MX2014003546A - Fixed dose pharmaceutical composition comprising mometasone and azelastine. - Google Patents
Fixed dose pharmaceutical composition comprising mometasone and azelastine.Info
- Publication number
- MX2014003546A MX2014003546A MX2014003546A MX2014003546A MX2014003546A MX 2014003546 A MX2014003546 A MX 2014003546A MX 2014003546 A MX2014003546 A MX 2014003546A MX 2014003546 A MX2014003546 A MX 2014003546A MX 2014003546 A MX2014003546 A MX 2014003546A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- weight
- nasal
- azelastine
- spray
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 54
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004574 azelastine Drugs 0.000 title claims abstract description 42
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 title claims abstract description 41
- 229960001664 mometasone Drugs 0.000 title claims abstract description 40
- 206010039083 rhinitis Diseases 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000007922 nasal spray Substances 0.000 claims abstract description 42
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- 238000011282 treatment Methods 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 35
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 60
- 239000007921 spray Substances 0.000 claims description 39
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 34
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 claims description 33
- YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 claims description 30
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- 229960002744 mometasone furoate Drugs 0.000 claims description 30
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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Abstract
The present invention relates to a fixed dose pharmaceutical composition comprising mometasone and azelastine. Particularly, the present invention provides a stable fixed dose pharmaceutical composition in the form of a nasal spray comprising mometasone or its salt and azelastine or its salt; a process for preparing such composition; and its use in treatment of rhinitis in a subject.
Description
PHARMACEUTICAL COMPOSITION OF FIXED DOSAGE COMPRISING MOMETHASONE
AND AZELASTINE
PRIORITY DOCUMENT
This patent application claims priority to the Interim Patent Application of India number 3454 / MUM / 2012 (filed on December 6, 2012) and the Brazilian Patent Application number BR 1020130008303 (filed on January 11, 2013), whose contents are incorporated herein by way of reference.
TECHNICAL FIELD OF THE INVENTION
The present patent application relates to a fixed dose pharmaceutical composition comprising mometasone and azelastine. In particular, the present patent application provides a stable fixed dose pharmaceutical composition in the form of a nasal spray comprising mometasone or its salt and azelastine or its salt; and a process for preparing said composition, and its use in the treatment of rhinitis in a subject.
BACKGROUND OF THE INVENTION
Rhinitis is a medical term for irritation and inflammation of the mucous membrane inside the nose. Rhinitis can cause additional symptoms, such as sneezing and itchy nose, cough, headache, fatigue, malaise and cognitive disability.
Mometasone furoate is a topical glucocorticoid used to reduce inflammation of the skin or respiratory tract. It is a free-form prodrug, mometasone. Mometasone furoate is commercially available under the name of NASONEX® (sold by Schering) as a nasal spray for diseases / diseases of the respiratory tract, such as inflammation of the sinuses. It has been approved for the treatment of nasal symptoms of allergic rhinitis, nasal congestion related to rhinitis due to seasonal allergies, nasal polyps and rhinitis prophylaxis due to seasonal allergies.
NASONEX (mometasone furoate nasal spray) 50 mcg Nasal Spray is a spray unit by hand pump with metered dose containing an aqueous suspension of mometasone futorate monohydrate equivalent to 0.05% by weight of mometasone furoate calculated at the base anhydrous, in an aqueous medium containing glycerin, microcrystalline cellulose and sodium carboxymethylcellulose, sodium citrate, citric acid, benzalkonium chloride and polysorbate 80. The pH is between 4.3 and 4.9.
The azelastine is (±) -1- (2H) -phthalazinone, 4 - [(4-chlorophenyl) methyl] -2- (hexahydro-1-methyl-1 H-azepin-4-yl) -, monohydrochloride. Azelastine hydrochloride is available commercially in the USA. As nasal spray ASTELIN® (azelastine hydrochloride), 137 micrograms (mcg), is an antihistamine formulated as a spray solution of measured dose for intranasal administration. The ASTELIN® nasal spray contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 ± 0.3. It also contains benzalkonium chloride (125 mcg / ml), disodium edetate, hypromellose, citric acid, dibasic sodium phosphate, sodium chloride and purified water. After priming, each spray with a measured dose delivers an average volume of 0.137 ml containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). It is indicated for the treatment of seasonal allergic rhinitis symptoms such as rhinorrhea, sneezing and nasal pruritus in adults and children over 5 years, and for the treatment of symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion and postnasal drip in adults and children over 12 years old.
