WO2014087347A1 - Fixed dose pharmaceutical composition comprising mometasone and azelastine - Google Patents

Fixed dose pharmaceutical composition comprising mometasone and azelastine Download PDF

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Publication number
WO2014087347A1
WO2014087347A1 PCT/IB2013/060638 IB2013060638W WO2014087347A1 WO 2014087347 A1 WO2014087347 A1 WO 2014087347A1 IB 2013060638 W IB2013060638 W IB 2013060638W WO 2014087347 A1 WO2014087347 A1 WO 2014087347A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
weight
azelastine
sodium
mometasone
Prior art date
Application number
PCT/IB2013/060638
Other languages
French (fr)
Inventor
Ulhas Dhuppad
Sunil Chaudhari
Suresh RAJURKAR
Piyush Agarwal
Original Assignee
Glenmark Pharmaceuticals Limited
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Filing date
Publication date
Priority claimed from BR102013000830A external-priority patent/BR102013000830A2/en
Application filed by Glenmark Pharmaceuticals Limited filed Critical Glenmark Pharmaceuticals Limited
Priority to EA201491769A priority Critical patent/EA037259B1/en
Priority to EP13861024.1A priority patent/EP2928302A1/en
Priority to MYPI2015701670A priority patent/MY196902A/en
Priority to MX2014003546A priority patent/MX2014003546A/en
Publication of WO2014087347A1 publication Critical patent/WO2014087347A1/en
Priority to PH12015501179A priority patent/PH12015501179A1/en
Priority to ZA2015/03799A priority patent/ZA201503799B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • 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
    • A61K47/06—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
    • 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

Definitions

  • the present patent application relates to a fixed dose pharmaceutical composition comprising mometasone and azelastine.
  • 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; a process for preparing such composition; and its use in treatment of rhinitis in a subject.
  • Rhinitis is a medical term for irritation and inflammation of the mucous membrane inside the nose. Rhinitis may cause additional symptoms, such as sneezing and nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment.
  • Mometasone furoate is a glucocorticosteroid used topically to reduce inflammation of the skin or in the airways. It is a prodrug of the free form, mometasone. Mometasone furoate is commercially available as NASONEX ® (marketed by Schering) as a nasal spray for upper respiratory conditions such as nasal sinus inflammation. It is approved for the treatment of nasal symptoms of allergic rhinitis, nasal congestion associated with seasonal allergic rhinitis, nasal polyps and prophylaxis of seasonal allergic rhinitis.
  • NASONEX ® (mometasone furoate nasal spray) Nasal Spray 50 meg is a metered- dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, citric acid, benzalkonium chloride, and polysorbate 80.
  • the pH is between 4.3 and 4.9.
  • Azelastine is ( ⁇ )-l-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2- (hexahydro-1 -methyl- lH-azepin-4-yl)-, monohydrochloride.
  • Azelastine hydrochloride is commercially available in the US as ASTELIN® (azelastine hydrochloride) Nasal Spray, 137 micrograms (meg), is an antihistamine formulated as a metered-spray solution for intranasal administration.
  • ASTELIN® Nasal Spray contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 ⁇ 0.3.
  • each metered spray delivers a 0.137 mL mean volume containing 137 meg of azelastine hydrochloride (equivalent to 125 meg of azelastine base).
  • European Publication No EP0780127A1 discloses a pharmaceutical composition
  • 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 inhibiting antihistamine selected from the group consisting of cetirizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemates thereof and mixtures thereof; and (c) an intranasal carrier.
  • a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof
  • a leukotriene inhibiting antihistamine selected from the group consisting of cetirizine,
  • European Publication No EP2072051A1 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.
  • PCT Publication No. WO2012074231 discloses a pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration, including thaumatin as a bitterness and irritation mitigant.
  • the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
  • the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising effective amount of mometasone or its salt and azelastine or its salt.
  • the present invention relates to a fixed dose pharmaceutical composition
  • a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight.
  • the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
  • the present invention relates to a fixed dose pharmaceutical composition
  • a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
  • the present invention relates to a fixed dose pharmaceutical composition
  • 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, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • the present invention relates to a fixed dose pharmaceutical composition
  • 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 as one spray per nostril twice daily to the subject in need thereof.
