WO2011141929A2 - Aqueous pharmaceutical compositions of fluticasone and olopatadine - Google Patents

Aqueous pharmaceutical compositions of fluticasone and olopatadine Download PDF

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Publication number
WO2011141929A2
WO2011141929A2 PCT/IN2011/000324 IN2011000324W WO2011141929A2 WO 2011141929 A2 WO2011141929 A2 WO 2011141929A2 IN 2011000324 W IN2011000324 W IN 2011000324W WO 2011141929 A2 WO2011141929 A2 WO 2011141929A2
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WIPO (PCT)
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pharmaceutically acceptable
nasal spray
spray solution
solution
aqueous nasal
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PCT/IN2011/000324
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French (fr)
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WO2011141929A3 (en
Inventor
Sunilendu Bhushan Roy
Kapileswar Swain
Shailesh Arvindbhai Patel
Laxman Magar
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Cadila Healthcare Limited
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Publication of WO2011141929A2 publication Critical patent/WO2011141929A2/en
Publication of WO2011141929A3 publication Critical patent/WO2011141929A3/en

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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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to aqueous nasal spray solutions of fluticasone and olopatadine.
  • the present invention relates to a stable aqueous nasal spray solution comprising combination of fluticasone and olopatadine or pharmaceutically acceptable salts thereof and process of manufacturing thereof.
  • the aqueous composition is particularly suitable for topical administration into the nose in the treatment of inflammatory conditions.
  • Inflammatory conditions such as allergic disorders are very prevalent throughout the world, causing a very significant cost to society for therapy and in the form of worker absenteeism and decreased worker productivity. These illnesses are frequently manifested in the form of acute or chronic rhinitis, sometimes also described, respectively, as seasonal and perennial rhinitis.
  • the symptoms of allergic rhinitis may include any number of: reddening of the eyes; ocular secretions; nasal congestion; ocular and palatial irritation; sneezing; and hypersecretion. Symptoms typically occur very promptly following exposure to allergens, of which the most common are grass, pollens and mold spores. The incidence of allergic rhinitis is greater during the spring and summer months, but some persons suffer the symptoms during the entire year, with exacerbations during the spring and summer.
  • rhinitis Several classes of drugs have been utilized for the treatment of inflammatory conditions such as allergic rhinitis, asthma.
  • Intranasal administration of drugs such as corticosteroids and their combinations with antihistaminics are frequently be used to treat nasal symptoms including seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis, recurrent sinusitis, asthma, grass pollen rhinitis, hay fever, snoring, cluster headache, and other diseases and disorders.
  • the nasal administration of drugs allows for their deposition to the nose, sinuses, and other nasal cavities.
  • antihistamines in nasal sprays and eye drops to treat allergy- related conditions.
  • the antihistamine olopatadine usually as hydrochloride salt
  • a corticosteroid which will suppress nasal and ocular inflammatory conditions.
  • corticosteroids known for nasal use are, for example, beclomethasone, mometasone, fluticasone, budesonide and cyclosenide.
  • Corticosteroids known for ocular anti-inflammatory use include betamethasone sodium, dexamethasone sodium and prednisolone acetate, for example.
  • Fluticasone is a synthetic corticosteroid used for the treatment of asthma, allergic rhinitis. It's salt, Fluticasone furoate is having scientific name S-(f!uoromethyl) (6S, 8S, 9R, 10S, 1 1 S, 13S, 14S, 16R, 17R) 6,9-difluoro-l 1, 17-dihydroxy- 10, 13, 16- trimethyl-3-oxo-6,7,8, l l , 12, 14, 15, 16-octahydrocyclopenta[a] phenantrhene -17- carbothiolate. Fluticasone furoate was first disclosed in US Patent No. 6,787,532.
  • fluticasone propionate having scientific name- S-fluoromethyl 6[alpha],9[alpha]-difluoro-ll[beta]-hydroxy-16[alpha]-methyl- 17- propionyloxy-3-oxoandrost-l,4-diene-17[beta]-carbothioate, was first disclosed in US Patent No. 4,335, 121.
  • Olopatadine hydrochloride is a selective histamine Hl-receptor antagonist and it is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis.
