Patent Description:
The technical problem is connected with the disadvantages of liquid pharmaceutical compositions based on xylometazoline hydrochloride (<NUM>) which is, as an alpha-adrenergic receptors agonist or as sympathomimetic, commonly used for the topical, intranasal treatment of nasal congestion connected with rhinitis, rhinosinusitis, and sinusitis of various aetiologies, such as:.

The present invention solves the above-defined technical problem by parallel use of the optimal amount of hyaluronic acid (<NUM>) or its pharmaceutically acceptable salt such as sodium hyaluronate (2a) of relative molecular mass (Mr) < <NUM> (or low-molecular-weight hyaluronic acid; LMW HA), which improve liquid pharmaceutical compositions based on xylometazoline hydrochloride (<NUM>) in terms of quality, safety and efficacy:.

Compound <NUM>-[<NUM>-(<NUM>,<NUM>-dimethylethyl)-<NUM>,<NUM>-dimethylbenzyl]-<NUM>,<NUM>-dihydro-<NUM>-imidazole hydrochloride, known under the generic name xylometazoline hydrochloride (<NUM>), is a known and widely employed active pharmaceutical ingredient (API) of α-adrenergic activity. It is used as a vasoconstrictor in various indications connected with nasal congestion at rhinitis and sinusitis. In the prior art there is known that the xylometazoline imidazole ring is prone to hydrolysis yielding its degradation product N-(<NUM>-aminoethyl)-<NUM>-[<NUM>-(<NUM>,<NUM>-dimethylethyl)-<NUM>,<NUM>-dimethylphenyl]acetamide (<NUM>), which is commonly known as xylometazoline "Impurity A"; see, for instance, literature reference <NUM>:
<CHM>.

The solution from literature reference <NUM> is based on stabilising effect of sorbitol and/or glycerol in combination with inorganic or organic (trometamol) buffer on the hydrolysis of xylometazoline hydrochloride (<NUM>). The present invention is not based on either glycerol or sorbitol.

The solution from literature reference <NUM> is based on stabilising the effect of zinc salts such as zinc gluconate and a buffer salt against hydrolytic cleavage of xylometazoline hydrocholoride (<NUM>) to Impurity A (<NUM>). The present invention solves this technical problem without any zinc salt.

In the literature reference <NUM>, xylometazoline hydrochloride (<NUM>; <NUM>% w/w) solution was stabilised with panthenol (<NUM>% w/w). Herein, the synergic effect of panthenol with API <NUM> is claimed. The present invention is not based on the use of D-panthenol.

On the other hand, the main disadvantage of xylometazoline in therapy are its negative effects on the ciliary function of the nasal mucosa, and its inhibitory effect on granulocyte chemotaxis. The ciliary function is an important element of mucociliary transport which is responsible for airway clearance and the overall health of the upper respiratory system. In extreme cases, prolonged use of xylometazoline can lead to repeated nasal congestion, rhinitis medicamentosa, and atrophy of the nasal mucosa.

Hyaluronic acid (<NUM>; HA) is a normal ingredient of the mucus from the nasal mucosa, which by its humectant activity moisturizes and lubricates nasal mucosa and is an important regulator of inflammatory response. Compound <NUM> in the form of shorter polymeric chains, with low molecular weight <<NUM> kDa (LMW HA), stimulates the proliferation of mucosal cells, and thus stimulates its regeneration and migration of healthy cells which replace those damaged by different reactive oxygen species (ROS), which are generated upon the inflammatory process on the mucosa. Under the influence of the inflammatory process, its fragmentation to very short chains takes place, which stimulates nasal mucosa clearance, or ciliary beat frequency (CBF). Hyaluronic acid (<NUM>) or its pharmaceutically acceptable salts such as sodium hyaluronate (2a) have been used as part of the composition in various topical preparations for intranasal administration. Mostly those products are categorized as Medical Devices used to improve hydration and maintenance of nasal mucosa in a good state, as well as in the treatment of rhinosinusitis; see for instance literature references <NUM>-<NUM>:.

In literature reference <NUM>, the attempt is made to elucidate the mechanism behind HA-stimulated CBF increase by examining the effect of endogenous HA and exogenous high-molecular weight HA (HMWHA). No medicinal product formulation was used during those experiments, nor it was implied that HA might be used as an active pharmaceutical ingredient.

