Pharmaceutical composition in solid form with analgesic activity

FIELD: chemistry.

SUBSTANCE: as active component pharmaceutical composition contains dihydrochloride of 9-(2-morpholine ethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidasol, and as additional substances - fillers, binding, sliding and film coatings, in quantities, given in the invention formula. Composition can be made in form of solid medication form, mainly in form of tablets and capsules.

EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

 

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

Despite widening the search for alternative routes of administration and methods of drug delivery, oral route of administration remains the most popular. About 70% of all dosage forms are intended for oral administration, as this method of administration is the most acceptable and convenient for patients. In addition, it is the most studied and developed methods of factory production, used for solid dosage pharmaceutical forms such as tablets and capsules). Solid dosages are cheap to manufacture, they have the best ratio price-quality. The advantages of the pill are: accurate dosing of drugs in the conditions of mass production; long action of the drug substance; sequential absorption of drugs, masking of unpleasant organoleptic properties (taste, odour or colouring properties of medicinal substances through the application of membranes; full mechanization of the manufacturing process, providing high performance, cleanliness and hygiene of the tablets.

The three most common technological schemes� production of tablets: using wet or dry granulation and direct compression.

The predominant method of producing tablets with the use of granulation. Granulation - a set of physical and physico-chemical processes, ensuring the formation of particles of a certain range of sizes, shapes, necessary structures and physical properties. Granulation is carried out with the aim of improving the quality of intermediate and finished products. Granulation can be "wet" and "dry". The first type of granulation is associated with the use of liquid solutions of the excipients; in the dry granulation to aid wetting fluids or don't use, or use them only on one specific preparation material for tableting.

Granulation allows you to adjust the technological properties of the powders of medicinal substances, such as flowability and others. In addition, Corning offers high accuracy the mass of the tablets and dose of a substance, the uniformity of distribution of the active component, which is especially important when receiving tablets of complex composition, reducing the influence of the temperature and humidity of environment on the quality of the tablets, reducing the possibility of dust formation.

Usually a blending operation and uniform wetting of the powder mixture of various granulating solutions combine and spend in one miscible�E. Sometimes the operations of mixing and granulation are combined in a single unit (high-speed mixer - granulator). Mixing is achieved through vigorous enforcement of the circular mixing particles and colliding them with each other. Other structure of the apparatus to align the operations of mixing and granulating - centrifugal mixer - granulator.

Compared to drying in the drying cabinets, which are inefficient and in which the drying duration reaches from 20 to 24 hours, more promising is the drying of the granules to boiling (pseudouridines) layer. The main benefits are: high intensity of the process; reducing the specific energy consumption; the possibility of full automation of the process.

In some cases, if the medicinal substance is decomposed in the presence of water, resort to dry granulation. To this end, the powder is pressed briquettes, which are then milled, yielding grains. After elimination from dust grains tableted. Currently under the dry granulation understand method in which a powder material is subjected to initial compaction (pressing) to obtain a granulate, which is then tableted - secondary seal. At initial condensation in weight enter dry adhesive substance, providing under pressure�amount of force coupling of the hydrophilic particles, and hydrophobic substances. Proven suitability for dry granulation of polyethylene oxide (PEO) in combination with starch and talc.

The technology of direct compression of tablets consists in mixing drugs with the required amount of excipients and compression on tabletting presses [Daragan A. G. Physics tableting and basic technological processes of manufacture of tablets / A. Daragan // Chemical and pharmaceutical industry: review, inform. / Cbti Minmedia. 1983. - Vol. 10. - 25 p.]. The most obvious advantage of direct compression over traditional wet granulation - efficiency is achieved by reducing the cost of equipment and production. However, the application of this method is possible due to the physico-chemical properties of substances, not all medicinal substances.

Most formulations of solid dosage forms (70-80%) is characterized by containing a larger amount of auxiliary ingredients than drugs. Due to the fact that most drugs have low flowability and poor physical-mechanical characteristics, the composition of the tablet and encapsulated masses to obtain the necessary rheological and technological properties introduced a variety of vspomogatelnymi. Excipients are not indifferent formers, and have a complex, multifaceted impact on the drug, its pharmacokinetics and, ultimately, therapeutic efficiency of a drug.

In the production of tablets and capsules with a wide range of excipients. For a correct choice of the formulation is necessary to know the properties of the substance the drug substance: flowability, compressibility, gliding ability, you also need to know whether the material is toxic, irritant, explosive, as it affects the moisture, heat, light, air, pressure, as it acts on the punches and dies [Gureeva S. N. Optimization of industrial production of tablets with a polymer shell containing insoluble and colored substances: author. dis. Cand. pharmaceutical. science / S. N. Gureeva. Kharkov, 1991. - 21 p.].

Based on the above research and informed choice of auxiliary substances, in each particular case is one of the important conditions for obtaining oral administration of drugs with therapeutic activity at the lowest dosages and side effects.

Known analgesics with large receptor selectivity and minimal morphine side effects - drugs mixed type of action and�unity-antagonists of opioid receptors. The pharmacology of these drugs is complex. Synthetic derivatives of phenanthrene (nalbuphine, buprenorphine) and morphinone (butorphanol) are agonists-antagonists, opioid analgesics mixed type of action with affinity to mu-, Delta - and Kappa subtypes of opioid receptors. Numerous pharmacological studies, work on ligand-receptor binding has led to the conclusion that nalbuphine acts as agonist and partial mu-antagonist, buprenorphine is a partial mu agonist and Kappa antagonist-opioid receptors, butorphanol is a partial agonist of the mu, agonist of Kappa-opioid receptors, and also has properties the Delta antagonist (Redkin A. N., Bunyatyan A. A., Nasonov E. L., Nikoda V. V., 2004).

Drugs mixed type of action (nalbuphine, buprenorphine, and butorphanol) have found limited use as anesthetics in the practice of medicine. Synthesized agonists-antagonists, a number of indicators significantly superior to traditional opiates, have kept most of the negative properties, and, above all, their narkogennost that was the basis of introducing them to the list of psychotropic drugs, which turn in the Russian Federation is limited.

Closest in execution dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazole is representative�yeol structural class of substances with a Kappa-receptor profile of pharmacological activity, that is, without effect on mu - and Delta-opioid receptors, and therefore, no narcotic potential (patent for invention of the Russian Federation No. 2413512, IPC AC 31/4188, 2011).

