EA037259B1 - Use of a fixed dose pharmaceutical composition comprising mometasone and azelastine in treating allergic rhinitis and method of treating allergic rhinitis - Google Patents

Abstract

The invention relates to the use of a fixed dose pharmaceutical composition comprising mometasone and azelastine in treating allergic rhinitis and a method of treating allergic rhinitis. The invention allows to increase the effectiveness of treating allergic rhinitis.

Description

Priority document

This patent application claims priority based on Indian Provisional Patent Application No. 3454 / MUM / 2012 (filed December 6, 2012) and Brazilian patent application No. BR 1020130008303 (filed January 11, 2013), the contents of which are incorporated herein through links.

Technology area

This patent application relates to a fixed dose pharmaceutical composition containing mometasone and azelastine. In particular, this patent application provides a stable, fixed dose pharmaceutical composition in the form of a nasal spray containing mometasone or a salt thereof and azelastine or a salt thereof, a method for preparing such a composition, and its use for treating rhinitis in a subject.

State of the art

Rhinitis is the medical term for irritation and inflammation of the nasal mucosa. Rhinitis can cause additional symptoms such as sneezing and itchy nose, cough, headache, fatigue, discomfort, and cognitive impairment.

Mometasone furoate is a glucocorticosteroid used topically to reduce skin inflammation or inflammation in the airways. Mometasone furoate is a prodrug, the free form of which is mometasone. Mometasone furoate, commercially available as NASONEX® (sold by Schering) as a nasal spray for the treatment of upper respiratory tract conditions such as sinus inflammation. It is approved for the treatment of nasal symptoms of allergic rhinitis, nasal congestion associated with seasonal allergic rhinitis, nasal polyps, and prevention of seasonal allergic rhinitis.

NASONEX® Nasal Spray (Mometasone Furoate Nasal Spray) 50 μg is a dispensing hand-held nebulizer containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w / w, mometasone furoate, anhydrous, in an aqueous medium containing glycerin, microcrystalline cellulose and sodium carboxymethyl cellulose, sodium citrate, citric acid, benzalkonium chloride and polysorbate 80. The pH ranges from 4.3 to 4.9.

Azelastine is (±) -1- (2H) -phthalazinone, 4 - [(4-chlorophenyl) methyl] -2- (hexahydro-1methyl-1H-azepin-4-yl) -, monohydrochloride. Azelastine hydrochloride is commercially available in the United States as ASTELIN® (azelastine hydrochloride) nasal spray, 137 μg, which is an antihistamine formulated as a metered-dose solution for intranasal administration. ASTELIN® Nasal Spray contains 0.1% azelastine hydrochloride in aqueous solution at pH 6.8 ± 0.3. This nasal spray also contains benzalkonium chloride (125 μg / ml), disodium edetate, hypromellose, citric acid, sodium hydrogen phosphate, sodium chloride and purified water. After initial filling, an average volume of 0.137 ml is delivered with each metered spray, containing 137 μg azelastine hydrochloride (equivalent to 125 μg azelastine base). This nasal spray is indicated for the treatment of symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing and itching in the nose in adults and children 5 years of age and older and for the treatment of symptoms of vasomotor rhinitis such as rhinorrhea, nasal congestion and postnasal syndrome in adults and children. 12 years and older.

European Patent Application Publication No. EP 0780127 A1 discloses a pharmaceutical composition comprising (a) a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, their pharmaceutically acceptable salts and mixtures of these compounds; (b) an antihistamine that inhibits leukotrienes selected from the group consisting of cetirizine, loratadine, azelastine, their pharmaceutically acceptable salts, their optically active racemic mixtures and mixtures of these compounds; and (c) an intranasal vehicle.

European Patent Application Publication No. EP 2072051 A1 discloses a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and mometasone or a pharmaceutically acceptable ester thereof.

In the publication of international application WO 2012074231 proposed a pharmaceutical composition for nasal administration, containing mometasone furoate and azelastine hydrochloride, and also containing thaumatin as an agent for reducing bitter taste and irritation.

However, there remains a need for an effective therapeutic treatment for rhinitis.

Brief description of the invention

The present invention relates to a fixed dose pharmaceutical composition in the form of a nasal spray that contains mometasone and azelastine.

In one embodiment, the present invention provides a fixed dose pharmaceutical composition in the form of a nasal spray containing an effective amount of mometasone or a salt thereof and azelastine or a salt thereof.