In literature reference <NUM>, patients with chronic rhinosinusitis were treated for <NUM> days per month (over <NUM> months) with <NUM> nebulized HA. The product used with HA in its composition was Yabro, IBSA Farmaceutici Italia, a medical device that contains HMWHA, and is used as adjunctive treatment of various respiratory tract diseases in children and adults, with the aim of restoration and maintenance of physiological conditions.

In literature reference <NUM>, patients with grade II nasal polyposis undergoing functional endoscopic sinus surgery were also treated with Yabro®, IBSA (<NUM> nebulized in <NUM> sodium chloride <NUM>%), twice a day, using the Fluirespira nasal douche device. The medical device Yabro has been used in most of the available trials assessing the use of HA in different nasal pathologies, mostly chronic and allergic rhinosinusitis. However, HA present in this product is not an active pharmaceutical ingredient and it also differs in terms of molecular weight, dose, dosage form, and posology from the composition that is disclosed in the present invention.

The compositions are based on a combination of one API xylometazoline hydrochloride (<NUM>) and hyaluronic acid as an inactive ingredient (excipient) (<NUM>) or its pharmaceutically acceptable salts such as sodium hyaluronate (2a), especially with high-molecular-weight (HMW) HA, have been described in the prior art, e.g., see literature references <NUM>-<NUM>:.

Typical products based on API <NUM> and HA as an excipient (<NUM>), like this disclosed in literature reference <NUM>, based on HMW HA. Also, the amount of the excipient used is <NUM> w/w. The composition from invention is not based on HMW HA, but on low-molecular-weight (LMW) HA (<NUM>) of Mr < <NUM>,<NUM> and with different amounts of LMW HA.

The solution from literature reference <NUM> is based on the use of a fixed combination of xylometazoline hydrochloride (<NUM>) and HA or its pharmaceutically acceptable salt, as an excipient. In contrast to the present invention, this document is silent about the stabilising effect of HA (<NUM>) on the hydrolysis of API <NUM> to impurity A (<NUM>).

The solution from literature reference <NUM> is based on the use of a ternary combination of sympathomimetic such as xylometazoline hydrochloride (<NUM>), D-panthenol (or pantothenic acid), and hyaluronic acid (<NUM>) or its salts. This document is considered the closest prior art document to the present invention. It deals with HMW HA of Mr from <NUM>,<NUM>-<NUM>,<NUM>,<NUM>. In contrast, the present invention is based on a binary fixed combination of API <NUM> and LMW HA (<NUM>) of Mr < <NUM>,<NUM>.

The composition based on a combination of two APIs, xylometazoline hydrochloride (<NUM>) and LMW hyaluronic acid (<NUM>) or its pharmaceutically acceptable salts, in particularly effective therapeutic concentrations, according to our best knowledge, has not been described for the treatment of rhinitis, sinusitis or rhinosinusitis of various aetiologies, including acute respiratory viral infection (ARVI). Besides this, the composition from the present invention significantly improves liquid pharmaceutical compositions based on xylometazoline hydrochloride as a single API (<NUM>) in terms of quality, safety, and efficacy:.

In this manner, the above-mentioned complex technical problem is solved by the present invention in a new and inventive way, as is disclosed in section Detailed Description of the Invention.

The present invention discloses an improved pharmaceutical composition for nasal use comprising:.

wherein said formulation exhibits increased stability of xylometazoline and increased mucociliary activity, an adequate level of viscosity not exceeding <NUM> mPas for efficient sterilisation filtration through <NUM> filter and for droplet size formation if used as a nasal spray, osmolality from <NUM>-<NUM> Osmol/kg and pH value of the said composition selected to be <NUM>-<NUM>, characterised by that the hyaluronic acid (<NUM>) or its pharmaceutically acceptable salt (2a) is used in a low-molecular-weight (LMW HA or SH) form, from <NUM>,<NUM> to <NUM>,<NUM> Daltons (Da).

