutes it is 18.4 ± 1.0 (106.7%).

For example 2c, the latent period after 60 minutes is 13.9 ± 1.1 (56.2%), after 120 minutes 18.1 ± 1.3 (103.4%).

In fig. Figure 3 shows the duration of the analgesic effect of the compound when administered subcutaneously at a dose of 1 mg / kg in the Hot Plate test.

With the introduction of the substance and the injectable dosage form of the compound, a slow increase in analgesic activity was observed with a peak of maximum effect 2 hours after their administration. This was followed by a slow decrease in the analgesic activity of the substance and injectable dosage form. The duration of the dosage form lasted up to 8 hours.

According to pharmacodynamic indicators, there were no statistically significant differences in analgesic activity between the substance and the injectable dosage form.

DEPENDENCE OF PHARMACODYNAMIC PROPERTIES OF THE COMPOUND ON PHARMACOKINETICS DURING ONE TIME SCRATCH INTRODUCTION.

When comparing the pharmacokinetic properties and pharmacodynamic curves, it should be noted that there is no direct dependence of the change in the threshold of pain sensitivity on the concentration of the compound during subcutaneous administration. Perhaps this is due to the fact that with subcutaneous administration of the studied compound, a sharp drop in its concentration in the blood is observed in the first minutes after administration, which can be explained by both its rapid distribution to organs with a high degree of vascularization and active metabolism. A drop in the concentration of the compound in the blood is accompanied by an increase in the pharmacological effect. This follows from fig. 4, which shows the dependence of the threshold of pain sensitivity (in% relative to the control) on the content of the compound in the blood plasma from the time after subcutaneous administration. The abscissa axis represents time (hours), the left ordinate axis shows the concentration of the compound in the blood plasma (μg / ml), the right ordinate axis represents the change in the threshold of pain sensitivity (Δ% relative to the control).

In fig. 5 shows the dependence of the change in the threshold of pain sensitivity (in% relative to the control) on the concentration of the compound in blood plasma after subcutaneous administration. R ² - the value of the reliability of the approximation. On the abscissa axis is the concentration of the compound in the blood plasma (μg / ml), on the ordinate axis, the change in the threshold of pain sensitivity.

The correlation dependence has a complex form, the approximation confidence coefficient is 0.7689 (Fig. 5). After the 4th hour, the nature of the correlation curve changes. There is a relationship between a change in the threshold of pain sensitivity and the concentration of the compound in blood plasma. This can be explained by the onset of equilibrium between the processes of distribution and elimination (Fig. 4).

Similar results were obtained for compositions of the composition, wt.%:

* 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride - 7.50, sodium chloride (isotonicity flavor) - 90.17, hydrochloric acid (pH flavor) - 0.045, unitiol (antioxidant) - 2.25 obtained in example 3 (lyophilisate),

* 9- (2-morpholinoethyl) -2- (4-fluorophenyl) -imidazo [1,2-α] benzimidazole dihydrochloride - 1.83, GP-β-cyclodextrin (cryoprotectant) - 48.00, mannitol (isotonicity flavor) - 50.17 obtained in example 4 (lyophilisate).

Thus, the proposed composition exhibits an analgesic effect.

Claims (12)