  • the compound may be administered in a solid oral dosage form or as an ophthalmic solution.
  • the scientific name of olopatadine hydrochloride is ([(Z)-3- (dimethylamino)propylidene]-6,U-dihydrodibenz[b,e]oxepin-2- acetic acid hydrochloride).
  • Olopatadine hydrochloride was first disclosed in US Patent No. 5, 1 16,863. Olopatadine is stated to be an effective treatment for symptoms of allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion), as well as in the treatment of various skin diseases, such as eczema and dermatitis.
  • olopatadine hydrochloride is commercially available from Alcon under the trademark PATANASE® which is in the form of aqueous nasal spray solution.
  • EP 0780127 A discloses a of glucocorticoid and a leukotriene inhibiting antihistamine with an intranasal carrier.
  • EP 1227812 B discloses use of desloratadine in the manufacture of medicament for treating rhinitis by a combination therapy comprising topical application of desloratadine and mometasone furoate.
  • US Patent Application No. 2009136430 discloses topically administrable formulation for the sustained remission of atopical dermatitis consisting essentially of at least one antihistamine and at least one compound selected from corticosteroids and glucocorticosteroids dissolved in a pharmacologically acceptable carrier.
  • European Patent No. EP 1519731 B discloses a pharmaceutical formulation which comprises azelastine or a salt, solvate or physiologically functional derivatives thereof, and fluticasone or a pharmaceutically acceptable ester thereof.
  • compositions comprising azelastine or pharmaceutically acceptable salts or esters thereof.
  • the patent application also discloses compositions of azelastine and fluticasone or pharmaceutically acceptable salts or esters thereof.
  • WO 97/01337 discloses nasal spray or nasal drops for the treatment of allergic rhinitis are comprising an effective amount of a topical antihistamine; an effective amount of a topical nasal steroid to reduce inflammation and sterile water.
  • Fluticasone furoate For developing suitable nasal formulation of drugs having limited aqueous solubility, such as Fluticasone furoate, it is usually developed in the form of suspension product.
  • fluticasone furoate is commercially available from Glaxosmithkline under the trademark VERAMYST® which is in the form of nasal spray containing aqueous suspension.
  • Fluticasone furoate is also known to possess low systemic bioavailability due to a combination of low aqueous solubility and limited mucosal contact time (Clinical Therapeutics
  • suspension product has limitations of systemic absorption, bioavailability, poor physical stability, dose variation with each administration and need of dispersing or shaking the product before dose administration to avail dose homogeny. Also, there are more issues in scaling up suspension products as compared to the solution products. It is also challenging to devise an aqueous formulation of fluticasone furoate in the form of solution which also renders stability to the formulation over the storage period.
  • a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.
  • a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants, wherein the solution retains at least 80% potency of fluticasone and olopatadine or pharmaceutically acceptable salts thereof after storage for three months at 40°C and 75% relative humidity.
  • a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; one or more surfactants; one or more chelating agents; one or more preservatives; one or more pH adjusting agents; one or more taste masking agents and optionally one or more pharmaceutically acceptable excipients.
  • a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof, olopatadine, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the pH of the composition ranges from about 3.5 to about 7.5.
  • Embodiments of the aqueous nasal spray solution may include one or more of the following features.
  • the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents, and the like.
  • a stable aqueous nasal spray solution for topical administration comprising combination of fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof and at least one active agent/s selected from the therapeutic category of corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants, antiallergic agents; and one or more pharmaceutically acceptable excipients.
  • Embodiments of the aqueous nasal spray solution may include one or more of the following features.
  • the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
  • a process for preparing a stable aqueous nasal spray solution for topical administration comprising preparing solution of fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof using one or more pharmaceutically acceptable excipients.
  • a process for preparing a stable aqueous nasal spray solution for topical administration comprising preparing solution of fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof using one or more water soluble polymers and one or more surfactants and optionally with one or more pharmaceutically acceptable excipients.
  • a process for preparing a stable aqueous nasal spray solution for topical administration comprising fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts the process comprising the steps of-
  • step (b) dispersing surfactant with fluticasone or pharmaceutically acceptable salts thereof and adding to the solution of step (a);
  • step (h) Filling the solution of step (h) into suitable containers.