The pharmaceutical composition according to the present invention contains xylometazoline hydrochloride (<NUM>) in a mass fraction from <NUM>-<NUM>% w/w, and hyaluronic acid (<NUM>) or sodium hyaluronate (2a) in a mass fraction above <NUM>% w/w and not exceeding <NUM>% w/w. Preferably, the pharmaceutical composition from the present invention contains two (<NUM>) active ingredients, (i) and (ii), and inactive excipients (iii) as given below:.

More preferably, the pharmaceutical composition from the present invention contains two (<NUM>) active ingredients, (i) and (ii), and inactive excipients (iii) as given below:.

Pharmaceutical composition from the present invention is used for the production of pharmaceutical products which are employed for the treatment of rhinitis, rhinosinusitis, sinusitis, nasal congestion connected with rhinitis, rhinosinusitis, and sinusitis of different aetiologies including acute respiratory viral infection (ARVI), and for restoring mucociliary activity.

wherein said formulation exhibits increased stability of xylometazoline and increased mucociliary activity, an adequate level of viscosity not exceeding <NUM> mPas for efficient sterilisation filtration through <NUM> filter, and droplet size formation when used as a nasal spray, osmolality from <NUM>-<NUM> Osmol/kg and pH value of the said composition selected to be <NUM>-<NUM>, characterised by that the hyaluronic acid (<NUM>) or its pharmaceutically acceptable salt (2a) is used in a low-molecular-weight (LMW HA or SH) form, from <NUM>,<NUM> to <NUM>,<NUM> Daltons (Da).

The pharmaceutical composition according to the present invention contains xylometazoline hydrochloride (<NUM>) in a mass fraction from <NUM>-<NUM>% w/w, and hyaluronic acid (<NUM>) or sodium hyaluronate (2a) in a mass fraction above <NUM>% w/w and not exceeding <NUM>% w/w.

API <NUM> as a starting material of pharmaceutical grade quality is used, which conforms to the specification defined by European Pharmacopoeia (Ph.

As API <NUM>, hyaluronic acid (<NUM>) or its pharmaceutically acceptable salts like sodium hyaluronate (2a) of pharmaceutical grade quality are employed, which are commercially available from different manufacturers worldwide.

Preferably, the pharmaceutical composition from the present invention contains two (<NUM>) active ingredients, (i) and (ii), and inactive excipients (iii) as given below:.

In a more preferred embodiment, the pharmaceutical composition from the present invention contains two (<NUM>) active ingredients, (i) and (ii), and inactive excipients (iii) as given below:.

Excipients are selected from the group comprising: purified water, tonicity adjusting agents, humectants, chelating agents, buffer salts, and preservatives.

Preferably, the pharmaceutical composition from the present invention contains excipients selected from the group comprising: purified water, sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl<NUM>), magnesium chloride (MgCl<NUM>), glycerol, <NUM>,<NUM>-propylene glycol, polyethylene glycol <NUM>, polyethylene glycol <NUM>, polyethylene glycol <NUM>, disodium edetate dihydrate (Na<NUM>EDTA•<NUM><NUM>O), sodium dihydrogenphosphate (NaH<NUM>PO<NUM>) or its monohydrate (NaH<NUM>PO<NUM>•H<NUM>O) or heptahydrate (NaH<NUM>PO<NUM>•<NUM><NUM>O), potassium dihydrogenphosphate (KH<NUM>PO<NUM>), disodium hydrogenphosphate dihydrate (Na<NUM>HPO<NUM>•<NUM><NUM>O), dipotassium hydrogenphosphate (K<NUM>HPO<NUM>) or its trihydrate (K<NUM>HPO<NUM>•<NUM><NUM>O), disodium citrate dihydrate (Na<NUM>C<NUM>H<NUM>O<NUM>•<NUM><NUM>O), tripotassium citrate monohydrate (K<NUM>C<NUM>H<NUM>O<NUM>•H<NUM>O), citric acid, benzalkonium chloride, chlorhexidine digluconate or dihydrochloride, benzethonium chloride, benzoic acid, sorbic acid, dehydroacetic acid, phenoxyethanol, and benzyl alcohol.

When the formulation is used as a nasal spray, equipped with the dosing device, pharmaceutical composition from the present invention exhibits such characteristics that generate aerosol whose droplet size distribution (DSD) is as given below:.

The process for the preparation of the pharmaceutical composition includes the following manufacturing steps:.

