Pharmaceutical composition containing sildenafil citrate, and method of using it

FIELD: medicine.

SUBSTANCE: invention refers to a new pharmaceutical composition in the form of spray for oral administration, containing an aqueous solution of sildenafil citrate as an active substance in the amount of 3-30 wt %. The composition contains stabilising agents in the form of pharmaceutically acceptable calcium salts taken in an amount required to reduce pH to 3.0 to 6.0. The calcium salts are specified in a group consisting of calcium lactate pentahydrate, calcium lactate trihydrate, calcium gluconate, calcium malate, calcium glycolate, calcium chloride hexahydrate and calcium chloride dihydrate. What is also described is a method for preparing the composition by introducing the pharmaceutically acceptable calcium salts as the stabilising agents into the aqueous solution of sildenafil citrate.

EFFECT: pharmaceutical composition in the form of oral spray is free from organic solvents and applicably for sexual dysfunction.

13 cl, 8 ex

 

The technical field to which the invention relates.

The invention relates to the pharmaceutical field, in particular to new pharmaceutical compositions in the form of a spray for oral administration, containing an aqueous solution of sildenafil citrate.

The level of technology

Solid oral dosage forms, which are absorbed in the gastrointestinal tract due to extensive first pass metabolism, have a lower bioavailability than, for example, dosage forms that deliver the active substance through the mucous membranes (buccal, sublingual, nasal). For example, a fast-acting medicine that contains sildenafil citrate, in the form of a nasal spray under the trade name Duromist™. Dose Duromist™ 20 mg bioequivalence pill Viagra® 25 mg, the time to reach maximum concentration not significantly different (1,10) and 1.04 hours respectively for Duromist™ and Viagra®), but the dose Duromist™ 20 mg has nearly 100% bioavailability compared to 25 mg tablet Viagra®, for which this value is 40%. [Lu HT, Chen RN Sheu MT and etc. Rarid-onset sildenafil nasal spray carried by microemulsion systems: in vitro evaluation and in vivo pharmacokinetic studies in rabbits. Xenobiotica. - 2011 - 41(7) - 567-77].

For the preparation of dosage forms suitable for buccal, sublingual and nasal application, in particular on the basis of the forces is enafil citrate, it is widely known application of polyvinylpyrrolidone. The composition of the solid composition for sublingual application, presented in the patent WO 0054777, publ. 21.09.2000, polyvinylpyrrolidone is included as a water-dispersible polymer as an agent contributing to the swelling; patent WO 0135926, publ. 25.05.2001, disclosed spray composition for nasal application, which included the polyvinylpyrrolidone is used as a solvent, as an agent of regulating the viscosity. As widespread use of polar solvents, such as propylene glycol (EN 2005109909, publ. 10.10.2006), polyethylene glycol (EN 2009145167, publ. 20.06.2011), ethanol (EN 2003108500, publ. 10.07.2004), etc. Using the above solvents or their mixtures in combination with water in the preparation of liquid dosage forms containing sildenafil, in the form of a solution, emulsion or suspension specified in the application RU 2009131749, publ. 27.02.2011 (WO 2008091855, publ. 31.07.2008).

Application WO 2004019909, publ. 11.03.2004 discloses spraying a composition for buccal application, which includes water propylene glycol or water-glycol and water-ethanol and the target additive (propellant and flavorings); content of active substance, vasodilator sildenafil, in particular, from 0.1 to 25 wt%. But the use of propylene glycol and polyethylene glycol can be nebesa the SNO. Quite often there are cases of contamination of propylene glycol nephro - and hepatotoxic cheap glycols (ethylene glycol and diethylene glycol), which can lead to a fatal outcome. That is, the use of propylene glycol and polyethylene glycol requires costly analysis of each package by GLC. Besides the water-organic concentrated solutions have a high coefficient of volume expansion, which can lead to tightness of the packing when the temperature; and the high viscosity makes it difficult to apply farbkomposition in the form of spray.

