RU2536425C2 - Pharmaceutical composition containing sildenafil citrate, and method of using it - Google Patents

Abstract

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

Description

FIELD OF THE INVENTION

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

State of the art

Solid oral dosage forms that are absorbed in the gastrointestinal tract due to extensive first-pass metabolism have lower bioavailability than, for example, dosage forms that deliver the active substance through the mucous membranes (buccal, sublingual, nasal). For example, a fast-acting drug containing sildenafil citrate in the form of a nasal spray under the trade name Duromist ™. The dose of Duromist ™ in 20 mg is bioequivalent to the Viagra® tablet in 25 mg, the time to reach the maximum concentration is not significantly different (1.10 and 1.04 hours for Duromist ™ and Viagra®, respectively), but the dose of Duromist ™ in 20 mg has practically 100% bioavailability compared to a 25 mg Viagra® tablet, for which this value is 40%. [Lu NT, 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 use, in particular based on sildenafil citrate, the use of polyvinylpyrrolidone is widely known. The composition of the solid composition for sublingual use presented in patent WO 0054777, publ. 09/21/2000, polyvinylpyrrolidone is included as a water-dispersed polymer, as an agent that promotes swelling; in patent WO 0135926, publ. 05/25/2001, a sprayable composition for nasal use is disclosed, in which polyvinylpyrrolidone is used as a solvent, as a viscosity regulating agent. The use of polar solvents such as propylene glycol (RU 2005109909, publ. 10/10/2006), polyethylene glycol (RU 2009145167, publ. 06/20/2011), ethanol (RU 2003108500, publ. 10.07.2004), etc. is also common. The use of the above solvents or mixtures thereof in combination with water in the preparation of a liquid dosage form containing sildenafil in the form of a solution, emulsion or suspension is indicated in the application RU 2009131749, publ. 02/27/2011 (WO2008091855, publ. 31.07.2008).

Application WO 2004019909, publ. 03/11/2004 discloses a sprayable composition for buccal use, which includes aqueous propylene glycol or aqueous polyethylene glycol and aqueous ethanol and a target additive (propellant and flavoring additives); the content of the active substance, sildenafil vasodilator, in particular, from 0.1 to 25% weight. But using propylene glycol and polyethylene glycol can be unsafe. Quite often, there are cases of contamination of propylene glycol with 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 a rather expensive analysis of each package by GLC. In addition, aqueous-organic concentrated solutions have a high coefficient of volume expansion, which can lead to a violation of the tightness of the package with increasing temperature; and high viscosity makes it difficult to use a pharmaceutical composition in the form of a spray.

In the application RU 2007141868, publ. 05/20/2009 (WO 2006108556, publ. 19.10.2006), which serves as a prototype, presents a sterile aqueous liquid composition for administration in the form of an aerosol that does not contain propylene, polyethylene glycol and glycerol for oral and nasal inhalation. The pH of this composition is mainly from 4 to 6, which is a definite plus. But the replacement of the solvent led to a significant decrease in the concentration of the active substance (from 0.001 to 1% weight), which, in turn, greatly complicates the use of the pharmaceutical composition in the form of a spray, since effective doses require a large volume, up to 2 ml. and higher. In addition, aqueous solutions with a concentration above 0.35% crystallize when the temperature is lowered, and the mechanical pump is disabled.

Disclosure of invention

The aim of the present invention was to obtain the composition of a liquid pharmaceutical composition (LPA), devoid of organic solvents, containing an aqueous solution of sildenafil citrate, with an acceptable pH of at least 3, with an active substance concentration of up to 30 wt.%.

The problem was solved by introducing calcium salts into the composition of the HPA as stabilizers of an aqueous solution of sildenafil citrate.