In another embodiment, the present invention relates to a pharmaceutical composition with

- 1,037259 a fixed dose containing from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof and a pharmaceutically acceptable excipient, said composition being administered as one spraying into each nasal opening twice a day to a subject in need of it. In one aspect of an embodiment of the present invention, the pharmaceutical composition comprises mometasone or a salt thereof, said compound being present in an amount from about 0.05 to about 1% by weight. In one aspect of an embodiment of the present invention, the pharmaceutical composition comprises azelastine or a salt thereof, said compound being present in an amount from about 0.1 to about 1% by weight.

In another embodiment, the present invention provides a fixed dose pharmaceutical composition comprising from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof in a weight ratio range from about 1: 1 to about 1: 5 and a pharmaceutically acceptable excipient, and the specified composition is administered in the form of one spray into each nasal opening twice a day to a subject in need thereof. In one aspect of this embodiment, each spray of the composition delivers about 50 μg of mometasone furoate and about 140 μg of azelastine hydrochloride.

In a specific embodiment, the present invention provides a fixed dose pharmaceutical composition comprising about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, said composition being administered as a single spray to each the nasal opening twice a day to a subject in need of it.

In a specific embodiment, the present invention provides a fixed dose pharmaceutical composition comprising about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride and neotame, said composition being administered as a single spray to each nasal opening two once a day to a subject in need of it.

In another embodiment, the present invention provides a fixed dose pharmaceutical composition comprising from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof and an excipient, selected from the group consisting of sodium carmellose, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotam and citric acid, or mixtures thereof.

In a specific embodiment, the present invention relates to a stable pharmaceutical composition with a fixed dose containing about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, as well as water, said composition being administered as a single spray into each nasal opening twice a day to a subject in need thereof.

In one embodiment, the stable, fixed dose pharmaceutical composition of the present invention has a pH in the range of about 4.0 to about 5.0, an osmolality in the range of about 270 to about 370 mosm, a viscosity in the range of about 50 to about 100 cps and weight / ml ranging from about 0.90 to about 1.20 g / ml.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07 % by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07 % by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

In another embodiment, the present invention relates to a method for alleviating nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal a spray containing about 0.07% by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, or

- 2 037259 monic acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

In another embodiment, the present invention relates to a method for treating rhinitis in a subject by alleviating nasal and non-nasal symptoms associated with rhinitis (such as sneezing, itchy nose, rhinorrhea, nasal obstruction, itchy eyes, excess lacrimation, etc.), a subject in need thereof, said method comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07% by weight of mometasone furoate, about 0, 2% by weight azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

Rhinitis in the context of the present invention includes, but is not limited to, irritation and inflammation of the nasal mucosa and the resulting nasal and non-nasal symptoms. Rhinitis includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infectious rhinitis, vegetative rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis, and their associated nasal and non-nasal symptoms.

In the context of the present invention, nasal and non-nasal symptoms associated with rhinitis include sneezing, itchy nose, rhinorrhea (runny nose), nasal obstruction, cough, itchy eyes, watery eyes, headache, fatigue, cold (also known as nasopharyngitis, rhinopharyngitis, acute viral rhinopharyngitis or catarrh of the upper respiratory tract), malaise and cognitive impairment.

Detailed description of the invention

The terms used in this application are defined as follows. If the definition given in this application and the definition given earlier in the provisional application, on the basis of which priority is claimed, contradict each other, the meaning of the terms should be determined by the definition in this application.

Definitions

The term effective amount or therapeutically effective amount means the amount of active ingredient that, when administered to a subject for treating rhinitis, provides the intended therapeutic effect in the subject. In this application, the term active ingredient (used interchangeably with active or active substance or drug) includes mometasone, azelastine, or a pharmaceutically acceptable salt of these compounds.

Salt or pharmaceutically acceptable salt means those salts and esters that, after careful medical evaluation, are suitable for use in contact with tissues of humans and lower animals in the absence of nonspecific toxicity, irritation and allergic reaction, correspond to a reasonable benefit / risk ratio and are effective in intended use. Typical acid addition salts include hydrochloride, furoate, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate tartrate, ascorbate, glucoheptonate, lactobionate and lauryl sulfate. Typical alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.

In this application, the term curative or treatment also encompasses prevention, amelioration, prevention, amelioration or suppression of a disorder modulated by mometasone or azelastine, or a combination of both, in a mammal.

The term “subject” includes mammals like humans and other animals such as pets (eg, pets, including cats and dogs) and non-domestic animals (such as wild animals). Preferably, the subject is a human.

