Solid dosage form

Abstract

FIELD: chemistry; pharmaceuticals.SUBSTANCE: medicinal product for the treatment of cerebrovascular pathology. The medicinal product is made in the form of hard capsules and consists of a gelatin or vegetable shell and an encapsulate enclosed therein, containing N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine as an active substance in an amount of 1–2 mg and auxiliary substances selected from a solvent and / or filler, a co-solvent, an adsorbent, an emulsifier, a stabilizer or mixtures thereof, while the total content of auxiliary substances is 170–270 mg.EFFECT: cerebrovasodilator with favorable biopharmaceutical properties.6 cl, 2 dwg, 9 tbl, 5 ex

Description

[0001] The invention relates to the field of the chemical-pharmaceutical industry and medicine and concerns drugs that release nitric oxide in the form of capsules.

[0002] Cerebral circulatory disorders, the most common of which are chronic disorders such as chronic cerebral ischemia, vascular dementia, and cerebrovascular insufficiency, are among the leading causes of death and permanent disability in most countries worldwide. These conditions are characterized by diffuse, progressive brain damage, often accompanied by episodes of acute cerebral ischemia. In less acute forms, cerebral circulatory disorders can lead to the development of depression, anxiety disorders, emotional instability, etc. The most common and significant risk factor for the development of cerebrovascular pathology is arterial hypertension.

[0003] Thus, the urgent task is to develop new drugs that have cerebrovasodilatory, anti-ischemic and hypotensive effects.

[0004] One class of compounds used as active ingredients with this activity are sydnonymines—exogenous NO donors. Nitric oxide (NO) plays a key role in the control of vascular tone, participates in the regulation of respiration, immunity, and neurotransmission mechanisms, and maintains cardiovascular homeostasis. A number of pathological conditions, such as cardiovascular, infectious, inflammatory, and thrombotic diseases, can be significantly associated with a deficiency or excess of nitric oxide in the body.

[0005] In clinical practice, an NO donor, Molsidomine-N-(Ethoxycarbonyl)-3-(4-morpholinyl)sydnonimine [1,2,3-Oxadiazoles. Comprehensive Heterocyclic Chemistry II, 1996], has shown effective action in the above-mentioned conditions. Molsidomine's metabolite, SIN-1, also shows promise in terms of pharmacological activity. Although SIN-1 exhibits the same effects as molsidomine, in some cases the degree of beneficial effect on the animal organism differs in a number of parameters.

[0006] Among the sydnone imines, substances with an effect on the central and peripheral nervous systems were also found, for example: the monoamine oxidase inhibitor Sydnofen [Mashkovsky M.D. "Medicines" 13th ed. v.1 Kharkov: Torsing, 1997 pp. 104-105] - 3-(β-phenylisopropyl)-sydnonimine hydrochloride and the indirect sympathomimetic Sydnocarb [GB 1262830] - N-phenylcarbamoyl-3-(β-phenylisopropyl)-sydnonimine). These drugs were introduced into medical practice.

[0007] Drugs with the specified pharmacological activity are available in various forms. There are reports in the literature of the use of infusion forms of sydnonimines (e.g., linsidomine solution), but these methods are not widely used in clinical practice. The optimal route of administration for sydnonimines is considered to be oral administration, preferably in tablet form. Therefore, the search for acceptable dosage forms has primarily focused on oral forms (DE 4443105 C2, RU2263506 C2, etc.).

[0008] The closest analogue may be the drug molsidomine in the form of tablets according to patent RU 2263506 C2 (prototype).

[0009] Molsidomine is useful for vasodilation and improving blood flow. However, vasodilation at high doses can cause hypotension and side effects, and tolerance limits its long-term effectiveness with chronic use. Therefore, although studies have been conducted on its use in the treatment of cerebral microcirculatory disorders caused by nitric oxide deficiency, in clinical practice, its primary use remains angina.

[0010] Recently, attention to the search for new sydnonimine compounds that could be potential therapeutic agents for a variety of medical conditions has declined. It was therefore unexpected that we discovered a new compound, sydnonimine, which is N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine. Its pharmacological properties allow it to be used for cerebrovascular accidents, intermittent cerebrovascular insufficiency and cerebral vasospasms, and partial arterial occlusion. An additional indication for use is pulmonary arterial hypertension. A separate patent application, RU 2024132865, has been filed for this compound and its pharmacological use.

