EP4694865A1

EP4694865A1 - Liquid composition of phosphodiesterase type 5 (pde-5) inhibitors, a method of preparation thereof and the use thereof for the treatment of erectile dysfunctions

Info

Publication number: EP4694865A1
Application number: EP24789131.0A
Authority: EP
Inventors: Arkadiusz Szterk; Karol OFIARA; Ilkhom ADBULLAEV; Dominik MIDAK
Original assignee: Sativa Med Spolka Akcyjna
Current assignee: Sativa Med Spolka Akcyjna
Priority date: 2023-04-08
Filing date: 2024-04-07
Publication date: 2026-02-18
Also published as: WO2024215214A1; PL247528B1; PL444363A1

Abstract

The object of the invention is a liquid composition of phosphodiesterase type 5 (PDE-5) inhibitors selected from sildenafil, vardenafil, salts thereof or a mixture thereof, a method of preparation thereof and the use thereof for the treatment of erectile dysfunctions, particularly as a composition in the form of an aerosol for administration from a throat atomizer with a dose in the range of 12.5-25 mg PDE-5.

Description

Liquid composition of phosphodiesterase type 5 (PDE-5) inhibitors, a method of preparation thereof and the use thereof for the treatment of erectile dysfunctions

DESCRIPTION

TECHNICAL FIELD

The object of the invention is a liquid composition of phosphodiesterase type 5 (PDE-5) inhibitors selected from sildenafil, vardenafil, salts thereof or a mixture thereof, a method of preparation thereof and the use thereof for the treatment of erectile dysfunctions, particularly as a composition in a form of an aerosol for administration from a throat atomizer with a dose in the range of 12.5-25 mg PDE-5.

STATE OF ART

Erectile dysfunctions is a persistent inability to obtain and/or maintain an erection enabling satisfactory sexual intercourse. Approx. 60% of erectile dysfunctions affects men aged 40-60. In the treatment of erectile dysfunction, the first-line drugs are oral drugs from the group of selective and reversible phosphodiesterase type 5 (PDE-5, phosphodiesterase-5) inhibitors. Currently, a number of drugs from this group are available on the market. Two of them, sildenafil (commonly called Viagra) and vardenafil (Levitra), are first-generation inhibitors with a short duration of action of 4-6 hours after taking the tablet. The newest oral drugs available on the market are tadalafil (Cialis), udenafil (Zydena, a drug not available in Europe), and the newest avanafil (Stendra, Spedra), which are also PDE-5 inhibitors, but already of the II generation, differing from the I generation inhibitors in their high effectiveness, lasting for at least approx. 24 hours. The mechanism of action of all drugs from this group is identical. After sexual stimulation, nitric oxide is secreted in the nerve endings and in the endothelium of the vessels of the afferent arterioles and the sinuses of the cavernous bodies of penis. Endogenous nitric oxide stimulates guanylate cyclase, an enzyme that causes the transformation of guanosine triphosphate (GTP) into the second messenger - cyclic guanosine monophosphate (cGMP), which is a strong activator of protein kinase and calcium channels, leading to relaxation of blood vessels, including coronary vessels. Cyclic guanosine monophosphate also strongly activates the enzyme that breaks down cGMP into an inactive form, thus - ending the erection process. This enzyme is phosphodiesterase type 5 (PDE-5) found mainly in the smooth muscles of the cavernous bodies of the penis and in the smooth muscles of arterial and venous blood vessels. Blocking this enzyme by drugs delays the breakdown of cGMP, causing an erection to last longer. The most important requirement from the patient's point of view for this type of medicinal products (apart from the obvious pharmacological effect, for sure) is the speed of achieving the therapeutic effect. The therapeutic effect of PDE-5 inhibitors for people with erectile dysfunctions is in many cases a crucial and very stressful issue that may cause further disorders, mainly of a mental nature. It is very important to develop drugs with the highest possible speed of action, which translates directly into the fastest possible absorption process in order to achieve the appropriate therapeutic concentration of the active substance in the blood.

About 86% of all drugs used are administered orally because it is the most convenient, most physiological and accepted by patients. It is the most desirable route of administration of a medicinal substance, however, achieving satisfactory therapeutic effects is not always possible due to numerous factors affecting the bioavailability of the medicinal substance administered in this way. The condition for obtaining a therapeutic effect of the administered medicinal substance is its reaching the site of action and obtaining a sufficiently high concentration there. In the case of a medicinal substance - a drug administered via the gastrointestinal tract, there are several fundamental factors determining its bioavailability. These factors can be divided into two groups: related to the physiology of the gastrointestinal tract and related to the drug (physicochemical properties of the form of the drug and the medicinal substance). From the point of view of pharmaceutical engineering and development works related to drug development, the appropriate development of the drug form is crucial. The physicochemical properties of a substance can be treated as playing a key role in predicting its possible use, as a medicine. In fact, these properties determine both the dissolution rate and the possibility and speed of penetration through biological membranes, and, as a result, the probability of achieving a concentration considered therapeutic at the site of action. Analyzing the physicochemical properties of PDE-5 inhibitors available on the market (sildenafil, avanafil, tadalafil, udenafil), it is concluded that, according to the biopharmaceutical classification system, they belong to the second class, i.e. they are characterized by low solubility but high permeability. Analyzing the PDE-5 inhibitor market, over 90% of all available medicinal products are in the form of tablets or capsules that release the active substance in the digestive tract and the absorption process begins in the stomach at the earliest, and the actual process takes place in the small intestine. The therapeutic effect is observed at the earliest one hour after taking the tablet. Such a long waiting time for a therapeutic effect is often not satisfactory and sufficient for people with erectile dysfunctions, which is why research and development works are carried out on developing pharmaceutical forms with the fastest possible action, i.e. achieving a therapeutic effect. In order to have an effect on the human body, phosphodiesterase type 5 inhibitors must first be delivered to the body, and then they must be absorbed from the digestive tract into the blood, and this is possible, if, and only if, they are dissolved in body fluids. PDE-5 are compounds that do not dissolve in water or their solubility is very limited, and what is more, they do not dissolve in plant and animal fats, which significantly hinders their bioavailability from the gastrointestinal tract. PDE-5 dissolve best in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), they also dissolve in ethanol, but it is necessary to heat the solution to the boiling point, i.e. about 78°C, then it is possible to dissolve relatively large amounts of these compounds, but after cooling the solution they crystallize. DMF and DMSO are classified by EMA as class 2 and 3 solvents, respectively. The acceptable daily dose of DMF is 8.8 mg/day and for DMSO it is 50 mg/day. This significantly limits the use of these solvents due to their potentially toxic effects at higher doses. Any use of these solvents would have to be preceded by clinical trials. Methods and ways of dissolving or dispersing phosphodiesterase type5 inhibitors in water are being sought, so that they can be introduced into the human or animal body in this form. An alternative route of administration of PDE-5 inhibitors is the oral cavity mucous membrane, where the process of their absorption begins at the moment of application, but a necessary condition for this process to occur effectively is their dissolution in the initial composition. Administering the medicinal product directly into the oral cavity has many benefits. First of all, in the case of solid forms of a medicinal product, the process of disintegration of the form and subsequent dissolution of the active substance in body fluids is eliminated. Only after the tablet or capsule disintegrates, the active substance (usually in a changed physical form, e.g. in the form of co-crystals or other) is gradually dissolved and absorbed. This process takes time and significantly affects the speed of achieving a therapeutic effect. The development of PDE-5 inhibitors in the form of an aerosol administered to the oral cavity mucous membrane will be an alternative to the existing forms of oral medicinal products for the indication of erectile dysfunction, which mainly include tablets and capsules.