European publication number EP0780127A1 discloses a pharmaceutical composition comprising (a) a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof; (b) a leukotriene inhibitor antihistamine selected from the group consisting of cetirizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemic mixtures thereof and mixtures thereof, and (c) an intranasal carrier.
European publication number EP2072051A1 discloses a pharmaceutical composition comprising azelastine, or a salt, a solvate or a physiologically functional derivative thereof, and mometasone or a pharmaceutically acceptable ester thereof.
PCT publication number WO2012074231 discloses a pharmaceutical composition which includes mometasone furoate and azelastine hydrochloride for nasal administration, including thaumatin as a reliever of bitterness and irritation.
There is still a need for effective therapeutic treatment of rhinitis.
SUMMARY OF THE INVENTION
The present invention relates to a fixed dose pharmaceutical composition in nasal spray form that includes mometasone and azelastine.
In one of the embodiments, the present invention relates to a fixed dose pharmaceutical composition in the form of a nasal spray comprising an effective amount of mometasone or its salt and azelastine or its salt.
In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising between 0.01% and 2%, approximately, by weight of mometasone or its salt and between 0.05% and 2%, approximately, by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as a spray through the nostril twice a day to the subject in need thereof. In one aspect of the representation, the pharmaceutical composition comprises mometasone or its salt present in an amount of between 0.05% and approximately 1% by weight. In one aspect of the representation, the pharmaceutical composition comprises azelastine or its salt present in an amount of between 0.1% and 1%, approximately, by weight.
In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising between 0.01% and 2%,
approximately, by weight of mometasone or its salt and between 0.05% and 2%, approximately, by weight of azelastine or its salt in a proportion of weight ranging from 1: 1 to 1: 5, approximately, and a pharmaceutically acceptable excipient, wherein the composition is administered as a spray by nasal orifice twice a day to the subject who needs it. In one aspect of this embodiment, each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.
In a specific representation, the present invention relates to a fixed dose pharmaceutical composition comprising approximately 0.07% by weight of mometasone furoate and approximately 0.2% by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition is administered in the form of spray by nasal orifice twice a day to the subject who needs it.
In a specific embodiment, the present invention relates to 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, wherein the composition is administered in the form of spray through the nostril twice a day to the subject who needs it.
In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising 0.01% to 2%, approximately, by weight of mometasone or its salt and approximately 0.05% to 2% by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, or mixtures thereof.
In a specific representation, the present invention relates to a stable fixed dose pharmaceutical composition comprising approximately 0.07% by weight of mometasone furoate and approximately 0.2% by weight of hydrochloride of
azelastine, carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, and water, where the composition is administered as a spray through the nostril twice daily to the subject who needs it.
In one embodiment, the stable fixed dose pharmaceutical composition of the present invention has pH within the range of about 4.0 to 5.0, osmolality within the range of 270 mOsm to about 370 mOsm, viscosity within the range of 50 cps to 100 cps approximately and weight per milliliter within the range of 0.90 g / ml to approximately 1.20 g / ml.
In another embodiment, the present invention relates to a method for treating rhinitis in a subject in need thereof, wherein said method comprises nasally administering to the subject in the form of a spray by nasal orifice twice a day a stable pharmaceutical composition of fixed dose in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, 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 treating rhinitis in a subject in need thereof, wherein said method comprises nasally administering to the subject in the form of a spray by nasal orifice twice a day a stable pharmaceutical composition of fixed dose in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80 , benzalkonium chloride, disodium edetate, neotame and water.
In another form of representation, the present invention relates to a method for alleviating nasal and non-nasal symptoms related to rhinitis in a subject who
need, wherein said method comprises nasally administering to the subject in nasal spray form twice a day a stable fixed dose pharmaceutical composition in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2 % by weight of azelastine hydrochloride, carmellose sodium, 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 by reducing nasal and non-nasal symptoms related to rhinitis (such as sneezing, itching of the nose, runny nose, nasal obstruction, ocular itching, excessive tearing). and similar symptoms) in a subject in need thereof, wherein said method comprises nasally administering to the subject in the form of a nasal spray two times a day a stable fixed dose pharmaceutical composition in the form of a nasal spray comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.