[0011] The objective of the present invention is to develop a preparative form of a new compound, devoid of the above-mentioned disadvantages of the prototype, which would make it possible to expand the arsenal of cerebrovasodilators with favorable biopharmaceutical characteristics (technical result).

[0012] To achieve the technical result, a drug for the treatment of cerebrovascular pathology is proposed. This drug is a solid capsule dosage form consisting of a shell and an encapsulate containing N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine as the pharmacologically active component (active ingredient). In addition to the active ingredient, various embodiments of the solid dosage form include excipients selected from the following group: a solvent and / or filler, a co-solvent, an adsorbent, an emulsifier, a stabilizer, and mixtures thereof.

[0013] The invention is a solid dosage form—hard capsules in a package for single-dose administration. The shell can be either conventional empty hard gelatin capsules or plant-based capsules, i.e., capsules based on alternative materials such as hydroxypropyl methylcellulose; alginic acid or its salts; pullulan; or pectin or its derivatives, such as modified citrus pectin.

[0014] The drug contains N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine (hereinafter referred to as VVR 2023) as an active (pharmacologically active) substance in the amount of 1-2 mg per capsule encapsulant (core).

[0015] In addition, the composition of the drug in different production options may include:

[0016] - solvent (filler) (including, but not limited to the following: vegetable oils (sunflower, olive, peach, apricot, almond, castor); long and medium chain triglycerides (MCT and LCT); silicone fluids; polyethylene glycol; polyethylene oxide; sucragel; sodium alginate);

[0017] co-solvent (including but not limited to: polyethylene glycol; diethylene glycol monoethyl ether; propylene glycol; propylene glycol dicaprylate / dicaprate; glycerol mono- and distearate; glycofurol);

[0018] - emulsifier (including but not limited to: polysorbate; polysorbitan ester; polyglycerol ether; sodium lauryl sulfate; sodium alkyl benzene sulfonate; proxanol-228; poloxamer 407);

[0019] - adsorbent (including but not limited to the following: colloidal silicon dioxide; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), cellulose derivatives; polyethylene glycol (PEG), starch and its derivatives;

[0020] - stabilizer (including but not limited to the following: tocopherol and its derivatives; propyl gallate; ascorbyl palmitate; phospholipids).

[0021] The amount of excipients in the encapsulate is generally from 170.0 to 270.0 mg.

[0022] Excipient content as a percentage of the total excipient mass, depending on the capsule production method. Examples of the following ranges may be given:

[0023] 1. Capsules with oil solution VVR 2023:

[0024] - Solvent 98.0-100.0

[0025] - Stabilizer 0-2.0

[0026] 2. Capsules with emulsion VVR 2023:

[0027] - Solvent 18.0-28.0

[0028] - Stabilizer 0-2.0

[0029] - Filler 70.0-80.0

[0030] - Emulsifier 1.5-5.0

[0031] 3. Capsules with paste / gel VVR 2023:

[0032] - Solvent 20.0-40.0

[0033] - Stabilizer 0-1.0

[0034] - Adsorbent 60.0-80.0

[0035] - Emulsifier 0-1.0

[0036] 4. Self-emulsifying liquid capsules (SEDDS):

[0037] - Solvent 60.0-80.0

[0038] - Stabilizer 0-2.0

[0039] - Co-solvent 10.0-15.0

[0040] - Emulsifier 10.0-25.0

[0041] 5. Solid self-emulsifying capsules (S-SEDDS):

[0042] - Solvent 20.0-35.0

[0043] - Stabilizer 0-1.0 - Co-solvent 1.0-4.0

[0044] - Emulsifier 1.0-9.0

[0045] - Adsorbent 60.0-80.0

[0046] 6. Capsules with mucoadhesive granules of the active substance:

[0047] - Solvent 10.0-25.0

[0048] - Stabilizer 0-2.0

[0049] - Filler 70.0-80.0

[0050] - Emulsifier 1.5-5.0

[0051] Example 1. Synthesis of the active component - N-(ethoxycarbonyl)-3-(4 methylhexan-2-yl)sydnonimine

[0052]

[0053] 4.7 grams (55 mmol) of acetone cyanohydrin and 2 grams (50 mmol) of sodium hydroxide are mixed with water (35 ml) and stirred at room temperature for 40 minutes. The resulting solution is evaporated on a rotary evaporator to half the volume.