  • the present invention relates to a the fixed dose pharmaceutical composition
  • a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
  • the present invention relates to a stable fixed dose pharmaceutical composition
  • a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
  • the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.
  • the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • nasal and non-nasal symptoms associated with rhinitis such as sneezing, nasal itching, rhinor
  • Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis.
  • the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
  • an effective amount denotes an amount of an active ingredient that, when administered to a subject for treating rhinitis, produces an intended therapeutic benefit in a subject.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes mometasone, azelastine or a pharmaceutically acceptable salt thereof.
  • salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the mometasone or azelastine, or by a combination of the two in a mammal.
  • subject includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • the subject is a human.
  • pharmaceutically acceptable excipients any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the therapeutically effective amount of mometasone (or its pharmaceutically acceptable salt) to be administered per day may range from about 100 meg to about 500 meg, preferably from about 200 meg to about 400 meg.
  • the discrete dosage strengths of mometasone (or its pharmaceutically acceptable salt) may be about 25 meg, about 50 meg, about 75 meg and about 100 meg.
  • the therapeutically effective amount of azelastine (or its pharmaceutically acceptable salt) to be administered per day may range from about 300 meg to about 2000 meg, preferably from about 500 meg to about 1800 meg.
  • the discrete dosage strengths of azelastine (or its pharmaceutically acceptable salt) to be administered per day may be about 100 meg, about 125 meg, about 140 meg, about 150 meg, about 200 meg, about 275 meg, about 300 meg and about 500 meg.
  • the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
  • the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising effective amount of mometasone or its salt and azelastine or its salt.
  • a specific dosing regimen i.e., one spray per nostril twice daily
  • the other dosing regimen i.e., two sprays per nostril once daily
  • the present invention relates to a fixed dose pharmaceutical composition
  • a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight.
  • the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
  • the present invention relates to a fixed dose pharmaceutical composition
  • a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
  • the present invention relates to a fixed dose pharmaceutical composition
  • 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, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
  • the present invention relates to a fixed dose pharmaceutical composition
  • 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 as one spray per nostril twice daily to the subject in need thereof.
  • the present invention relates to a the fixed dose pharmaceutical composition
  • a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
  • the present invention relates to a stable fixed dose pharmaceutical composition
  • a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
  • the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.
  • the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; preservatives, buffering agents, chelating agents, polymers, surfactants, sweeteners, solvents and the like.
  • buffering agents may be selected from, but not limited to phosphate, borate, sodium citrate and other organic acids like citric acid; carbohydrates dextrose, mannose, or dextrins and the like.
  • suitable water soluble polymers may be selected from, but not limited to polyhydroxy 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 methoxyl pectin, guar gum, gum arabic, carrageenan, cellulose derivatives such as carmellose sodium, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or mixtures thereof.
  • polyhydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, 1,2,6-hexanetriol and
  • the above polyoxyethylene polyoxypropylene glycol is a series of polymers in which ethylene oxide has been addition-polymerized to a polypropylene glycol obtained by polymerization of propylene oxide, and are classified into several types by the difference in the mean degree of polymerization of propylene oxide and ethylene oxide.
  • Particularly preferred water soluble polymers are polyhydroxy alcohols such as polyethylene glycol, propylene glycol, glycerol and cellulose derivatives such as hydroxypropyl methyl cellulose.
  • the amount of water soluble polymer may ranges from about 0.001% to about 30% w/w relative to the total weight of the solution.
  • Suitable surfactants which can be used may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.
  • Suitable surfactants may be selected from, but not limited to polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, 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 mixed fatty and resin acids, polyethoxylated sorbitan derivatives or esters of fatty acids (e.g., polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxy
  • Polysorbates polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, 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 oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or mixtures thereof.
  • Particularly preferred surfactants are polyethoxylated sorbitan derivatives.
  • preservatives examples include, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium- 1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide.
  • chelating agents which can be employed may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA.
  • EDTA edetate disodium
  • edetate trisodium edetate trisodium
  • edetate tetrasodium edetate tetrasodium
  • diethyleneamine pentaacetate preferably EDTA.
  • suitable sweeteners which can be employed may be selected from, but not limited to sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor.