1. An injectable pharmaceutical composition with kappa-opioid agonist activity, exhibiting an analgesic effect, characterized in that it contains 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride, and as auxiliary substances, isotonicity correcting agent, which is at least one substance selected from the group consisting of salts of organic or inorganic acids, including sodium citrate, sodium benzoate, sodium chloride, sodium metabisulfite, sodium bromide, sodium hydr carbonate, potassium iodide, potassium chloride, calcium chloride, magnesium sulfate, copper sulfate containing polyols include glucose, mannitol, sorbitol, lactose, galactose, containing amino acids, including proline, glycine, with the following component ratio, wt.%:
9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 99.99-0.10 Corrigent of Isotonicity 0.01-99.90 2. The pharmaceutical composition according to claim 1, characterized in that it further comprises a co-solvent, a pH flavorant, a cryoprotectant, an antioxidant in the following ratio of components, wt.%:
Co-solvent up to 10.00 Corrigent pH solution up to 0.045 Cryoprotectant up to 48.00 Antioxidant up to 2.25 3. The pharmaceutical composition according to claim 2, characterized in that, as a flavoring agent, the pH of the solution contains at least one substance selected from the group consisting of inorganic acids, including hydrochloric acid, containing organic acids, including ascorbic acid, acetic acid, citric acid containing salts of organic acids, including sodium citrate, sodium acetate. 4. The pharmaceutical composition according to claim 2, characterized in that as a cryoprotectant contains at least one substance selected from the group consisting of polyols including mannitol, sucrose, lactose, containing glycerin, dimethyl sulfoxide, polyethylene oxide and cyclodextrins, including γ- and β-cyclodextrins. 5. The pharmaceutical composition according to claim 2, characterized in that the antioxidant contains at least one substance selected from the group consisting of inorganic acid salts, including sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium sulfoxylate containing sulfur-containing excipients, including thioglycerol, thiourea, thiosorbitol, cysteine hydrochloride containing formaldehyde, ascorbic acid, isoascorbic acid, hydroquinone, propyl gallate, lecithin, tocopherols, ascorbic esters and gallic acid. 6. The pharmaceutical composition according to claim 2, characterized in that the co-solvent contains at least one substance selected from the group consisting of ethyl alcohol, glycerin, propylene glycol, benzyl benzoate, benzyl alcohol, ethyl oleate and fatty oils, including olive oil and peach oil. 7. An injectable pharmaceutical composition with kappa-opioid agonist activity, exhibiting an analgesic effect, characterized in that it contains 9- (2-morpholinoethyl) -2- (4-fluorophenyl) imidazo [1,2-α] benzimidazole dihydrochloride, and as auxiliary substances, a co-solvent, which is at least one substance selected from the group consisting of ethyl alcohol, glycerin, propylene glycol, benzyl benzoate, benzyl alcohol, ethyl oleate and fatty oils, including olive oil and peach oil, with the following the ratio of components, wt.%:
9- (2-Morpholinoethyl) -2- (4-fluorophenyl) dihydrochloride - imidazo [1,2-α] benzimidazole 99.99-0.10 Co-solvent 0.01-99.90 8. The pharmaceutical composition according to claim 7, characterized in that it further comprises isotonicity flavoring agent, pH solution flavoring agent, cryoprotectant, antioxidant in the following ratio, wt.%:
Corrigent of Isotonicity up to 48.00 Corrigent pH solution up to 0.045 Cryoprotectant up to 48.00 Antioxidant up to 2.25 9. The pharmaceutical composition according to claim 7, characterized in that at least one substance selected from the group consisting of salts of inorganic compounds including sodium chloride, sodium citrate, sodium metabisulfite, sodium benzoate, sodium bromide, sodium is used as an isotonicity flavoring agent. bicarbonate, potassium iodide, potassium chloride, calcium chloride, magnesium sulfate, copper sulfate containing polyols including glucose, mannitol, sorbitol, lactose, galactose, and containing amino acids including proline and glycine. 10. The pharmaceutical composition of claim 8, characterized in that the pH of the solution contains at least one substance selected from the group consisting of inorganic acids, including hydrochloric acid, containing organic acids, including ascorbic acid, acetic acid and citric acid containing salts of organic acids, including sodium citrate and sodium acetate. 11. The pharmaceutical composition according to claim 7, characterized in that as a cryoprotectant contains at least one substance selected from the group consisting of polyols including mannitol, sucrose and lactose, containing glycerin, dimethyl sulfoxide, polyethylene oxide and cyclodextrins, including γ- and β-cyclodextrins. 12. The pharmaceutical composition according to claim 7, characterized in that the antioxidant contains at least one substance selected from the group consisting of salts of inorganic compounds including sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium sulfoxylate containing sulfur-containing excipients, including thioglycerol, thiourea, thiosorbitol and cysteine hydrochloride containing formaldehyde, ascorbic acid, isoascorbic acid, hydroquinone, propyl gallate, lecithin, tocopherols, ascorb esters new and gallic acids.

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