[0054] A solution of 4-methylhexane-2-amine hydrochloride (7.6 g, 50 mmol) and concentrated hydrochloric acid (0.15 ml) in water (40 ml) is prepared. This solution is cooled to 0°C (ice bath cooling). A solution of formaldehyde (3.75 ml, 37% aqueous) is added to the cooled solution. Then a partially evaporated solution of acetone cyanohydrin and alkali is added to this mixture in portions over 30 minutes. The resulting mixture is stirred for 12 hours at room temperature. Then the reaction mixture is extracted with diethyl ether (3 times with 40 ml). The organic extracts are combined and washed with a saturated solution of potassium chloride (2 times with 50 ml), dried over anhydrous sodium sulfate and evaporated on a rotary evaporator at a temperature not exceeding 35°C. The resulting light yellow oil of 2-((4-methylhexan-2-yl)amino)acetonitrile (7.5 grams, 97% yield) was used further without further purification in step 2.

[0055] 2-((4-methylhexan-2-yl)amino)acetonitrile. 1H-NMR (300 MHz, CDCl3): 3.65 to 3.56 (m, 2H), 2.99 to 2.89 (m, 1H), 1.49 to 1.10 (m, 5H), 1.08 to 1.03 (m, ZN), 0.93 to 0.84 (m, 6H).

[0056]

[0057] 144 grams (0.94 mol) of 2-((4-methylhexan-2-yl)amino)acetonitrile obtained in Step 1 are dissolved in tetrahydrofuran (600 ml). A solution of hydrochloric acid (aqueous, concentration 1 M, 950 ml) is added to the mixture and cooled to 0 °C (cooling with an ice bath). A solution of sodium nitrite (71 grams, 1.03 mol) in water (190 ml) is prepared. This solution is added portionwise to the cooled solution of 2-((4-methylhexan-2-yl)amino)acetonitrile described above, portionwise over 60 minutes. The mixture is kept for another 30 minutes at 0 °C (cooling with an ice bath), and then for another 2 hours at room temperature. The reaction mixture is then extracted with diethyl ether (3 x 300 ml). The organic extracts are combined and washed with saturated potassium chloride solution (2 x 100 ml), dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator at a temperature no higher than 25°C.The resulting product is purified by flash chromatography on silica gel using a 1:1 mixture of methylene chloride and hexane as eluent. Fractions are monitored by TLC in a similar mixture; the product has an Rf of 0.5 and is clearly visible under a UV lamp.

[0058] 98 grams (57% yield) of yellowish oil of N-(4-methylhexan-2-yl)-N-(cyanomethyl)nitrosamine with a purity of at least 95% according to NMR were obtained.

[0059] N-(4-methylhexan-2-yl)-N-(cyanomethyl)nitrosamine. 1 H-NMR (300 MHz, DMSO-d6): δ 5.04-4.84 (m, 1H), 4.72-4.55 (m, 2H), 1.68-1.58 (m, 1H), 1.51-0.96 (m, 7H), 0.90 - 0.78 (m, 6H).

[0060]

[0061] 98 grams (0.54 mol) of N-(cyanomethyl)-N-(4-methylhexan-2-yl)nitrosamide are dissolved in methanol (200 ml) and cooled to 0°C (ice bath cooling). A solution of hydrochloric acid in methanol (3 M concentration, 250 ml) is added to this solution. The mixture is kept for another 30 minutes at 0°C (ice bath cooling), and then for another 1 hour at room temperature. The resulting clear solution is evaporated on a rotary evaporator at a temperature not exceeding 45°C. The resulting crystalline product is mixed with diethyl ether (300 ml) and isopropanol (30 ml) and vigorously stirred until a homogeneous suspension is formed. The suspension is filtered and washed on the filter with diethyl ether (3 times 100 ml). The resulting product was dried in vacuum to constant weight. 90 grams (76% yield) of crystalline 5-imino-3-(4-methylhexan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide hydrochloride was obtained, with a purity of at least 95% according to NMR.