In the application EN 2007141868, publ. 20.05.2009 (WO 2006108556, publ. 19.10.2006), serving as a prototype, presents a sterile aqueous liquid composition for administration in the form of aerosol that does not contain propylene-glycol and glycerol, for oral and nasal inhalation. the pH of this composition mainly from 4 to 6, which is an advantage. But replacement of the solvent resulted in a significant decrease in the concentration of the active substance (from 0.001 to 1 wt%), which, in turn, greatly complicates the use of farbkomposition in the form of a spray, as of the effective dose require a large volume to 2 ml and above. Moreover, aqueous solutions with concentrations higher than 0.35% of crystallize at lower temperatures, unsettling the mechanical pump.

Disclosed is s inventions

The aim of the present invention was to obtain the composition of the liquid pharmaceutical composition (JFK), devoid of organic solvents, containing an aqueous solution of sildenafil citrate, with an acceptable pH value of not lower than 3, with the concentration of the active substance to 30 wt.%.

The problem was solved by the introduction of JFK calcium salts as stabilizers aqueous solution of sildenafil citrate.

Known pharmaceutical composition (EN 2009131749, publ. 27.02.2011; WO 2008091855, publ. 31.07.2008) containing multiphase pharmaceutical composition in liquid and in solid oral dosage form. Sildenafil as the active pharmaceutical ingredient is in the form of particles, in dissolved form or in the form of particles and dissolved form; and as solvents used propylene, glycol, ethanol, N-organic and other calcium Salts used in the preparation of solid oral dosage forms as additional connections as absorbent media that is mixed with the emulsified mixture of the active pharmaceutical ingredient, solvent, immiscible liquid and water. It is known the use of calcium salts as biodegradable agents to control crystallization in the composition of the fluid composition suitable for use as the implant for the controlled release (EN 2007115853, publ. 10.11.2008, WO 2006041942, publ. 20.04.2006). Biologically active agent, a vasodilator, sildenafil, in particular, is contained in a quantity amounting to within 0.00001 to 10% by weight of the composition, the composition includes a biodegradable, biocompatible thermoplastic polymer and a biocompatible organic liquid which dissolves thermoplastic polymer. For implantable fluid polymeric composition is important to the maintenance of a biologically active agent in solid fine condition with evenly distributed particles in the polymer, since the formation of the concentrated liquid phases, is not compatible with the polymer, will lead to unpredictable selection of these phases on the surface of the implant that will violate specified pharmacokinetic parameters and can be dangerous for health. Calcium salts, predominantly insoluble in aqueous-organic media, act as crystallization centers. A number of salts of calcium and sodium, both inorganic and organic, soluble in water or organic media, act as substances with wycliffism action.

It was unexpectedly found that with the introduction of some calcium salts in aqueous suspensions of sildenafil citrate can be obtained concentrated aqueous solutions of salts of sildenafil. Low-soluble calcium citrate, obrazumit is during the procedure of preparation JFK, without difficulty filtered. Cleaned from mechanical impurities aqueous solutions of salts of sildenafil have a low viscosity and does not crystallize upon cooling. The calcium contained in the solution, and improves the portability of this IFC, exerting a protective effect on tissues of the teeth and oral cavity. Not difficult getting JFK with the concentration of the active substance, in terms of sildenafil citrate, from 3 to 30 wt.%. By direct injection of the calcium salt (or mixture of salts), changing the molar ratio of sildenafil citrate: calcium salt or mixture of salts) from 1.0:0.1 to 1.0:2,0, you can obtain a pH value of from 3 to 6, mostly from 4 to 5. As calcium salts use of calcium lactate pentahydrate, or(and) calcium lactate trihydrate, or(and) calcium gluconate, or calcium malate, or calcium glycolate, or(and) calcium uranyl chloride, or calcium chloride dehydrate. When receiving calcium(s) salt(s) in situ using publicly available calcium carbonate and the corresponding hydroxycarboxylic acid (or mixture of acids), at a molar ratio of sildenafil citrate: hydroxycarboxylic acid (or mixture of acids) 0,1÷2,0:1, while calcium carbonate is introduced to achieve the required pH in the range from 3.0 to 6.0, mostly from 4 to 5. As hydroxycarboxylic acids using glycolic, Elijah) milk, or Apple, or gluconic acid.