Typical preparations of various versions of the composition are disclosed in Examples <NUM>-<NUM>.

For a typical version of the composition from the present invention, P2, whose preparation is disclosed in Example <NUM>, stability testing was performed in comparison to the control formulation C from Example <NUM> and formulation P1 from the prior art (in line with reference <NUM>) that contains high molecular weight hyaluronic acid (HA; Mr = <NUM>,<NUM>,<NUM>). Sample were tested under an accelerated stability study according to ICH guidelines at <NUM> and <NUM>% RH during <NUM> months. The results of this study are presented in Table <NUM>, and <FIG>.

All excipients and their concentrations in the control formulation C, formulation P1 from the prior art, and formulation P2 from the present invention are the same.

The results of this study showed significantly increased stability of xylometazoline in the formulation from the present invention due to the presence of <NUM>% w/w low-molecular-weight (LMW) hyaluronic acid (<NUM>). The latter also acts as a stabilising agent which decreases the hydrolysis rate of compound <NUM> to impurity A (<NUM>). In this manner, LMW hyaluronic acid (<NUM>) stabilizes API <NUM> against its hydrolytic degradation.

The detailed protocol of the stability study of the composition from the present invention is described in Example <NUM>.

Pre-clinical study of the composition from the present invention as described in Examples <NUM> and <NUM> (formulation P2 and P3) was performed and compared with:.

against the parameter of ciliary beat frequency (CBF). The reason for the use of additional controls CAL and CLL was due to preliminary testing with MucilAir™ cultures and measurement of CBF parameter, where we found that treatment with CLL mildly increases CBF, as well as the basic control with untreated cells (CAL).

The starting hypothesis was that the difference between the CBF parameter of the cultures treated with tested compositions P2 and P3 and untreated (CAL) control will be higher than between tested nasal sprays (P2 and P3) and control treated with a common medium for the maintenance of such cultures (CLL). CBF parameter of the tested compositions P2 and P3 in comparison to P1 was also compared and the hypothesis could not be established based on available prior art. The results of this study are presented in Table <NUM>.

The results of the study showed that only both tested compositions P2 and P3 from the present invention do provide an increased mucociliary activity which is manifested through significantly increased CBF parameter. The key results of this study are presented in <FIG>, while the details of the study protocol are described in Example <NUM>.

In continuation of our research, an open, comparative, randomised, prospective, and multicenter-controlled clinical study on parallel groups was performed with the aim to study the safety and efficacy of:.

at patients with acute rhinitis with acute respiratory viral infection (ARVI) in the background.

Targeted population: adults (<NUM>-<NUM> years of age).

Group size involved in the study: <NUM> patients per group; overall <NUM> patients of both sexes.

Patients with a diagnosis of acute rhinitis connected with acute respiratory viral infection (ARVI) were included in the study in the phase of the disease not older than <NUM>. After the examination period, patients were randomised into the ratio <NUM>:<NUM>, in the group of treated with the testing composition and in the group with the control formulation C.

Study duration: for each group the treatment was no longer than <NUM> days, which is in accordance with typical therapeutic treatment for analogous products from the prior art based on xylometazoline hydrochloride (<NUM>; <NUM>/mL); see for instance literature reference <NUM>:
<NUM>) <NPL>.

Total study duration in patients was no longer than <NUM> days.

Intervention into the study: intranasal; <NUM> application with the nasal spray 3x per day. An interval among repeated applications was at least <NUM>. The daily dose was not higher than 3x applications in each nostril.

in patients with acute rhinitis connected with ARVI;.

The efficacy was confirmed on the basis of the following parameters:.

The severity of each symptom was evaluated on <NUM>-point scale as follows:.

The grading of dynamics of the quality of life was performed by scoring according to special scales and questionnaires.

Other details of the clinical study of the composition from the present invention are described in Example <NUM>.

Pharmaceutical composition from the present invention is used for the production of pharmaceutical products which are employed for the treatment of rhinitis, rhinosinusitis, sinusitis of different aetiologies including acute respiratory viral infection (ARVI), nasal congestion connected with rhinitis, rhinosinusitis, and sinusitis, and for restoring mucociliary activity.