[0062] 1H NMR (700 MHz, DMSO-d6): 9.84 (s, 2H), 8.22 (s, 1H), 5.14 - 5.04 (m, 1H), 2.13 -1.56 (m, 5H), 1.44 - 1.10 (m, 3H), 0.92-0.78 (m, 6H). 13C-MP (176 MHz, DMSO-d6): 169.2, 169.1, 101.1, 100.9, 61.2, 61.1, 41.4, 41.2, 30.3, 30.3, 28.7, 28.2, 20.4, 19.6, 18.4, 18.2, 10.8, 10.7.

[0063]

[0064] 26.3 grams (0.12 mol) of 5-imino-3-(4-methylhexan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide hydrochloride are dissolved in acetonitrile (500 ml) at room temperature. Diethyl pyrocarbonate (52 ml, 0.36 mol) is added to the mixture in one portion, followed by triethylamine (21 ml, 0.144 mol) in small portions over 10 minutes. The mixture is kept at room temperature for 1 hour. The resulting clear solution is evaporated on a rotary evaporator at a temperature not exceeding 45°C. The resulting product is purified by flash chromatography on silica gel using a mixture of methylene chloride and ethanol (100 to 2) as eluent. Fractionation control is performed by TLC in a similar mixture; the product has an Rf of 0.3 and is clearly visible under a UV lamp. This yields 20 grams (66% yield) of N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine as a colorless oil with a purity of at least 95% according to NMR.

[0065] 1H-NMR (700 MHz, CDCl3): 7.63 (s, 1H), 4.78 - 4.66 (m, 1H), 4.13 (q, J 7.1, 2H), 2.04 -1.55 (m, 5H), 1.45 - 1.09 (m, 6H), 0.96-0.74 (m, 6H). 13C-NMR (176 MHz, CDCl3): δ 175.3, 162.1, 162.0, 101.7, 101.5,61.3,60.5, 60.4,42.9,42.9,31.1,30.9, 29.4, 28.8,21.4,20.6, 18.8, 18.4, 14.6, 11.0, 10.9. HR-MS (ESI) m / z: found 256.1660

[0066] Example 2. Technology for producing an encapsulated drug

[0067] Option 1. Obtaining capsules with oil solution VVR 2023

[0068] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 20 ml of sunflower oil and homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is dosed 0.2 ml into size 4 hard gelatin or vegetable capsules.

[0069] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components. Option 2. Production of capsules with oil solution VVR 2023

[0071] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 19.6 ml of apricot oil and 0.4 ml of α-tocopherol. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is dosed 0.2 ml into size 4 hard gelatin or vegetable capsules.

[0072] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0073] Option 3. Obtaining capsules with oil solution VVR 2023

[0074] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 19.8 ml of caprylic triglyceride and 0.15 mg of propyl gallate. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is dosed 0.2 ml into size 4 hard gelatin or vegetable capsules.

[0075] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components. Option 4. Production of capsules with VVR 2023 emulsion

[0077] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 4.75 ml of sunflower oil, 1 g of poloxamer 407, and 0.5 g of ascorbyl palmitate. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. At the same time, melt and mix 10 g of PEG 1500 and 2 g of PEG 400 at 40-50°C. Combine the resulting solutions and sonicate at 50 Hz for 10 minutes, then dose into size 4 hard gelatin or vegetable capsules.

[0078] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components. Option 5. Production of capsules with VVR 2023 emulsion

[0080] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 3 ml of liquid silicone and 0.5 ml of polyglycerol ether. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. Simultaneously, mix, melt, and combine 11 g of PEG 1500 and 2.5 g of PEG 400 at 40-50°C. Combine the resulting solutions and sonicate at 50 Hz for 10 minutes, then dose into size 4 hard gelatin or vegetable capsules. Depending on the equipment used and the specifics of the technological process, process waste is taken into account when calculating the required amount of starting components.