The oral cavity is lined with a mucous membrane (Latin: membrana mucosa), which consists of the epithelium (Latin: epithelium) and the connective tissue lamina propria of the mucous membrane (Latin: lamina propria membranae mucosae). The mucous membrane of these areas of the oral cavity is involved in the chewing of food (hard palate, gums) and, due to the possibility of damage or irritation, it is covered with multilayer keratinized squamous epithelium. This epithelium contains neutral lipids - ceramides, what significantly limits the transport of water and, therefore, active substances. The upper surface of the tongue is covered with a specialized mucous membrane (partially keratinized), which function is the perception of taste. The remaining part (60%) of the oral cavity mucous membrane, located on the lips, cheeks, soft palate, underside of the tongue and on the floor of the mouth, is covered with multilayered non-keratinized squamous epithelium. The penetration of the medicinal substance through the oral cavity mucous membrane may take place through the non-keratinized tissues of the sublingual membrane and through the buccal mucous membrane, and it is assumed that the intensity of this process is up to 4,000 times greater than after administration of the drug to the skin. Penetration is easiest through the sublingual route, more difficult through the buccal membrane, and relatively difficult through the palate tissue. Therefore, when designing oral formulations of PDE-5 inhibitors, their sublingual administration in the form of e.g. an aerosol should be taken into account.

In the world literature, there are many solutions available for the formulation of PDE-5 inhibitors in forms used in the oral cavity, both in the form of aerosols and semi-liquid (e.g. gels) or solid forms (e.g. lozenges or chewing gum). The solution to the solubility of sildenafil in patent application WO 2005/013937 was to prepare sildenafil base in the presence of sodium docosunate and hydroxypropyl methylcellulose, mannitol and/or pullulan (carriers). The preparation of the composition consisted in appropriate dry grinding of the ingredients, which resulted in the formation of co-crystals which, in water, formed a dispersion system with a particle size not exceeding 2 pm. The invention, to some extent, solves the problem of the solubility of sildenafil, but it is still in a solid state and the added value is in the acceleration of its solubility in body fluids. Absorption in the mouth will be significantly ineffective, and the maximum concentration of sildenafil is 5%. The next solution was to produce an appropriate solvent consisting of specific proportions of water, ethanol and organic acid (malic acid) in a single oral dose the content of sildenafil citrate was 40 mg (US 2015/0133459 A1). The main disadvantage of such a composition is the crystallization of sildenafil citrate during storage. The inventors did not solve the problem of crystallization of sildenafil citrate during storage, and additionally, this formulation contains large amounts of ethanol, which makes it impossible to sell it on Muslim markets (the product is not a halal). The solution for the solubility of sildenafil citrate described in WO 02/05820 A1 consisted in the preparation of co-crystals of sildenafil citrate with xylitol and then dispersion in an aqueous solution containing various excipients depending on the final pharmaceutical form. The most important ingredients are: carbopol, poloxamer L-44, EDTA, propylene glycol, benzoic acid, NaHCOs, metocel E15, cremofor RH-40, polypro 5000, propylene glycol, sodium croscarmellose. The invention relates to the production of sildenafil citrate in the form of water-soluble co-crystals with xylitol. The basic problem of co-crystallization is the precipitation of crystals after their dissolution. Co-crystallization significantly increases the solubility of sparingly soluble substances, such as sildenafil citrate, but the thermodynamic stability of such a system is low. Such solutions are ideal for hard forms, where the composition breaks down in the small intestine, due to which the active substance is quickly dissolved and then absorbed. Subsequent solutions were based on the preparation of an inhalation composition in the form of a powder aerosol of sildenafil in combination with carboxymethylcellulose, sodium alginate, sodium hyaluronate, L-leucine and tween-80. The main disadvantage of such a composition is the administration of powder, which dissolves only when combined with saliva in the oral cavity. An additional problem is the rather unpleasant form of administration, which may cause choking after administering the powder aerosol. Sildenafil in this composition is not dissolved, but is in the form of microparticles that must be dissolved in body fluids. The added value of this form is the omission of the disintegration phase that accompanies solid compositions, what may translate into faster penetration of the active substance into the bloodstream. A similar solution is a composition consisting of sildenafil citrate and gellan gum. As before, sildenafil is available in the form of microspheres with a grain size of 9-11 pm. In the patent publication US 2007/0031349 A1 , the inventors describe a method of dissolving sildenafil citrate or vardenafil hydrochloride in a solution of water and ethanol, achieving a dose of 5 mg in sublingual administration. Patent US 2007/0031349 A1 is a similar solution to the invention described in US 2015/0133459 A1 , however, no organic acid was added. The main disadvantage of this approach is the use of ethyl alcohol, which cannot always be used by all patients, especially for religious reasons, but in addition, both sildenafil and vardenafil crystallize in such a solution over time, which often disqualifies the production of the medicinal product without solving this problem. Particularly problematic is the issue of temperature changes, e.g. when transferring the medicinal product by the end user, e.g. in winter, when the temperature drops, which negatively affects the crystallization of both compounds. Another technological solution was proposed by Hosny et al. (2020), who described a method of producing a nanoemulsion of sildenafil citrate dissolved in clove oil, oleic acid, propylene glycol and the addition of tween-20 emulsifier. The nanoemulsion prepared in this way was applied to a mixture of carriers consisting of: colloidal silica, HPMC, sodium starch gluconate (explotab), microcrystalline cellulose and mannitol. However, this composition was used to produce tablets (solid form) with a rapid action. The inventors managed to achieve Tmax after 30 minutes compared to classic Viagra. Another solution involves the production of nanoemulsions by microfluidization of a dispersion system consisting of sildenafil citrate and an appropriate structuring agent: carbopol 971 , sodium dodecylbenzosulfonate or polyvinyl alcohol, (WO 2010/146407 A1). This composition was used to produce lamelas glued to the inner surface of the cheek. As a result of dissolving the lamel, the active substance is gradually released and absorbed into the bloodstream. The main disadvantage of this composition is that the PDE-5 inhibitor does not exist in a dissolved form, but as a nanoemulsion and must be dissolved in the oral cavity. US patent 6,200,591 B1 describes a method of preparing a nasal aerosol consisting of sildenafil hydrochloride and the phosphate buffer at pH 4.4 with the addition of sodium chloride or apomorphine hydrochloride. The addition of HPMC allows the preparation of a nasal gel by increasing the viscosity. The essence of this patent is the production of sildenafil hydrochloride, which dissolves better in water than sildenafil citrate, and its combination with apomorphine hydrochloride, which is also used in erectile dysfunctions. A certain modification of the solutions known from: US 2007/0031349 A1 and US 2015/0133459 A1 is the method described by Lu et al. (2011) based on dissolving sildenafil citrate in a mixture of oleic acid, water, tween 80 and ethanol. This system made it possible to produce a microemulsion with a grain size of approximately 20 pm and an active substance content of approximately 100 mg/ml. The inventors in the publication WO 2004/017976 A1 described a method of preparing tablets with sildenafil citrate that quickly dissolve in the oral cavity. The basis of the solution was the method of producing co-crystals of sildenafil with mannitol and sodium starch gluconate. Elshafeey et al. (2009) described a solvent that allowed the dissolution of sildenafil citrate in the amount of approximately 23 mg/ml. Their solvent consisted of a mixture of oleic acid, labrasol, transcutol and distilled water. The disadvantage of this system is the relatively low concentration of sildenafil citrate, just over 2%. In the description WO 2014/024193 A1 a method of preparing sildenafil citrate in the form of an oral emulsion was presented. The emulsion consisted of sildenafil citrate, methylsulfonylmethane, sucrose, lecithin, sunflower oil, tween-80 and glycerin. Unfortunately, the main disadvantage of this formulation is the low concentration of sildenafil. According to the description, in order to achieve a concentration of 25 mg (a single dose of sildenafil), it is necessary to spray the aerosol into the oral cavity 7 times. Beck-Broichsitter et al., (2017) and Rashid et al., (2018) developed solutions based on the production of inhalation powders consisting of sildenafil citrate deposited on a polymer based on various modifications of PLGA - poly(lactide-co-glycolide, P(VS-VA)- gPLGA - poly(vinyl sulfonate-co-vinyl alcohol)-graft-PLGA, polyethyleneimine (PEI) with PLGA and polyvinyl alcohol. All of these compositions are powdered oral inhalation sprays in which sildenafil must be dissolved, which most often occurs after swallowing the dose/doses. Further common solutions include all types of emulsion systems based on propylene glycol, PEG 400 or 200, isobutanol or isopropyl myristate with the addition of various surfactants such as: cremofor RH40, maisine 35-1 , caproyl 90, tween 80, poloxamer 108, span 20, pyrrolidone. In the description WO 2011/156405 A2, the inventors described a method of producing a 12-14% aerosol containing dissolved sildenafil citrate. Their solution involves the production of a solvent consisting of a mixture of: propylene glycol, ethanol with the addition of HCL and NaOH. Their aerosol in a single dose (120 pl) contains 10-14 mg of sildenafil citrate, i.e. from 7.14 to 10 mg of active sildenafil. In order to achieve a therapeutic dose, it is necessary to administer 2 or 3 doses, depending on the recipe of the described composition. The main disadvantage of this composition is the use of ethyl alcohol, which for religious reasons cannot be used to produce medicines in many regions of the world. Additionally, sildenafil citrate in this type of solutions crystallizes during storage, especially when the temperatures change. Another limitation is the concentration that can be achieved, which is a maximum of 14%. DISCLOSURE OF THE INVENTION