  • Embodiments of the aqueous nasal spray solution may include one or more of the following features.
  • the nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
  • a method for treating an allergic and/or inflammatory symptom or disorder in a subject in need thereof comprising nasally administering said subject a nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.
  • Embodiments of the aqueous nasal spray solution may include one or more of the following features.
  • the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
  • the inventors of the present invention have surprisingly found that it is possible to develop a stable aqueous nasal spray solution of fluticasone and olopatadine combination by using judicial combination of pharmaceutically acceptable excipients.
  • present inventors have found that a stable pharmaceutical aqueous composition of fluticasone and olopatadine combination can be obtained by using pharmaceutically acceptable excipients comprising one or more water soluble polymer. Further, the inventors of the present invention have found that that the resulting pharmaceutical aqueous composition of fluticasone and olopatadine may remain stable when subjected to storage at accelerated stability conditions.
  • present invention provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
  • the present invention further provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof can be obtained by using one or more water soluble polymers. Further the inventors of the present invention have found that that the resulting pharmaceutical aqueous solution may remain stable for at least one month when stored at accelerated stability conditions (e.g. 40°C, 75% relative humidity or 60°C or greater).
  • accelerated stability conditions e.g. 40°C, 75% relative humidity or 60°C or greater.
  • present invention provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
  • the present invention further provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; at least one water soluble polymer with one or more pharmaceutically acceptable excipients.
  • the ratio of the amount of the drug combination to the amount of water soluble polymer present in the aqueous nasal spray solution ranges from about 1 :2 to about 1 :80.
  • fluticasone and olopatadine may be provided as the free base, or in the form of an appropriate pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically acceptable ' ester, a pharmaceutically acceptable enantiomer, a pharmaceutically acceptable derivative, a pharmaceutically acceptable polymorph or a pharmaceutically acceptable prodrug thereof.
  • Particularly preferred ester of fluticasone is its furoate ester, and particularly preferred salt of olopatadine is its hydrochloride salt.
  • the present invention in particular, provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; optionally one or more surfactants and one or more pharmaceutically acceptable excipients.
  • the ratio of amount of surfactant to the amount of water soluble polymer in the aqueous solution of fluticasone and olopatadine ranges from about 1 :0.01 to about 1 :6.
  • the solvent present in the aqueous nasal spray solution is preferably water or aqueous based solvent.
  • Further solvent constituents that may be present are all solvents which are suitable for nasal administration, in particular alcohols, such as, for example, ethanol, propanol, propanediol or glycerol.
  • the aqueous nasal spray solution preferably comprises water or ethanol/water mixtures as solvent, the solvent more preferably consists of water.
  • a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; one or more surfactants; one or more chelating agents; one or more preservatives; one or more pH adjusting agents; one or more sweetener/taste masking agents and optionally with one or more pharmaceutically acceptable excipients.
  • suitable water soluble polymers which can be employed in the aqueous nasal spray solution 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- 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,
  • 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 hydroxylpropyl 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.
  • combination of water soluble polymers may be used to achieve stable aqueous solution of the present invention. Examples of combination of water soluble polymers include hydroxypropyl methylcellulose - propylene glycol mixture, and polyethylene glycol - propylene glycol mixture.
  • Suitable "surfactants" which can be used for preparing aqueous nasal spray solution may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.
  • Suitable surfactants which can be employed in the aqueous nasal spray solution 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.
  • the amount of surfactant may range from about 1% to about 20% w/w relative to the total weight of the solution.
  • the HLB value of the surfactant employed in the aqueous nasal spray solution is approximately 10 or greater.
  • the osmolality can be set by variation of the amounts of the dissolved substances present in the aqueous nasal spray solution besides fluticasone, olopatadine and any further substances present, and/or by addition of an isotonicity agent, preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.
  • an isotonicity agent preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.
  • the aqueous nasal spray solution of fluticasone and olopatadine has an osmolality of about less than 350 mOsm kg.
  • Examples suitable of the preservatives which can be employed in the aqueous nasal spray solution 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.
  • the amount of the preservative present in the aqueous nasal spray solution may range from about 0.005 to about 0.2% w/w relative to the total weight of the solution. Preferably, the preservative is present at a concentration of about 0.01% relative to the final weight of the solution.