[0081] Option 6. Obtaining capsules with VVR 2023 emulsion

[0082] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 5 ml of capric acid triglyceride and 1 ml of polyglycerol ester, homogenize by mechanical stirring or ultrasound while heating to 40-50°C. In parallel, mix, melt, and combine 11 g of PEG 1500 and 2.5 g of PEG 400 at 40-50°C. Combine the resulting solutions and sonicate at 50 Hz for 10 minutes, then dose into size 4 hard gelatin or vegetable capsules.

[0083] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components. Option 7. Obtaining capsules with paste / gel VVR 2023

[0085] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 5 ml of sunflower oil and homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 16 g of aerosil and mixed in a mixer until uniformly distributed and a paste-like consistency is achieved. 0.18 g is dispensed into size 4 hard gelatin or vegetable capsules. Depending on the equipment used and the specifics of the manufacturing process, process waste is taken into account when calculating the required quantities of the starting components. Option 8. Obtaining capsules with paste / gel VVR 2023

[0087] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 5 ml of apricot oil and 0.1 ml of α-tocopherol, homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 16 g of Sucragel, mixed in a mixer until uniformly distributed and a gel-like consistency is achieved, and dosed into 0.18 g of hard gelatin or vegetable capsules of size 4.

[0088] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components. Option 9. Obtaining capsules with paste / gel VVR 2023

[0090] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 5 ml of sunflower oil and 0.1 ml of α-tocopherol, homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 15 g of starch, mixed in a mixer until uniformly distributed and a gel-like consistency is achieved, and dosed into 0.18 g of hard gelatin or vegetable capsules of size 4.

[0091] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0092] Option 10. Production of capsules with a liquid self-emulsifying system (SEDDS) VVR 2023

[0093] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 13 ml of sunflower oil, 5 ml of Tween 80, and 2 ml of PEG 400. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is dosed 0.2 ml into size 4 hard gelatin or vegetable capsules. Depending on the equipment used and the specifics of the technological process, process waste is taken into account when calculating the required quantities of the starting components.

[0094] Option 11. Production of capsules with a liquid self-emulsifying system (SEDDS) VVR 2023

[0095] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 15 ml of sunflower oil, 3 ml of sodium alkylbenzenesulfonate, and 2 ml of glycerol distearate. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is dosed 0.2 ml into size 4 hard gelatin or vegetable capsules.

[0096] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0097] Option 12. Production of capsules with a solid self-emulsifying system (S-SEDDS) VVR 2023

[0098] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 5 ml of castor oil, 1 ml of Tween 60, and 0.7 ml of glycerol monostearate. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 15.6 g of aerosil, mixed in a mixer until uniformly distributed and a pasty consistency is achieved, and dosed into 0.18 g of hard gelatin or vegetable capsules of size 4.

[0099] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0100] Option 13. Production of capsules with a solid self-emulsifying system (S-SEDDS) VVR 2023

[0101] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 6 ml of castor oil, 0.6 g of sodium lauryl sulfate, and 0.4 ml of PEG 400. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 14.5 g of hydroxypropyl methylcellulose, mixed in a mixer until uniformly distributed and a pasty consistency is obtained, and dosed into 0.18 g of hard gelatin or vegetable capsules of size 4.

[0102] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0103] Option 14. Production of capsules with a solid self-emulsifying system (S-SEDDS) VVR 2023

[0104] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 6 ml of castor oil, 0.6 g of sodium lauryl sulfate, and 0.4 ml of PEG 400. Homogenize by mechanical stirring or ultrasound while heating to 40-50°C. The resulting solution is mixed with 14.5 g of PVP, mixed in a mixer until uniformly distributed and a gel-like consistency is achieved, and dosed into 0.18 g of hard gelatin or vegetable capsules of size 4.

[0105] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0106] Option 15. Obtaining capsules with mucoadhesive granules VVR 2023

[0107] To obtain 100 hard capsules, mix 200 mg of VVR 2023 with 3 ml of sunflower oil, 0.1 ml of Tween 80, and 15 ml of 4% sodium alginate solution. Mix mechanically or ultrasonically until a uniform suspension is obtained. The resulting suspension is granulated by spray drying or extrusion, dried to a residual moisture content of no more than 5%, and dosed into 0.18 g hard gelatin or vegetable capsules of size 4.