A known pharmaceutical composition (RU 2009131749, publ. 02/27/2011; WO 2008091855, publ. 07/31/2008) containing a multiphase pharmaceutical composition in both liquid and solid oral dosage forms. Sildenafil as an active pharmaceutical ingredient is in the form of particles, in dissolved form or both in particulate form and in dissolved form; and as solvents use propylene, polyethylene glycol, ethanol, N-methylpyrrolidone, etc. Calcium salts are used in the preparation of solid oral dosage forms as additional compounds as adsorbent carriers that are mixed with an emulsified mixture of the active pharmaceutical ingredient, solvent, immiscible liquid and water . It is known to use calcium salts as biodegradable agents for controlling crystallization in a fluid composition suitable for use as a controlled release implant (RU 2007115853, publ. 10.11.2008, WO 2006041942, publ. 20.04.2006). The biologically active agent, the sildenafil vasodilator, in particular, is contained in an amount of 0.00001-10% by weight of the composition, the composition also includes a biodegradable biocompatible thermoplastic polymer and a biocompatible organic liquid in which the thermoplastic polymer is dissolved. For an implantable fluid polymer composition, it is important to maintain the biologically active agent in a solid fine state with uniformly distributed particles in the polymer, since the formation of concentrated liquid phases incompatible with the polymer will lead to unpredictable release of these phases on the implant surface, which will violate the specified pharmacokinetic parameters and may become hazardous to health. Calcium salts, mainly insoluble in aqueous organic media, act as crystallization centers. A number of calcium salts, as well as sodium, both inorganic and organic, soluble in water or organic environments, act as substances with salting out effect.

Unexpectedly, it was found that with the introduction of certain calcium salts into aqueous suspensions of sildenafil citrate, concentrated aqueous solutions of sildenafil salts can be obtained. The sparingly soluble calcium citrate formed during the preparation of the HPLC is filtered without difficulty. Aqueous solutions of sildenafil salts purified from mechanical impurities have a low viscosity and do not crystallize upon cooling. Calcium contained in the solution improves the tolerance of this exercise liquid, providing a protective effect on the tissues of the teeth and oral cavity. It is not difficult to obtain an HPA with a concentration of the active substance, in terms of sildenafil citrate, from 3 to 30 wt.%. With the direct introduction of a calcium salt (or a mixture of salts), changing the molar ratio of sildenafil citrate: calcium salt (or a mixture of salts) from 1.0: 0.1 to 1.0: 2.0, you can get a pH from 3 to 6, mainly from 4 to 5. As calcium salts, calcium lactate pentahydrate, or (and) calcium lactate trihydrate, or (and) calcium gluconate, or (and) calcium malate, or (and) calcium glycolate, or (and) calcium chloride are used hexahydrate, and / or calcium chloride dihydrate. When preparing the calcium salt (s) in situ, commonly available calcium carbonate and the corresponding hydroxycarboxylic acid (or mixture of acids) are used, with a molar ratio of sildenafil citrate: hydroxycarboxylic acid (or mixture of acids) 0.1 ÷ 2.0: 1, at this calcium carbonate is introduced to achieve the desired pH in the range from 3.0 to 6.0, mainly from 4 to 5. As hydroxycarboxylic acids use glycolic, or (and) lactic, or (and) malic, or (and) gluconic acids.

In the course of the study, it was found that the introduction of nonionic surfactants into the composition of the LPA at the stage of its preparation, selected from the group of ethoxylated phenols, or (and) ethoxylated sugars, or (and) ethoxylated acylsugar (TWINs), or (and) ethoxylated steroid alcohols (in including ethoxylated lanolin), has an inhibitory effect on the crystallization of sildenafil salts, including during prolonged storage at low temperatures. In addition, the filtration of a solution containing sildenafil salts from calcium citrate and solids improves. For example, the presence of hydroxyethylated tocopherol (a commercial product “Ferol A”) in the composition of the LPA, which is a very effective surfactant, suggests a decrease in side effects from this LPA. For in vivo ethoxylated tocopherol, all biological effects of tocopherol are retained, including normalization of fertile functions, hepatoprotective and antihypoxic effects. The minimum sufficient amount of non-inogenic surfactant to inhibit crystallization is 0.001 wt.%, The addition of more than 1 wt.% Is impractical, since the inhibition effect is not enhanced, but the HPLC begins to form a stable foam, which, of course, is undesirable.