During the study it was found that the introduction of JFK at the stage of its preparation of nonionic surfactants selected from the group of ethoxylated phenols, and / or ethoxylated sugar, and / or the ethoxylated allshare (Twins), and / or ethoxylated steroid alcohols (including ethoxylated lanolin), has an inhibitory effect on the crystallization of salts of sildenafil, including during prolonged storage at low temperatures. In addition, improved filtration of the solution containing salt of sildenafil, calcium citrate and mechanical impurities. For example, the presence JFK ethoxylated tocopherol (commercial product "Feral A"), which is very effective surfactants involves the reduction of side effects from this JFK. For ethoxylated tocopherol in vivo retains all the biological effects of tocopherol, including normalization of reproductive functions, hepatoprotective and antihypoxic action. The minimum sufficient number neinogennye surfactant for inhibiting crystallization is 0.001 wt.%, the addition of more than 1 wt.% impractical, because the effect of inhibition is not increased, but JFK starts to form a stable foam, which, of course, is undesirable.

Because malakili aqueous solutions with what she sildenafila are a good substrate for microorganisms, it is expedient to introduce into the composition JFK preservatives in effective doses. For example, as preservatives can be used ethanol, preferably in the amount of 30 wt.%, but the minimum effective quantity of at least 15 wt.%; JFK remains stable and acceptable for use in the ethanol content up to 50 wt.%. Can also be used and esters of p-oksibenzoynoy acid (parabens), but the optimum is the use of carboxylic acids of bacteriostatic, and / or their esters, or their pharmaceutically acceptable salts in an amount of 0.1-0.5 wt.%. As the carboxylic acid bacteriostatic, and / or their esters, or their pharmaceutically acceptable salts are used propionic acid, or(and) sorbic acid, or potassium sorbate, or(and) potassium benzoate, or(and) nipagin, or(and) nipazol.

As a taste modifier in the composition JFK it is expedient to introduce glycyrrhizinic acid or its pharmaceutically acceptable salts (e.g. ammonium glycyrrhizinate) in an amount of 0.001-0.1 wt.%, this additive imparts specific sweet taste, partly masking strongly bitter taste of sildenafil citrate. Surface activity of glycyrrhizinate additionally prevents possible crystallization of the components JFK during prolonged storage at low temperatures.

Thus, there is a new what I JFK, containing an aqueous solution of sildenafil citrate, and the method of its preparation. This JFK allows to obtain a dosage form for the treatment of sexual dysfunction with extremely optimized consumer properties (fast, easy to use and completely safe).

The implementation of the invention

The following examples further describe and make it possible for a person skilled in the art to make and use the invention. However, it will be clear that these implementation options are presented to illustrate the invention and should not be discussed as limiting the scope of invention, which is defined in the claims.

Example 1 obtaining the calcium salt in situ, with a ratio of sildenafil citrate : hydroxycarboxylic acid = 1:0,1.

In chemical beaker equipped with a stirrer, pH meter and thermometer, download 0.27 g (of 0.003 mol) of lactic acid and 60.0 g of distilled water (pH=2,42). To the solution, heated to 60°C, with stirring, in small portions was added to 0.30 g (of 0.003 mol) of calcium carbonate (pH=5,78). It cooled to a room temperature suspension add 19,0 g (0.03 mol) of sildenafil citrate. The reaction mass is heated and stirred at a constant temperature of 40±5°C for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary the cost, through a folded filter. To 30.0 g of the obtained solution further add 0.03 g monoammonium salts of glycyrrhizic acid, 0.05 g of sorbic acid and 0.10 g of potassium sorbate.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is the 10.40 wt.%.