In the context of the present invention, rhinitis includes, without limitation, irritation and inflammation of the mucous membrane which is inside the nose and the nasal and non-nasal symptoms related thereto. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, rhinitis vasomotor, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, rhinitis induced by drugs, atrophic rhinitis and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and the associated nasal and non-nasal symptoms.
In the context of the present invention, nasal and non-nasal symptoms related to rhinitis include sneezing, itchy nose, runny nose (nasal mucus), nasal obstruction, cough, ocular itching, excessive tearing, headache, fatigue,
common cold (also known as rhinopharyngitis, acute rhinitis or cold), malaise and cognitive disability.
DETAILED DESCRIPTION OF THE INVENTION
The terms used herein are defined below. In the event that a definition established in the present application and a definition established in a provisional application for which priority is claimed are in conflict, the definition of the present application will govern the meaning of the terms.
Definitions
The terms "effective amount" and "therapeutically effective amount" denote an amount of an active ingredient that, when administered to a subject to treat rhinitis, produces the therapeutic benefit sought in a subject. The term "active ingredient" (used interchangeably with "active (a)" or "active substance" or "medicament") as used herein includes mometasone, azelastine or a pharmaceutically acceptable salt thereof.
"Sal" and "pharmaceutically acceptable salt" refer to salts or esters which, within the scope of a sound medical judgment / evaluation, are suitable to be in contact with human and lower animal tissues without toxicity, irritation and allergic response undue, in accordance with a reasonable proportion between benefit and risk, and effective for the intended use. Salts with the addition of representative acids include salts of hydrochloride, furoate, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, esterate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate and lauryl sulfate. Alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.
The terms "treat" and "treatment" as used herein encompass the prophylaxis, mitigation, prevention, amelioration or suppression of a disorder modulated by mometasone or azelastine, or by a combination of both in a mammal.
The term "subject" includes mammals such as humans and other animals, such as domestic animals (eg, domestic pets such as dogs and cats) and non-domestic animals (such as wild animals). Preferably, the subject is human.
"Pharmaceutically acceptable excipients" means any of the components of a pharmaceutical composition that are different from the assets approved by the authorities in charge of regulation or that are considered generally safe for use with humans or animals.
The therapeutically effective amount of mometasone (or its pharmaceutically acceptable salt) to be administered per day may vary from 100 mcg to 500 mcg, approximately, preferably from 200 mcg to 400 mcg, approximately. Preferably, the strengths of the discrete dose of mometasone (or its pharmaceutically acceptable salt) may be about 25 mcg, 50 mcg, 75 mcg, and 100 mcg.
The therapeutically effective amount of azelastine (or its pharmaceutically acceptable salt) to be administered per day may vary from 300 mcg to 2000 mcg, approximately, preferably from 500 mcg to 1800 mcg, approximately. Preferably, the strengths of the discrete dose of azelastine (or its pharmaceutically acceptable salt) to be administered per day can be 100 mcg, 125 mcg, 140 mcg, 150 mcg, 200 mcg, 275 mcg, 300 mcg and 500 mcg, approximately.
Combinations
The present invention relates to a fixed dose pharmaceutical composition in nasal spray form that includes mometasone and azelastine.
In one embodiment, the present invention relates to a fixed dose pharmaceutical composition in the form of a nasal spray comprising an effective amount of mometasone or its salt and azelastine or its salt.
The inventors of the present invention surprisingly found that for the combination therapy of mometasone or its salt and azelastine or its salt in a subject suffering from allergic rhinitis, a specific dose regimen (ie, a spray per nostril twice at day) is superior over both individual monotherapeutic branches, while surprisingly, the other dose regimen (ie, two sprays per nostril once a day) showed no such superiority in the treatment of allergic rhinitis in the subject.
Thus, in a form of representation, the present invention relates to a fixed dose pharmaceutical composition comprising between 0.01% and 2%, approximately, by weight of mometasone or its salt and between 0.05% and 2%, approximately, by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as a spray by nasal orifice twice a day to the subject who needs it. In one aspect of the representation, the pharmaceutical composition comprises mometasone or its salt present in an amount between 0.05% and approximately 1% by weight. In one aspect of the representation, the pharmaceutical composition comprises azelastine or its salt present in an amount between 0.1% and 1%, approximately, by weight.