The task of the invention is to provide pharmaceutical compositions for oral administration with a Kappa-opioid agonist activity, i.e. with no effect on mu - and Delta-opioid receptors.

The technical result is a pharmaceutical composition in solid form with a Kappa-opioid agonist activity, exhibiting analgesic effect.

The technical result is achieved by a pharmaceutical composition, characterized by containing as an active beginning dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazole as excipients filler that provides adequate mass of solid dosage forms, represents at least one substance selected from the group: microcrystalline cellulose, lactose, calcium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate dehydrate, calcium sulfate dehydrate, calcium carbonate basic, polyvinylpyrrolidone derivatives; dextrin, amylopectin, ultra-amylopectin, sorbitol, mannitol, pectin, basic magnesium carbonate, magnesium oxide, gelatin, methylcellulose (MC), pregelatinization starch, ludipress, potatoes�th and corn starch carboxymethylcellulose, hydroxypropylmethyl cellulose, excipients with high sorption capacity: colloidal silica (Aerosil, Syloid®), alumosilicate magnesium (Neusilin®, Fuji, Japan), a moving substance, and optionally a binding agent, the strength of granules and tablets, represents at least one substance selected from the group: purified water, ethyl alcohol, starch paste, sugar syrup, solution of carboxymethyl cellulose (CMC), oxyethilcellulose (CECS), oksipropilmetiltselljulozy (OPMC); polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, methylcellulose, hydroxypropylmethylcellulose, starch is preferably used potato and/or corn or starch brand Starch-1500, and film coating, with the following ratio of components, wt. %:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1 and 99.4
fillerof 0.5 to 99.8
moving substance0,1-3,0
the binding agent 60.0
film coatingto 15.0

Pharmaceutical composition in a particular case may contain components when following their ratio, wt. % /part 1/:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazoleof 0.1 to 99.3
the binding agent0,1-60,0
filler0,5-99,7
moving substance0,1-3,0

Pharmaceutical composition in a particular case may contain components when following their ratio, wt. % /part 2/:

dihydrochloride-9-morpholinoethyl-
2(4-fluorophenyl)imidazo[1,2-α]benzimidazolof 0.1 to 99.3
filler0,5-99,7
moving substance0,1-3,0
film coating0.1 to 1.0

Pharmaceutical composition in a particular case may contain components at the following ratio /composition 3/ wt. %:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1-99,2
the binding agent0,1-0,0
filler0,5-99,6
moving substance0,1-3,0
film coating0,1-15,0

Pharmaceutical composition in a particular case may contain components when following their ratio, wt. % /part 4/:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1 and 99.4
fillerof 0.5 to 99.8
moving substance0,1-3,0

As moving excipients that prevent cash�the Panyu and ensuring the ejection from the matrix the composition may contain at least one substance selected from the group: stearic acid and/or its salts, for example magnesium stearate, Aerosil.

In the film coating composition can include one or a mixture of the following excipients: polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethylcellulose and hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose (é YellowT, Colorcon Corp.), oksipropilmetiltselljulozy phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methylcellulose phthalate, copolymer of methacrylic acid or methyl esters of methacrylic acid (Eudragit R, Acrylic-out), Calicut® MAE 100 P, Collicut® MAE 30 D, Collicut® MAE 100 D, ethyl cellulose, cellulose acetate, copolymers of polyvinyl alcohol and maleic anhydride, polyethylene glycol (polyethylene glycol 6000), triethylcitrate, diethyl, propylene glycol, glycerin, butylphthalate, titanium dioxide and dyes, iron oxide, aluminum dyes.

The pharmaceutical composition is made in solid dosage form, preferably in the form of tablets or capsules. Tablet or capsule mass produced by wet granulation, by dry granulation or by direct compression.

To ensure the long shelf life of the proposed compositions is important that the resulting �ranula had humidity, not to exceed 3% and preferably not more than 2%.

The drying process is carried out in the chute dryer, or drying in a fluidized bed, the latter is preferable. Drying is usually carried out at a temperature of about 40°C and a relative humidity of less than 50%.

The resulting particles are then mixed with other excipients, for example binders, lubricants, etc. of the present composition obtained by any of the above methods, formed into any dosage form using known in the field of technologies and methods, for example by tabletting, by incorporating in a gelatin capsule, etc. of the proposed compositions are manufactured dosage forms by known methods of ensuring uniform doses of the inventive compounds for oral administration, for example 50 mg, 100 mg, 200 mg, 300 mg, etc. in the form of capsules, tablets and the like.

Received a tablet or capsule dosage form must be protected during storage from external factors (heat or light, and moisture). In order to ensure a specific positive effect on dosage form can be applied film coating.

Film coating of dosage forms using aqueous film-forming composition should be maintained�ü when the temperature of the cores of the tablets from 30 to 50°C, the inlet temperature of 50-80°C and a relative humidity of less than 50%.

The coating applied to the dosage form to increase its weight by about 1-15, preferably 8-10 wt. %.

Film coating can be applied well-known ways: by immersion in a solution of film-forming substance, the formation of layers in the respective perforated drum, the coating in fluidized bed. Stop applying a film coating on reaching the required weight pills. Drum with side ventilation provides high speed of evaporation of the solvent, whereby the coating of tablets used in pharmaceutical technology film coating is carried out in a relatively short time. Filing in one direction of the spray environment and prepared warm air, and the reduction of turbulence in the drum to minimise drying of the sprayed material, providing the coating efficiency is more than 95%. The mass gain of the coated tablets may be in the range of 1 to 15%.

Film-coated tablets or capsules have a time release of about 10 to 30 minutes. Tablets or capsules with enteric coating have the time release is usually from 30 minutes to 6 hours.

As the film former in the manufacture of tablets you can apply Opadry II (�hypromellose, lactose monohydrate, Polydextrose, macrogol, titanium dioxide, iron oxide yellow, iron oxide red). Coating resistant to gastric juice, it is possible to apply aqueous suspension, for example, Acrylic -, or Collicut® MAE 100 P, or Collicut® MAE 30 D.

Capsules and tablets obtained from the proposed pharmaceutical compositions having the requisite stability during storage.

The following examples illustrate two ways of obtaining pharmaceutical compositions.