  • suitable solvents are all solvents which are suitable for nasal administration, in particular water and alcohols, such as, for example, ethanol, propanol, propanediol or glycerol.
  • the optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.
  • compositions according to the present invention can comprise insufflation powder formulations, nasal sprays, nasal inhalation solutions or aerosols substantially as hereinbefore described.
  • the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
  • the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
  • nasal and non-nasal symptoms associated with rhinitis such as sneezing, nasal itching, rhinor
  • Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and nasal and non-nasal symptoms associated therewith.
  • the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
  • EXAMPLE 1 Compositions of mometasone and azelastine for nasal administration.
  • Glycerin/ Dextrose was dissolved in purified water. Sifted microcrystalline cellulose- carboxymethyl cellulose sodium and carmellose sodium were dispersed in the above solution under homogenization.
  • Azelastine hydrochloride was dissolved in purified water under stirring and neotame was added under homogenization. This solution was added to step 2 under homogenization.
  • Disodium edetate was dissolved in purified water under stirring and added to step 4 under homogenization.
  • Benzalkonium Chloride was dissolved in purified water under stirring and added to step 5 under homogenization.
  • the pH was adjusted with 10 % citric acid solution and the volume was made up with purified water.
  • composition was homogenized and filled in container suitable for nasal administration.
  • the composition was subjected to stability studies at different conditions. The results of the same are as follows:
  • EXAMPLES 2 - 5 Compositions of mometasone and azelastine for nasal administration.
  • Citric acid 0.0150 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to 12 Citric acid 0.0150 0.0150 0.0
  • EXAMPLE 6 Multicenter, Open-Label, Randomized, Parallel-Group, Comparative Study To Evaluate Efficacy, Safety and Tolerability of Fixed Dose Combination of Azelastine and Mometasone Nasal Spray Compared to Azelastine Nasal Spray and Mometasone Nasal Spray in Patients with Seasonal Allergic Rhinitis.
  • nasal congestion severity score must be at least 2 at screening.
  • Study Duration for Each Patient Total study duration was 15 to 18 days. This included screening period, 14 days active treatment period and allowable window period for the study visits. Investigational Product, Dosage and Mode of Administration:
  • TEST 1 (Tl): Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
  • TEST 2 Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
  • REFERENCE 1 (Rl): Azelastine hydrochloride Nasal Spray (lmg/ml) (RINOLASTIN, ACHE PHARMACEUTICALS). The dose was 1 spray per nostril twice daily for two weeks.
  • R2 Mometasone furoate 50 meg Nasal Spray (NASONEX, SCHERING-PLOUGH). The dose was 2 sprays per nostril once daily for two weeks.
  • the primary efficacy variable was mean change in Total Nasal Symptoms Score (TNSS, sum of scores of Nasal Congestion, Rhinorrhea, Itching and Sneezing) from Baseline to End of treatment (two weeks).
  • TNSS Total Nasal Symptoms Score
  • Rhinoconjunctivitis Quality-of-Life Score ⁇ questionnaire containing 28 items in seven domains (Activity, Sleep, Nose Symptoms, Eye Symptoms, Non- Nose/Eye Symptoms, Practical Problems and Emotional Functions) ⁇ from Baseline to End of treatment (two weeks).
  • All Patients enrolled in the trial were randomized in 1: 1: 1: 1 to receive either the 1 spray per nostril twice daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 2 sprays per nostril once daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 1 spray per nostril twice daily of Azelastine Nasal Spray (lmg/ml) or 2 sprays per nostril once daily of Mometasone 50 meg Nasal Spray.
  • the study medications were given for fourteen days.
  • TNSS Total Nasal Symptoms Score
  • TNSS is sum of scores of Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing.
  • TNSS at Baseline visit Morning TNSS of Baseline visit (Day 1) + Evening TNSS of day prior to baseline visit (Day 1).
  • TNSS at End of Treatment Average of Morning TNSS for Day 2 to Day 15 + Average of Evening TNSS for Day 1 to Day 14.
  • TNSS Total Nasal Symptoms Score
  • p-value is calculated for the comparison of baseline and end of treatment values within each treatment group by using paired t-
  • TNSS Total Nasal Symptoms Score
  • the LS means, standard error, 95% confidence intervals are using ANCOVA with treatment and centre as factors and baseline data as covariate.