Specifically, the composition from the present invention is for use in the treatment of nasal congestion connected with rhinitis, rhinosinusitis, and sinusitis.

All quantitative compositions are expressed as a mass fraction or weight percentages (% w/w) of each particular ingredient within the corresponding composition. The term "room temperature" is related to a temperature interval from <NUM>-<NUM>. A stirring rate of a mixing element is expressed in the number of revolutions per minute (r. The relative humidity is expressed with an abbreviation RH and expressed as a percentage (%) of relative humidity at a given temperature.

Various grades of sodium hyaluronate (2a) were purchased from Contripro a. , Czech Republic (EU).

Measurement of the droplet size distribution (DSD) of droplets generated during the application of the composition from the present invention in the form of a spray from an adequate dosing device, is conducted with the instrument Malvern Spraytec equipped with a Vereo NSx spray pump for activation under the following conditions:.

Viscosity is measured on Brookfield LV DV-II+Pro instrument equipped with UL-Y spindle at <NUM> r. and measurement during <NUM> seconds (single point measurement). The temperature of the samples was adjusted to <NUM> ± <NUM>. Sample size: <NUM> ± <NUM>.

Composition (<NUM> solution of a nasal spray):.

Preparation: To purified water (<NUM>; <NUM>% w/w), ingredients (<NUM>-<NUM>) were added and dissolved by stirring at <NUM>-<NUM> r. at room temperature during <NUM> minutes. Then, the rest of the purified water (<NUM>; <NUM>% w/w) was added, and homogenized by stirring for <NUM> minutes at room temperature. Thus, obtained solution was filtered through <NUM> polypropylene (PP) filter. Then, the solution was sterilized by passing through <NUM> polyvinylidene difluoride (PVDF) filter and filled into sterile containers with pumps under aseptic conditions.

The product is a clear, colourless solution, pH = <NUM>. Osmolality: <NUM> Osmol/kg. Analysis of droplet size distribution (DSD) at application gave the following result: DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>.

Preparation: To purified water (<NUM>; <NUM>% w/w), ingredients (<NUM>-<NUM>) were added and dissolved by stirring at <NUM>-<NUM> r. at room temperature for <NUM> minutes. Then, the rest of the purified water (<NUM>,<NUM>; <NUM>,<NUM>% m/m) was added, and homogenized by stirring for <NUM> minutes at room temperature. Thus, the obtained solution was filtered through <NUM> polypropylene (PP) filter. Then, the solution was sterilized by passing through <NUM> polyvinylidene difluoride (PVDF) filter and filled into sterile containers with pumps under aseptic conditions.

Preparation: To purified water (<NUM>; <NUM>% w/w), ingredients (<NUM>-<NUM>) were added and dissolved by stirring at <NUM>-<NUM> r. at room temperature for <NUM> minutes. Then, the rest of the purified water (<NUM>; <NUM>% w/w) was added, and homogenized by stirring for <NUM> minutes at room temperature. Thus, the obtained solution was filtered through <NUM> polypropylene (PP) filter. Then, the solution was sterilized by passing through <NUM> polyvinylidene difluoride (PVDF) filter and filled into sterile containers with pumps under aseptic conditions.

The product is a clear, colourless solution, pH = <NUM>. Osmolality: <NUM> Osmol/kg. Viscosity: <NUM> mPas. Analysis of droplet size distribution (DSD) at application gave the following result: DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>.

Preparation: To purified water (<NUM>; <NUM>% w/w), ingredients (<NUM>-<NUM>) were added and dissolved by stirring at <NUM>-<NUM> r. at room temperature for <NUM> minutes. Then, the rest of purified water (<NUM>; <NUM>% w/w) was added, and homogenized by stirring for <NUM> minutes at room temperature. Thus, the obtained solution was filtered through <NUM> polypropylene (PP) filter. Then, the solution was sterilized by passing through <NUM> polyvinylidene difluoride (PVDF) filter and filled into sterile containers with pumps under aseptic conditions. The product is a clear, colourless solution, pH = <NUM>. Osmolality: <NUM> Osmol/kg. Viscosity: <NUM> mPas. Analysis of droplet size distribution (DSD) at application gave the following result: DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>.

Composition (<NUM> solution of a nasal drops):.

Composition (<NUM> solution of nasal wash):.