Example 1. A composition of composition 1 by wet granulation with subsequent tableting

4,32 g of the dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (15 wt. %), 22,59 g of lactose (80,45 wt. %) /filler/ and 0.8 g of microcrystalline cellulose (2.85 wt. %) /filler/ mixed in the mixer. Moisturize the weight of a 5.0% solution of PVP in an amount (calculated on the pure substance) 0.2 g (0.7 wt. %) /binder/. The moistened mass is subjected to wet granulation. The wet granulate is dried in an oven for 2-3 hours at a temperature of 40± 5°C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of the milled granules in a granulator with a hole diameter of the mesh of 1.0-1.5 mm. the dry Weight of the granules dusted with magnesium stearate (1 wt. %) /moving/ in the amount of 0.28 g Flowability obtained�Oh the tablet weight was system 6.34 g/s.

The granulate is compressed into tablets. Tabletting produced on a rotary press of the firm "Killian" with oblong punches. Average weight of tablets in the production process had a value at a dose of 10 mg, 0,115 g. the Value of compressive strength obtained tablets, which was determined on the device type TV-24 company Erweka (Germany), was 80 N. Strength values of resistance, as defined on friabilator type TAR company Erweka (Germany) accounted for less than 0.5%. The disintegration of tablets, specified on the device "Swinging basket" type VZ-4 firms Erweka (Germany), was in the water no more than 15 minutes at a temperature of 37±2°C. the Test "Dissolution" of the tablets was determined on the device company Erweka (Germany).

Visual examination of the surface of the obtained tablets are smooth and uniform, pills do not crumble. The tablets obtained have an average mass of 0.07 g, disintegration is 7-10 minutes. The tablets obtained meet the requirements of the State Pharmacopoeia.

Example 2. A composition of composition 1 by wet granulation with subsequent encapsulation process

10.0 g of the dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α] benzimidazol (8.7 wt. %), with 98.5 g of lactose (85,65 wt. %) /filler/, 5 g of MCC 102 (4,35 wt. %) /filler/ mixed in the mixer. Moisturize the weight of a 5.0% solution of PVP in an amount (calculated on the pure substance) of 0.04 g (0.4 wt. %) /binder�/. The moistened mass is subjected to wet granulation. The wet granulate is dried in an oven for 2-3 hours at a temperature of 40-50°C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of the milled granules in the granulator company Erweka (Germany) with a pore size of 1.0 to 1.5 mm. the dry Weight of the granules dusted with magnesium stearate /moving/ in the amount of 1.0 g (0.9 wt. %). The obtained granulate enter into a capsule in hard gelatin capsules. The capsules meet the requirements of the State Pharmacopoeia.

Example 3. A composition of composition 1 by wet granulation by drying in a drying oven, followed by tableting

10.0 g of the dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo [1,2-α]benzimidazole (to 9.3 wt. %), 87.0 g of lactose (80,6 wt. %) /filler/ and 5.0 g of microcrystalline cellulose (4,6 wt. %) /filler/ mixed in the mixer. Moisturize the weight of 8.0% starch paste in the amount (calculated on the pure substance) of 5.0 g (4.6 wt. %) /binder/. The wet granulate is dried in an oven for 2-3 hours at a temperature of 40±5°C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of the milled granules in a granulator with a hole diameter of the mesh of 1.0-1.5 mm. the dry Weight of the granules dusted with stearic acid in an amount of 1 g (0,9 �AC. %) /moving/. The flowability of the obtained tablet mass consisted of 7.14 g/s.

The granulate is compressed on a rotary press of the firm "Killian". Visual examination of the surface of the tablets smooth and uniform, pills do not crumble. The tablets obtained have an average mass 0.20 g, disintegration - 5-7 minutes. The tablets obtained meet the requirements of the State Pharmacopoeia.

Example 4. A composition of composition 1 by wet granulation by drying in a drying oven, followed by tableting

10.0 g of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo [1,2-α]benzimidazole (up to 7.7 wt. %), 90,0 g of calcium carbonate core (69,2 wt. %) /filler/, 10.0 g of microcrystalline cellulose (up to 7.7 wt. %) /filler/ and 19.0 g of starch brand Starch-1500 (of 14.6 wt. %) /binder/ mix, then moisten the mixture with purified water, then moistened mass is granulated and dried in a drying oven to a residual moisture content of 2-3%. The dried granules are milled in a mill company Erweka (Germany). Dry granules dusted 1.0 g (0.8 wt. %) of magnesium stearate /moving/. Get pills containing dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.01 g. the resulting solid dosage forms meet the requirements of the State Pharmacopoeia.

Example 5. A composition composition 4 by direct compression with subsequent�brilliant tableting

Obtaining pharmaceutical compositions dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole is carried out by mixing the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazol 50.0 g (5 wt. %), lactose 100 g (10.0 wt. %) /filler/, ludipress 840,0 g (84 wt. %) /filler/ and 10.0 g of magnesium stearate (1 wt. %) /moving/ in the mixer for 10-15 min. the Mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets of 0.20 g Get pills containing dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.01 g, which meets all the requirements of the State Pharmacopoeia.

Similarly, the resulting compositions instead of using lactose as a filler, or microcrystalline cellulose, or calcium phosphate or calcium dihydrogen phosphate, or calcium hydrogen phosphate dihydrate or calcium sulfate dihydrate, or calcium carbonate, basic, or polyvinylpyrrolidone derivatives, or dextrin, or amylopectin, or ultra-amylopectin, or sorbitol, or mannitol, or pectin, or magnesium carbonate basic, or magnesium oxide, or gelatin or methylcellulose (MC), or pregelatinization starch, and instead of ludipress or potato and corn starch carboxymethylcellulose, or hydroxypropylmethylcellulose, or excipients with high sorption capacity: colloidal silica (Aerosil, Syloid®), alumosilicate magnesium (Neusilin®, Fuji, Japan).

Example 6. A composition of structure 1 with drying in a fluidized bed, followed by tableting

Obtaining pharmaceutical compositions on the basis of the dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole is carried out by mixing the components in the ratio, as in example 3, with drying in a fluidized bed. The flowability of the obtained tablet mass is 6.1 g/S. Get pills containing dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo [1,2-α]benzimidazole 0.01 g and a disintegration time of 6-8 min, meets all the requirements of the State Pharmacopoeia.