  • p-value is calculated for the pair wise comparison between each of the FDC Nasal Spray versus each of the monotherapy Nasal Spray by using ANCOVA.
  • Tl i.e., one spray per nostril twice daily
  • T2 i.e., two sprays per nostril once daily
  • Tl i.e., one spray per nostril twice daily
  • dosing regimen is a preferred dosing regimen for treating allergic rhinitis in a subject.

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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

FIXED DOSE PHARMACEUTICAL COMPOSITION COMPRISING
MOMETASONE AND AZELASTINE
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent Application number 3454/MUM/2012 (filed on 6 Dec 2012) and Brazilian Patent Application No. BR 1020130008303 (filed on 11 January 2013), the contents of which are incorporated by reference herein.
TECHNICAL FIELD OF THE INVENTION
The present patent application relates to a fixed dose pharmaceutical composition comprising mometasone and azelastine. Particularly, 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; a process for preparing such composition; and its use in 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 may cause additional symptoms, such as sneezing and nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment.
Mometasone furoate is a glucocorticosteroid used topically to reduce inflammation of the skin or in the airways. It is a prodrug of the free form, mometasone. Mometasone furoate is commercially available as NASONEX® (marketed by Schering) as a nasal spray for upper respiratory conditions such as nasal sinus inflammation. It is approved for the treatment of nasal symptoms of allergic rhinitis, nasal congestion associated with seasonal allergic rhinitis, nasal polyps and prophylaxis of seasonal allergic rhinitis.
NASONEX® (mometasone furoate nasal spray) Nasal Spray 50 meg is a metered- dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, citric acid, benzalkonium chloride, and polysorbate 80. The pH is between 4.3 and 4.9.
Azelastine is (±)-l-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2- (hexahydro-1 -methyl- lH-azepin-4-yl)-, monohydrochloride. Azelastine hydrochloride is commercially available in the US as ASTELIN® (azelastine hydrochloride) Nasal Spray, 137 micrograms (meg), is an antihistamine formulated as a metered-spray solution for intranasal administration. 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), edetate disodium, hypromellose, citric acid, dibasic sodium phosphate, sodium chloride, and purified water. After priming, each metered spray delivers a 0.137 mL mean volume containing 137 meg of azelastine hydrochloride (equivalent to 125 meg of azelastine base). It is indicated for the treatment of the symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and for the treatment of the symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion and postnasal drip in adults and children 12 years and older.
European Publication No 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 inhibiting antihistamine selected from the group consisting of cetirizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemates thereof and mixtures thereof; and (c) an intranasal carrier.
European Publication No EP2072051A1 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.
PCT Publication No. WO2012074231 discloses a pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration, including thaumatin as a bitterness and irritation mitigant.
There still exists a need for effective therapeutic treatment of rhinitis. SUMMARY OF THE INVENTION
The present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
In an embodiment, the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising 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 from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of the embodiment, the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight. In an aspect of the embodiment, the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
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 its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of this embodiment, each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
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 a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
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 as one spray per nostril twice daily to the subject in need thereof.
In another embodiment, the present invention relates to a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
In a specific embodiment, the present invention relates to a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
In an embodiment, the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml 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, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
In another embodiment, the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
In another embodiment, the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and nasal and non-nasal symptoms associated therewith. In the context of present invention, the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
DETAILED DESCRIPTION OF THE INVENTION
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth earlier in a provisional application from which priority is claimed are in conflict, the definition in the present application shall control the meaning of the terms.
Definitions
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating rhinitis, produces an intended therapeutic benefit in a subject. The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes mometasone, azelastine or a pharmaceutically acceptable salt thereof.
By "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
The term "treating" or "treatment" as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the mometasone or azelastine, or by a combination of the two in a mammal. The term "subject" includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.
By "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
The therapeutically effective amount of mometasone (or its pharmaceutically acceptable salt) to be administered per day may range from about 100 meg to about 500 meg, preferably from about 200 meg to about 400 meg. Preferably, the discrete dosage strengths of mometasone (or its pharmaceutically acceptable salt) may be about 25 meg, about 50 meg, about 75 meg and about 100 meg.