By pharmaceutically acceptable excipients is meant any of the components of the pharmaceutical composition other than the active components that are approved by regulatory authorities or are generally considered safe for human or veterinary use.

A therapeutically effective amount of mometasone (or a pharmaceutically acceptable salt thereof) for administration per day may range from about 100 to about 500 μg, preferably from about 200 to about 400 μg. Preferably, individual dosages of mometasone (or a pharmaceutically acceptable salt thereof) can be about 25 μg, about 50 μg, about 75 μg, and about 100 μg.

A therapeutically effective amount of azelastine (or a pharmaceutically acceptable salt thereof) for administration per day may range from about 300 to about 2000 μg, preferably from about 500 to about 1800 μg. Preferably, individual dosages of azelastine (or a pharmaceutically acceptable salt thereof) for administration per day can be about 100 mcg, about 125 mcg, about 140 mcg, about 150 mcg, about 200 mcg, about 275 mcg, about 300 mcg, and about 500 mcg.

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Combinations

The present invention relates to a fixed dose pharmaceutical composition in the form of a nasal spray that contains mometasone and azelastine.

In one embodiment, the present invention provides a fixed dose pharmaceutical composition in the form of a nasal spray containing an effective amount of mometasone or a salt thereof and azelastine or a salt thereof.

The inventors have surprisingly found that for the combination therapy of mometasone or a salt thereof and azelastine or a salt thereof in a subject suffering from allergic rhinitis, a particular dosing regimen (i.e., one spray into each nasal opening twice a day) is more effective than both. separate groups of monotherapy, while the other dosing regimen (ie, two sprays into each nasal opening once a day) unexpectedly did not show such better efficacy in treating allergic rhinitis in a subject.

Thus, in one embodiment, the present invention provides a fixed dose pharmaceutical composition comprising from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof and a pharmaceutically acceptable excipient, said composition being administered as a single spray into each nasal opening twice a day to a subject in need thereof. In one aspect of an embodiment of the present invention, the pharmaceutical composition comprises mometasone or a salt thereof, said compound being present in an amount from about 0.05 to about 1% by weight. In one aspect of an embodiment of the present invention, the pharmaceutical composition comprises azelastine or a salt thereof, said compound being present in an amount from about 0.1 to about 1% by weight.

In another embodiment, the present invention provides a fixed dose pharmaceutical composition comprising from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof in a weight ratio range from about 1: 1 to about 1: 5 and a pharmaceutically acceptable excipient, and the specified composition is administered in the form of one spray into each nasal opening twice a day to a subject in need thereof. In one aspect of this embodiment, each spray of the composition delivers about 50 μg of mometasone furoate and about 140 μg of azelastine hydrochloride.

In a specific embodiment, the present invention provides a fixed dose pharmaceutical composition comprising about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride, as well as a pharmaceutically acceptable excipient, said composition being administered as a single spray into each nasal opening twice a day to a subject in need of it.

In a specific embodiment, the present invention provides a fixed dose pharmaceutical composition comprising about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride, as well as neotame, said composition being administered as a single spray to each nasal hole twice a day to a subject in need of it.

In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 to about 2% by weight of mometasone or a salt thereof and from about 0.05 to about 2% by weight of azelastine or a salt thereof, as well as an auxiliary a substance selected from the group consisting of sodium carmellose, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotam and citric acid, or a mixture of these compounds.

In a specific embodiment, the present invention relates to a stable pharmaceutical composition with a fixed dose containing about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, as well as water, said composition being administered as a single spray into each nasal opening twice a day to a subject in need thereof.

In one embodiment, the stable, fixed dose pharmaceutical composition of the present invention has a pH in the range of about 4.0 to about 5.0, an osmolality in the range of about 270 to about 370 mosm, a viscosity in the range of about 50 to about 100 cps and weight / ml ranging from about 0.90 to about 1.20 g / ml.

As mentioned above, the pharmaceutical composition contains at least one pharmaceutically acceptable excipient, which includes, but is not limited to, one or more of the following groups of substances: preservatives, buffering agents, chelating agents, polymers, surfactants, sweeteners, solvents and etc.

Examples of suitable buffering agents can be selected from, but are not limited to, phosphate, borate, sodium citrate, and other organic acids like citric acid; carbohydrates dextrose, mannose or dextrins; and the like.