Example 7. A composition composition 4 dry granulation with subsequent tableting

10.0 g of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (of 6.25 wt. %), 129,0 g of lactose (80,62 wt. %) /filler/ and 20.0 g of microcrystalline cellulose (12.5 wt. %) /filler/ stirred, after which the mixture is briquetted powders on tableting or briquetting press (diameter of briquettes - from 12 mm up to 50 m�). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Dusted potassium stearate 1.0 g (0,63 wt. %) /moving/. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets 0,160 g Get tablets or capsules with a content of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.1 g, meeting all regulatory requirements. The resulting solid dosage forms meet the requirements of the State Pharmacopoeia.

Example 8. A composition composition 3 by direct compression with subsequent tableting and coating film cover

Obtaining the pharmaceutical composition is carried out by mixing the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole of 20.0 g (5 wt. %), lactose 336,0 g (84 wt. %) /filler/ and 4.0 g of stearic acid (1 wt. %) /moving/ in the mixer for 10-15 min. the Mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets of 0.20 g Get pills containing dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.01 g, meeting all regulatory requirements. Getting the tablet core is coated with a film coating Opadry II (polymer, lactose monohydrate, Polydextrose, macrogol, titanium dioxide, iron oxide yellow, iron oxide red) 40,0 g (10 wt. %) /film coating/. The application of membranes is carried out in a known manner (fluidization or drum type) and stop after reaching the required weight pills. The resulting solid dosage forms meet the requirements of the State Pharmacopoeia.

Example 9. A composition of composition 2 wet granulation with subsequent tableting and coating film cover

10.0 g of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (7.0 wt. %), 90,0 g of lactose (62,9 wt. %) /filler/, 10.0 g of microcrystalline cellulose (7.0 wt. %) /filler/ and 19.0 g of starch brand Starch-1500 (13.3 wt. %) /binder/ mix, then moisten the mixture with purified water, then moistened mass is granulated and dried to a residual moisture content of 2-3%. The dried granules are milled in a mill company Erweka (Germany). Dry granules dusted 1.0 g (0.7 wt. %) of magnesium stearate /moving/.

Getting the tablet core is coated with a film coating Collicut MAY D 100 (copolymer of methacrylic acid with acrylate (1:1)) of 13.0 g (9,1 wt. %) /film covered�e/. The resulting solid dosage forms meet the requirements of the State Pharmacopoeia.

Similarly, the obtained composition using a instead of starch brand Starch-1500 as a binder, or ethyl alcohol, or starch paste, or sugar syrup, or solution of carboxymethyl cellulose (CMC), oxyethilcellulose (CECS), oksipropilmetiltselljulozy (OPMC), or polyvinyl alcohol (LAN), or polyvinylpyrrolidone (PVP), or alginic acid or sodium alginate, or gelatin, or methylcellulose, or hydroxypropylmethylcellulose, or potato starch and/or corn, or starch brand Starch-1500.

Example 10. A composition of composition 2 by direct compression with subsequent tableting and coating film cover

Obtaining pharmaceutical compositions dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole is carried out by mixing the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazol 50.0 g (4.5 wt. %), lactose, 100 g (9,1 wt. %) /filler/, ludipress 830,0 g (of 75.5 wt. %) /filler/ and 10.0 g of magnesium stearate (0.9 wt. %) /moving/ in the mixer for 10-15 min. the Mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0 - 1.5 mm. T�platerowanie produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets of 0.22 g Get pills containing dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.01 g, meeting all regulatory requirements. Getting the tablet core is coated with a film coating Opadry II (polymer, lactose monohydrate, Polydextrose, macrogol, titanium dioxide, iron oxide yellow, iron oxide red) 110.0 g (10.0 wt. %) /film coating/. The application of membranes is carried out in a known manner (fluidization or drum type) and stop after reaching the required weight pills. The resulting solid dosage forms meet the requirements of the State Pharmacopoeia.

Example 11. A composition composition 4 dry granulation with subsequent tableting

198,8 g dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (and 99.4 wt. %), 6 g of lactose (0.3 wt. %) and 4 g of microcrystalline cellulose (0.2 wt. %) /filler/ stirred, after which the mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Dusted potassium stearate 2 g (0.1 wt. %) /moving/. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets ,160 g Get tablets or capsules with a content of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0,198 g that meets all regulatory requirements of the State Pharmacopoeia.

Example 12. A composition composition 4 dry granulation with subsequent tableting

0.2 g of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (0.1 wt. %), 160,0 g of lactose (80,0 wt. %) and 39.6 g of microcrystalline cellulose (of 19.8 wt. %) /filler/ stirred, after which the mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Dusted potassium stearate 2 g (0.1 wt. %) /moving/. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets 0,160 g Get tablets or capsules with a content of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.2 mg, which meets all regulatory requirements of the State Pharmacopoeia.

Example 13. A composition composition 4 dry granulation with subsequent tableting

0.2 g of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (0.1 wt. %), 160,0 g of lactose (80,0 wt. %) and 39.2 g of microcrystalline cellulose (to 19.6 wt. %) /filler/ mix�, after which the mixture is briquetted powders on tableting or briquetting press (diameter of briquettes from 12 mm to 50 mm). Obtained pellets breaking open in pellet mill with the dimensions of the mesh openings of 1.0-1.5 mm. Dusted potassium stearate 6 g (0.3 wt. %) /moving/. Tabletting produced on a rotary press of the firm "Killian". The diameter of the punches 8.0 mm, average weight of tablets 0,160 g Get tablets or capsules with a content of the dihydrochloride-9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole 0.2 mg, which meets all regulatory requirements of the State Pharmacopoeia.

Example 14. A composition of composition 1 by wet granulation with subsequent tableting

30,0 g of the dihydrochloride 9-morpholinoethyl-2(4-fluorophenyl)imidazo[1,2-α]benzimidazole (15,0 wt. %), 30,0 g of lactose (15,0 wt. %) /filler/ and 20.0 g of microcrystalline cellulose (10 wt. %) /filler/ mixed in the mixer. Moisten the mass with a solution of PVP in an amount (calculated on the pure substance) 120,0 g (60,0 wt. %) /binder/. The moistened mass is subjected to wet granulation. The wet granulate is dried in an oven for 2-3 hours at a temperature of 40±5°C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of the milled granules in a granulator with a hole diameter of the mesh of 1.0-1.5 mm. the Granulate is compressed into tablets.

P�tablets obtained have an average mass 0,200 g, disintegration is 7-10 minutes. The tablets obtained meet the requirements of the State Pharmacopoeia.

Table 1 shows the indicators of the quality of the obtained tablets.