The therapeutically effective amount of azelastine (or its pharmaceutically acceptable salt) to be administered per day may range from about 300 meg to about 2000 meg, preferably from about 500 meg to about 1800 meg. Preferably, the discrete dosage strengths of azelastine (or its pharmaceutically acceptable salt) to be administered per day may be about 100 meg, about 125 meg, about 140 meg, about 150 meg, about 200 meg, about 275 meg, about 300 meg and about 500 meg.
Combinations
The present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes mometasone and azelastine.
In an embodiment, the present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray comprising 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 having allergic rhinitis, a specific dosing regimen (i.e., one spray per nostril twice daily) is superior over both individual mono-therapy arms, whereas unexpectedly the other dosing regimen (i.e., two sprays per nostril once daily) did not exhibit such superiority in the treatment of allergic rhinitis in the subject. Thus, in an embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of the embodiment, the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight. In an aspect of the embodiment, the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.
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 its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1: 1 to about 1:5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of this embodiment, each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
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 a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.
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 as one spray per nostril twice daily to the subject in need thereof.
In another embodiment, the present invention relates to a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
In a specific embodiment, the present invention relates to a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
In an embodiment, the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.
As set forth above, the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; preservatives, buffering agents, chelating agents, polymers, surfactants, sweeteners, solvents and the like.
Examples of suitable buffering agents may be selected from, but not limited to phosphate, borate, sodium citrate and other organic acids like citric acid; carbohydrates dextrose, mannose, or dextrins and the like.
Examples of suitable water soluble polymers may be selected from, but not limited to polyhydroxy 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 methoxyl pectin, guar gum, gum arabic, carrageenan, cellulose derivatives such as carmellose sodium, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or mixtures thereof. The above polyoxyethylene polyoxypropylene glycol is a series of polymers in which ethylene oxide has been addition-polymerized to a polypropylene glycol obtained by polymerization of propylene oxide, and are classified into several types by the difference in the mean degree of polymerization of propylene oxide and ethylene oxide. Particularly preferred water soluble polymers are polyhydroxy alcohols such as polyethylene glycol, propylene glycol, glycerol and cellulose derivatives such as hydroxypropyl methyl cellulose. The amount of water soluble polymer may ranges from about 0.001% to about 30% w/w relative to the total weight of the solution.
Suitable surfactants which can be used may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.
Examples of suitable surfactants may be selected from, but not limited to polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, 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 mixed fatty and resin acids, polyethoxylated sorbitan derivatives or esters of fatty acids (e.g. Polysorbates), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, 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 oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or mixtures thereof. Particularly preferred surfactants are polyethoxylated sorbitan derivatives.
Examples suitable of the preservatives which can be employed may be selected from, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium- 1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide. Examples of suitable chelating agents which can be employed may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA.
Examples of suitable sweeteners which can be employed may be selected from, but not limited to sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor.
Examples suitable solvents are all solvents which are suitable for nasal administration, in particular water and alcohols, such as, for example, ethanol, propanol, propanediol or glycerol.
The optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.
The process for making the pharmaceutical composition as described, the process comprises admixing a pharmaceutically acceptable carrier with: (i) mometasone pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) azelastine, or a pharmaceutically acceptable salt. Preferably pharmaceutical compositions according to the present invention can comprise insufflation powder formulations, nasal sprays, nasal inhalation solutions or aerosols substantially as hereinbefore described.
Methods of treatment
In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water. In an aspect of this embodiment, each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
In another embodiment, the present invention relates to a method of relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
In another embodiment, the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
Rhinitis in the context of present invention includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and nasal and non- nasal symptoms associated therewith. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, it includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and nasal and non-nasal symptoms associated therewith.
In the context of present invention, the nasal and non-nasal symptoms associated with rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache, fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise and cognitive impairment.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLES
EXAMPLE 1: Compositions of mometasone and azelastine for nasal administration.