Preparation: To purified water (<NUM>; <NUM>% w/w), ingredients (<NUM>-<NUM>) were added and dissolved by stirring at <NUM>-<NUM> r. at room temperature for <NUM> minutes. Then, the rest of purified water (<NUM>; <NUM>% w/w) was added, and homogenized by stirring for <NUM> minutes at room temperature. Thus, the obtained solution was filtered through <NUM> polypropylene (PP) filter. Then, the solution was sterilized by passing through <NUM> polyvinylidene difluoride (PVDF) filter and filled into sterile containers with pumps under aseptic conditions. The product is a clear, colourless solution, pH = <NUM>. Analysis of droplet size distribution (DSD) at application gave the following result: DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>, DSD(<NUM>)= <NUM>.

A typical variant of the composition from the present invention P2, whose preparation is disclosed in Example <NUM>, was tested for stability against prior art formulations: an analogous control formulation C from Example <NUM> and formulation P1 as disclosed in Example <NUM>. The samples were subjected to an accelerated stability study according to ICH guidelines at <NUM> and <NUM>% RH for <NUM> months.

The content of xylometazoline hydrochloride (<NUM>) was determined by the use of ultra-high-performance liquid chromatography (UPLC) with photo-diode array/diode-array detector (PDA/DAD) at <NUM> with a detection option between <NUM>-<NUM>. The column was fluorophenyl derived stationary phase with reverse-phase mode, at <NUM>, with a flow of <NUM>/min, and a run time <NUM>. The mobile phase consisted of phase A and phase B of the following composition:.

where the phosphate buffer was <NUM> potassium dihydrogenphosphate (KH<NUM>PO<NUM>) solution, pH = <NUM>, and the composition of mobile phase was gradually modified as follows:.

A commercially available analytical standard of xylometazoline hydrochloride (<NUM>) was employed as a standard for the preparation of the reference solution.

Samples and reference solution were dissolved in solvent A up to a theoretical xylometazoline concentration of <NUM>/mL. For the calculation of xylometazoline content, areas of the reference solution and test samples were compared.

For analysis of impurity A (<NUM>) the same method was employed as for the determination of xylometazoline content, but the run time was extended from <NUM> to <NUM> minutes. Within this extended run time, the composition of the mobile phase was the same as for xylometazoline determination at <NUM> minutes. As a standard, the commercially available analytical standard of compound <NUM> was used as a primary standard. Sample solutions and reference substances solutions were prepared in solvent A as follows:.

The content of impurity A (<NUM>) was determined by discarding all the peaks that appear in the chromatogram of the placebo solution, and the areas under the peaks in the reference solution and the test sample were compared and multiplied by the correction factor as stated below:.

The same UPLC device with said DAD detector was employed for this analysis, at a wavelength of <NUM>, with C18 reverse-phase column, at a temperature of <NUM>, with a run time of <NUM> minutes. The mobile phase consisted of two solvents, A and B, of the following composition:.

with the following gradient composition of the resulting mobile phase and employed flows:.

The phosphate buffer was <NUM> potassium dihydrogenphosphate (KH<NUM>PO<NUM>) solution of pH = <NUM>. A solution of potassium hydroxide R of <NUM>/L concentration in water for chromatography was prepared. As a standard for the preparation of reference solution, sodium hyaluronate (2a) with molecular weight (MW) of <NUM>-<NUM> Da (<NUM>-<NUM> kDa), with declared 2a content.

The sample solution and reference solution were prepared in R water for chromatography so that the theoretical sodium hyaluronate (2a) concentration was <NUM>/mL. To calculate the content of sodium hyaluronate (2a), the areas under the corresponding peaks of reference and test samples solutions were compared.

Key results of the stability study of the composition from the present invention are presented in Table <NUM>.

Pre-clinical study of the composition from the present invention analogous to the products from Examples <NUM> and <NUM> (P2 and P3) was performed in comparison to prior art compositions:.

where the parameter ciliary beat frequency (CBF) was determined.

The aim of this study was to confirm the assumed positive influence of hyaluronic acid (<NUM>) on mucociliary activity compared to xylometazoline (<NUM>) itself and to find the appropriate dose (concentration) of hyaluronic acid in the formulation. For this purpose, the MucilAir™ in vitro model was used. It represents a 3D model of human epithelium that is prepared from cells originating from different donors and was developed for respiratory pharmacology research.