The PHARMACOKINETIC properties of the COMPOUNDS IN SOLID dosage PHARMACEUTICAL FORM

Research methods the pharmacokinetic properties of the compound

In the process of studying the pharmacokinetic properties of the compounds were used physico-chemical approach to measure biomaterial concentration of the test substance is high-performance liquid chromatography. The experiments were conducted on rabbits breed "Chinchilla" weighing 2-2. 5 kg. Substance and dosage form administered orally. Twelve hours before the experiments, animals were deprived of access to food without water constraints.

Quantitative determination of the studied compounds was performed using high performance liquid chromatography on a computer system Shimadzu (Japan) with UV detector at λ=205 nm analytical column (SUPELCOSIL LC-18 (5 µm; 100 mm×4.6 mm). The mobile phase consisted of acetonitrile (J. T. Baker, USA) and a buffer system consisting of onesemester potassium phosphate 50 mm pH 5.0, at a ratio of 1:1 [Smirnova L. A. Rudenko A. I., The wildfire A. F., Kuznetsov K. A., Suchkov Y. A. // quantification of the compounds RU-1205 in biological samples / Volgograd scientific-medical journal, 2/2012. - S. 15-17].

The dependence of the areas of peaks on the concentration of the studied compounds were analyzed by regression analysis. Statistical processing of the results was performed using the computer program Excel [A. A. Firsov, V. P. Zherdev, etc. / / Methodical recommendations for study of analgesic activity of drugs / guidance on the preclinical testing of drugs under the editorship of V. P. Fisenko. M., 2012. - Pp. 843-851].

The study materials

1. Substance connections dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazol.

2. Solid dosage form obtained in example 10 (composition of tablets: the dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazol - 0,011 g (4.5 wt %); lactose - 0.02 g (9.1 wt %); ludipress - 0,1661 g (of 75.5 wt %); magnesium stearate - 0,002 grams (0.9 wt %), opodry 200f - 0,02 (10.0 wt %)).

In Fig. 1 shows the content of active start (connection) of the above composition obtained in example 10, and substance in the blood of rabbits after oral administration in the dose of 50 mg/kg (per connection) depending on time.

Table 2 shows the pharmacokinetic parameters connected�I in rabbits by oral administration of the substance and the above tablets in the shell at a dose of 50 mg/kg.

Based on these data found that the pharmacokinetic profiles of the substances and solid dosage forms differ in the time of occurrence of maximum concentration in the blood. For dosage forms phase exhibit characteristic absorption and smoother elimination phase (Fig. 1). This is due to the disintegration of the tablet mass in the gastrointestinal tract of animals, further to the dissolution and redistribution in the blood. In the analysis of pharmacokinetic parameters was no statistically significant difference was found between substance and tablet dosage form. The value of area under the curve connection in the form of dosage forms is only slightly higher than the indicator compound in the form of substance. The half-life, mean retention time, clearance, and apparent volume of distribution, characteristic of the substance compound, is higher relative to the dosage form. It was found that for solid dosage pharmaceutical forms for oral administration characterized by high relative bioavailability (table. 2).

Analgesic PROPERTIES of COMPOUNDS IN SOLID dosage PHARMACEUTICAL FORM

Methods study analgesic activity of the compound

The hot plate test [Kitchen I. Assessment of the hot-plate antinociceptive test in mice. 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 to evaluate the Central analgesic mechanism of action and based on the behavioral reactions that are controlled supraspinally structures, in response to the impact of pain [Voronina T. A., Housewatch HP / Methodical recommendations for study of analgesic activity of drugs // guidance on the preclinical testing of drugs / edited by V. P. Fisenko. M., 2012. P. 202]. An experimental study was conducted on mice-males. The investigated compound was administered at a dose of 5 mg/kg Via various time intervals after administration of the studied compounds, the animal was placed on a heated to 55°C copper plate surrounded by a plastic cylinder. Fixed latency of nociceptive response in the form of licking of the hind paws, which appears in animals with the threshold of pain sensitivity [D. le Bars, Μ. Gozariu. Animal models of nociception / D. le Bars, M. Gozariu, S. W. Cadden. //, Pharmacol. Rev. - 2001. Vol. 53 No. 4 - P. 611]. Criterion analgesic effect was considered statistically significant increase in the latent period of reaction after administration of the substance. Statistical data processing was performed using the criteria, Kruskal-Wallis and Mann-Whitney test.

The study materials

1. Substance connections dihydrochloride 9-(2-morpholinoethyl)-2-(4-PIF�phenyl)imidazo[1,2-α]benzimidazol.

2. Solid dosage form composition obtained in example 10 (composition of tablets: the dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo [1,2-α]benzimidazol - 0,011 g (4.5 wt %); lactose - 0.02 g (9.1 wt %); ludipress - 0,1661 g (of 75.5 wt %); magnesium stearate - 0,002 grams (0.9 wt %), opodry 200f - 0,02 (10.0 wt %)).

Table 3 shows the joint effect on the antinociceptive effects in the test "Hot plate" when administered orally at a dose of 5 mg/kg (M±m).

In Fig. 2 shows the duration of the analgesic potency of the compounds when administered orally at a dose of 5 mg/kg in the test "Hot plate".

15 minutes after administration of the substance compounds the pain reaction threshold was statistically significantly increased by 81.8 per cent and reached the maximum effect to 60 minutes. In the study of anaesthetic activity of solid dosages were observed slow increase of analgesic action with the peak maximum effect on the 300 min of the study (table. 3). Duration of action dosage forms was maintained up to 500 minutes (Fig. 2).

By pharmacodynamic effect there was some prolongation and amplification of the anaesthetic activity of solid dosage dosage forms of the studied compounds compared with the substance.

Similar results are obtained for the compositions, p�obtained in examples 1, 5 and 8.

Thus, the proposed pharmaceutical composition can be used as an anaesthetic.