No. Ingredients Composition ( %w/w)
1 Mometasone furoate 0.07143
2 Azelastine Hydrochloride 0.200
3 Carmellose sodium 0.030
Microcrystalline Cellulose and
4 Carboxymethylcellulose Sodium 1.300
(Avicel RC591)
5 Dextrose 5.000 6 Citric Acid Monohydrate 0.015
7 Sodium citrate 0.030
8 Polysorbate 80 0.025
9 Benzalkonium Chloride 0.020
10 Di-sodium Edetate 0.050
12 Neotame 0.001
13 Water for injection q.s. to 100%
14 Citric Acid Monohydrate (For pH adjustment) —
Manufacturing procedure:
1. Glycerin/ Dextrose was dissolved in purified water. Sifted microcrystalline cellulose- carboxymethyl cellulose sodium 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/Disodium hydrogen phosphate dihydrate was dissolved in purified water under stirring and citric acid was added to this. 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 made up with purified water.
8. The composition was homogenized and filled in container suitable for nasal administration. The composition was subjected to stability studies at different conditions. The results of the same are as follows:
Test Initial 3 months 6 months
Stability condition (25°C ± 2°C & 60% RH ± 5 % RH)
PH 4.5 4.5 4.5
Osmolality 332 mOsm 330 mOsm 325 mOsm
Viscosity by Brookfield viscometer 70 cPs 75 cPs 73 cPs
Weight per ml 1.02 g/ml 1.02 g/ml 0.99 g/ml
Assay of mometasone furoate 103.7% 104.0% 103.7%
Assay of azelastine hydrochloride 104.0% 104.3% 102.8%
Related substances for mometasone furoate
Impurity D 0.02% 0.05% 0.07%
Single maximum impurity 0.05% 0.07% 0.06%
Total impurities 0.15% 0.29% 0.20%
Related substances for azelastine hydrochloride
Single maximum impurity Below limits of 0.05% 0.06%
detection
Total impurities Below limits of 0.05% 0.06%
detection
Stability condition (40°C ± 2°C & 75% RH ± 5 % RH)
PH 4.5 4.5 4.5
Osmolality 332 mOsm 326 mOsm 328 mOsm
Viscosity by Brookfield viscometer 70 cPs 74 cPs 73 cPs
Weight per ml 1.02 g/ml 1.02 g/ml 0.99 g/ml
Assay of mometasone furoate 103.7% 102.8% 103.6%
Assay of azelastine hydrochloride 104.0% 102.9% 101.8%
Related substances for mometasone furoate
Impurity D 0.02% 0.16% 0.23%
Single maximum impurity 0.05% 0.07% 0.06% Test Initial 3 months 6 months
Total impurities 0.15% 0.36% 0.36%
Related substances for azelastine hydrochloride
Single maximum impurity Below limits of 0.08% 0.13%
detection
Total impurities Below limits of 0.08% 0.13%
detection
EXAMPLES 2 - 5: Compositions of mometasone and azelastine for nasal administration.
Sr. Composition ( %w/w)
Ingredients
No. Example Example Example Example
2 3 4 5
1 Mometasone furoate 0.0714 0.0714 0.0714 0.0714
2 Azelastine Hydrochloride 0.2000 0.2000 0.2000 0.2000
Microcrystalhne Cellulose and
3 Carboxymethylcellulose 1.2000 1.2000 1.2000 1.2000 Sodium (Avicel RC 591 )
4 Glycerin(Glycerol) 2.5000 2.5000
5 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
8 Disodium edetate 0.0500 0.0500 0.0500 0.0500
9 Neotame 0.0010 0.0010 0.0010 0.0010
10 Sodium citrate 0.0300 0.0300
Disodium hydrogen phosphate
11 0.0300 0.0300 dihydrate
12 Citric acid 0.0150 0.0150 0.0150 0.0150 q.s. to q.s. to q.s. to q.s. to
13 Purified water
100% 100% 100% 100% Manufacturing procedure:
The procedure was similar to that mentioned in Example 1.
EXAMPLE 6: Multicenter, Open-Label, Randomized, Parallel-Group, Comparative Study To Evaluate Efficacy, Safety and Tolerability of Fixed Dose Combination of Azelastine and Mometasone Nasal Spray Compared to Azelastine Nasal Spray and Mometasone Nasal Spray in Patients with Seasonal Allergic Rhinitis.