The results of this study are presented in Table <NUM>.

An open, comparative, randomised, prospective, and multicenter-controlled clinical study on parallel groups was performed to study the safety and efficacy of:.

Patients with a diagnosis of acute rhinitis connected with acute respiratory viral infection (ARVI) were included in the study in the phase of the disease not older than <NUM>. After the examination period, patients were randomised into the ratio of <NUM>:<NUM> in the group treated with the testing composition and in the group with the control formulation C.

Study duration: for each group the treatment was no longer than <NUM> days, what is in accordance with typical therapeutic treatment for analogous products from the prior art based on xylometazoline hydrochloride (<NUM>; <NUM>/mL); see for instance literature reference <NUM>. The total study duration in patients was no longer than <NUM> days.

Inclusion criteria: written consent of the patient included in the study; patients aged <NUM>-<NUM> years, of both sexes; diagnosis of "acute rhinitis" according to clinical indications that the underlying cause is ARVI; nasal clearance not less than <NUM> according to VAS <NUM>-<NUM>; presence of at least two (<NUM>) ARVI symptoms: cough, runny nose, headache, pain in muscles or eyeballs, weakness, fever or chills; duration of illness not longer than <NUM>; the sum of points on the TNSS scale <NUM> or less; patients who did not receive therapy with antiallergic or antibacterial drugs within previous <NUM>; consent to the use of suitable contraceptive methods from the moment of examination during the study, until the moment of its completion; the patient understands the requirements of the study and agrees to all the restrictions it requires; and a negative pregnancy test.

Exclusion criteria: allergy and suspicion of allergy to any of the ingredients of the composition or similar products; allergic and/or chronic rhinitis; ophthalmic symptoms (itching, pain or watery eyes); confirmed bacterial aetiology of rhinitis; chronic, vasomotor and atrophic rhinitis; suspected meningococcal infection; temperature above <NUM>; injuries of the nose, polyposis, curvature of the nasal septum or other anomalies of the nasal cavity or nasopharynx; asthma; condition after meningeal surgery; hypophysectomy or other trans-nasal operations; participation in studies with other drugs at the same time or within <NUM> days before the start of the present study; pregnancy or breastfeeding; predisposition to nosebleeds, cystic fibrosis, paralytic intestinal obstruction, sensitivity to adrenergic drugs; the necessity of taking drugs that are not approved by the protocol of this study; acute productive mental symptoms: psychosis, delirium, hallucinations; hyperthyroidism; arterial hypertension, tachycardia, history of ischemic heart disease, severe atherosclerosis; increased intraocular pressure, glaucoma; hyperplasia of the prostate; porphyria; history of chronic alcoholism, addiction to drugs or other chemical agents; hesitancy to enter the clinical trial; inability or unwillingness to understand the rules for participating in the study; serious, decompensated or unstable somatic disease: cirrhosis of the liver, HIV infection, syphilis, hepatitis B and C, diabetes, urethral stenosis, prostatic hyperplasia, or any other disease or condition, which may cause, in the opinion of the researcher, a difficult interpretation of treatment results during the study.

Claim 1:
An improved pharmaceutical composition for nasal use comprising two active ingredients (i) and (ii):
(i) xylometazoline hydrochloride <<NUM>>,
(ii) hyaluronic acid <<NUM>; HA> or its pharmaceutically acceptable salts such as sodium hyaluronate <2a; SH>:
<CHM>
and,
(iii) one or more excipients required for the preparation of sterile final dosage forms for nasal use selected from the group consisting of: nasal drops, nasal wash, and nasal spray intended for single or multiple use from the corresponding container;
wherein said formulation exhibits increased stability of xylometazoline and increased mucociliary activity, osmolality from <NUM>-<NUM> Osmol/kg and pH value of the said composition selected to be <NUM>-<NUM>, characterised by that the hyaluronic acid <<NUM>> or its pharmaceutically acceptable salt 2a is used in a low-molecular-weight <LMW HA or SH> form, from <NUM>,<NUM>-<NUM>,<NUM> Daltons.