1. Pharmaceutical composition with a Kappa-opioid agonist activity, exhibiting analgesic effect, characterized by containing as an active beginning dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidazole as excipients filler represents at least one substance selected from the group: microcrystalline cellulose, lactose, calcium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate dehydrate, calcium sulfate dehydrate, calcium carbonate basic, polyvinylpyrrolidone derivatives; dextrin, amylopectin, ultra-amylopectin, sorbitol, mannitol, pectin, basic magnesium carbonate, magnesium oxide, gelatin, methylcellulose (MC), pregelatinization starch, ludipress, potato and corn starch, carboxymethyl cellulose, hydroxypropylmethyl cellulose, excipients with high sorption capacity: colloidal silica (Aerosil, Syloid®), alumosilicate magnesium (Neusilin®, Fuji, Japan), a moving substance, and optionally a binding agent that represents at least one substance selected from the group: purified water, ethyl alcohol, starch paste,sugar syrup, a solution of carboxymethyl cellulose (CMC), oxyethilcellulose (CECS), oksipropilmetiltselljulozy (OPMC); polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, methylcellulose, hydroxypropylmethylcellulose, starch is preferably used potato and/or corn or starch brand Starch-1500, and film coating, with the following ratio of components, wt. %:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1 and 99.4
fillerof 0.5 to 99.8
moving substance0,1-3,0
the binding agent60.0
film coatingto 15.0

2. Pharmaceutical composition according to claim 1, characterized in that it contains components when following their ratio, wt. %:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazol�and of 0.1 to 99.3
the binding agent0,1-60,0
filler0,5-99,7
moving substance0,1-3,0

3. Pharmaceutical composition according to claim 1, characterized in that it contains components when following their ratio, wt. %:

dihydrochloride-9-morpholinoethyl-
2(4-fluorophenyl)imidazo[1,2-α]benzimidazoleof 0.1 to 99.3
filler0,5-99,7
moving substance0,1-3,0
film coating0,1-15,0

4. Pharmaceutical composition according to claim 1, characterized in that it contains components when following their ratio, wt. %:

td align="right"> 0,1-60,0
dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1-99,2
the binding agent
filler0,5-99,6
moving substance0,1-3,0
film coating0,1-15,0

5. Pharmaceutical composition according to claim 1, characterized in that it contains components when following their ratio, wt. %:

dihydrochloride 9-(2-morpholinoethyl)-2-(4-fluorophenyl)-
imidazo[1,2-α]benzimidazole0,1 and 99.4
fillerof 0.5 to 99.8
moving substance0,1-3,0

6. Pharmaceutical composition according to claim 1, characterized by the fact that the moving comprises at least one substance selected from the group: stearic acid and/or its salts, for example magnesium stearate, Aerosil.

7. Pharmaceutical composition according to claim 1, characterized in that the film coating contains at least one substance selected from the group: polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethylcellulose and hydroxypropylmethyl�vine (é YellowT, Colorcon Corp.), oksipropilmetiltselljulozy phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methylcellulose phthalate, copolymer of methacrylic acid or methyl esters of methacrylic acid (Eudragit R, Acrylic-out), Calicut® MAE 100 P, Collicut® MAE 30 D, Collicut 100 MAY D, ethylcellulose, cellulose acetate, copolymers of polyvinyl alcohol and maleic anhydride, polyethylene glycol (polyethylene glycol 6000), triethylcitrate, diethyl, propylene glycol, glycerin, butylphthalate, titanium dioxide and dyes, iron oxide, aluminum dyes.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a percutaneously absorbable layer having a base and an adhesive layer which is placed on the base and which comprises an adhesive agent and a therapeutic ingredient. The adhesive agent contains a mixture of resins containing 100 portions by weight of an acrylic copolymer (A) and 0.1 to 30 portions by weight of an acrylic copolymer (B) or 0.05 to 2 portions by weight of a low-molecular polyamine compound having at least two amino groups in one molecule and non-polymerising with a polymer or an oligomer formed. The adhesive layer additionally contains an organic acid. The acrylic copolymer (A) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains 3 to 45 wt % of diacetone acrylamide as a target monomer ingredient, but free from a free carboxylic group. The acrylic copolymer (B) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains a primary amino group and/or carboxyhydrazidase group on side chains, but free from a free carboxylic group.

EFFECT: reducing the aging period of the adhesive layer considerably.

7 cl, 8 tbl, 39 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains hypromellose, boric acid and a consistency base; it additionally contains anesthesin or lidocaine as an analgesic in an amount of 0.00001-0.5 g.

EFFECT: fixing a lubricating agent on the catheter enabling preventing mucosal injuries accompanying a drainage procedure, and eliminating side effects.

3 cl, 6 ex

FIELD: medicine.

SUBSTANCE: anterior chamber anaesthesia and pupil dilatation accompanying anterior eye segment surgeries experimentally involve a preoperative administration of a composition in an amount of 0.1-0.2 ml representing 0.005% 1-(3-pyrrolidinopropyl)-2-phenylimidazo[1,2-a]benzimidazole dihydrochloride into the anterior eye segment. The composition is prepared in 1% viscoelastic solution, visiton PEG.

EFFECT: prolonging anaesthetic effect and pupil dilatation with no mydriatics used.

2 ex

FIELD: veterinary medicine.

SUBSTANCE: intramesovarian blockade of ovarian and cranial uterine nerves is carried out by laparotomy and administration in the mesovarium of 0.5-1% solution of novocaine or lidocaine. Blockade is carried out by inserting the needle of the syringe into the mesovarium in the vicinity of the ovarian bursa and uterine horn at an acute angle to the surface of the ovarian mesenterium to a depth of 3-4 cm. At that 3 ml of anaesthetic is administered to small breeds of dogs and fur-bearing animals, and from 3 to 9 ml of anaesthetic is administered to large and giant breeds of dogs as from one and from the opposite side of the body.

EFFECT: effective implementation of intramesovarian blockade by taking into account the anatomical and the breed features of the animal category.

1 tbl

FIELD: medicine.

SUBSTANCE: patient is laid on his/her side opposite a block region. A guide mark is a vertical line in a projection of Petit's triangle from the twelfth rib to a wing of ilium. A needle is pricked into the skin on the vertical line at 1.5-2.5cm above the wing of ilium. 0.25% Novocaine is administered in layers into the skin and subcutaneous fat. The needle is advanced into the lumbar region from back to front in the medial direction along the lateral edge of broadest muscle of back at 6-8cm. Novocaine 120ml is administered into the lower order of the lumboiliac fossa formed in this region.

EFFECT: effective and safe pain management in the given category of patients by providing the required Novocaine concentration in the retroperitoneal space.

1 dwg, 1 ex

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: radionuclide indicator is administered to record the dynamics of its distribution in limb tissues by a radionuclide method. The examination is performed at rest and during a load test. The load test represents an epidural block by gradual administration of bupivacaine 25-30 mg between L2-L3 vertebrae for 5-7 minutes. That is followed by measuring a blood flow as a percentage of its value to the same level in an analogous segment of a collateral limb.