Since low acidic aqueous solutions of sildenafil salts are a good substrate for microorganisms, it is advisable to introduce preservatives in effective doses into the composition of the physical activity. For example, ethanol can be used as a preservative, preferably in an amount of 30 wt.%, But in a minimum effective amount of at least 15 wt.%; LPA remains stable and acceptable for use with ethanol content up to 50 wt.%. Esters of p-hydroxybenzoic acid (parabens) can also be used, but the use of bacteriostatic carboxylic acids, or (and) their esters, or (and) their pharmaceutically acceptable salts in an amount of 0.1-0.5 wt.% Is optimal. Propionic acid, or (and) sorbic acid, or (and) potassium sorbate, or (and) potassium benzoate, or (and) are used as carboxylic acids of bacteriostatic agents, or (and) their esters, or (and) their pharmaceutically acceptable salts. nipagin, or (and) nipazole.

It is advisable to introduce glycyrrhizic acid or its pharmaceutically acceptable salts (for example, ammonium glycyrrhizinate) in an amount of 0.001-0.1 wt% as a taste modifier in the composition of the liquid fat complex, this additive gives the composition a sweet specific taste, partially masking the very bitter taste of sildenafil citrate. Also, the surface activity of glycyrrhizinates additionally prevents the possible crystallization of the components of LPA during prolonged storage at low temperatures.

Thus, a new LPA is presented containing an aqueous solution of sildenafil citrate, and a method for its preparation. This LF makes it possible to obtain dosage forms for the treatment of sexual dysfunction with extremely optimized consumer properties (fast-acting, convenient to use, as safe as possible).

The implementation of the invention

The following examples further describe and make it possible for a person skilled in the art to carry out and apply the invention. However, it will be understood that these embodiments are presented to illustrate the invention and should not be discussed as limiting the scope of the invention as defined in the claims.

Example 1 to obtain a calcium salt in situ, with a ratio of sildenafil citrate: hydroxycarboxylic acid = 1: 0.1.

0.27 g (0.003 mol) of lactic acid and 60.0 g of distilled water (pH = 2.42) are charged into a beaker equipped with a stirrer, pH meter and thermometer. 0.30 g (0.003 mol) of calcium carbonate (pH = 5.78) is added to the solution, heated to 60 ° C, with stirring in small portions. To a suspension cooled to room temperature, 19.0 g (0.03 mol) of sildenafil citrate was added. The reaction mass is heated and stirred at a constant temperature of 40 ± 5 ° C for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. 0.03 g of monoammonium salt of glycyrrhizic acid, 0.05 g of sorbic acid and 0.10 g of potassium sorbate are additionally added to 30.0 g of the resulting solution.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

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

The pharmaceutical composition (pH = 4.44) is stable when kept for two months, the active substance does not crystallize, its content does not change.

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

In a beaker equipped with a stirrer, a pH meter and a thermometer, 2.7 g (0.03 mol) of lactic acid and 60.0 g of distilled water are charged. To a solution heated to 60 ° C, 3.0 g (0.03 mol) of calcium carbonate (pH = 5.97) are added in small portions with stirring. To a suspension cooled to room temperature, 19.0 g (0.03 mol) of sildenafil citrate was added. The reaction mass is heated and stirred at a constant temperature of 40 ± 5 ° C for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution, 0.02 g of glycyrrhizic acid, 0.12 g of potassium sorbate and 0.3 g of ethoxylated tocopherol are added.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

The content of the active substance in terms of sildenafil citrate is 27.34 mass%.

The pharmaceutical composition (pH = 3.94) is stable when kept for two months, the active substance does not crystallize, its content does not change.

Example 3 to obtain a calcium salt in situ, with a ratio of sildenafil citrate: hydroxycarboxylic acid = 1: 2.