In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising between 0.01% and 2%, approximately, by weight of mometasone or its salt and between 0.05% and 2%, approximately, by weight of azelastine or its salt in a weight ratio ranging from 1: 1 to 1: 5, approximately, and a pharmaceutically acceptable excipient, wherein the composition is administered as a spray through the nostril twice a day to the subject in need thereof. In one aspect of this representation, each spray of the composition
administers approximately 50 mcg of mometasone furoate and approximately 140 mcg of azelastine hydrochloride.
In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising approximately 0.07% by weight of mometasone furoate and approximately 0.2% by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition It is administered as a spray through the nostril twice a day to the subject who needs it.
In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising approximately 0.07% by weight of mometasone furoate and approximately 0.2% by weight of azelastine hydrochloride and neotame, wherein the composition is administered in spray form by nasal orifice twice a day to the subject who needs it.
In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising between 0.01% and 2%, approximately, by weight of mometasone or its salt and between 0.05% and 2%, approximately, by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, or mixtures thereof.
In a specific embodiment, the present invention relates to a stable fixed dose pharmaceutical composition comprising approximately 0.07% by weight of mometasone furoate and approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose , dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, edetate disodium, neotame and citric acid, and water, wherein the composition is administered as a spray by nasal orifice twice a day to the subject who needs it.
In one embodiment, the stable fixed dose pharmaceutical composition of the present invention has a pH within the range of 4.0 to 5.0, approximately, osmolality within the range of 270 mOsm to approximately 370 mOsm, viscosity within the range of 50 cps and 100 cps, approximately, and weight per milliliter within the range of 0.90 g / ml to 1.20 g / ml, approximately.
As previously stated, the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, including but not limited to one or more of the following: preservatives, buffers, chelating agents, polymers, surfactants, swners, solvents and the like.
It is possible to select, without limitation, examples of suitable buffers of phosphate, boron, sodium citrate and other organic acids such as citric acid, dextrose carbohydrates, mannose or dextrins and the like.
It is possible to select, without limitation, examples of water-soluble polymers of polyhydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl pentane-2,4-diol, 1, 2,6-hexanetriol and thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, low methoxyl pectin, guar gum, gum arabic, carrageenans, cellulose derivatives such as carmellose sodium, methylcellulose, sodium carboxymethylcellulose, xanthan gum, hydroxypropylcellulose, hydroxypropylmethylcellulose or mixtures thereof. The polyoxyethylene polyoxypropylene glycol above is a series of polymers in which ethylene oxide has been polymerized by addition to a polypropylene glycol obtained by polymerization of propylene oxide, and is classified into several types according to the difference in the average degree of polymerization of the oxide. of propylene and ethylene oxide. Particularly preferred water-soluble polymers are polyhydroxy alcohols such as polyethylene glycol, propylene glycol, glycerol and cellulose derivatives such as hydroxypropylmethylcellulose. The amount of water-soluble polymer may vary from 0.001% to 30%, approximately, by weight relative to the total weight of the solution.
Suitable surfactants that may be used include one or more anionic, cationic, nonionic or zwitterionic surfactants.
It is possible to select, without limitation, examples of suitable surfactants of polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by the reaction of sorbitan esters with ethylene oxide, polyethylene alkyl phenol, polyoxyethylene cetyl ether, alkyl aryl ether polyoxyethylene, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecylether, polyoxyethylene sorbitan esters of fatty acids and mixed resin, polyethoxylated sorbitan derivatives or fatty acid esters (eg, polysorbates), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether , fatty alcohol polyoxyethylene, polyoxyethylene alkyl amine, polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivative, sodium oleate, quaternary ammonium derivative, potassium, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulphate or mixtures thereof. Particularly preferred surfactants are polyethoxylated sorbitan derivatives.
Suitable examples of the preservatives that can be used can be selected, without limitation, from benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium-1 halides and benzalkonium. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide.
Examples of suitable chelating agents that can be used can be selected, without limitation, from disodium edetate (EDTA), trisodium edetate, tetrasodium edetate and diethylene amine pentaacetate, preferably EDTA.
Examples of suitable sweeteners that may be used may be selected, without limitation, from sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol , eucalyptus oil, camphor.