EFFECT: qualitative assessment of the circulation reserve in various categories of patients, including disabled ones by inhibiting sympathetic and minimally sensory activity with maintaining the patients' motor activity.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to abdominal surgery and anaesthesiology, and can be used where it is necessary to anaesthetise after the prosthetic hernioplasty for median postoperative ventral hernias. That is ensured by placing an endoprosthesis under the aponeurosis, a polyvinylchloride catheter is placed into the formed spaced around the periphery of a postoperative wound in the form of an oval above the endoprosthesis plane at 2.5-3 cm from its edges. Along its full length, the catheter has multiple side holes. Single openings are created in a projection of a lower corner of the wound, and the catheter ends are brought out onto the skin. An inlet of the catheter is attached to a local anaesthetic dosage device by means of a cannula. That is followed by a controlled prolonged irrigation with 2.5% Ropivacaine 20 ml every 6-8 hours during 2-3 days.

EFFECT: method enables the adequate postoperative anaesthesia, as well as the length of the postoperative intestinal distention by providing the uniform controlled administration of the local anaesthesia solution.

7 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to anaesthesiology and surgery, and can be used in case of anaesthesia necessity in patients after herniorrhaphy with inguinal access in case of inguinal hernias. For this purpose after the main stage of operation - hernioplasty, before suturing of the aponeurosis of the external oblique abdominal muscle, through subcutaneous adipose cellular tissue a puncture of 1 cm more medially and 1 cm higher than the anterior-superior iliac spine is made. A multiperforated catheter is introduced through the puncture under finger and visual control in such a way that its distal end is near the pubic tubercle. The catheter is placed under the aponeurosis of the external oblique abdominal muscle in the inguinal canal above and parallel to the spermatic cord in men or the round ligament of uterus in women. All the side holes of the catheter must be located in the subaponeurotic space. The first 48 hours of the post-operation period the local anaesthetic is continuously introduced by drop infusion at a rate of 2-4 ml/h or by bolus introduction in a dose of 10 ml each 4-6 hours through the catheter. After 48 hours the catheter is removed.

EFFECT: method provides adequate anaesthesia in the said category of patients in the post-operation period without application of additional anaesthetic preparations due to blockade of ilioinguinal, ilioceliac and hollow branch of genitofemoral nerves.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and may be used in treating the patients suffering headaches and facial pains. There are presented versions of a drug delivery device comprising an injector a first end of which is left outside patient's nasal passages. Another end of the injector comprises one or more holes for spraying a drug upwards, and/or to the side, and/or to the front towards a sphenopalatine ganglion, an input device interacting with a patient's nostril and comprising a canal for receiving the injector. Additionally, the device can comprise a handle connected to the input device and provided for receiving the canal of the input device. The injector can move between a storage position before the interaction, and an interaction position related to the interaction. There are also presented versions of the method of using the above device that involve introducing the injector through the nasal passage into median and/or posterior and/or inferior region in relation to the patient's sphenopalatine ganglion, and spraying the drug.

EFFECT: group of inventions provides faster and more effective headache and facial pain relief by safe and accurate drug delivery of the therapeutic substances blocking the sphenopalatine ganglion.

49 cl, 4 dwg, 30 ex

FIELD: medicine.

SUBSTANCE: at the initial stage of the intraoperative period, immediately before the local anaesthesia and the femoral artery puncture, ketorolac tromethamine is administered intravenously as an analgesic, and propofol as a sedative agent. Ketorolac tromethamine is administered in a dose of 15-75 mg, while propofol is administered in a dose of 50-250 mg.

EFFECT: method prevents developing pain and psychoemotional responses caused by the given interventions, including postoperatively by the fast development of the adequate analgesic effect accompanied by the controlled sedation level.

1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to benzimidazole derivatives of general formula (I) and to their pharmaceutically acceptable salts, mixed stereoisomers and enantiomers, wherein R1 is L1C(O)OL2C(O)OT; R2 is unsubstituted C1-C10alkyl; L1 is a bond; L2 is unsubstituted C2-C10alkylene; T is C1-C10alkyl. Also, the invention refers to a pharmaceutical composition of the compound of formula (I) and a method of anaesthetising on the basis of using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective as an anaesthetising agent.

15 cl, 9 dwg, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely to (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxol-7,3'-indole]-2'(1'H)-one of formula (I), and a method for preparing it which is effective for treating diseases and conditions, such as pain, an intensity of which can be reduced or relieved by modulating potential-dependent sodium channel gatings.

EFFECT: invention refers to the pharmaceutical composition of the above compound, methods of treating and a method of relieving an ion flux through the potassium channel gating in a cell.

10 cl, 5 tbl, 6 dwg, 11 ex

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: what is involved is infusion therapy with crystalloid solutions at 15 ml/kg of a patient's body weight. That is followed by puncturing and catheterising an epidural space at the level of ThVII-ThVIII according to the standard practice and introducing a test dose of 2% lidocaine 3 ml. If observing no signs of intrathecal introduction of local anaesthetics 10 minutes later, a basic dose containing 0.75-1% naropin 10 ml or 0.25-0.5% marcaine 10 ml and clofelin 3-5 mcg/kg is introduced. Total intravenous anaesthesia follows 20 minutes after pre-medication with atropine 0.01 mg/kg, 1% diphenylhydramine 1 ml and relanium 10 mg and urethral catheterisation. A narcosis is induced with propofol in a dose of 2 mg/kg. Anaesthesia is maintained with propofol 2-4 mg/kg·h. After that, within the first hour following the detoxification, naloxone 12 mg is introduced intravenously; a naloxone measurement rate is supposed to make 0.8 mg/h for 4-5 following hours of general anaesthesia. The repeated introduction of 0.75-1% naropin 6 ml or 0.25-0.5% marcaine 6 ml and clofelin 2-3 mcg/kg into the epidural space is performed 90 minutes later. After the procedure is terminated, and the patient recovers, prolonged epidural analgesia is conducted by introducing 0.2% naropin 10 ml and clofelin 1 mcg/kg into the epidural space every 4 hours for 24-48 hours.