Pharmaceutical composition (pH of 4.44) stable during curing within two months, the active substance is not distilled, its content is not changed.

Example 2 obtaining the calcium salt in situ, with a ratio of sildenafil citrate : hydroxycarboxylic acid = 1:1.

In chemical beaker equipped with a stirrer, pH meter and thermometer, download 2.7 g (0.03 mol) of lactic acid and 60.0 g of distilled water. To the solution, heated to 60°C, when displacement is Ivanyi small portions was added 3.0 g (0.03 mol) of calcium carbonate (pH=5,97). It cooled to a room temperature suspension add 19,0 g (0.03 mol) of sildenafil citrate. The reaction mass is heated and stirred at a constant temperature of 40±5°C for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution was added 0.02 g of glycyrrhizic acid, 0.12 g of potassium sorbate and 0.3 g of polyoxyethylene tocopherol.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 27,34 mass %.

Pharmaceutical composition (pH=3,94) stable during curing within two months, the active substance is not distilled, its content is not changed.

Example 3 obtaining calcium from the in-situ, when the ratio of sildenafil citrate : hydroxycarboxylic acid = 1:2.

In chemical beaker equipped with a stirrer, pH meter and thermometer, load of 5.4 g (0.06 mol) of lactic acid and 60.0 g of distilled water (pH=1,67). To the solution, heated to 60°C, with stirring, in small portions was added 6.0 g (0.06 mol) of calcium carbonate (pH=5,30). It cooled to a room temperature suspension add 19,0 g (0.03 mol) of sildenafil citrate. The reaction mass is heated and stirred at a constant temperature of 40±5°C for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution was added 30.0 g of ethyl alcohol (95%), incubated for 6 hours, filtered through a folded filter. To 30.0 g of the filtrate add additional 0.02 g of glycyrrhizic acid and 0.3 g of ethoxylated lanolin.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=20 (70:30, about/about). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate, is 17,28 wt.%.

Pharmaceutical composition (pH=3,98) stable during curing within two months, the active substance is not distilled, its content is not changed.

Example 4 obtaining calcium salts in situ, with a ratio of sildenafil citrate : hydroxy carboxylic acid = 1:1.

In chemical beaker equipped with a stirrer, pH meter and thermometer, load of 1.9 g (0,021 mol) of lactic acid, 1.2 g (0,009 mol) of malic acid and 60.0 g of distilled water (pH=2,00). To the solution, heated to 60°C, with stirring, in small portions was added to 3.9 g (0,039 mol) of calcium carbonate (pH=5,55). It cooled to a room temperature suspension add 19,0 g (0.03 mol) of sildenafil citrate and, optionally, of 45.0 g of distilled water. The reaction mass is heated and stirred at a constant temperature of 40±5°C for one hour; cooled, leave the shutter speed at night. To the product type of 45.0 g of distilled water, heated and stirred at a constant temperature of 30±5°C, cooled, filtered on a filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution in addition to ablaut 0.03 g of glycyrrhizic acid, 0.05 g of sorbic acid and 0.10 g of potassium sorbate and 0.3 g of polyoxyethylene tocopherol.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 4.63 wt.%.

The pharmaceutical composition is stable (pH=4,17) during curing within two months, the active substance is not distilled, its content is not changed.

Example 5 direct introduction of a calcium salt at a ratio of sildenafil citrate : calcium salt = 1:2.

In chemical beaker equipped with a stirrer, pH meter and thermometer, download 19,0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water. To the suspension with stirring in small portions add to 13.1 g (0.06 mol) of calcium lactate pentahydrate (pH 4,01). The reaction mass is heated at 40±5°C and stirred at constant temperature for one hour; after, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution further add 0.03 g monoammonium salts of glycyrrhizic acid, 0.04 g of sorbic acid, 0.12 g of potassium sorbate and 0.3 g of polyoxyethylene tocopherol.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 14.02 wt.%.