The inventors of this solution set themselves the following goals and technical problems to solve: development of composition of dissolved sildenafil (e.g. sildenafil citrate) and/or vardenefil (e.g. vardenefil hydrochloride) and mixtures thereof with the highest possible concentration for the production of aerosol forms administered to the oral cavity mucous membrane, e.g. in sublingual administration, with the highest possible concentration for the production of aerosol forms administered to the oral cavity mucous membrane, e.g. in sublingual administration, easily available, and therefore with a significant absorbability of the active substance in the oral cavity and with prolonged storage. Therefore, after dissolving the active substances, the crystallization process cannot occur for such a composition for a period of at least 6 months when stored in the temperature range of 1 ,0-45°C. Moreover, a composition consisting of active substances must consist only of components that can be used in the human oral cavity, i.e. they do not irritate the oral cavity and do not cause bothersome symptoms after application in the form of strong burning, stinging, a feeling of bitterness or astringency, which would prevent the use of the medicinal product. All components used must be safe for human health in accordance with current knowledge in this field and approved for pharmaceutical and food use. The therapeutic dose should be achievable by the smallest possible number of applications, e.g. two applications of the aerosol into the oral cavity in a single dose of 100-150 pl. The composition must ensure complete dissolution of the active substances, including flavor and fragrance substances improving the usability of the medicinal product, and be invisible to the naked human eye.

The aim of the invention is therefore to overcome the indicated disadvantages resulting from the state of art. This goal was achieved by developing a formulation solution, as well as a method of its production and a medicinal product for the treatment of erectile dysfunctions obtained in this way, enabling the preparation of an oral aerosol with dissolved phosphodiesterase type 5 inhibitors, in the form of sildenafil and/or vardenefil and/or mixtures thereof, wherein all substances used in the method of preparing such a composition are substances approved for use in the production of medicinal products for oral administration.

The inventors of the invention have unexpectedly found that the use of a non-obvious solvent system in the form of: a base solvent of benzyl alcohol, combined with a co-solvent: glycerin, 2-(2- ethoxyethoxy)-ethanol or a mixture thereof, and water as a complementary solvent, while maintaining the pH of the solution in the pH range 1 .25-3.0, preferably with the addition of an organic or inorganic acid as an acidity regulator, particularly preferably with the addition of an complementary solvent consisting of water with the addition of an organic or inorganic acid, preferably lactic acid or HCL, allows for the production of the main solvent, in which the solubility of the active substance, i.e. phosphodiesterase type 5 (PDE-5) inhibitors selected from sildenafil, preferably sildenafil citrate and/or vardenefil, preferably vardenefil hydrochloride, in the amount reaching even up to 42% of the active substance, is achieved. Moreover, the obtained medicinal product in the form of a liquid aerosol containing from 13 to 42% of the active substance being a PDE-5 inhibitor showed the desired physico-chemical and sensory properties. The active substance was completely dissolved, did not crystallize and it is not in the form of a nano-, micro- or sub-micro-emulsion. Such composition has proven to be useful for oral administration in the form of an atomizer/spray, where one or preferably two doses are sufficient to administer a therapeutic dose. By supplementing the compositions with additives approved for use in pharmacy and in the food industry, a composition with a pleasant, sweet-refreshing taste and a pleasant smell was obtained.

The essence of the invention is a liquid composition of phosphodiesterase type 5 (PDE-5) inhibitors, which contains PDE-5 in the amount of 13-42 wt. % of the composition, where PDE-5 is selected from sildenafil, vardenafil, salts thereof or a mixture thereof; a main solvent R, which consists of a base solvent, which is benzyl alcohol in the amount of 16.0-65 wt. % of the main solvent R; a co-solvent, which is anhydrous glycerin, 2-(2-ethoxyethoxy)-ethanol or a mixture thereof in the amount of 22-35 wt. % of the main solvent R; a complementary solvent, which is water or water with an acidity regulator in the amount of 22-30 wt. % of the main solvent R, wherein water with an acidity regulator is water with an organic or inorganic acid or a mixture thereof, approved for pharmaceutical use, wherein the main solvent R is optionally supplemented with water to obtain 100 wt. % of the main solvent R, wherein the pH of the main solvent R is in the range of pH 1.25-3.0, preferably has the pH in the range of 1.5-2.0; wherein, preferably, the liquid composition of PDE-5 inhibitor further contains pharmaceutically acceptable additives.

In the preferred liquid composition of PDE-5 inhibitors sildenafil citrate, sildenafil hydrochloride, vardenafil citrate, vardenafil hydrochloride or a mixture thereof is present.

In the preferred liquid composition of PDE-5 inhibitors sildenafil citrate is present.

In the preferred liquid composition of PDE-5 inhibitors, the composition comprises between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of sildenafil or a salt thereof, more preferably sildenafil citrate.

In the preferred liquid composition of PDE-5 inhibitors, the composition comprises between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of vardenafil or a salt thereof, more preferably vardenafil hydrochloride.

In the preferred liquid composition of PDE-5 inhibitors, the main solvent R is optionally additionally supplemented with an acidity regulator selected from a pharmaceutically acceptable organic acid, an inorganic acid or a mixture thereof to adjust the pH of the main solvent R to the pH in the range of 1.25- 3.0, preferably with the pH in the range 1 .5-2.0.

In the preferred liquid composition of PDE-5 inhibitors, the organic acid is selected from lactic acid, malic acid, tartaric acid, acetic acid, and the inorganic acid is selected from HCL, H3PO4, preferably is selected from lactic acid and/or HCL.

In the preferred liquid composition of PDE-5 inhibitors, the base solvent, which is benzyl alcohol, is in the amount of 18.5, 20, 25, 30, 35, 40, 45, 50, 55, 59 wt. % of the main solvent R.

In the preferred liquid composition of PDE-5 inhibitors, the co-solvent is 24-30 wt. %, preferably 25 wt. % of the main solvent R. In the preferred liquid composition of PDE-5 inhibitors, the co-solvent is anhydrous glycerin.

The liquid composition of PDE-5 inhibitors preferably further contains pharmaceutically acceptable additives in the amount of up to 20 wt. % of the composition, more preferably up to 10 wt. % of the composition.

In the preferred liquid composition of PDE-5 inhibitors, the additive is a sweetener, preferably selected from sucralose, steviol glycosides, sucrose, glucose, mannose, fructose or a mixture thereof, preferably a mixture of sucralose and steviol glycosides in a 1 to 1 ratio, preferably the sweetener is in the amount of 0.1-10 wt. % of the composition, more preferably in the amount of 2 wt. % of the composition.

In the preferred liquid composition of PDE-5 inhibitors, the additive is a flavor and fragrance substance, preferably selected from the flavor and fragrance substance of fruits, herbs or mixtures thereof, preferably selected from the aromas of fruits, apple, pear, apricot, cherry, plum, berries, strawberry, wild strawberry, raspberry, blueberry, currant, citrus fruits, orange, lemon, lime, grapefruit, mango, tangerine, banana, melon or mint, preferably the flavor and fragrance substance is in the amount of 0.1-10 wt. % of the composition, more preferably 4 to 7 wt. % of the composition.

In the preferred liquid composition of PDE-5 inhibitors, the additive is a thickener, preferably selected from alginate, carrageenan, guar gum, starch, xanthan gum, cellulose and derivatives thereof, polyacrylic acid in the amount of up to 20 wt. %, preferably 5 wt. %.