EFFECT: method provides safety of ultrafast opioid detoxification and prolongs the remission in the given category of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to anaesthesiology and resuscitation, and may be used in epidural anaesthesia. That is ensured by administering slowly intravenously a basic dose of the local anaesthetic: 0.2-1% naropin or 0.2-0.5% marcaine, or 1-2% lidocaine; 1% Sol. Nicotini acidi 1% - 0.5-1 ml into the epidural space 10-20 minutes later. After 5-10 minutes, nicotine test results are visually evaluated by determining a clear interface of skin colour - hyperemic and normal - along an axillary line from both sides. The normal skin interface corresponds to the sympathetic block.

EFFECT: method provides higher accuracy and simplification of measuring the sympathetic block.

1 ex

FIELD: medicine.

SUBSTANCE: thoracic epidural analgesia is conducted by puncturing and catheterisation of an epidural space at ThVIII - ThIX before the expiry of 24 hours from the onset of a disease after a moderate intravenous infusion therapy in the amount of 15-20 mg/kg of crystalloid solutions. 20 minutes before an expected endoscopic papillosphincterotomy, a catheter is moved 4-5 cm in a cranial direction. At ThV-ThX, 0.4% naropin 10-12 ml or 0.2% Marcaine 10-12 ml and clonidine 100 mcg are administered through a catheter. That is followed by a pre-medication by administering 0.1% atropine 0.5-1 ml and 0.5% relanium 1-2 ml. Thereafter, the patient is taken to an X-ray operation room to conduct the endoscopic papillosphincterotomy without an endoscopic retrograde cholangiopancreatography with general pancreatic duct stenting. After the operation has been completed, the patient is taken to an intensive care unit wherein an extended epidural analgesia is conducted by administering 0.2% naropin 10-12 ml or 0.15% marcaine 10-12 ml into the epidural space every 4 hours until the patient is taken to a department of surgery.

EFFECT: early intestinal motility recovery, increased pancreatic secretion, prevented spasm of the gastrointestinal sphincter ensured by a pathological complete blockade of sympathetic impulsing.

1 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and can be used in need of the delivery of therapeutic compositions for local application, including for local analgesic therapy. That is ensured by a system comprising a container having a first chamber with a therapeutic composition for local application with at least one active ingredient, and a second chamber containing a coating composition. The composition for local application and the coating composition is dispensed through a valve and supplied through one nozzle gradually. The delivery can be also gradual by dispensing the composition for local application by pressing a first release button, while the coating composition is dispensed from the system by pressing a second release button.

EFFECT: invention provides the most convenient delivery of the therapeutic compositions ensured by the gradual release of the two compositions having different consistence through the same nozzle.

22 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to paediatric anaesthesiology, and may be used for executing the surgical operations of neck and head cancers in children. A pre-operative Kerdo index is determined. If observing an initial sympathicotonia, the anaesthesia is induced by sevoflurane inhalations and potentiated by administration of 1% propofol to be followed by sevoflurane inhalations.

EFFECT: method enables optimising the course of anaesthesia, achieving the normotonic sympathovagal balance and providing the haemodynamic stability by taking into account the individual vegetative response, as well as the separate and sequential administration of propofol and sevoflurane.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to anaesthesiology, and may be used as an anaesthesia care of a surgical intervention for carotid endaterectomy or internal carotid artery resection after pathological deformation thereof. That is ensured by general anaesthesia in a combination with deep and superficial cervical plexus blockade. Pre-medication is used the day before the operation and on the operative day in the morning. Diazepam is introduced intramuscularly 30 minutes before the operation in a combination with phentanyl; the introduction is followed by ECG monitoring and heart rate count, plethysmography with arterial blood saturation, non-invasive blood pressure measurement and neuromonitring according to a bispectral index or entropy. Catheterisation of patient's peripheral or central vein is followed by an infusion therapy, an ionotropic therapy, a cardiotropic therapy, peripheral resistance maintenance. If heart rate is no more than 80 beats per minute, the anaesthesia is induced to reach an anaesthetic depth according to the bispectral index or entropy within 40-60 units. Analgesia is provided by the intravenous introduction of 0.005% phentanyl; myoplegia is ensured by the intravenous introduction of a myorelaxant. After tracheal intubation, the patient is transferred to forced volumentic artificial pulmonary ventilation with the CO2 level within 35-45 mm Hg according to capnography. The anaesthesia is maintained by supplying an inhalation anaesthetic to the steam level of 0.8-1.0 MAK 0.8-0.9 litre of the air and oxygen flow containing 50% oxygen with controlling the inhalation anaesthetic volume by the level of the anaesthetic depth according to the bispectral index or entropy. That is followed by deep cervical plexus blockade. A tubercle of the VI cervical vertebra (a carotid tubercle) and a mastoid process are localised; thereafter a line connecting the above reference points is drawn on skin. The second line is drawn 1 cm below the first one in parallel. To verify an injection point of a local anaesthetic, the spines of IV, III, II cervical vertebras being at 1.5 cm from each other are palpated, and the reference point is the VI cervical vertebra. The needle is inserted perpendicularly to the skin and slightly in the caudal direction to reach the spines. The anaesthetic is introduced in a dose of 5-7 ml in each point C4, C3, C2. Another 5-7 ml of the anaesthetic is introduced in a point found in an apex of the mastoid process. The superficial cervical plexus blockade requires introducing he fan-shaped introduction of the anaesthetic solution in a dose of 15 ml in a point found in the middle of a lateral crus of the nodding muscle under the above muscle, 4-5 ml in each direction from the same point; the first and following injections are performed at a depth of a usual intramuscular needle perpendicularly to nodding muscle.

EFFECT: method provides the adequate and safe anaesthesia ensured by avoiding linear blood velocity reduction in the medial cerebral artery during the surgical intervention, preventing intracranial pressure increase, reducing cerebral perfusion pressure in a combination with providing adequate protection against surgical invasion with maintaining stroke volume and arterial pressure.

4 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, namely to manufacturing drug preparations for treating allergic diseases, such as allergic rhinitis and urticaria. According to the first version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including citric acid, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, lactose, magnesium stearate, and talc. According to the second version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including Pearlitol 100SD-Mannitol, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, magnesium stearate, and talc. According to the third version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, colloidal silicone dioxide, and sodium sodium stearyl fumarate. According to the fourth version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, Pearlitol 100SD-Mannitol, magnesium stearate, and talc. The pharmaceutical composition is presented in the form of a film-coated tablet.

EFFECT: pharmaceutical composition according to the invention is storage-stable and releases the active substance quickly in the gastrointestinal tract.

10 cl, 9 tbl, 20 ex

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