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Examples of suitable water-soluble polymers can be selected from, but are not limited to, polyhydric alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, 1,2,6-hexanetriol, and thioglycol , alginic acid, polyoxyethylene polyoxypropylene glycol, pectin, low methoxylated pectin, guar gum, gum arabic, carrageenan, cellulose derivatives such as sodium carmellose, methyl cellulose, sodium carboxymethyl cellulose, xanthan gum, hydroxypropyl cellulose, or a mixture of these compounds. The aforementioned polyoxyethylene polyoxypropylene glycol is a family of polymers in which ethylene oxide is polyadded to a polypropylene glycol obtained by polymerizing propylene oxide, and which are classified into several types according to the difference in the average degree of polymerization of propylene oxide and ethylene oxide. Particularly preferred water-soluble polymers are polyhydric alcohols such as polyethylene glycol, propylene glycol, glycerin, and cellulose derivatives such as hydroxypropyl methylcellulose. The amount of water-soluble polymer can range from about 0.001% to about 30% w / w. relative to the total mass of the solution.

Suitable surfactants that can be used may include one or more anionic, cationic, nonionic, or zwitterionic surfactants.

Examples of suitable surfactants can be selected from, but are not limited to, polyethoxylated sorbitan derivatives such as polysorbates, ether ethoxylates obtained by reacting sorbitol esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene acetyl ether, polyoxyethylene ethylene alkyloxy polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecyl ether, polyoxyethylene and mixed fatty acid esters of sorbitol e.g. polysorbates), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxye tilenoleilovogo ether polioksietilentridetsilovogo ester, polyoxyethylene fatty alcohol, polyoxyethylene alkylamines, polyoxyethylene monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polioksietilenoksipropilena stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivatives, sodium oleate, quaternary ammonium derivatives, potassium oleate, N-tsetilN-ethylmorpholine ethosulfate, sodium lauryl sulfate or mixtures of these compounds. Particularly preferred surfactants are polyethoxylated sorbitan derivatives.

Examples of suitable preservatives that can be used can be selected from, but are not limited to, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, edetate disodium. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium-1 and benzalkonium halides. The preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide.

Examples of suitable chelating agents that can be used may be selected from, but are not limited to, disodium edetate (EDTA), trisodium edetate, tetrasodium edetate, and diethyleneamine pentaacetate, preferably EDTA.

Examples of suitable sweeteners that can be used may be selected from, but are not limited to, sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotam, mannitol, menthol, eucalyptus oil, camphor.

Examples of suitable solvents are all solvents which are suitable for nasal administration, in particular water and alcohols such as, for example, ethanol, propanol, propanediol or glycerin.

The optimal dose of the active ingredient or combination of active ingredients may vary depending on the severity of the disease, the route of administration, the type of composition, the patient's body weight, the patient's age and general state of mind, and the response to the action of the active ingredient or combination of active ingredients.

The method for preparing a pharmaceutical composition according to the description comprises mixing a pharmaceutically acceptable carrier with (i) mometasone, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) azelastine or a pharmaceutically acceptable salt. Preferably, the pharmaceutical compositions according to the present invention may include powder formulations for insufflation, nasal sprays, solutions or aerosols for nasal inhalation, essentially described above.

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Treatment methods

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07 % by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07 % by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water. In one aspect of this embodiment, each spray of the composition delivers about 50 μg of mometasone furoate and about 140 μg of azelastine hydrochloride.

In another embodiment, the present invention relates to a method for alleviating nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal a spray containing about 0.07% by weight of mometasone furoate, about 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, neotamium edetate and water.

In another embodiment, the present invention relates to a method for treating rhinitis in a subject by alleviating nasal and non-nasal symptoms associated with rhinitis (such as sneezing, itchy nose, rhinorrhea, nasal obstruction, itchy eyes, excess lacrimation, etc.) a subject in need thereof, said method comprising nasally administering to the subject as a single spray into each nasal opening twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07% by weight of mometasone furoate, about 0, 2% by weight azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.

Rhinitis in the context of the present invention includes, but is not limited to, irritation and inflammation of the nasal mucosa and the resulting nasal and non-nasal symptoms. Rhinitis includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infectious rhinitis, vegetative rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, the rhinitis includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and their associated nasal and non-nasal symptoms.

In the context of the present invention, nasal and non-nasal symptoms associated with rhinitis include sneezing, itchy nose, rhinorrhea (runny nose), nasal obstruction, cough, itchy eyes, excess tears, headache, fatigue, colds (also known as nasopharyngitis, rhinopharyngitis, acute viral rhinopharyngitis or catarrh of the upper respiratory tract), malaise and cognitive impairment.