Examples of suitable solvents are all solvents that 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 the 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 mood, and the response to the behavior of the active ingredient or combination of active ingredients.
The process for making the pharmaceutical composition as described comprises administering a pharmaceutically acceptable carrier with: (i) pharmaceutically acceptable mometasone salt, solvate or a physiologically functional derivative thereof, and (ii) azelastine or a pharmaceutically acceptable salt. Preferably, the pharmaceutical compositions according to the present invention may comprise powdered insufflation formulas, nasal sprays, nasal inhalation solutions or aerosols substantially as previously described herein.
Treatment methods
In another embodiment, the present invention relates to a method for treating rhinitis in a subject in need thereof, wherein said method comprises nasally administering to the subject in the form of a spray by nasal orifice twice a day a stable pharmaceutical composition of fixed dose in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, cellulose
microcrystalline 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 treating rhinitis in a subject in need thereof, wherein said method comprises administering nasally to the subject in the form of a spray by nasal orifice twice a day a stable fixed dose pharmaceutical composition in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, chloride of benzalkonium, disodium edetate, neotame and water. In one aspect of this embodiment, each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.
In another form of representation, the present invention relates to a method for relieving nasal and non-nasal symptoms related to rhinitis in a subject in need thereof, wherein said method comprises administering nasally to the subject in the form of a spray through a nostril two times a day a stable fixed dose pharmaceutical composition in the nasal spray form comprising approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, acid 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 by reducing nasal and non-nasal symptoms related to rhinitis (such as sneezing, itching of the nose, runny nose, nasal obstruction, ocular itching, excessive tearing and similar symptoms). ) in a subject in need thereof, wherein said method comprises administering nasally to the subject in nasal spray form twice a day a stable fixed dose pharmaceutical composition in the form of a nasal spray comprising approximately 0.07% by weight of furoate of mometasone,
about 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.
In the context of the present invention, rhinitis includes, without limitation, irritation and inflammation of the mucous membrane which is inside the nose and the nasal and non-nasal symptoms related thereto. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, rhinitis vasomotor, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, rhinitis induced by drugs, atrophic rhinitis and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and the associated nasal and non-nasal symptoms.
In the context of the present invention, nasal and non-nasal symptoms related to rhinitis include sneezing, itchy nose, runny nose (nasal mucus), nasal obstruction, cough, eye itching, excessive tearing, headache, fatigue, cold common (also known as rhinopharyngitis, acute rhinitis or cold), malaise and cognitive disability.
It will be understood that various modifications may be made to the representations disclosed herein. Therefore, the above description should not be considered as limiting, but as simple examples of preferred representations. It is possible for those of skill in the art to implement other arrangements and methods without departing from the scope and spirit of the present invention.
The following examples are provided to enable the person skilled in the art to practice the invention and are solely to illustrate the invention. The examples should not be considered as limiting the scope of the invention.
EXAMPLES
EXAMPLE 1: Compositions of mometasone and azelastine for nasal administration.
Manufacturing procedure:
1. Glycerin / dextrose was dissolved in purified water. Sifted microcrystalline cellulose - sodium carboxymethylcellulose and carmellose sodium were dispersed in the above solution under homogenization.
2. Polysorbate 80 was dissolved in purified water under stirring and mometasone furoate was added and stirred. This suspension was added to step 1 under homogenization.
3. Azelastine hydrochloride was dissolved in purified water under stirring and neotame was added under homogenization. This solution was added to step 2 under homogenization.
4. Sodium citrate / sodium hydrogen phosphate dihydrate was dissolved in purified water under stirring and citric acid was added thereto. This solution was added to step 3 under homogenization.
5. Disodium edetate was dissolved in purified water under stirring and added to step 4 under homogenization.
6. Benzalkonium chloride was dissolved in purified water under stirring and added to step 5 under homogenization.
7. The pH was adjusted with 10% citric acid solution and the volume was compensated with purified water.
8. The composition was homogenized and filled into a container suitable for nasal administration.
The composition was subjected to stability studies under different conditions. The results were as follows:
Compositions of mometasone and azelastine
Manufacturing procedure:
The procedure was similar to that mentioned in Example 1.