  • Suitable antioxidants which can be employed in the aqueous nasal spray solution may be selected from, but not limited to ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione and the like.
  • the amount of the antioxidant present in the aqueous nasal spray solution may ranges from about 0.0002 to about 0.5% w/w relative to the total weight of the solution.
  • the amount of the chelating agent present in the aqueous nasal spray solution of the present invention may range from about 0.0002 to about 0.5% w/w relative to the total weight of the solution.
  • pH adjusting agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphate salts, or combinations thereof.
  • the solution of the present invention comprises an amount of a pH adjusting agent sufficient to adjust the pH of the composition to from about 4 to about 7, preferably from about 4.5 to about 6.5 and more preferably from about 3.5 to about 6.5.
  • the amount of pH adjusting agent ranges from about 0.005% to about 1% w/w relative to the total weight of the solution.
  • suitable sweetener/taste masking agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to sucralose, thaumatin (e.g., Talin (R) ) sucrose, saccharin (including the salt forms: sodium, calcium, etc.), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents.
  • Particularly preferred taste masking agent is sucralose.
  • the amount of the sweetener/taste masking agent present in the aqueous nasal spray solution may range from about 0.05 to about
  • the aqueous nasal spray solution further may include a crystallization inhibitor.
  • suitable crystallization inhibitors may include, but not limited to hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, poly(2-propenoic acid), and other cellulose derivatives, and combinations of these cellulose derivatives with low viscosity grades.
  • the amount of crystallization inhibitor that can be used may ranges from about 0.01% to about 10.0% w/w relative to the total weight of the solution.
  • composition of the present invention in order to improve the physical properties, appearances, or smells of the composition of the present invention, one or more further pharmaceutically acceptable excipients may be added as desired.
  • the stable aqueous nasal spray solution of fluticasone and olopatadine may comprise one or more additional pharmaceutical active agent/s selected from the therapeutic category of, but not limited to, corticosteroids, non- steroidal antiinflammatory agents, antihistaminic agents, decongestants, antiallergic agents and the like.
  • Suitable corticosteroid may be selected from, but not limited to beclomethasone, flunisolide, triamcinolone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof.
  • Other corticosteroids may be also be selected from aldosterone, beclomethasone, betamethasone, ciclesonide, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, paramethas
  • Suitable non-steroidal anti-inflammatory agents may be selected from, but not limited to acetaminophen, acetylsalicylic acid, ibuprofen, etodolac, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, oxaprozin, sulindac, etodolac, droxicam, lornoxicam, licofelone pharmaceutically-acceptable salts thereof, optically active racemates thereof and mixtures thereof.
  • Suitable antihistaminic agents may be selected from, but not limited to drug belonging from class of piperazines, phenothiazines, piperidines such as azelastine, cetirizine, loratadine, azelastine, chlorpheniramine, fexofenadine, desloratadine, loratadine, astemizole, cyclizine, bepotastine, promethazine, diphenhydramine, dimenhydrinate, pheniramine, ebastine, levocetirizine, quetiapine, meclizine, ciproxifan, clobenpropit, thioperamide pharmaceutically acceptable salts or mixtures thereof
  • Suitable decongestants may be selected from, but not limited to pseudoephedrine, desoxyephedrine, propylhexedrine, phenylpropanolamine, xylometazoline, phenylephrine, tetrahydrozoline, naphazoline, oxymetazoline, tramazoline and pharmaceutically acceptable salts or mixtures thereof.
  • Suitable antiallergic agents may be selected from but not limited to cromolyn, ketotifen, N-allyl-(dichloro-3, 4-benzyl)-2-methylamino-2-propanol-l, Andolast, oxatamide, nedocromil, emedastine, pyrilamine, levocabastine, and pharmaceutically- acceptable salts or mixtures thereof.
  • the aqueous nasal spray solution can be administered as a drop or any other form suitable for topical administration.
  • the composition may also be administered using a nasal tampon or a nasal sponge.
  • the aqueous nasal spray solution is provided in the form of nasal spray.