[0108] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0109] Option 16. Obtaining capsules with mucoadhesive granules VVR 2023

[0110] To obtain 100 hard capsules, mix 100 mg of VVR 2023 with 2 ml of olive oil, 2 g of aerosil, and 15 ml of 4% sodium alginate solution. Mix mechanically or ultrasonically until a uniform suspension is obtained. The resulting suspension is granulated by spray drying or extrusion, dried to a residual moisture content of no more than 5%, and dosed into 0.18 g hard gelatin or vegetable capsules of size 4.

[0111] Depending on the equipment used and the characteristics of the technological process, the technological consumption is taken into account when calculating the required amount of initial components.

[0112] Example 3. Study of biopharmaceutical characteristics of the obtained forms

[0113] To study and confirm the properties and applicability of the developed solid dosage forms, laboratory studies were conducted, confirming their key characteristics.

[0114] The technological properties of the VVR 2023 substance were studied, primarily the rheological characteristics as key and limiting factors in the planning and implementation of technological processes for producing capsules with VVR 2023. The research results demonstrated a consistent decrease in the dynamic viscosity of VVR 2023 with an increase in temperature from 3279.50±33.23 mPa*s at 20°C to 147.00±12.73 mPa*s at 60°C. The change in characteristics upon application of external influence was studied by constructing a flow rheogram (Fig. 1). Fig. 1 illustrates the flow rheogram of VVR 2023.

[0115] As follows from the presented data, the substance VVR 2023 exhibits the properties of a non-Newtonian fluid with a pronounced rheopexy phenomenon in the region of 30-50 s -1at a temperature of 25°C. Weak thixotropy of the system was also noted. Based on the obtained data, the optimal external exposure conditions during the technological processing of VVR 2023 are a temperature range of 50-60°C, and a shear rate range of 60-80 s -1 .

[0116] The potential risks of interactions and changes in the physicochemical properties of VVR 2023 during co-processing and storage with excipients used in the production of dosage forms were also assessed. For this purpose, compatibility studies of VVR with solvents (fillers), co-solvents, emulsifiers, adsorbents, and stabilizers were conducted. The studies were conducted under stress conditions using a constant climate chamber at a temperature of 40°C and 60% humidity for 15 days. Potential changes in the physicochemical properties of the substance were assessed during identity testing and quantitative determination of VVR 2023 after the stress test. The study results are presented in Table 1.

[0117] The presented results indicate acceptable compatibility and the absence of risks of changes in the physicochemical properties of the substance VVR 2023 with various possible excipients in different variants of drug production.

[0118] To further plan and optimize process operations and stages, studies of critical parameters of VVR mixtures with excipients were conducted in terms of mixing homogeneity. The time to loss of mixing homogeneity at various temperatures was studied. The results are presented in Table 2.

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] As can be seen from the presented data, liquid semi-finished products are susceptible to stratification, with the rate of stratification increasing at elevated temperatures. Therefore, additional homogenization of semi-finished products during the process is warranted, specifically the use of a dosing device equipped with a stirrer.

[0125] Based on previous studies of the active substance VVR 2023, taking into account its solubility (low solubility) and permeability through biological barriers (bioavailability 33-48%), VVR 2023 was preliminarily assigned to class IV of the biopharmaceutical classification (low solubility and low permeability). It was deemed appropriate to conduct studies to improve the bioavailability characteristics of the active substance in the final dosage form.

[0126] The development of finished dosage forms (FDF) in the form of liquid (SEDDS) and solid (S-SEDDS) self-emulsifying systems, as well as capsules with mucoadhesive granules VVR 2023, was carried out within the framework of the concept of creating delivery systems - such dosage forms in which the entire complex of excipients is an active participant in the process of delivering the active substance to the therapeutic target and maximizes the biopharmaceutical characteristics of the drug.

[0127] Self-emulsifying systems are isotropic mixtures of lyophilic liquid components (SEDDS) or liquid components adsorbed on a solid carrier (S-SEDDS), which spontaneously form micro- and nanoemulsions upon interaction with an aqueous medium and slight shaking. These conditions fully correspond to the lumen of the gastrointestinal tract; peristaltic contractions of the gastrointestinal smooth muscles provide the necessary external influence, initiating the formation of micro- and nanoemulsions. Thus, the lipophilic component passes into a state optimal for its absorption (lipophilic fraction droplet size 0.1-5 μm). The co-solvent included in SEDDS and S-SEDDS further facilitates paracellular transport and also promotes more complete absorption, thereby increasing the bioavailability of the lipophilic active substance.