Pharmaceutical composition (pH=4,12) stable during curing within two months, the active substance is not distilled, its content is not changed.

Example 6 direct introduction of a calcium salt at a ratio of sildenafil citrate : calcium salt = 1:0,1.

In chemical beaker equipped with a stirrer, pH-tube and a thermometer, download 19,0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water. To the suspension with stirring in small portions add 0.65 g (of 0.003 mol) of calcium lactate pentahydrate (pH=4,18). The reaction mass is heated to 40±5°C and stirred at constant temperature for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution further add 0.01 g monoammonium salts of glycyrrhizic acid, 0.07 g of sorbic acid and 0.08 g of potassium sorbate.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 7,72 wt.%.

Pharmaceutical composition (pH=4,22) stable during curing within two months, the operating substance is not distilled, its content is not changed.

Example 7 direct introduction of calcium salts, the ratio of sildenafil citrate : calcium salt = 1:1,2.

In chemical beaker equipped with a stirrer, pH meter and thermometer, download 6.5 g (0.015 mol) of calcium gluconate, 4.6 g (0,021 mol) of calcium lactate pentahydrate and 60.0 g of distilled water. To the solution was added with stirring 19,0 g (0.03 mol) of sildenafil citrate (pH=4,17). The reaction mass is heated to 40±5°C and stirred at constant temperature for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter. To 30.0 g of the obtained solution was added 6.0 g of ethyl alcohol (95%), incubated for 6 hours, filtered through a folded filter. To 30.0 g of the filtrate add additional 0.02 g of glycyrrhizic acid and 0.15 g of ethoxylated lanolin.

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, vol/vol. The feed rate of eluent is 1 ml/min Detector - spectrophotometric detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 28,53 wt.%.

The pharmaceutical composition is stable (pH=3,93) during curing within two months, the active substance is not distilled, its content is not changed.

Example 8 without the introduction of calcium salts

In chemical beaker equipped with a stirrer, pH meter and thermometer, download 19,0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water. The suspension is heated to 40±5°C and stirred at constant temperature for one hour; cooled, leave the shutter speed at night. Filter on the filter SCHOTT and, if necessary, through a folded filter (pH=4,12).

A sample of the product analyzed by HPLC. The content of active substance in wt.% expect with regard to the content of sildenafil citrate in FSO sildenafil citrate. The process of chromatography was carried out carried out on a column (150×4.6 mm, filled porous silica with grafted octadecylphenol phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile and 0.01% (V/V) solution of triethylamine provided by phosphoric acid (85%) to pH=2,0 (70:30, V/V). The feed rate of eluent is 1 ml/min Detector spectrophotomet is practical, detection at a wavelength of 215 nm.

The content of active substance in terms of sildenafil citrate is 2.67 wt.%.

1. Pharmaceutical composition for oral administration in the form of a spray containing an aqueous solution of sildenafil citrate and target additives (stabilizers, inhibitors of crystallization, taste modifiers, preservatives), characterized in that the content of active substance in the pharmaceutical composition ranges from 3 to 30 wt.% and as the stabilizer composition comprises a pharmaceutically acceptable calcium salts, taken in the quantity necessary to obtain a pH in the range from 3.0 to 6.0; pharmaceutically acceptable calcium salt selected from the group comprising calcium lactate pentahydrate, or(and) calcium lactate trihydrate, or(and) calcium gluconate, or calcium malate, or calcium glycolate, or(and) calcium uranyl chloride, or calcium chloride dehydrate.

2. The pharmaceutical composition under item 1, characterized in that as preservative use ethanol in the amount of 15-50 wt.%.

3. The pharmaceutical composition under item 1, characterized in that as preservatives used carboxylic acid bacteriostatic, and / or their esters, or their pharmaceutically acceptable salts in an amount of 0.1-0.5 wt.%.