5.4 g (0.06 mol) of lactic acid and 60.0 g of distilled water (pH = 1.67) are charged into a beaker equipped with a stirrer, pH meter and thermometer. To a solution heated to 60 ° C, 6.0 g (0.06 mol) of calcium carbonate (pH = 5.30) are added in small portions with stirring. To a suspension cooled to room temperature, 19.0 g (0.03 mol) of sildenafil citrate was added. The reaction mass is heated and stirred at a constant temperature of 40 ± 5 ° C for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution add 30.0 g of ethyl alcohol (95%), stand for 6 hours, filter through a pleated filter. 0.02 g of glycyrrhizic acid and 0.3 g of ethoxylated lanolin are additionally added to 30.0 g of the filtrate.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

The content of the active substance in terms of sildenafil citrate is 17.28 wt.%.

The pharmaceutical composition (pH = 3.98) is stable when kept for two months, the active substance does not crystallize, its content does not change.

Example 4 to obtain calcium salts in situ, with a ratio of sildenafil citrate: hydroxycarboxylic acids = 1: 1.

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) are charged into a beaker equipped with a stirrer, a pH meter and a thermometer. 3.9 g (0.039 mol) of calcium carbonate (pH = 5.55) are added to the solution, heated to 60 ° C, with stirring in small portions. To a suspension cooled to room temperature, 19.0 g (0.03 mol) of sildenafil citrate and, in addition, 45.0 g of distilled water are added. The reaction mass is heated and stirred at a constant temperature of 40 ± 5 ° C for one hour; cooled, leave to stand overnight. 45.0 g of distilled water is added to the product, heated and stirred at a constant temperature of 30 ± 5 ° C; having cooled, they are filtered on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution, 0.03 g of glycyrrhizic acid, 0.05 g of sorbic acid and 0.10 g of potassium sorbate and 0.3 g of ethoxylated tocopherol are additionally added.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

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

The pharmaceutical composition is stable (pH = 4.17) when kept for two months, the active substance does not crystallize, its content does not change.

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

In a beaker equipped with a stirrer, pH meter and thermometer, 19.0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water are charged. To the suspension, 13.1 g (0.06 mol) of calcium lactate pentahydrate (pH = 4.01) are added in small portions with stirring. The reaction mass is heated to 40 ± 5 ° C and stirred at constant temperature for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution, 0.03 g of monoammonium salt of glycyrrhizic acid, 0.04 g of sorbic acid, 0.12 g of potassium sorbate and 0.3 g of ethoxylated tocopherol are additionally added.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

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

The pharmaceutical composition (pH = 4.12) is stable when kept for two months, the active substance does not crystallize, its content does not change.

Example 6 with the direct introduction of a calcium salt, with a ratio of sildenafil citrate: calcium salt = 1: 0.1.

In a beaker equipped with a stirrer, pH meter and thermometer, 19.0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water are charged. To the suspension, 0.65 g (0.003 mol) of calcium lactate pentahydrate (pH = 4.18) is added in small portions with stirring. The reaction mass is heated to 40 ± 5 ° C and stirred at constant temperature for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution, 0.01 g of monoammonium salt of glycyrrhizic acid, 0.07 g of sorbic acid and 0.08 g of potassium sorbate are additionally added.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

The content of the active substance in terms of sildenafil citrate is 7.72 wt.%.

The pharmaceutical composition (pH = 4.22) is stable when kept for two months, the active substance does not crystallize, its content does not change.

Example 7 with the direct introduction of calcium salts, with a ratio of sildenafil citrate: calcium salts = 1: 1.2.

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 are charged into a beaker equipped with a stirrer, pH meter and thermometer. To the solution, with stirring, 19.0 g (0.03 mol) of sildenafil citrate (pH = 4.17) are added. The reaction mass is heated to 40 ± 5 ° C and stirred at constant temperature for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter. To 30.0 g of the resulting solution add 6.0 g of ethyl alcohol (95%), stand for 6 hours, filter through a pleated filter. 0.02 g of glycyrrhizic acid and 0.15 g of ethoxylated lanolin are additionally added to 30.0 g of the filtrate.

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

The content of the active substance in terms of sildenafil citrate is 28.53 wt.%.

The pharmaceutical composition is stable (pH = 3.93) when kept for two months, the active substance does not crystallize, its content does not change.