EXAMPLE 6: Multicenter, open, randomized, parallel group trial, comparative study to evaluate the efficacy, safety and tolerability of the dose combination
fixed dose of azelastine and mometasone in nasal spray compared to nasal spray of azelastine and nasal spray of mometasone in patients with seasonal allergic rhinitis.
Objective. The aim of the present study is to evaluate whether the fixed dose combination of azelastine and mometasone in nasal spray is superior in comparison to the nasal spray of azelastine and the nasal spray of mometasone alone in patients with seasonal allergic rhinitis.
Inclusion criteria:
1. Patients between the ages of = 12 and = 65 years, including both sexes.
2. The combined rating of nasal symptoms (nasal congestion, runny nose, itchy nose and sneezing) must be at least 6, and the congestion severity score must be at least 2 at the time of examination.
3. Patient with documented clinical history of seasonal allergic rhinitis (for at least 2 years) with exacerbations (clinical evidence of active symptoms) during the study season and / or with a positive skin prick test (wheal diameter at least 3 mm greater than saline control) to one of the active regional allergens during the study season.
4. Patient with the capacity to understand and sign an informed consent form, which must have been obtained before the exam. Subjects who are under the age of consent must have provided an agreement and had the written informed consent of the parent or guardian.
5. Patients willing to comply with the requirements of the protocol.
Number of patients: 491 subjects.
Duration of the study for each patient: The total duration of the study was 15 to 18 days. This included the period of the exam, 14 days of active treatment and a window period allowable for study visits.
Product, dose and mode of administration in the clinical research phase:
1 . TEST 1 (T1): Fixed-dose combination of 140 mcg of azelastine hydrochloride 50 mcg of mometasone furoate nasal spray (as in Example 1). The dose administered was 1 spray per nostril twice a day for two weeks.
2. TEST 2 (T2): Fixed dose combination of 140 mcg of azelastine hydrochloride 50 mcg of mometasone furoate nasal spray (as in Example 1). The dose administered was 2 sprays per nostril once a day for two weeks.
Therapy, dose and mode of reference administration:
1. REFERENCE 1 (R1): Nasal spray azelastine hydrochloride (1 mg / ml) (RINOLASTIN, ACHE PHARMACEUTICALS). The dose was 1 spray per nostril twice a day for two weeks.
2. REFERENCE 2 (R2): 50 mcg of nasal spray mometasone furoate (NASONEX, SCHERING-PLOUGH). The dose was 2 sprays per nostril once a day for two weeks.
Evaluation criteria: Security:
1. Changes in the vital signs of the reference at the end of the treatment.
2. Changes in the safety parameters of the laboratory (hematology, serum biochemistry and urinalysis) and ECG of the reference at the end of the treatment.
3. Comparison of the incidence and the rate of adverse events among the branches.
Effectiveness:
The main efficacy variable was the mean change in the total score of nasal symptoms (TNSS in English, the sum of the nasal congestion scores, rhinorrhea, itching and sneezing) of the reference at the end of the treatment (two weeks).
Secondary efficacy variables (v endpoints) including the following:
1. Average change in individual symptom ratings (nasal and non-nasal) of the reference at the end of treatment (two weeks).
2. Average change in the total score of nasal symptoms of the reference to each day of the study.
3. Self-evaluation of the patient on the general response to treatment at the end of treatment (two weeks).
4. Overall assessment of the doctor on the overall response to treatment at the end of treatment (two weeks).
5. Average change in the quality of life score with rhinoconjunctivitis. { questionnaire containing 28 items in seven areas (activity, sleep, nasal symptoms, eye symptoms, non-nasal / eye symptoms, practical problems and emotional functions)} of the reference at the end of the treatment (two weeks).
Study design:
Assuming an abandonment rate of 20%, a total of 560 subjects (140 per branch) with seasonal allergic rhinitis were enrolled in a 1: 1: 1: 1 ratio to four study arms.
All patients enrolled in the trial were randomized 1: 1: 1: 1 to receive either the 1 spray per nostril twice a day option of the fixed combination dose of 140 mcg of azelastine and 50 mcg of mometasone in nasal spray or 2 sprays per nostril once a day of the fixed dose combination of 140 mcg of azelastine and 50 mcg of mometasone nasal spray or 1 spray per nostril twice a day of nasal spray azelastine (1 mg / ml) or 2 sprays per nostril once a day of 50 mcg of mometasone nasal spray. The study medications were provided for fourteen days.