In the preferred liquid composition of PDE-5 inhibitors, the additive is a preservative, preferably selected from sodium benzoate, sorbate (sodium sorbate, potassium sorbate or a mixture thereof) in the amount of up to 1 wt. %, preferably 0.1 wt. %.

In the preferred liquid composition of PDE-5 inhibitors, the additive is a substance that increases adhesion to the mucous membrane, preferably selected from cellulose derivatives, starch, povidone, polyvinyl alcohol, hydroxypropyl methylcellulose HPMC with a concentration of 0.1 to 20 wt. %, more preferably hydroxypropyl methylcellulose HPMC at a concentration of 0.5 up to 20 wt. %

The liquid composition of PDE-5 inhibitors is preferably placed in a container with a throat atomizer dosing from 100 pl to 250 pl, most preferably 130-150 pl of the liquid composition per dose, preferably the dose comprises 5-50 mg, preferably 12.5-25 mg of sildenafil per dose.

The liquid composition of PDE-5 inhibitors is preferably placed in a container with a throat atomizer dosing from 100 pl to 250 pl, most preferably 130-150 pl of the liquid composition per dose, containing 12.5-25 mg of vardenafil per dose.

The invention also relates to a method of preparing a liquid composition of PDE-5 inhibitors, which includes the steps of: a) the main solvent R is prepared, with the pH of 1 .25-3.0, preferably with the pH in the range of 1.5-2.0, for this purpose, the base solvent, which is benzyl alcohol in the amount of 16.0-65 wt. % of the main solvent R, is mixed with a co-solvent, which is anhydrous glycerin, 2-(2-ethoxyethoxy)- ethanol or a mixture thereof in the amount of 22-35 wt. % of the main solvent R, with an complementary solvent, which is water or water with an acidity regulator in the amount of 22-30 wt. % of the main solvent R, wherein the water with the acidity regulator is water with an organic or inorganic acid or a mixture thereof, approved for pharmaceutical use; wherein the main solvent R is optionally supplemented with water to obtain 100 wt. % of the main solvent R, and wherein, optionally, the pH of the main solvent R is adjusted with the acidity regulator in the range of pH 1 .25-3.0, preferably to the pH in the range of 1 .5-2.0; b) to the main solvent R produced in a) PDE-5 is added in the amount of 13-42 wt. % of the composition, wherein PDE-5 is selected from sildenafil, vardenafil, salts thereof or a mixture thereof; c) the mixture from step b) is heated to a temperature in the range of 10-32°C, preferably to about 30°C±5% and brought to complete dissolution and homogeneity, preferably by mechanical mixing; d) optionally, the liquid composition is further supplemented with pharmaceutically acceptable additives, preferably in the amount of up to 20 wt. % of the composition, more preferably up to 10 wt. % of the composition.

Preferably, in step b), sildenafil citrate, sildenafil hydrochloride, vardenafil citrate, vardenafil hydrochloride or a mixture thereof is added, preferably sildenafil citrate.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors in step b) PDE-5 is added between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of the composition.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors in step a), the main solvent R is optionally additionally supplemented with an acidity regulator selected from an organic acid, an inorganic acid or a mixture thereof, approved for pharmaceutical use, to adjust the pH of the main solvent R, with the pH in the range of 1 .25-3.0, preferably pH in the range of 1 .5-2.0.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors, the organic acid is selected from lactic acid, malic acid, tartaric acid, acetic acid, and the inorganic acid is selected from HCL, H3PO4, preferably it is selected from lactic acid and/or HCL.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors in step a), benzyl alcohol is added in the amount to obtain 18.5, 20, 25, 30, 35, 40, 45, 50, 55, 59 wt. % of the main solvent R.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors, in step a) the co-solvent is added in the amount of 24-30 wt. %, preferably 25 wt. % of the main solvent R.

Preferably, in the method of preparing a liquid composition of PDE-5 inhibitors, in step a) anhydrous glycerin is added as a co-solvent.

In the preferred method of preparing a liquid composition of PDE-5 inhibitors, the composition is supplemented with an additive that is selected from:

- a sweetener, preferably selected from sucralose, steviol glycosides, sucrose, glucose, mannose, fructose or mixtures thereof, preferably a mixture of sucralose and steviol glycosides in a ratio of 1 to 1 , preferably the sweetener is in the amount of 0.1-10 wt. % of the composition, more preferably in the amount of 2 wt. % of the composition;

- a flavor and fragrance substance, preferably from fruits, herbs or mixtures thereof, preferably from fruit aromas, apple, pear, apricot, cherry, plum, berry fruit, strawberry, wild strawberry, raspberry, blueberry, currant, citrus fruit, orange, lemon, lime, grapefruit, mango, tangerine, banana, melon or mint, preferably the flavor and fragrance substance is in the amount of 0.1-10 wt. % of the composition, more preferably 4 to 7 wt. % of the composition;

- a thickener, preferably selected from alginate, carrageenan, guar gum, starch, xanthan gum, cellulose and derivatives thereof, polyacrylic acid in the amount of up to 20 wt. %, preferably 5 wt. %,

- a preservative, preferably selected from sodium benzoate, sorbate in the amount of up to 1 wt. %, preferably 0.1 wt. %,

- a substance that increases adhesion to the mucous membrane, preferably selected from cellulose derivatives, starch, povidone, polyvinyl alcohol, hydroxypropyl methylcellulose HPMC at a concentration of 0.1 to 20 wt. %, more preferably hydroxypropyl methylcellulose HPMC at a concentration of 0.5 to 20 wt. % of the composition.

Preferably, in the method after step c) or d), the composition is placed in a container dosing from 100 pl to 250 pl, more preferably 130-150 pl of the liquid composition per dose, preferably the dose comprises 5-50 mg, preferably 12.5-25 mg of PDE-5 per dose, preferably the dosing container is a throat atomizer.

The invention also relates to the liquid composition of PDE-5 inhibitors according to the invention and/or as prepared by the method according to the invention for use in the treatment of erectile dysfunctions in men.

Preferably, the composition in use is used in the form of an aerosol, atomizer, spray, suspension, drops, liquid for use in the oral cavity, more preferably for sublingual use, preferably in the form of an aerosol from a throat atomizer.

Preferably, the composition in use is used in the amount from 100 pl to 250 pl, more preferably 130-150 pl of liquid composition per dose, wherein, preferably the dose comprises 5-50 mg, preferably 12.5-25 mg of PDE-5 per dose.

Preferably, the composition in use is used in the form of an aerosol for sublingual use with a dose of 12.5- 25 mg of sildenafil citrate per dose.

When the term "comprising" or "including" is used in the description and claims, it does not exclude other elements. For the purposes of the present invention, the term "consisting of is considered to be a preferred embodiment of the term "comprising”, “including”. The terms "about" or "approximately" in the context of the present invention mean a range of precision that a person skilled in the art would understand to be sufficient to still provide the technical effect of the feature. The term "typically", "about" means a deviation from the indicated numerical value of ± 10%, preferably ± 5%.

Technical terms are used according to their typical meaning. If a specific meaning is used, the meaning will be described in detail with reference to the context in which the given term is used.

The research carried out by the inventors has shown that when the main solvent produced by combining solvents is used to dissolve the active substance: base solvent (SOLV-1): benzyl alcohol, with co-solvent (Co-SOLV-2) in the form of: glycerin, 2-(2-ethoxyethoxy)-ethanol or a mixture thereof, then combining with a supplementary solvent - water (Suppl-SOLV-3), preferably water with the addition of an organic or inorganic acid, allows for the obtaining the main solvent in which a solution of sildenafil citrate or avanafil hydrochloride in concentrations exceeding even 42% can be obtained. Additionally, the inventors found that it is important to maintain a low pH <3, and therefore, when necessary, organic and/or inorganic acid, especially lactic acid or hydrochloric acid (HCL), which have a positive effect on the stability of physical solutions of dissolved PDE-5 inhibitors are added. PDE-5 inhibitors are dissolved in the so-prepared mixture, at a temperature of 2-32°C, preferably about 30°C, and then cooled. The cooled solution is characterized by high thermodynamic stability. PDE-5 inhibitors do not crystallize over time, and various sweeteners and flavor-fragrance substances can be added to the mixture to produce a sensory- acceptable medicinal product used in the oral cavity in the form of an aerosol.