4. The pharmaceutical composition according to p. 3, characterized in that as carboxylic acid bacteriostatic, and / or their esters, or their pharmaceutically acceptable salts are used propionic acid, or(and) sorbic acid, or potassium sorbate, or(and) potassium benzoate, or(and) nipagin, or(and) nipazol.

5. The pharmaceutical composition under item 1, characterized in that as modifiers of taste use glycyrrhizinic acid or its pharmaceutically acceptable salt in an amount of 0.001-0.1 wt.%.

6. The pharmaceutical composition according to p. 5, characterized in that as pharmaceutically acceptable salts of glycyrrhizic acid using ammonium glycyrrhizinate.

7. The pharmaceutical composition under item 1, characterized in that it further contains a nonionic surfactant as inhibitors of crystallization in the amount of 0.001-1.0 wt.%.

8. The pharmaceutical composition according to p. 7, characterized in that as the nonionic surfactants used ethoxylated phenols, and / or ethoxylated sugar, and / or the ethoxylated allshare (Twins), and / or ethoxylated steroid alcohols.

9. The pharmaceutical composition according to p. 8, characterized in that as ethoxylated steroid alcohol use ethoxylated lanolin.

10. The pharmaceutical composition according to p. 8, characterized in that as ethoxylated phenol using ethoxylated tocopherol.

11. Method of preparation of the pharmaceutical is tion of the composition under item 1, characterized in that the pharmaceutically acceptable salt of calcium, taken in a molar ratio to the sildenafil citrate 0,1÷2,0:1, directly injected into an aqueous solution of sildenafil citrate.

12. The method of preparation of the pharmaceutical composition under item 1, characterized in that the pharmaceutically acceptable salt of calcium receive in situ by introduction of calcium carbonate and optionally one hydroxycarboxylic acids, taken in a molar ratio of sildenafil citrate : hydroxy carboxylic acid of 1:0,1÷2,0, while calcium carbonate is injected until the desired pH value in the range from 3.0 to 6.0.

13. The method according to p. 12, characterized in that as a hydroxycarboxylic acid is used glycolic, or lactic, or Apple, or gluconic acid.



 

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1 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically urology. A method involves the complex postoperative rehabilitation. From the 10th postoperative day, the patient is exposed to electric myostimulation at current intensity to pelvic floor muscle contraction, frequency 30-50 Hz, modulation depth 100% for 10-15 minutes. The therapeutic course is 12-20 daily procedures. In one month from the operation, the ischiocavernous and bulbospongiosus muscles are trained. That involves doing three exercises thinking of 'penis contraction'. The first exercise represents 5 tensions with maximum intensity (100%), length 5 seconds and tension pauses 90 seconds. The second exercise represents 5 tensions with intensity 50% of maximum intensity, length 15 seconds and tension pauses 20 seconds. The second exercise represents 5 tensions with intensity 30% of maximum intensity, length 30 seconds and tension pauses 20 seconds. The exercises are done min. 3 times, once a week in the morning and evening. They are added with doing the interval exercises for lower extremity muscles. The exercises include 15-minute warm-up activities and doing the exercises of intensity 70-80% of maximum intensity, 50-60% of maximum heart rate, repeated for 5 times with 3-minute pauses. The exercises are done not less than 3 times. From the second postoperative month, a phosphodiesterase-5 inhibitor is administered.

EFFECT: method provides improving the quality of erection ensured by erection compression of the superficial veins of penis and blood outflow blocking from the cavernous body and prolonged therapeutic effect.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel 7-piperidinoalkyl-3,4-dihydroquinolone derivatives and a pharmaceutically acceptable salt or hydrate thereof, where R is a hydrogen atom or a C1-6-alkyl group; A1, A2 and A3, which can be identical or different, are each a hydrogen atom, a halogen atom; X is a C1-6-alkylene group; Y is a bond or a C1-6-alkylene group; Z is a bond or a C1-6-alkylene group, where the C1-6-alkylene group can be substituted with a phenyl group; W is a bond or an oxygen atom; and Cy is a phenyl group or a pyridyl group, where the phenyl or pyridyl group can have 1-3 substitutes which can be identical or different and are selected from a group consisting of a halogen atom, a cyano group, a C1-6-alkyl group, C1-6-alkoxy group, where the C1-6-alkyl group or C1-6-alkoxy group can be substituted with 1-3 halogen atoms, and a C2-6-alkanoyl group. The invention also relates to a pharmaceutical composition and a preventive or therapeutic drug based on the compound of formula (I) .