[0128] The mucoadhesive properties of some polymers ensure longer contact of the granules with the active substance with the mucous membrane of the small intestine without irritation of the contact site, which promotes more complete absorption and increased bioavailability.

[0129] Thus, all of the above approaches to the development of a final dosage form with VVR 2023 potentially contribute to a significant increase in the bioavailability of drugs and make it possible to partially mitigate the limitations associated with the low solubility and permeability of the active substance.

[0130] To confirm these hypotheses, the formation modes of microemulsions and droplet sizes were studied. Self-emulsifying systems were placed in thermostatted containers, a buffer solution simulating the lumenal environment of the gastrointestinal tract was added, and the systems were subjected to rhythmic shaking at low amplitude. Spontaneous formation of a microemulsion was observed, stable upon shaking and undergoing coacervation followed by separation of the lipophilic and aqueous phases at rest. The results of the droplet size study are presented in Table 3 and Fig. 2.

[0131] Fig. 2 illustrates a micrograph of lipophilic phase droplets (SEDDS 1).

[0132]

[0133] Thus, it can be stated that under conditions close to the conditions of the gastrointestinal tract, self-emulsifying systems exist in the form of microemulsions with a droplet size optimal for absorption.

[0134] To confirm the quality and applicability of the developed pharmaceutical dosage forms, disintegration and dissolution tests were conducted. The disintegration test was conducted under conditions compliant with the requirements of the Pharmacopoeia Monograph, in a 0.1 M hydrochloric acid solution. For all capsules, loss of capsule integrity was observed within 0.5-2 minutes of the test start, with complete disintegration of the dosage form occurring no later than 7 minutes after the start of the test.

[0135] The dissolution test was conducted according to the adapted OFS method using a paddle stirrer. The stirrer speed was 100 rpm, and the volume of the dissolution medium was 500 ml. The dissolution medium for the dissolution test was selected empirically, taking into account the solubility of the active ingredient and excipients. A 0.1 M hydrochloric acid medium with 0.2% Tween 80 as a surfactant was used. Samples were collected at 5, 10, and 20 minutes from the start of the test. The results of the quantitative determination of VVR 2023 are presented in Table 4.

[0136]

[0137] These data confirm the almost complete dissolution of the obtained solid dosage forms within 5 minutes of the test.

[0138] In vitro biopharmaceutical studies were also conducted to examine the dynamics of VVR 2023 permeation through a semipermeable membrane. An uncoated cellophane film with an area of ​​0.785 cm was used as the dialysis semipermeable membrane. 2 The capsule was placed in a 0.1 M hydrochloric acid solution supplemented with 0.2% Tween 80; the receiving medium consisted of purified water supplemented with 0.2% Tween 80. Quantitative determination of VVR 2023 in the receiving medium was performed after 5, 15, 25, 40, 50, 70, 90, and 120 minutes from the start of the experiment. The results of the study are presented in Table 5.

[0139]

[0140]

[0141] As can be seen from the presented data, the SEDDS composition demonstrated the greatest penetration through the semipermeable membrane (78.5% after 120 minutes), the active substance was released from the capsules most rapidly and penetrated through the membrane as part of the emulsion (20.0% after 15 minutes).

[0142] Example 4. Study of the pharmacokinetics of BVR2023 with intragastric administration of gelatin capsules at a dose of 1 and 2 mg

[0143] Hard gelatin capsules were administered to rabbits intragastrically using a tube. The animals were deprived of food for 12 hours before drug administration; access to drinking water was not limited. During the experiment, blood was collected from the marginal vein of the ear. For this purpose, peripheral venous catheters (22G 0.7×19 mm) were installed in the animals in advance. Blood was collected after the last intragastric administration of the drug at the following time points: 0.034; 0.084, 0.17, 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 12 and 24 hours. Individual curves of the concentration dependence of BBP2023 capsules for variant 2 on time are presented in Table 6.