In one of the embodiments, a liquid composition of PDE-5 inhibitors was prepared, in which sildenafil citrate or vardenafil hydrochloride in the amount of 20 wt. % was dissolved in the main solvent, the main solvent contained: 18 wt. % of benzyl alcohol as (SOLV-1), 28% of glycerin (Co-SOLV-2), 4% of lactic acid (REG-pH-4) and from 25 wt. %, preferably 30% of water (Suppl-SOLV-3), wherein, if there are no other additives such as flavors, fragrances, sweeteners, adhesion enhancing substances, etc., water is added to 100 wt. % of the liquid composition.

The liquid compositions of PDE-5 according to the invention were prepared by adding the previously prepared main solvent R to a weighed amount of sildenafil and/or vardenafil or salts thereof, the mixture was heated in the range of 10-32°C, generally to about 30°C and allowed to completely dissolve and homogenize, e.g. by mechanical mixing.

The liquid compositions of PDE-5 according to the invention may contain various additives. To obtain a sweet taste of the composition, a sweetener can be added, for example sucralose and/or steviol glycosides, e.g. in a ratio of 1 to 1 with a weight share of 35 to 40% to the main solvent R, additionally, flavoring substances such as berry or citrus fruit or mint aromas can be used, preferably with a share of 5 to 7 wt. % of the composition.

To increase adhesion on the mucous membrane, adhesion-increasing substances are added to the composition, which are cellulose and starch derivatives or povidone or polyvinyl alcohol with a weight concentration of 0.1 to 20 wt. %. Hydroxypropyl methylcellulose HPMC at a concentration of 0.5 to 20 wt. % of the composition can also be used for this purpose.

Liquid compositions of PDE-5 according to the invention may contain preservative additives, e.g. sodium benzoate, sorbates in the amount of up to 1 wt. %, preferably 0.1 wt. %.

For convenient use of the liquid composition of PDE-5 inhibitors according to the invention, it is placed in a container with a throat atomizer dosing e.g. from 100 to 250 pl, most preferably about 130-150 pl, more preferably 140 pl, so that a single dose of PDE-5 active substance is between 5 a 50 mg, more preferably 12.5-25 mg, most preferably 12.5 mg.

It was unexpectedly found that the liquid composition of PDE-5 inhibitors according to the invention is characterized by faster bioavailability compared to traditional forms in the form of tablets, capsules or suspensions, i.e. active substances reach the desired concentration in the blood faster after applying the aerosol under the tongue than after swallowing a tablet or drinking a gel or administering a suspension. Moreover, it was found that the effect of PDE-5 inhibitors lasts longer. Therefore, a stable liquid composition of PDE-5 inhibitors was prepared for use in the treatment of erectile dysfunctions.

Additionally, the liquid composition of PDE-5 inhibitors according to the invention has the following preferable features:

• The liquid composition of PDE-5 inhibitors according to the invention is prepared without the use of ethanol and can be used for the production of medicines intended for the Muslim market (halal product).

• The medicinal product based on the liquid composition of PDE-5 inhibitors according to the invention is sensory acceptable - the taste of the product can be freely selected by adding various sweeteners and flavor-fragrance substances.

• The liquid composition of PDE-5 inhibitors according to the invention allows for the preparation of a medicinal product in the form of an aerosol administered to the oral cavity mucous membrane, e.g. as a sublingual application, in which the full dose of the medicinal product is achieved in just one or two applications.

• The liquid composition of PDE-5 inhibitors according to the invention allows the dissolution of very large amounts of PDE-5 inhibitors, even up to 42%, and therefore the active substance is in a high concentration, unknown for the compositions of this type for PDE-5 inhibitors.

When a medicinal product in the form of a liquid composition of PDE-5 inhibitors does not contain sugar, it can be safely used by people with diabetes because it does not contribute to changing the glycemic index.

DESCRIPTION OF DRAWINGS

For a better understanding of the invention, it has been illustrated in the non-limiting embodiments and in the accompanying figures, in which:

Fig. 1 shows: A) A chromatogram of the sample, i.e. the liquid composition of PDE-5 inhibitors according to the invention (2) with the superimposed chromatogram of the active substance (API) (1), B) A chromatogram of the sample, i.e. the liquid composition of PDE-5 inhibitors according to the invention (1) with the superimposed chromatogram of a placebo (2), C) A chromatogram of the sample, i.e. the liquid composition of PDE-5 inhibitors according to the invention (1) with the superimposed chromatogram of the solution A (2) and the solution B (3), D) A chromatogram of the sample (1) at the time TO (1) and the chromatogram of the sample after time T8 (2).

Fig. 2 shows the determined concentration of sildenafil citrate as results of a stability test of the prepared liquid composition of PDE-5 inhibitors according to the invention.

Fig. 3 shows the determined concentration of impurities in the stability test of the composition in Fig. 2.

EXAMPLES

The following examples were presented merely to illustrate the invention and to clarify its various aspects, but are not intended to be limitative, and should not be equated with all its scope, which is defined in the appended claims. In the following examples, unless it was otherwise indicated, standard materials and methods used in the field were used, or the manufacturers’ instructions for specific materials and methods were followed. Percentage shares, unless stated otherwise are indicated in weight (wt.) %.

I. Methods used

1.1. Method for determining phosphodiesterase type 5 (PDE-5) inhibitors and related substances:

For determining PDE-5, especially sildenafil in the form of various salts: sildenafil citrate and sildenafil hydrochloride, and impurities, the high-performance liquid chromatography method using a UV-VIS detector (HPLC-UV/VIS) was used in the finished product in the form of the physical solution (completely dissolved active substance).

This analytical method was developed by the authors and was used to determine the content of PDE-5, especially sildenafil, e.g. in the form of a salt with citric acid, and related products (impurities) in homogeneous physical solutions comprising sildenafil in the form of e.g. sildenafil citrate. For illustrative purposes, the following method description applies specifically to sildenafil only.

The assays were carried out using a liquid chromatograph with a UV-VIS or DAD detector (the maximum pressure during analysis is about 160 bar);

Chromatography was carried out under the following conditions:

• Column: COSMOSIL 5C18-AR-II; 250 mm x 4.6 mm; 5 pm or equivalent;

• Injection volume: 100 pl;

• Needle rinsing solution: H2O : ACN : MeOH (5:4:1 , v/v/v);

• Thermostat temperature 30°C;

• Autosampler temperature 20°C;

• Detection at A = 230 nm

• Slit width 1 .2 nm (for DAD detector);

• Reference beam disabled (for DAD detector);

• Data collection speed 1 ,56 Hz;

• Sampling speed 5 pl/s;

• Rinsing volume 500 pl;

• Flow rate of the mobile phase: 1 ,5 ml/min;

• Elution type: gradient.

Preparation of mobile phases:

Buffer solution: 2.72 g of potassium dihydrogen phosphate was dissolved in 900 ml of water and adjusted to pH = 6.5 (approximately 2.8 ml) with a solution (120 g/L) of potassium hydroxide. Filled with water to 1 L.

Mobile phase:

Phase A: Acetonitrile: Buffer solution (20:80, v/v)

Phase B: Methanol: Buffer solution: Acetonitrile (20:20:60, v/v/v) Gradient Slope: 0 (linear)

Time ( min) %A %B

0.00 25 75

3.00 25 75

26.00 70 30

30.00 70 30

32.00 25 75

40.00 25 75

In the case the system does not stabilize, the "post time" should be extended.

Preparation of working solutions

Solvent of samples and reference materials: mixture of Phase A and Phase B (3:1 , v/v).

Tested solution a: About 100 mg of the product was weighed into a 100 ml flask, filled to the mark (certified volume) with the solvent and mixed.

• The concentration of sildenafil citrate should be approx. 0.135 mg/ml.

Tested solution b: 0.5 ml of the tested solution a was taken into a 100 ml flask, filled to 100 ml with the solvent and mixed.