  • MDI metered dose inhaler
  • a metered dose inhaler Several types of MDIs are regularly used for administration by inhalation. These types of devices can include breath-actuated MDI, spacer/holding chambers in combination with MDI, and nebulizers.
  • MDI refers to an inhalation delivery system comprising, for example, a canister containing mixture of active agent and a propellant optionally with one or more excipients, a metered dose valve, an actuator, and a mouthpiece.
  • the canister is usually filled with a solution of an active agent, such as the nasal spray composition, and a propellant, such as one or more hydrofluoroalkanes [e.g. 1 , 1 , 1 ,2-tetrafluoroethane (HFA-134a) and 1, 1, 1 ,2,3,3,3-heptafluoropropane (HFA-227)]; chlorofluorocarbons; and alcohols such as ethanol, isopropanol, butanol, propanol or mixtures thereof.
  • a propellant such as one or more hydrofluoroalkanes [e.g. 1 , 1 , 1 ,2-tetrafluoroethane (HFA-134a) and 1, 1, 1 ,2,3,3,3-heptafluoropropane (HFA-227)]; chlorofluorocarbons; and alcohols such as ethanol, isopropanol, butanol, propanol or mixtures thereof.
  • the amount of fluticasone and olopatadine or pharmaceutically acceptable salt thereof is a therapeutically effective amount and can be determined depending on the type and the degree of the disease, the age and the weight of the patient, and the like.
  • the invention further provides a process of preparing the stable aqueous nasal spray solution comprising preparing solution of fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
  • the process of preparing the stable aqueous nasal spray solution comprises steps of preparing solution of fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof with one or more water soluble polymers and further addition of one or more pharmaceutically acceptable excipients to the said solution.
  • a process of preparing the stable aqueous nasal spray solution comprising fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof comprises steps of-
  • step (b) dispersing surfactant with fluticasone or pharmaceutically acceptable salts thereof and adding to the solution of step (a);
  • step (d) adding the solution of step (c) into solution of step (b); (e) preparing a solution of olopatadine or pharmaceutically acceptable salts thereof in water;
  • step (h) Filling the solution of step (h) into suitable containers.
  • the clear solution formulations are filled in to commercially available bottles and fit with metered dose pumps for nasal delivery of the drug products.
  • the aqueous solution can, for nasal administration, be applied in all medicament forms which are suitable for nasal administration, such as, for example, nasal drops by means of dispensing devices suitable for this purpose, such as bottles with drop device or nasal spray pumps.
  • the invention further provides a stable aqueous nasal spray solution comprising combination of fluticasone or pharmaceutically acceptable salts thereof and fluticasone or pharmaceutically acceptable salts thereof for use in the preparation of a medicament for treatment of inflammatory disorders comprising administering the said composition to the patient in need thereof.
  • the invention provides a method for treating an allergic and/inflammatory symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a stable aqueous nasal spray solution comprising a therapeutically effective amount of combination of fluticasone or pharmaceutically acceptable salts thereof and fluticasone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
  • a solution of hydroxypropyl methylcellulose was prepared with water. Separately, fluticasone furoate and polysorbate 80 were dispersed and added to the above glycol solution to prepare Fluticasone furoate solution.
  • a bulk solution containing edetate disodium, citric acid monohydrate, sodium Citrate dihydrate and sucralose was prepared with purified water and added to the hydroxypropyl methylcellulose solution followed by addition of fluticasone furoate solution.
  • Olopatadine solution was prepared separately by adding olopatadine hydrochloride to water.
  • a solution of benzalkonium chloride was also prepared separately and added to the olopatadine solution which was then added to the bulk solution containing fluticasone furoate. Finally, the solution was filled into suitable containers.
  • a solution of propylene Glycol and polyethylene glycol was prepared to make glycol solution. Separately, fluticasone furoate and polysorbate 80 were dispersed and added to the above glycol solution to prepare fluticasone furoate solution.
  • a bulk solution containing edetate disodium, citric acid monohydrate, sodium citrate dihydrate and sucralose was prepared with purified water and added to the solution of fluticasone furoate.
  • Olopatadine solution was prepared separately by adding olopatadine hydrochloride to water.
  • a solution of benzalkonium chloride was also prepared separately and added to the olopatadine solution which was then added to the bulk solution containing Fluticasone furoate. Finally, the solution was filled into suitable containers.