It should be understood that various modifications can be made to the embodiments of the present invention as provided herein. Therefore, the above description should not be construed as limiting, but only as illustrative examples of preferred embodiments of the present invention. Other variations and methods can be implemented by those skilled in the art without departing from the scope and spirit of the present invention.

The following examples are provided to enable a person skilled in the art to practice the present invention and are merely illustrative of the present invention. These examples should not be construed as limiting the scope of the present invention.

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Examples of

Example 1. Compositions of mometasone and azelastine for nasal administration

No. Ingredients Composition (% w / w) one Mometasone furoate 0.07143 2 Azelastine hydrochloride 0.200 3 Carmellose sodium 0.030 four Microcrystalline Cellulose and Sodium Carboxymethyl Cellulose (Avicel RC591) 1,300 five Dextrose 5,000 6 Citric acid monohydrate 0.015 7 Sodium citrate 0.030 eight Polysorbate 80 0.025 nine Benzalkonium chloride 0.020 10 Disodium edetat 0.050 12 Neotam 0.001 13 Water for injections Sufficient amount to bring up to 100% fourteen Citric Acid Monohydrate (for pH adjustment) -

Production technology.

1. Glycerin / dextrose was dissolved in purified water. Sieved microcrystalline cellulose-sodium carboxymethylcellulose and sodium carmellose were dispersed in the above solution under homogenization.

2. Polysorbate 80 was dissolved in purified water with stirring, after which mometasone furoate was added and mixed. This suspension was added to the product obtained in step 1 with homogenization.

3. Azelastine hydrochloride was dissolved in purified water with stirring and neotame was added with homogenization. This solution was added to the product obtained in step 2 with homogenization.

4. Sodium citrate / sodium hydrogen phosphate dihydrate was dissolved in purified water with stirring, and citric acid was added to the solution. This solution was added to the product obtained in step 3 with homogenization.

5. Disodium edetate was dissolved in purified water with stirring and added to the product obtained in step 4 with homogenization.

6. Benzalkonium chloride was dissolved in purified water with stirring and added to the product from step 5 with homogenization.

7. The pH was adjusted using 10% citric acid solution, the volume was brought to the required volume using purified water.

8. The composition was homogenized and loaded into a container suitable for nasal administration.

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The composition was subjected to stability studies under various conditions. The results of these studies are as follows. _____________________________________

Impurity D 0.02% 0.05% 0.07% Maximum content of a single impurity 0.05% 0.07% 0.06% Total impurity content 0.15% 0.29% 0.20% Substances related to azelastine hydrochloride Maximum content of a single impurity Below detection level 0.05% 0.06% Total impurity content Below detection level 0.05% 0.06% Conditions stability ⁽⁴⁰ ± 2 C ^e C and 75% rel. Ow. ± 5% RH. Is). ph 4.5 4.5 4.5 Osmolality 332 my 326 my 328 my Viscosity measured with a Brookfield viscometer 70 cP 74 cps 73 cps Weight per ml 1.02 g / ml 1.02 g / ml 0.99 g / ml Mometasone furoate content 103.7% 102.8% 103.6% Azelastine hydrochloride content 104.0% 102.9% 101.8% Substances related to mometasone furoate Impurity D 0.02% 0.16% 0.23% Maximum content of a single impurity 0.05% 0.07% 0.06% Total impurity content 0.15% 0.36% 0.36% Substances related to azelastine hydrochloride Maximum content of a single impurity Below the limits of definition 0.08% 0.13% Total impurity content Below the limits of definition 0.08% 0.13%

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Examples 2-5. Compositions of mometasone and azelasgine for nasal administration

P / p No. Ingredients Composition (% w / w) Example 2 Example 3 Example 4 Example 5 one Mometasone furoate 0.0714 0.0714 0.0714 0.0714 2 Azelastine hydrochloride 0.2000 0.2000 0.2000 0.2000 3 Microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel RC 591) 1.2000 1.2000 1.2000 1.2000 four Glycerin (glycerol) 2.5000 2.5000 five Dextrose 5.0000 5.0000 6 Polysorbate 80 0.0250 0.0250 0.0250 0.0250 7 Benzalkonium chloride 0.0200 0.0200 0.0200 0.0200 eight Disodium edetat 0.0500 0.0500 0.0500 0.0500 nine Neotam 0.0010 0.0010 0.0010 0.0010 10 Sodium citrate 0.0300 0.0300 eleven Sodium hydrogen phosphate dihydrate 0.0300 0.0300 12 Lemon acid 0.0150 0.0150 0.0150 0.0150 13 Purified water Sufficient quantity to bring up to 100% Sufficient quantity to bring up to 100% Sufficient quantity to bring up to 100% Sufficient quantity to bring up to 100%

Preparation method.