• The concentration of sildenafil citrate should be approx. 0.675 pg/ml = 675 ng/ml

To test the content, 3 independent solutions of the tested solutions were prepared.

Reference solution a: 2 mg of sildenafil impurity A were weighed into a 10 ml flask, filled to the mark (certified volume) with the tested solution and mixed. 1 ml was taken into a 20 ml flask, filled to the mark (certified volume) with the solvent and mixed.

• Sildenafil citrate concentration = 0.025 mg/ml.

• Impurity A concentration = 0.01 mg/ml

Reference solution b: 5 mg of sildenafil for peak identification (containing impurity D) was weighed into a 10 ml flask, filled to the mark (certified volume) with solvent and mixed.

• Impurity D concentration = 0.5 mg/ml

Reference solution c: 1 ml of the tested solution a was taken into a 100 ml flask, filled to the mark (certified volume) with the solvent and mixed. 1 ml of this solution was taken into a 10 ml flask, filled to the mark (certified volume) and mixed.

Sildenafil citrate concentration = 0.0005 mg/ml = 0.5 pg/ml (0.1% relative to the tested solution a)

A comparative solution c was prepared for each prepared tested solution.

The placebo solution should be prepared in the same way as the solution of the tested sample.

The limit concentration of 0.05% is 250 ng/ml.

The tested solution a, the reference solution b, c and the placebo solution were introduced onto the chromatographic column.

Calibration curve: About 10 mg of sildenafil citrate reference material was weighed into a 100 ml flask, filled to the mark (certified volume) with the solvent and mixed.

• Sildenafil citrate concentration = 0.1 mg/ml = 100 pg/ml 1 ml of the original solution was taken into a 10 ml volumetric flask, filled to the mark (certified volume) with the solvent and mixed.

• Sildenafil citrate concentration = 10 pg/ml

0.45 ml, 0.60 ml; 0.75 ml and 0.90 ml of standard solution (Sildenafil citrate at a concentration of 10 pg/ml) were taken, respectively, into 10 ml flasks, filled to the mark (certified volume) with the solvent and mixed. Calibration solutions were prepared:

K1 Sildenafil citrate = 0.45 pg/ml.

K2 Sildenafil citrate = 0.60 pg/ml.

K3 Sildenafil citrate = 0.75 pg/ml.

K4 Sildenafil citrate = 0.90 pg/ml.

K1 -K4 solutions are stable for 2 days at the autosampler temperature.

Calibration solutions K1-K4 were introduced onto the chromatographic column with a minimum of 3 injections of each solution.

Calculations were performed to determine the amount of sildenafil.

Based on the recorded chromatograms of standard and tested solutions, the content of sildenafil citrate in the finished product was calculated according to the following formula:

% Sildenafil citrate content = (Ax2000)/m where:

A - sample concentration determined from the curve in pg/ml; m- Sample weight, mg

2000- factor resulting from dilutions and unit changes

Related substances - impurities:

In the chromatogram of solutions tested to determine impurities, peaks originating from the solvent, placebo and citrate were omitted. Based on the recorded chromatograms of standard solutions and tested solutions, the content of a single impurity in the finished product was calculated according to the following formula:

% Impurities = (P_PX0.1XF)/P_WZ

Where:

Pp- Surface area of the impurity in the tested solution a,

Pwz- Surface area of sildenafil in the reference solution c,

F- Response factor: It is 1 for all impurities, for impurity D it is 0.7.

Identification and interpretation of the results: Peaks from the solvent, placebo, citrate should be omitted to calculate the content of impurity D, a correction coefficient of 0.7 should be used (multiply the surface area of impurity D by the coefficient) the value of impurities should be calculated based on the reference solution c.

I.2. Determination of crystallization of sildenafil in a physical solution

The crystallization of PDE-5, preferably sildenafil, was determined by observing the prepared solutions with unaided human eye at equal time points: just after preparation of the solution (0D), after one day (1 D), after 7 (7D), 14 (14D), 21 (21 D) days and after one month (30D) from the date of preparation when stored at 2°C and 25°C (room temp.). The assessment was performed by 4 independent people who assessed the formation of crystal structures or the turbidity of the solution.

1.3. Method of preparing liquid compositions of PDE-5 phosphodiesterase inhibitors

To prepare a liquid composition of phosphodiesterase type 5 inhibitors, which were sildenafil citrate, vardenafil hydrochloride, or mixtures thereof, the main solvent R was initially prepared, in which the appropriate phosphodiesterase type 5 (PDE-5) inhibitors were then dissolved.

To obtain the main solvent (labeled as R with a subsequent numerical index in the following embodiments), it was prepared from a base solvent (SOLV-1) mixed with a co-solvent (Co-SOLV-2) and an optional supplementary solvent (Suppl-SOLV-3), and an optional acidity regulator (REG-pH-4) in the form of e.g. lactic, malic, tartaric, acetic acid or inorganic acid in the form of, e.g., HCL, H3PO4, so as to achieve the pH in the range of 1.25-3.0. In some embodiments, the acidity regulator was added with the supplementary solvent or, if the pH of the solution was appropriate, it was not added. The prepared main solvent should have the pH of less than or equal to 3, preferably in the pH range of 1.25 to 3, most preferably in the pH range of 1 .5 to 2.0.

Liquid compositions of PDE-5 were prepared by adding the previously prepared main solvent R to a weighed amount of sildenafil and/or vardenafil or salts thereof, the mixture was heated in the range of 10- 32°C, generally to about 30°C, and brought to complete dissolution and homogeneity, e.g., by mechanical mixing.

Unexpectedly, it turned out that the solution prepared in this way, after complete dissolution of phosphodiesterase type 5 inhibitors and cooling, does not crystallize and remains stable for a long time - at least for 6 months, preferably for 8, 12, 24, 36 months from preparation.

Due to the fact that the prepared composition is intended for oral dosing, in order to improve the taste, smell and consistency, and therefore the texture and flavor-fragrance sensations, the composition was optionally prepared with an addition of flavor-fragrance additives, thickeners and other additives approved for food and pharmaceutical applications. For greater stability, the composition can be supplemented with preservatives known and approved for food and pharmaceutical applications. For higher adhesion to the oral cavity mucous membrane, it can be supplemented with substances known and approved for food and pharmaceutical applications, which increase adhesion, etc.

Therefore, as additional substances, i.e. additives and fillers, substances such as sweeteners, a sweetener sucralose and/or steviol glycosides, sucrose, glucose, mannose, etc. were used in a 1 to 1 ratio. Preferably, the sweeteners, before adding to the liquid composition of PDE-5 inhibitors, were dissolved in the main solvent R, preferably in the amount of 35 to 40 wt. % of the main solvent R, and then the liquid formulation was supplemented with such a solution to obtain an appropriately diluted final concentration of the sweetener. To improve the taste or smell, flavors and fragrances were added to the liquid composition of PDE-5 inhibitors, such as herbal and fruit aromas, fruit (apple, pear, apricot, banana), berry fruit (strawberry, raspberry, blueberry, currant) or citrus fruit (orange, lemon, lime, grapefruit) or mint, preferably with a share of 4 to 7%, preferably 5 wt. % of the liquid formulation of PDE- 5 were added at the very end of preparing the formulation. Cellulose and starch derivatives, povidone or polyvinyl alcohol with a concentration of 0.1 to 20 wt. %, or hydroxypropyl methylcellulose HPMC with a concentration of 0.5 to 20 wt. % were used as adhesion enhancing substances. These substances are added before or together with the aromatizing substances.

L4. Determination of the stability of the prepared liquid compositions of PDE-5 inhibitors Stability studies were conducted for 8 months based on ICH guidelines (Q1 A-Q1 F), WHO Annex 2.

IL Implementation examples

Example 1. Preparation of the composition with the main solvent R1

The main solvent R1 was prepared as described in the common methods from the ingredients shown in Table 1. After adding solvent R1 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months.