[0144]

[0145]

[0146]

[0147]

[0148] The pharmacokinetic parameters of VVR2023 in rabbit blood plasma after a single intragastric administration of capsules containing VVR2023 at a dose of 2 mg are shown in Table 7.

[0149] The concentrations of the metabolite BVR2023 A in the blood plasma samples of rabbits after repeated intragastric administration of the APS BVR2023 in the form of capsules of variant 7 at a dose of 1 mg are given in Table 8.

[0150] Example 5. Results of a pharmacodynamic study with intragastric administration of gelatin capsules

[0151] The study was conducted on 6 Soviet Chinchilla rabbits weighing 3.0-3.2 kg using a crossover design. In the first period, three rabbits were administered a single intragastric administration of a gelatin capsule containing an oil solution of VVR2023 at a dose of 2 mg, while the other three rabbits were given a single intragastric administration of a 2 mg molsidomine tablet (Sopharma JSC, Bulgaria). After a 2-week plasma clearance period, the animals were swapped: the first subgroup was administered a molsidomine tablet (2 mg) intragastrically, while the second subgroup received a capsule containing VVR2023 at a dose of 2 mg according to variant 14 and at a dose of 1 mg according to variant 1.

[0152] Blood pressure was determined invasively using an Angioton-bK tonometer (Biosoft-M LLC, Russia) in the right common carotid artery for 1 hour after administration of the comparison drugs. Before inserting a catheter into the common carotid artery, the rabbits were anesthetized subcutaneously with 0.4 ml of the combined injection anesthetic Zoletil 100 (Virbac, France).

[0153] The systolic blood pressure measurement results are shown in Table 9.

[0154] The effect of VVR2023 on heart rate and basilar artery diameter was also assessed. Basilar artery diameter significantly increased compared to baseline values. However, there was no significant increase in heart rate or decrease in blood pressure in the central auricular artery. Therefore, the drug does not have a significant effect on systemic hemodynamics, and therefore, it is more suitable as a cerebral vasodilator compared to other sydnonimines, such as molsidomine.

[0155]

[0156] Based on the results of the study, the mechanism of action of the proposed medicinal product has been confirmed. It involves the release of NO, followed by the activation of guanylate cyclase and the accumulation of cGMP in nerve tissue. The presence of a lipophilic fragment in the molecule's structure significantly prolongs the vasodilatory effect due to its slow elimination from brain tissue.

[0157] Thus, the claimed invention is new, since the totality of its essential features is not known from the prior art.

[0158] The information provided in the description allows a specialist to implement the invention using the specified means and methods, and the described advantages of the invention are manifested objectively and do not clearly follow from the prior art.

Claims

1. A medicinal product for the treatment of cerebrovascular pathology in the form of hard capsules, characterized in that it consists of a gelatin or vegetable shell and an encapsulate enclosed therein, containing N-(ethoxycarbonyl)-3-(4-methylhexan-2-yl)sydnonimine as the active substance in an amount of 1-2 mg, and as auxiliary substances - substances selected from the group: a solvent and / or filler, a co-solvent, an adsorbent, an emulsifier, a stabilizer, or mixtures thereof, with a total content of auxiliary substances of 170-270 mg.

2. The medicinal product according to claim 1, wherein the solvent and / or filler is a vegetable oil selected from sunflower, olive, peach, apricot, almond, castor, long and / or medium chain triglycerides (MCT and LCT); silicone fluid; polyethylene glycol; polyethylene oxide; sucragel or sodium alginate.

3. The medicinal product according to claim 1 or 2, wherein the co-solvent is polyethylene glycol; diethylene glycol monoethyl ether; propylene glycol; propylene glycol dicaprylate / dicaprate; glycerol mono- and distearate, or glycofurol.

4. The medicinal product according to claim 1 or 2, wherein the emulsifier is polysorbate; polysorbate ester; polyglycerol ether; sodium lauryl sulfate; sodium alkylbenzenesulfonate; proxanol-228 or poloxamer 407.

5. The medicinal product according to claim 1, wherein the adsorbent is colloidal silicon dioxide; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), cellulose derivatives or polyethylene glycol (PEG).

6. The medicinal product according to claim 1, wherein the stabilizer is tocopherol or its derivatives; propyl gallate; ascorbyl palmitate or phospholipids.

Images