The procedure was similar to that shown in example 1.

Example 6 A multicenter, open-label, randomized, parallel group study to evaluate the efficacy, safety and tolerability of a fixed-dose combination of azelastine and mometasone nasal spray versus azelastine nasal spray and mometasone nasal spray in patients with seasonal allergic rhinitis

Objective: The present study was aimed at evaluating that a fixed dose combination of azelastine and mometasone nasal spray is more effective than azelastine only nasal spray and mometasone alone nasal spray in patients with seasonal allergic rhinitis.

Inclusion criteria.

1. Patients aged> 12 and <65 years of both sexes.

2. When selected, the total nasal symptom score (nasal congestion, rhinorrhea, itching in the nose and sneezing) should be at least 6, and the severity of nasal congestion should be at least 2.

3. Patient with a documented history of seasonal allergic rhinitis (lasting at least 2 years) with exacerbations (clinical manifestation of active symptoms) during the study period and / or demonstrating a positive injection skin test (blister with a diameter of at least 3 mm larger, than when controlled using saline) to one of the regional allergens acting during the study period.

4. A patient who has the ability to understand and sign a written informed consent form to be obtained prior to selection. Minors must consent to participate in the study and have written informed consent from a parent or guardian.

5. Patients willing to comply with protocol requirements.

Number of patients: 491 subjects.

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Study duration for each patient: total study duration ranged from 15 to 18 days. The specified period included the selection period, the active treatment period of 14 days, and the study visit interval.

Test product, dosage and route of administration.

1. Study 1 (I1): nasal spray combination of 140 μg azelastine hydrochloride and 50 μg mometasone furoate with a fixed dose (as in example 1). The dose administered was 1 spray into each nasal opening twice a day for two weeks.

2. Study 2 (R2): nasal spray combination of 140 mcg azelastine hydrochloride and 50 mcg mometasone furoate in a fixed dose (as in example 1). The dose administered was 2 sprays into each nasal opening once a day for two weeks.

Control therapy, dosage and route of administration.

1. Control 1 (K1): azelastine hydrochloride nasal spray (1 mg / ml) (RINOLASTIN, ACHE PHARMACEUTICALS). The dosage was 1 spray into each nasal opening twice a day for two weeks.

2. Control 2 (K2): 50 μg mometasone furoate nasal spray (NASONEX, SCHERINGPLOUGH). The dosage was 2 sprays into each nasal opening once a day for two weeks.

Criteria for evaluation.

Safety.

1. Changes in the main indicators of the state of the body from the initial level to the end of treatment.

2. Changes in laboratory safety parameters (hematological analysis, biochemical analysis of blood serum and urinalysis) and ECG from baseline to completion of treatment.

3. Comparison of incidence and frequency of adverse events between groups.

Efficiency.

The primary efficacy variable was the mean change in total nasal symptom score (ABNS, sum of nasal congestion, rhinorrhea, pruritus, and sneezing) from baseline to completion of treatment (i.e., over two weeks).

Secondary efficacy variables (and endpoints) included the following.

1. Average change in the severity scores of individual symptoms (nasal and non-nasal) from baseline to completion of treatment (within two weeks).

2. Average change in total nasal symptom score from baseline to each study day.

3. Self-assessment of the patient in relation to the overall response to treatment at the end of treatment (after two weeks).

4. General physician's assessment of the overall response to treatment at the end of treatment (after two weeks).

5. Average change in the assessment of the quality of life in rhinoconjunctivitis (using a questionnaire containing 28 items in seven sections (activity, sleep, nasal symptoms, eye symptoms, non-nasal / ocular symptoms, problems in practice and emotional state)) from baseline to completion of treatment (within two weeks).

Study plan.

Based on a dropout rate of 20%, a total of 560 subjects (140 per group) with seasonal allergic rhinitis in a 1: 1: 1: 1 ratio were recruited into the four study groups.