Example 2 Preparation of the liquid composition of PDE-5 inhibitors in the form of a pharmaceutical product for administration in the form of aerosol

Using the solvent R1 prepared as in Example 1 , a solution S1 R1 supplemented with sweeteners was prepared according to Table 2 below. Solvent R1 3 60

The composition of the pharmaceutical product produced for aerosol administration is presented in Table 3: The entirety was dissolved in a closed vessel at 30°C, cooled and poured into bottles with atomizers with a dose of 140 pl. As calculated, one dose (140 pl) contains 25 mg of sildenafil citrate.

Example 3 Preparation of the composition with the main solvent R2

The main solvent R2 was prepared as described in the common methods from the ingredients shown in Table 4. After adding the solvent R2 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months.

Example 4 Preparation of the composition with the main solvent R3 The main solvent R3 was prepared as described in the common methods from the ingredients shown in Table 5. After adding solvent R3 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months.

Example 5 Preparation of the composition with the main solvent R4 The main solvent R4 was prepared as described in the common methods from the ingredients shown in Table 6. After adding solvent R4 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months.

Example 6 Preparation of the composition with the main solvent R5 The main solvent R5 was prepared as described in the common methods from the ingredients shown in Table 7. After adding solvent R5 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months.

Example 7 Preparation of the composition with the main solvent R6

The main solvent R6 was prepared as described in the common methods from the ingredients shown in Table 8. After adding solvent R6 to sildenafil citrate and/or vardenafil hydrochloride, the mixture was heated to 30°C and stirred until completely dissolved. After complete dissolving, the solution did not crystallize after cooling and remained stable for a long time, as demonstrated by stability tests lasting 8 months. Example 8 Determination of the physicochemical characteristics of the prepared pharmaceutical forms of PDE-5 inhibitors

The composition from Example 1 containing sildenafil citrate at a concentration of 13.5 wt. % (the rest was filled up with a complementary solvent) was subjected to detailed stability tests based on the ICH guidelines (Q1A-Q1 F), WHO Annex 2 using the most drastic test conditions, i.e. 40°C, relative humidity 75%, wherein the recommended test duration was extended from 6 months to 8 months. The acceptance parameters were adopted in accordance with the requirements of the European Pharmacopoeia (Ph.Eur.) for sildenafil citrate (sildenafil citras Ph.Eur. 01/1017:2270), where: Content of impurity A, D: not more than 0.15%; Individual unspecified impurities: for each impurity, not more than 0.10%; Total impurities: not more than 0.5%; Omission cutoff: 0.05%.

Identification of the related substances was performed by recording the chromatogram of the sample, placebo, solvent, as well as pharmacopoeial (Ph.Eur.) reference materials: impurities A and D and a standard for identifying sildenafil peaks with other impurities. The results are summarized in Table 9. Fig. 1 A-D shows the recorded chromatograms at time TO (just after preparing the composition) and after 8 months of the stability test (time T8).

Table 9 Stability test results:

The average sildenafil citrate content was determined = 14.02%, Standard Deviation (SD) for sildenafil citrate content = 0.274, %RSD variability for sildenafil citrate content < 1 .95%.

Changes in the content of sildenafil citrate in the tested composition from the stability test are shown in Fig. 2.

Changes in the concentration of impurities arising during stability tests of the tested composition from Example 1. In the prepared composition of PDE-5 inhibitors, the content of impurities does not exceed the permissible 0.5%, what is in accordance with the pharmacopoeial (Ph.Eur.) requirements.

For the liquid composition of PDE-5 inhibitors prepared according to Examples 2-7, similar tests were performed and similar stability and impurity results were obtained. Example 9 Comparative example

Additionally, for the liquid formulation of PDE-5 inhibitors from Example 1 with a weight concentration of sildenafil citrate of 13.5%, comparative tests were performed with PDE-5 inhibitor compositions known in the art. The recipes of individual compositions were recreated in accordance with the given method of their preparation, always dissolving 13.5% of sildenafil citrate, so that they could be compared.

Table 10. Comparison of the liquid formulation of PDE-5 inhibitors with sildenafil citrate (API) according to the invention with other compositions known in the art

Example 9 Comparison of the biological action and physico-chemical properties of the PDE-5 composition

Biological effects of the PDE-5 liquid pharmaceutical composition according to the invention and compositions known from the state of the art were tested on healthy male volunteers aged 30-60 years. The most important features of the developed liquid pharmaceutical composition for selected phosphodiesterase type 5 inhibitors are presented below in relation to a classic hard tablet and a similar product described in publication WO 2011/156405A2. The same dose of API was compared, i.e. 25 mg of sildenafil (in the case of using PDE-5 salt, the administered dose was converted to sildenafil) in a single administration or in the physico-chemical test.

Table 11. Comparison of the properties of PDE-5 inhibitors compositions

The liquid composition of PDE-5 inhibitors according to the invention shows increased bioavailability, longer effect in the patient, is stable in storage, does not crystallize, has a higher concentration in liquid form, and therefore it is sufficient to administer it orally from an atomizer once or twice to obtain the target biologically effective dose, meets halal requirements.

Thus, an improved stable liquid composition of PDE-5 inhibitors has been prepared for use in the treatment of erectile dysfunctions.

LITERATURE

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Claims

1. A liquid composition of phosphodiesterase type 5 (PDE-5) inhibitors, characterized in that it comprises

PDE-5 in the amount of 13-42 wt. % of the composition, wherein PDE-5 is selected from sildenafil, vardenafil, salts thereof or mixtures thereof, a main solvent R, which consists of a base solvent, which is benzyl alcohol in the amount of 16.0-65 wt. % of the main solvent R; a co-solvent, which is anhydrous glycerin, 2-(2-ethoxyethoxy)-ethanol or a mixture thereof in the amount of 22-35 wt. % of the main solvent R; a complementary solvent, which is water or water with an acidity regulator in the amount of 22-30 wt. % of the main solvent R, wherein the water with the acidity regulator is water with a pharmaceutically acceptable organic or inorganic acid or a mixture thereof; wherein the main solvent R is optionally supplemented with water to obtain 100 wt. % of the main solvent R, wherein the pH of the main solvent R is in the range of pH 1 .25-3.0, preferably at pH in the range of 1.5-2.0; wherein, preferably, the liquid composition of PDE-5 inhibitors further comprises pharmaceutically acceptable additives.

2. The liquid composition of PDE-5 inhibitors according to claim 1 , characterized in that the PDE-5 is sildenafil citrate, sildenafil hydrochloride, vardenafil citrate, vardenafil hydrochloride or a mixture thereof.

3. The liquid composition of PDE-5 inhibitors according to claim 2, characterized in that the PDE-5 is sildenafil citrate.

4. The liquid composition of PDE-5 inhibitors according to claims 1-3, characterized in that it comprises between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of sildenafil or salts thereof, more preferably sildenafil citrate.

5. The liquid composition of PDE-5 inhibitors according to claims 1-4, characterized in that it comprises between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of vardenafil or salts thereof, more preferably vardenafil hydrochloride.

6. The liquid composition of PDE-5 inhibitors according to claim 1-5, characterized in that the main solvent R is optionally additionally supplemented with an acidity regulator selected from a pharmaceutically acceptable organic acid, an inorganic acid or a mixture thereof to adjust pH of the main solvent R at the pH in the range of 1 .25 - 3.0, preferably, pH in the range 1.5-2.0.

7. The liquid composition of PDE-5 inhibitors according to claim 6, characterized in that the organic acid is selected from lactic acid, malic acid, tartaric acid, acetic acid, and the inorganic acid is selected from HCL, H3PO4, preferably is selected from lactic acid and/or HCL.

8. The liquid composition of PDE-5 inhibitors according to claims 1-7, characterized in that the base solvent, which is benzyl alcohol, is in the amount of 18.5, 20, 25, 30, 35, 40, 45, 50, 55, 59 wt. % of the main solvent R.

9. The liquid composition of PDE-5 inhibitors according to claim 1-8, characterized in that the co-solvent is in the amount of 24-30 wt. %, preferably 25 wt. % of the main solvent R.

10. The liquid composition of PDE-5 inhibitors according to claims 1-9, characterized in that the cosolvent is anhydrous glycerin.

11. The liquid composition of PDE-5 inhibitors according to claims 1-10, characterized in that the composition further contains pharmaceutically acceptable additives, preferably in the amount of up to 20 wt. % of the composition, more preferably up to 10 wt. % of the composition.