Objective: The present study was aimed to evaluate that Fixed Dose Combination of Azelastine and Mometasone Nasal Spray is superior as compared to Azelastine Nasal Spray and Mometasone Nasal Spray alone in Patients with Seasonal Allergic Rhinitis.
Inclusion Criteria:
1. Patients age >12 and < 65 years inclusive of either sex.
2. The combined score of nasal symptoms (nasal congestion, rhinorrhea, nasal itching and sneezing) must be at least 6; and nasal congestion severity score must be at least 2 at screening.
3. Patient with a 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 exhibiting a positive skin prick test (wheal diameter at least 3 mm greater than saline control) to one of the regional allergens active during the study season.
4. Patient with ability to understand and sign written informed consent form, which must have been obtained prior to screening. Subjects under the legal age of consent must have provided assent and have had the written informed consent of the parent or guardian.
5. Patients willing to comply with the protocol requirements.
Number of Patients: 491 subj ects .
Study Duration for Each Patient: Total study duration was 15 to 18 days. This included screening period, 14 days active treatment period and allowable window period for the study visits. Investigational Product, Dosage and Mode of Administration:
1. TEST 1 (Tl): Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
1 spray per nostril twice daily for two weeks.
2. TEST 2 (T2): Fixed Dose Combination of Azelastine hydrochloride 140 meg and Mometasone furoate 50 meg Nasal Spray (as in Example 1). The dose administered was
2 sprays per nostril once daily for two weeks.
Reference Therapy, Dosage and Mode of Administration:
1. REFERENCE 1 (Rl): Azelastine hydrochloride Nasal Spray (lmg/ml) (RINOLASTIN, ACHE PHARMACEUTICALS). The dose was 1 spray per nostril twice daily for two weeks.
2. REFERENCE 2 (R2): Mometasone furoate 50 meg Nasal Spray (NASONEX, SCHERING-PLOUGH). The dose was 2 sprays per nostril once daily for two weeks.
Criteria for Evaluation: Safety:
1. Changes in Vital Signs from Baseline to End of treatment.
2. Changes in Laboratory Safety Parameters (Hematology, Serum Biochemistry and Urine Analysis) and ECG from Baseline to End of treatment.
3. Comparison of incidence and rate of Adverse Events between the Arms.
Efficacy:
The primary efficacy variable was mean change in Total Nasal Symptoms Score (TNSS, sum of scores of Nasal Congestion, Rhinorrhea, Itching and Sneezing) from Baseline to End of treatment (two weeks).
Secondary efficacy variables (and endpoints) included the following
1. Mean change in individual symptom scores (Nasal and Non Nasal) from Baseline to End of treatment (two weeks).
2. Mean change in Total Nasal Symptoms Score from Baseline to each study day 3. Patient's Self Evaluation for overall Response to Treatment at the End of treatment (two weeks).
4. Physician's Global Evaluation for overall Response to Treatment at the End of treatment (two weeks).
5. Mean change in Rhinoconjunctivitis Quality-of-Life Score {questionnaire containing 28 items in seven domains (Activity, Sleep, Nose Symptoms, Eye Symptoms, Non- Nose/Eye Symptoms, Practical Problems and Emotional Functions)} from Baseline to End of treatment (two weeks).
Study design:
Assuming a dropout rate of 20%, a total of 560 subjects (140 per arm) with seasonal Allergic Rhinitis were enrolled in 1: 1: 1: 1 ratio to four study arms.
All Patients enrolled in the trial were randomized in 1: 1: 1: 1 to receive either the 1 spray per nostril twice daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 2 sprays per nostril once daily of Fixed Dose Combination of Azelastine 140 meg and Mometasone 50 meg Nasal Spray or 1 spray per nostril twice daily of Azelastine Nasal Spray (lmg/ml) or 2 sprays per nostril once daily of Mometasone 50 meg Nasal Spray. The study medications were given for fourteen days.
Efficacy assessment:
Primary Efficacy Variable: Mean change in Total Nasal Symptoms Score (sum of scores of Nasal Congestion, Rhinorrhea, Itching and Sneezing) from Baseline to End of treatment (two weeks).