EFFECT: obtaining novel 7-piperidinoalkyl-3,4-dihydroquinolone derivatives, having antagonistic action on MCH receptor.

6 cl, 4 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, particularly to sexual pathology, and concerns sexual interest (libido) recovery in males. That is ensured by administering a dietary supplement containing L-arginine, pollen and bee-bread, male bee brood, a substance containing zinc, vitamin B 6, and one to three herbal ingredients specified in barrenwort, true or false ginseng and Rhaponticum carthamoides or Serratula coronata in effective amounts.

EFFECT: complex of the biologically active ingredients provides the libido recovery ensured by blood androgen increase in a combination with an anti-stress and psychostabilising effect.

8 cl, 8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, namely to using ipidacrine as an agent for treating disturbed potency.

EFFECT: pharmaceutical composition of ipidacrine represents a tablet, including a prolonged action tablet, or a solid gel capsule.

4 cl, 4 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing a medicinal agent containing vardenafil hydrochloride trihydrate in the solid form wherein vardenafil hydrochloride trihydrate is treated with suitable pharmaceutical additives at temperature from approximately 20°C to approximately 45°C. The ambient relative humidity of the procedure makes 30% to 90%. The treated medicinal agent is film-coated at temperature within the range from 40°C to 55°C.

EFFECT: method according to the invention provide the additional stage of repeated hydration for the purpose of preparing the trihydrate form of vardenafil hydrochloride.

20 cl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using 3-alpha-androstanediol and 5-HT1A agonist for preparing a drug for sexual dysfunction on demand, wherein above 3-alpha-androstanediol and 5-HT1A agonist substantially release at the same time approximately from one to two hours before sexual activity, thereby peak effects of 3-alpha-androstanediol and 5-HT1A agonist (particularly, of flesinoxan) coincide in time at least partially; the respective pharmaceutical composition and kit for treating sexual dysfunction on demand. The declared drug, composition and kit may additionally contain type 5 phosphodiesterase inhibitor (PDE5 - sildenafil).

EFFECT: invention provides a short (over a few hours) superphysiological peak of blood 3-alpha-androstanediol that provides calling the greatest possible attention to erotic symbols and sexual motivation, and relieving the depressed behavioral responses to the maximum.

11 cl

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine. Described is a composition for the transdermal introduction of medications (M) into a human and animal organism, including cases of urgent drug treatment and prevention of acute pathological conditions. The composition consists of a solution of one or several M in a mixture of at least two solvents: dialkylamide of lower carboxylic acid and (or) alkylpyrrolidone and monoterpenes and (or) monoterpenoids. The total volume concentration of N,N-dialkylamides of lower carboxylic acids or N-alkylpyrrolidones constitutes from 1% to 99% of the mixture volume.

EFFECT: composition makes it possible to realise urgent drug treatment and prevention of acute pathological conditions of a human and animal organism by a simple in implementation, safe and cheap method.

12 cl, 6 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to therapy, namely to pulmonology, and can be used for suppressing bacteria Pseudomonas aeruginosa, growing in anaerobic conditions, as well as for the treatment of the pulmonary bacterial infection, caused by them. For this purpose an effective quantity of an aerosol of a fluoroquinolone antibiotic, selected from the group, consisting of levofloxacin and ofloxacin, in a concentration of 0.125-0.128 mg/l is introduced.

EFFECT: application of the claimed inventions makes it possible to influence the said bacteria with the quantity of the fluoroquinolone antibiotic, effective of their growth suppression.