Evaluation of effectiveness:
Main efficacy variable: Average change in the total score of nasal symptoms (the sum of the nasal congestion scores, rhinorrhea, itching and sneezing) of the reference at the end of the treatment (two weeks).
Total change in the total score of nasal symptoms (TNSS) =
qualification at the end of the treatment [(TNSS average of morning day 1 (morning after the ip dose) -15) + (TNSS average of night days 1-15)] - qualification of the
reference visit [(TNSS from the morning of the reference visit) + (TNSS from the night of the day before the reference view)]
Secondary efficacy variables:
1. Average change in the individual rating of symptoms (nasal and non-nasal) of the reference at the end of treatment (two weeks).
Average change in the individual symptom score (ISS) = rating at the end of the treatment [(average ISS on morning day 1 (next morning after the 1st dose of IP) -15) + (average ISS on night days 1 -15)] - qualification of the reference visit [(ISS on the morning of the reference visit) + (ISS on the night of the day preceding the reference view)]
2. Average change in the total score of nasal symptoms of the reference to each day of the study.
Average change in the total score of nasal symptoms in a day = Qualification of the treatment in a day [(TNSS in the morning on average day 1- a day) + (TNSS in the night on average day 1- a day)] - Qualification of the reference visit [(TNSS of the morning on reference visit) + (TNSS of the night on the day before the reference visit)]
3. Self-evaluation of the patient on general response to treatment at the end of treatment (two weeks).
4. Overall evaluation of the doctor on general response to treatment at the end of treatment (two weeks).
5. Average change in the quality of life score with rhinoconjunctivitis of the reference at the end of the treatment (two weeks).
Data analysis:
· TNSS is the sum of grades of nasal congestion, runny nose, itchy nose and sneezing.
• TNSS at the reference visit = TNSS on the morning of the reference visit (day 1) + TNSS on the night of the day before the reference visit (day 1).
• TNSS at the end of the treatment = average of TNSS from the morning of day 2 to day 15 + average of TNSS from the night of day 1 to day 14.
• Day 1 = day of the first IP dose.
Results:
Table 1: Summary and analysis of the total score of nasal symptoms (TNSS)
• The p value for the comparison of the reference values and at the end of the treatment within each treatment group, a paired t test is used.
5
Table 2: Average change in the total score of nasal symptoms of the reference to each day of the study.
• LS means, standard error, 95% confidence intervals use ANCOVA with treatment and center as reference factors as a covariant.
• The p-value is calculated for the comparison by pairing between each one of the nasal sprays of dosage composition 5 each of the monotherapy nasal sprays using ANCOVA.
Conclusion:
Based on these results, it is clear that the combination of fixed doses comprising azelastine and mometasone showed efficacy in the treatment of seasonal allergic rhinitis. The dose regimen T1 (ie, a spray per nostril twice a day) showed superiority over each of the monotherapy branches R1 (p = 0.0119) and R2 (p = 0.0498), while the dose regimen T2 (ie, two sprays per hole) nasal once a day) showed no superiority over each of the monotherapy branches R1 (p = 0.1472) and R2 (p = 0.3769). These surprising results show that the T1 dose regimen (ie, a spray per nostril twice a day) is the preferred dose regimen for treating allergic rhinitis in a subject.
Although the invention herein has been described with reference to particular representations, it will be understood that these representations merely illustrate the principles and application of the present invention. Therefore, it will be understood that numerous modifications can be made to the illustrative representations.
All publications, patents and patent applications cited in this application are hereby incorporated by reference to the extent to which each publication, patent or patent application was specifically and individually indicated as being incorporated herein by reference.
Claims (12)
1. A fixed dose pharmaceutical composition in the form of nasal spray comprising between 0.01% and 2%, approximately, by weight of mometasone or its salt, between 0.05% and 2%, approximately, by weight of azelastine or its salt and a pharmaceutically excipient acceptable, where the composition is administered as a spray by nasal orifice twice a day to the subject who needs it.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of mometasone or its salt to azelastine or its salt ranges from about 1: 1 to about 1: 5.
3. The pharmaceutical composition according to claim 1, wherein the composition comprises between 0.05% and 1%, approximately, by weight of mometasone or its salt and between 0.1% and 1%, approximately, by weight of azelastine or its salt.