Mean change in Total Nasal Symptoms Score (TNSS) =
End of treatment score [(Morning TNSS average Day l(next morning after 1st dose of IP) -15) + (Evening TNSS average Day 1-15)] - Baseline visit score [(Morning TNSS of Baseline visit) + (Evening TNSS of day prior to baseline visit)] Secondary Efficacy Variables:
1. Mean change in Individual Symptom Score (Nasal and Non Nasal) from Baseline to End of treatment (two weeks)
Mean change in Individual Symptom Score (ISS) = End of treatment score [(Morning ISS average Day l(next morning after 1st dose of IP) -15) + (Evening ISS average Day 1-15)] - Baseline visit score [(Morning ISS of Baseline visit) + (Evening ISS of day prior to baseline visit)]
2. Mean change in Total Nasal Symptoms Score from Baseline to each study day.
Mean change in Total Nasal Symptoms Score at individual day = Individual day treatment score [(Morning TNSS average Day 1 -individual day) + (Evening TNSS average Day 1- individual day)] - Baseline visit score [(Morning TNSS of Baseline visit) + (Evening TNSS of day prior to baseline visit)]
3. Patient's Self Evaluation for overall Response to Treatment at the End of treatment (two weeks).
4. Physician's Global Evaluation for overall Response to Treatment at the End of treatment (two weeks)
5. Mean change in Rhinoconjunctivitis Quality-Of-Life Score from Baseline to End of Treatment (two weeks)
Analysis of data:
• TNSS is sum of scores of Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing.
• TNSS at Baseline visit = Morning TNSS of Baseline visit (Day 1) + Evening TNSS of day prior to baseline visit (Day 1).
• TNSS at End of Treatment = Average of Morning TNSS for Day 2 to Day 15 + Average of Evening TNSS for Day 1 to Day 14.
• Day 1 = Day of first dose of IP. Results:
Table 1: Summary and Analysis of Total Nasal Symptoms Score (TNSS)
Figure imgf000022_0001
p-value is calculated for the comparison of baseline and end of treatment values within each treatment group by using paired t-
Table 2: Mean change in Total Nasal Symptoms Score (TNSS) from baseline to end of treatment
Figure imgf000023_0001
The LS means, standard error, 95% confidence intervals are using ANCOVA with treatment and centre as factors and baseline data as covariate.
p-value is calculated for the pair wise comparison between each of the FDC Nasal Spray versus each of the monotherapy Nasal Spray by using ANCOVA.
Conclusion:
Based on these results, it is clear that the fixed dose combination comprising Azelastine and Mometasone showed efficacy in the treatment of Seasonal Allergic Rhinitis. Tl (i.e., one spray per nostril twice daily) dosing regimen showed superiority over both individual mono-therapy arms Rl (p=0.0119) and R2 (p=0.0498), whereas T2 (i.e., two sprays per nostril once daily) dosing regimen did not show superiority over both individual mono-therapy arms Rl (p=0.1472) and R2 (p=0.3769). These surprising results show that Tl (i.e., one spray per nostril twice daily) dosing regimen is a preferred dosing regimen for treating allergic rhinitis in a subject.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS We claim:
1. A fixed dose pharmaceutical composition in the form of nasal spray comprising from about 0.01 % to about 2 % by weight of mometasone or its salt, from about 0.05 % to about 2% by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
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 from about 0.05 % to about 1 % by weight of mometasone or its salt, and from about 0.1 % to about 1 % by weight of azelastine or its salt.
4. The pharmaceutical composition according to claim 1 , wherein each spray of the composition delivers about 50 meg of mometasone furoate and about 140 meg 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 one of claims 1-5, 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, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid, or mixtures thereof.
8. A stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water, wherein the composition is administered as one spray per nostril twice daily to a subject in need thereof.
9. Use of the pharmaceutical composition according to any one of claims 1-8, for the treatment of rhinitis in a subject.
10. The pharmaceutical composition according to any one of claims 1-8, for use in the treatment of rhinitis in a subject.
11. A method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate,
polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, and water.
12. The method according to claim 11 , wherein each spray of the composition
delivers about 50 meg of mometasone furoate and about 140 meg of azelastine hydrochloride.
PCT/IB2013/060638 2012-12-06 2013-12-04 Fixed dose pharmaceutical composition comprising mometasone and azelastine WO2014087347A1 (en)

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