All patients included in the study were randomly assigned in a 1: 1: 1: 1 ratio to obtain either 1 spray into each nasal opening twice a day with a nasal spray combination of 140 μg azelastine and 50 μg mometasone with a fixed dose, or 2 sprays per each nasal opening once a day nasal spray combination of 140 mcg azelastine and 50 mcg mometasone with a fixed dose, or 1 spray into each nasal opening twice a day with azelastine nasal spray (1 mg / ml), or 2 sprays into each nasal opening one once a day nasal spray 50 mcg mometasone. The investigational drugs were administered for fourteen days.

Efficiency mark.

Primary efficacy variable: mean change in total nasal symptom score (sum of nasal congestion, rhinorrhea, pruritus, and sneezing) from baseline to completion of treatment (over two weeks).

Average change in total nasal symptom score (OBNS) = score at the end of treatment ((average OBNS in the morning of day 1 (the next morning after the 1st dose of PI) -15) + (average OBNS in the evening of days 1-15)) - score at a visit to the baseline level ((OBNS in the morning of the day on which the visit was at the baseline level) + (OBNS in the evening of the day preceding the day on which the visit was at the baseline level)).

Secondary Efficiency Variables.

1. The average change in the score of the severity of individual symptoms (nasal and non-nasal) from is

- 10 037259 running level until the end of treatment (within two weeks);

average change in individual symptom score (BFB) = treatment completion score ((average BFB in the morning of day 1 (the next morning after the 1st dose of PI) -15) + (average BFB in the evening of days 1-15)) - score at the baseline visit ((BFB in the morning of the day on which the visit was at the baseline level) + (BFB in the evening of the day preceding the day on which the visit was at the baseline level)).

2. Average change in total nasal symptom score from baseline to each study day;

average change in the total score of nasal symptoms for each specific day = point for each specific day of treatment ((average OBNS in the morning of the day 1 - a specific day) + (average OBNS in the evening of day 1 - a specific day)) - score at a visit at the initial level ((OBNS in the morning of the day on which the visit was at the baseline level) + (OBNS in the evening of the day preceding the day on which the visit was at the baseline level)).

3. Self-assessment of the patient in relation to the total response to treatment at the end of treatment (after two weeks);

4. General physician's assessment of the overall response to treatment at the end of treatment (after two weeks).

5. The average change in the assessment of the quality of life in rhinoconjunctivitis from the initial level to the end of treatment (within two weeks).

Data analysis:

OBNS is the sum of the points of nasal congestion, rhinorrhea, itching in the nose, and sneezing;

OBNS at a visit at the baseline = OBNS in the morning of the day on which the visit was at the baseline level, (day 1) + OBNS in the evening of the day preceding the day on which the visit was at the baseline level (day 1);

OBNS at the end of treatment = average OBNS in the morning of days 2-15 + average OBNS in the evening of days 1-14;

Day 1 is the day of the first dose of PI.

results

Table 1. Summarized results and analysis of the total nasal symptom score (NSS)

I1 (No. 128) I2 (No. 129) K1 (No. 115) K2 (No. 119) Visit Statistics Experimental data Change from baseline Experimental data Change from baseline Experimental data Change from baseline Experimental data Change from baseline Baseline visit P 128 129 115 119 Average (SD) 17.2 (3.42) 16.9 (3.41) 17.5 (3.24) 17.7 (3.63) Median value 17.0 16.0 17.0 17.0 Min., Max. nine; 24 eleven; 24 eleven; 24 10; 24 Completion of treatment P 128 128 129 129 115 115 119 119 Average (SD) 9.8 (3.50) -7.4 (3.53) 9.9 (3.57) -7.0 (3.50) 10.4 (3.53) -7.1 (3.79) 10.3 (3.76) -7.3 (4.01) Median value 9.2 -7.2 9.0 -6.8 10.4 -7.1 9.9 -7.1 Min., Max. one; eighteen -eighteen; 0 2; eighteen -17; 2 2; eighteen -17; 3 one; eighteen -eighteen; 2 P value <0.0001 <0.0001 <0.0001 <0.0001

* p value is calculated to compare the baseline value and at the end of treatment in each treated group using the paired Student's t test.