Example 8 without the introduction of calcium salts

In a beaker equipped with a stirrer, pH meter and thermometer, 19.0 g (0.03 mol) of sildenafil citrate and 60.0 g of distilled water are charged. The suspension is heated to 40 ± 5 ° C and stirred at constant temperature for one hour; cooled, leave to stand overnight. Filter on a Schott filter and, if necessary, through a pleated filter (pH = 4.12).

A sample of the product is analyzed by HPLC. The active substance content in wt.% Is calculated taking into account the content of sildenafil citrate in the FSO sildenafil citrate. The chromatography process is carried out on a column of size 150 × 4.6 mm filled with porous silica gel grafted with an octadecyl phase (sorbent C18) with a particle size of 5 μm. Mobile phase: acetonitrile - 0.01% (v / v) triethylamine solution, adjusted with phosphoric acid (85%) to pH = 2.0 (70:30, v / v). The flow rate of the eluent is 1 ml / min. Detector - spectrophotometric, detection at a wavelength of 215 nm.

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

Claims (13)

1. The pharmaceutical composition for oral use in the form of a spray containing an aqueous solution of sildenafil citrate and target additives (stabilizers, crystallization inhibitors, flavor modifiers, preservatives), characterized in that the content of the active substance in the pharmaceutical composition is from 3 to 30 wt.% And as stabilizers, the composition contains pharmaceutically acceptable calcium salts, taken in the amount necessary to obtain a pH in the range from 3.0 to 6.0; wherein the pharmaceutically acceptable calcium salts are selected from the group consisting of calcium lactate pentahydrate, or (and) calcium lactate trihydrate, or (and) calcium gluconate, or (and) calcium malate, or (and) calcium glycolate, and / or calcium chloride hexahydrate, and / or calcium chloride dihydrate. 2. The pharmaceutical composition according to claim 1, characterized in that ethanol is used as a preservative, in an amount of 15-50 wt.%. 3. The pharmaceutical composition according to claim 1, characterized in that bacteriostatic carboxylic acids, or (and) their esters, or (and) their pharmaceutically acceptable salts in an amount of 0.1-0.5 wt.% Are used as preservatives. 4. The pharmaceutical composition according to claim 3, characterized in that propionic acid, or (and) sorbic acid, or (and) sorbate is used as carboxylic acids of bacteriostatics, or (and) their esters, or (and) their pharmaceutically acceptable salts. potassium, or (and) potassium benzoate, or (and) nipagin, or (and) nipazole. 5. The pharmaceutical composition according to claim 1, characterized in that glycyrrhizic acid or its pharmaceutically acceptable salts in the amount of 0.001-0.1 wt.% Are used as flavor modifiers. 6. The pharmaceutical composition according to claim 5, characterized in that ammonium glycyrrhizinate is used as a pharmaceutically acceptable salt of glycyrrhizic acid. 7. The pharmaceutical composition according to claim 1, characterized in that it further comprises nonionic surfactants as crystallization inhibitors in an amount of 0.001-1.0 wt.%. 8. The pharmaceutical composition according to claim 7, characterized in that as nonionic surfactants use ethoxylated phenols, or (and) ethoxylated sugars, or (and) ethoxylated acylsugar (TWIN), or (and) ethoxylated steroid alcohols. 9. The pharmaceutical composition according to claim 8, characterized in that the use of ethoxylated steroid alcohol is ethoxylated lanolin. 10. The pharmaceutical composition of claim 8, characterized in that the use of ethoxylated phenol is ethoxylated tocopherol. 11. The method of preparing the pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable calcium salts, taken in a molar ratio to sildenafil citrate of 0.1 ÷ 2.0: 1, are directly introduced into an aqueous solution of sildenafil citrate. 12. The method of preparing the pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable calcium salts are obtained in situ by introducing calcium carbonate and optionally one of the hydroxycarboxylic acids, taken in a molar ratio of sildenafil citrate: hydroxycarboxylic acid, equal to 1: 0.1 ÷ 2.0, while calcium carbonate is introduced to achieve the desired pH in the range from 3.0 to 6.0. 13. The method according to p. 12, characterized in that glycolic, or (and) lactic, or (and) malic, or (and) gluconic acid is used as hydroxycarboxylic acid.