12. The liquid composition of PDE-5 inhibitors according to claims 1-11 , characterized in that the additive is a sweetener, preferably selected from sucralose, steviol glycosides, sucrose, glucose, mannose, fructose or a mixture thereof, preferably a mixture of sucralose and steviol glycosides in a ratio of 1 to 1 , preferably the sweetener is in the amount of 0.1-10 wt. % of the composition, more preferably in the amount of 2 wt. % of the composition.

13. The liquid composition of PDE-5 inhibitors according to claims 1-12, characterized in that the additive is a flavor and fragrance substance, preferably selected from the flavor and fragrance substance of fruits, herbs or mixtures thereof, preferably selected from the aromas of fruits, apple, pear, apricot, cherry, plum, berries, strawberry, wild strawberry, raspberry, blueberry, currant, citrus fruits, orange, lemon, lime, grapefruit, mango, tangerine, banana, melon or mint, preferably the flavor and fragrance substance is in the amount of 0.1-10 wt. % of the composition, more preferably 4 to 7 wt. % of the composition.

14. The liquid composition of PDE-5 inhibitors according to claims 1-13, characterized in that the additive is a thickener, preferably selected from alginate, carrageenan, guar gum, starch, xanthan gum, cellulose and derivatives thereof, polyacrylic acid in the amount of up to 20%, preferably 5 wt. %.

15. The liquid composition of PDE-5 inhibitors according to claims 1-14, characterized in that the additive is a preservative, preferably selected from sodium benzoate, sorbate in the amount of up to 1 %, preferably 0.1 wt. %.

16. The liquid composition of PDE-5 inhibitors according to claims 1-15, characterized in that the additive is a substance that increases adhesion to the mucous membrane, preferably selected from cellulose derivatives, starch, povidone, polyvinyl alcohol, hydroxypropyl methylcellulose HPMC with a concentration of 0.1 to 20 wt. %, more preferably hydroxypropyl methylcellulose HPMC at a concentration of 0.5 to 20 wt. %.

17. The liquid composition of PDE-5 inhibitors according to claims 1-16, characterized in that it is placed in a container with a throat atomizer dosing from 100 pl to 250 pl, most preferably 130-150 pl of the liquid composition per dose, preferably the dose comprises 5-50 mg, preferably 12.5-25 mg of sildenafil per dose.

18. The liquid composition of PDE-5 inhibitors according to claims 1-17, characterized in that it is placed in a container with a throat atomizer dosing from 100 pl to 250 pl, most preferably 130-150 pl of the liquid composition per dose, containing 12.5-25 mg of vardenafil per dose.

19. A method of preparing a liquid composition of PDE-5 inhibitors, characterized by the steps in which: a) the main solvent R with the pH of 1.25-3.0 is prepared, preferably with the pH in the range of 1.5-2.0, for this purpose the base solvent, which is benzyl alcohol in the amount of 16.0-65 wt. % of the main solvent R, is mixed with a co-solvent, which is anhydrous glycerin, 2-(2-ethoxyethoxy)-ethanol or a mixture thereof in the amount of 22-35 wt. % of the main solvent R, with a complementary solvent, which is water or water with an acidity regulator in the amount of 22-30 wt. % of the main solvent R, wherein the water with the acidity regulator is water with an organic or pharmaceutically acceptable inorganic acid or a mixture thereof; wherein the main solvent R is optionally supplemented with water to obtain 100 wt. % of the main solvent R, wherein, optionally, the pH of the main solvent R is adjusted with the acidity regulator in the range of pH 1 .25-3.0, preferably to the pH in the range of 1 .5-2.0; b) to the main solvent R obtained in a) PDE-5 is added in the amount of 13-42 wt. % of the composition, wherein PDE-5 is selected from sildenafil, vardenafil, salts thereof or a mixture thereof, c) the mixture from step b) is heated to a temperature in the range of 10-32°C, preferably to about 30°C±5% and brought to complete dissolution and homogeneity, preferably by mechanical mixing; d) optionally, the liquid composition is further supplemented with additives approved for use in food and pharmaceutically acceptable, in the amount of up to 20 wt. % of the composition, more preferably up to 10 wt. % of the composition.

20. The method according to claim 19, characterized in that in step b) sildenafil citrate, sildenafil hydrochloride, vardenafil citrate, vardenafil hydrochloride or a mixture thereof is added, preferably sildenafil citrate.

21. The method according to claims 19-20, characterized in that in step b) PDE-5 is added between 13.5-41 wt. % of the composition, more preferably 20-40 wt. %, more preferably 25-38 wt. % of the composition.

T1

22. The method according to claims 19-21 , characterized in that in step a) the main solvent R is optionally additionally supplemented with an acidity regulator selected from an organic acid, an inorganic acid or a mixture thereof, approved for pharmaceutical use, to adjust the pH of the main solvent R with the pH in the range 1 .25-3.0, preferably pH in the range 1 .5-2.0.

23. The method according to claim 22, characterized in that the organic acid is selected from lactic acid, malic acid, tartaric acid, acetic acid and the inorganic acid is selected from HCL, H3PO4, preferably it is selected from lactic acid and/or HCL.

24. The method according to claims 19-23, characterized in that in step a) benzyl alcohol is added in the amount to obtain 18.5, 20, 25, 30, 35, 40, 45, 50, 55, 59 wt. % of the main solvent R.

25. The method according to claims 19-24, characterized in that in step a) the co-solvent is added in the amount of 24-30 wt. %, preferably 25 wt. % of the main solvent R.

26. The method according to claims 19-25, characterized in that in step a) anhydrous glycerin is added as a co-solvent.

27. The method according to claims 19-26, characterized in that the composition is supplemented with an additive selected from:

- a sweetener, preferably selected from sucralose, steviol glycosides, sucrose, glucose, mannose, fructose or a mixture thereof, preferably a mixture of sucralose and steviol glycosides in a ratio of 1 to 1 , preferably the sweetener is in the amount of 0.1-10 wt. % of the composition, more preferably in the amount of 2 wt. % of the composition;

- a flavor and fragrance substances, preferably from fruits, herbs or mixtures thereof, preferably from fruit aromas, apple, pear, apricot, cherry, plum, berry fruits, strawberry, wild strawberry, raspberry, blueberry, currant, citrus fruits, orange, lemon, lime, grapefruit, mango, tangerine, banana, melon or mint, preferably the flavor and fragrance substance is in the amount of 0.1-10 wt. % of the composition, more preferably 4 to 7 wt. % of the composition;

- a thickener, preferably selected from alginate, carrageenan, guar gum, starch, xanthan gum, cellulose and derivatives thereof, polyacrylic acid in the amount of up to 20%, preferably 5 wt. %,

- a preservative, preferably selected from sodium benzoate, sodium sorbate, potassium sorbate up to 1 wt. %, preferably 0.1 wt. %,

28. Method according to claims 19-27, characterized in that after step c) or d) the composition is placed in a container dosing from 100 pl to 250 pl, more preferably 130-150 pl of the liquid composition per dose, wherein, preferably, the dose comprises 5-50 mg, preferably 12.5-25 mg PDE-5 per dose, preferably the dosing container is a throat atomizer.

29. The liquid composition of PDE-5 inhibitors as defined in claims 1 -18 and/or as obtained by the method defined in claims 19-28 for use in the treatment of erectile dysfunctions in men.

30. The liquid composition of PDE-5 inhibitors for use according to claim 29, characterized in that it is used in the form of an aerosol, atomizer, spray, suspension, drops, liquid for use in the oral cavity, more preferably for sublingual use, preferably in the form of an aerosol from a throat atomizer.

31. The liquid composition of PDE-5 inhibitors for use according to claims 29-30, characterized in that it is used in the amount from 100 pl to 250 pl, more preferably 130-150 pl of the liquid composition per dose, wherein, preferably, the dose comprises 5-50 mg, preferably 12.5-25 mg PDE-5 per dose.

32. The liquid composition of PDE-5 inhibitors for use according to claims 29-31 , characterized in that it is in the form of an aerosol for sublingual use with a dose of 12.5-25 mg of sildenafil citrate per dose.