4. The pharmaceutical composition according to claim 1, wherein each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.
5. The pharmaceutical composition according to claim 1, wherein the composition comprises about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride.
6. The pharmaceutical composition according to any of claims 1 to 5, wherein the pharmaceutically acceptable excipient is neotame.
7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and citric acid, or mixtures thereof.
8. A stable fixed dose nasal spray pharmaceutical composition comprising about 0.07% by weight of mometasone furoate and about 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, citric acid, citrate sodium, polysorbate 80, benzalkonium chloride, edetate disodium, neotame and water, wherein the composition is administered as a spray by nasal orifice twice a day to the subject who needs it.
9. The use of the pharmaceutical composition according to any of claims 1 to 8, for the treatment of rhinitis in a subject.
10. The pharmaceutical composition according to any of claims 1 to 8, for use in the treatment of rhinitis in a subject.
1 1. A method for treating rhinitis in a subject in need thereof, wherein said method comprises administering nasally to the subject in the form of a spray by nasal orifice twice a day a stable fixed dose pharmaceutical composition in the form of a nasal spray. comprises approximately 0.07% by weight of mometasone furoate, approximately 0.2% by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and sodium carboxymethylcellulose, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, disodium edetate, neotame and water.
12. The method according to claim 11, wherein each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3454MU2012 | 2012-12-06 | ||
| BR102013000830A BR102013000830A2 (en) | 2013-01-11 | 2013-01-11 | PHARMACEUTICAL COMPOSITION FOR NASAL ADMINISTRATION, AND, USE OF THE SAME |
| PCT/IB2013/060638 WO2014087347A1 (en) | 2012-12-06 | 2013-12-04 | Fixed dose pharmaceutical composition comprising mometasone and azelastine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2014003546A true MX2014003546A (en) | 2014-12-09 |
Family
ID=50882873
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2014003546A MX2014003546A (en) | 2012-12-06 | 2013-12-04 | Fixed dose pharmaceutical composition comprising mometasone and azelastine. |
| MX2019001701A MX390789B (en) | 2012-12-06 | 2013-12-04 | FIXED-DOSE PHARMACEUTICAL COMPOSITION COMPRISING MOMETASONE AND AZELASTINE. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2019001701A MX390789B (en) | 2012-12-06 | 2013-12-04 | FIXED-DOSE PHARMACEUTICAL COMPOSITION COMPRISING MOMETASONE AND AZELASTINE. |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP2928302A1 (en) |
| EA (1) | EA037259B1 (en) |
| MX (2) | MX2014003546A (en) |
| MY (1) | MY196902A (en) |
| PH (1) | PH12015501179A1 (en) |
| WO (1) | WO2014087347A1 (en) |
| ZA (1) | ZA201503799B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109288790A (en) * | 2017-07-25 | 2019-02-01 | 健乔信元医药生技股份有限公司 | Nasal pharmaceutical composition and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2389530B (en) * | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| US20070020330A1 (en) * | 2004-11-24 | 2007-01-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
-
2013
- 2013-12-04 WO PCT/IB2013/060638 patent/WO2014087347A1/en not_active Ceased
- 2013-12-04 EP EP13861024.1A patent/EP2928302A1/en not_active Withdrawn
- 2013-12-04 MX MX2014003546A patent/MX2014003546A/en unknown
- 2013-12-04 MX MX2019001701A patent/MX390789B/en unknown
- 2013-12-04 EA EA201491769A patent/EA037259B1/en unknown
- 2013-12-04 MY MYPI2015701670A patent/MY196902A/en unknown
-
2015
- 2015-05-27 ZA ZA2015/03799A patent/ZA201503799B/en unknown
- 2015-05-27 PH PH12015501179A patent/PH12015501179A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EA037259B1 (en) | 2021-03-01 |
| WO2014087347A1 (en) | 2014-06-12 |
| MX390789B (en) | 2025-03-21 |
| PH12015501179A1 (en) | 2015-08-17 |
| MX2019001701A (en) | 2019-08-14 |
| EP2928302A1 (en) | 2015-10-14 |
| ZA201503799B (en) | 2016-02-24 |
| EA201491769A1 (en) | 2015-06-30 |
| MY196902A (en) | 2023-05-09 |
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