22 cl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a composition for the external treatment and prevention of infections caused by the type 1, 2 herpes virus and bacterial complications caused by the herpetic infection, containing lysozyme, peroxidase, povyargol as active ingredients, escin and glycyrrhizinic acid or its salts as anti-inflammatory ingredients, liposomes on the basis of high-active hydrated lecithin in a combination with cholesterol as carriers and pharmaceutically acceptable carriers and excipients, with the ingredients of the composition being taken in certain proportions, wt %.

EFFECT: invention provides extending the range of products for treating and preventing the infections caused by type 1, 2 herpes virus and bacterial complications caused by the herpetic infection.

4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics and represents a pharmaceutical composition for parenteral administration containing sub-micron particles of dosocahexaenoic acid ester dispersed in a water phase with the use of mixture of at least two surfactants specified in a) at least one fatty acid polyoxyethylene ester and b) at least one phospholipide derivative, as well as a method for preparing the above pharmaceutical composition.

EFFECT: invention provides higher pharmacological activity.

14 cl, 3 dwg, 3 tbl, 2 ex

FIELD: pharmacology.

SUBSTANCE: method involves preparing a liquid composition containing a pharmaceutical active ingredient, a mixture of solvents containing water, isopropanol in an amount of 5 wt % to 20 wt % and propylene glycol in an amount of 2 wt % to 25 wt %, and a phospholipid foaming agent in an amount of 2 wt % to 25 wt %, foaming the liquid composition mechanically with no propellant used, and measuring the foam volume and stability. That is followed by transforming the nature and/or changing the concentration of the pharmaceutically active ingredient and/or the phospholipid foaming agent and/or changing the concentration of one of the solvents to produce 250 ml of the liquid composition. The above liquid composition is expected to produce foam in the volume of 400 ml and with the stability so that 50% of an initial foam volume is observed so far after the 10-minute hold-up and measured by the standard SITA procedure. The invention also relates to a composition applicable for topical use and prepared by the method described above.

EFFECT: preparing the composition presented by the stable foam.

22 cl, 18 dwg, 1 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: stabiliser includes modified chitosan which is obtained by modifying chitosan particles located in an emulsion of an organic solvent - water, with pH 6.0-6.5, by first reacting a mixture consisting of a carboxylic acid in an organic solvent and a condensing agent, and then with an organic base, wherein the carboxylic acid used is either palmitic acid or stearic acid or dodecanoic acid, the condensing agent used is a mixture of hydroxysuccinimide and an aliphatic carbodiimide or formaldehyde and an aliphatic isocyanide, and the organic base used is triethylamine.

EFFECT: effective liposome composition stabiliser which can be obtained using a simple method.

8 cl, 3 tbl, 5 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a carrier applicable for the local drug delivery. A drug is enclosed in a carrier, and the carrier comprises a coating able to release an enclosed drug as a result of a local stimulus. The coating additionally surrounds the contrast agent MR 19F which changes its detectability after being released from the carrier. The invention refers to a method for the drug delivery to an MRT-controlled individual, wherein the method involves administering the above carrier into the individual enabling the carrier releasing the drug, and forming MR 19F images with the use of a contrast produced by the contrast agent MR 19F.

EFFECT: invention enables monitoring the beginning of the drug release from the carrier.

18 cl, 11 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns irinotecan liposomes or its hydrochloride containing irinotecan or its hydrochloride, neutral phospholipid and cholesterol, wherein the weight ratio of cholesterol to neutral phospholipid makes 1:3-5, and a method for preparing them.

EFFECT: liposomes have higher stability.

15 cl, 3 dwg, 10 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: inhalation aerosol formulation for treating respiratory diseases contains salmeterol or salmeterol xinafoate, fluticasone or fluticasone propionate, a propellent modifier representing perfluorodecalin, and a propellent specified in 1,1,1,2 tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HPA-227ea).

EFFECT: higher respirable fraction and effective pulmonary delivery of the active ingredient; the aerosol has higher stability.

1 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

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