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Table 2. Mean change in total nasal symptom score (OEHC) from baseline to completion of treatment

Statistics Comparison of FSC with monotherapy I1 (N = 128) I2 (N = 129) K1 ¢ 4 = 115) K2 (N = 119) Limits of Average (LSM) (SE) -8.558 (0.2424) -8.270 (0.2470) -7.880 (0.2505) -8.035 (0.2420) 95% CI (-9.034, -8.082) (-8.756, -7.785) (-8.372, -7.388) (-8.511, -7.559) Difference CHK (SE) I1 0.678 (0.2688 0.523 (0.2661) 95% CI for the difference I1 (0.150, 1.207) (0.000, 1.046) p-value I1 0.0119 0.0498 Difference CHK (SE) AND 2 0.391 (0.2690) 0.235 (0.2663) 95% CI for the difference AND 2 (-0.138, 0.919) (-0.288, 0.759) p-value AND 2 0.1472 0.3769

* Limits of means, standard error, 95% confidence intervals obtained using ANCOVA with treatment and research center as factors and baseline data as covariates * p - value calculated for pairwise comparison of each CPS nasal spray with each nasal spray used in monotherapy , using ANCOVA

Output.

Based on these results, it is clear that a fixed dose combination of azelastine and mometasone has been shown to be effective in the treatment of seasonal allergic rhinitis. The I1 dosage regimen (that is, one spray into each nasal opening twice a day) showed greater efficacy compared to both separate groups of monotherapy K1 (p = 0.0119) and K2 (p = 0.0498), while the regimen dosing I2 (that is, two sprays into each nasal opening once a day) did not show greater efficacy compared to both separate groups of monotherapy K1 (p = 0.1472) and K2 (p = 0.3769). These unexpected results indicate that the I1 dosing regimen (i.e., one spray into each nasal opening twice a day) is the preferred dosing regimen for treating allergic rhinitis in a subject.

Although the present invention has been described with reference to specific embodiments, it should be understood that these embodiments of the present invention are merely illustrative of the principles and applications of the present invention. Thus, it should be understood that numerous modifications can be made to the illustrative embodiments of the present invention.

All publications, patents, and patent applications cited in this application are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and separately indicated as incorporated herein by reference.

Claims (10)

CLAIM 1. The use of a pharmaceutical composition with a fixed dose in the form of a nasal spray for nasal administration to a subject suffering from allergic rhinitis, in the form of one spray into the nostril twice a day, the composition containing from about 0.01 to about 2% by weight of mometasone furoate, from about 0.05 to about 2% by weight of azelastine hydrochloride; and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises neotame. 2. The use of a pharmaceutical composition according to claim 1, wherein the weight ratio of mometasone furoate to azelastine hydrochloride is in the range from about 1: 1 to about 1: 5. 3. The use of a pharmaceutical composition according to claim 1, wherein said composition comprises from about 0.05 to about 1% by weight of mometasone furoate and from about 0.1 to about 1% by weight of azelastine hydrochloride. 4. The use of a pharmaceutical composition according to claim 1, wherein each spray of said composition delivers about 50 μg of mometasone furoate and about 140 μg of azelastine hydrochloride. 5. The use of a pharmaceutical composition according to claim 1, wherein said composition comprises about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride. 6. The use of a pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient further comprises sodium carmellose, microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, sodium citrate, polysorbate 80, benzalko - 12 037259 chloride, disodium edetate, citric acid or their mixture. 7. The use of a pharmaceutical composition with a fixed dose in the form of a nasal spray for nasal administration to a subject suffering from allergic rhinitis as a single spray into the nostril twice a day, the composition containing about 0.07% by weight of mometasone furoate, about 0.2 % by weight azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water. 8. A method of treating allergic rhinitis in a subject in need thereof, comprising nasally administering to the subject as a single nostril spray twice a day of a stable fixed dose pharmaceutical composition in the form of a nasal spray containing about 0.07% by weight of mometasone furoate, about 0.2% by weight azelastine hydrochloride, sodium carmellose, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water. 9. The method of claim 8, wherein each spray of the composition delivers about 50 μg of mometasone furoate and about 140 μg of azelastine hydrochloride. 10. Use of a fixed dose pharmaceutical composition in the form of a nasal spray for the treatment of allergic rhinitis, the composition comprising: mometasone furoate - 0.0714%; azelastine hydrochloride - 0.200%; carmellose sodium - 0.030%; microcrystalline cellulose and sodium carboxymethyl cellulose - 1,300%; dextrose 5,000%; citric acid monohydrate - 0.015%; sodium citrate - 0.030%; polysorbate 80 - 0.025%; benzalkonium chloride - 0.020%; disodium edetate - 0.050%; neotame - 0.001%; water for injection — an amount sufficient to adjust to 100%, wherein the composition has a pH of about 4.5, an osmolality of about 332 mosm and a viscosity of about 70 cps.