  • Stability study of the aqueous nasal spray solution of the present invention was carried out at accelerated stability conditions (40°C, 75% relative humidity (RH) and 60°C) placing containers both in upright (Up) and inverted (Inv) positions. The result indicates that the solution of the present invention remains stable and retains at least 80% potency of fluticasone furoate and olopatadine hydrochloride over the storage period.

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Abstract

The present invention relates to aqueous nasal spray solutions of fluticasone and olopatadine. In particular, the present invention relates to a stable aqueous nasal spray solution comprising combination of fluticasone and olopatadine or pharmaceutically acceptable salts thereof and process of manufacturing thereof. The aqueous composition is particularly suitable for topical administration into the nose in the treatment of inflammatory conditions.

Description

AQUEOUS PHARMACEUTICAL COMPOSITIONS OF FLUTICASONE AND OLOPATADINE
FIELD OF THE INVENTION
The present invention relates to aqueous nasal spray solutions of fluticasone and olopatadine. In particular, the present invention relates to a stable aqueous nasal spray solution comprising combination of fluticasone and olopatadine or pharmaceutically acceptable salts thereof and process of manufacturing thereof. The aqueous composition is particularly suitable for topical administration into the nose in the treatment of inflammatory conditions.
BACKGROUND OF THE INVENTION
Inflammatory conditions such as allergic disorders are very prevalent throughout the world, causing a very significant cost to society for therapy and in the form of worker absenteeism and decreased worker productivity. These illnesses are frequently manifested in the form of acute or chronic rhinitis, sometimes also described, respectively, as seasonal and perennial rhinitis. The symptoms of allergic rhinitis may include any number of: reddening of the eyes; ocular secretions; nasal congestion; ocular and palatial irritation; sneezing; and hypersecretion. Symptoms typically occur very promptly following exposure to allergens, of which the most common are grass, pollens and mold spores. The incidence of allergic rhinitis is greater during the spring and summer months, but some persons suffer the symptoms during the entire year, with exacerbations during the spring and summer.
Several classes of drugs have been utilized for the treatment of inflammatory conditions such as allergic rhinitis, asthma. Intranasal administration of drugs such as corticosteroids and their combinations with antihistaminics are frequently be used to treat nasal symptoms including seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis, recurrent sinusitis, asthma, grass pollen rhinitis, hay fever, snoring, cluster headache, and other diseases and disorders. The nasal administration of drugs allows for their deposition to the nose, sinuses, and other nasal cavities.
It is known to use antihistamines in nasal sprays and eye drops to treat allergy- related conditions. Thus, for example, it is known to use the antihistamine olopatadine (usually as hydrochloride salt) as a nasal spray for treating seasonal or perennial allergic rhinitis, or as eye drops against seasonal or perennial allergic conjuctivitis. It is also known to treat these conditions using a corticosteroid, which will suppress nasal and ocular inflammatory conditions. Among the corticosteroids known for nasal use are, for example, beclomethasone, mometasone, fluticasone, budesonide and cyclosenide. Corticosteroids known for ocular anti-inflammatory use include betamethasone sodium, dexamethasone sodium and prednisolone acetate, for example.
Fluticasone is a synthetic corticosteroid used for the treatment of asthma, allergic rhinitis. It's salt, Fluticasone furoate is having scientific name S-(f!uoromethyl) (6S, 8S, 9R, 10S, 1 1 S, 13S, 14S, 16R, 17R) 6,9-difluoro-l 1, 17-dihydroxy- 10, 13, 16- trimethyl-3-oxo-6,7,8, l l , 12, 14, 15, 16-octahydrocyclopenta[a] phenantrhene -17- carbothiolate. Fluticasone furoate was first disclosed in US Patent No. 6,787,532.
Another salt of fluticasone known as fluticasone propionate having scientific name- S-fluoromethyl 6[alpha],9[alpha]-difluoro-ll[beta]-hydroxy-16[alpha]-methyl- 17- propionyloxy-3-oxoandrost-l,4-diene-17[beta]-carbothioate, was first disclosed in US Patent No. 4,335, 121.
Olopatadine hydrochloride is a selective histamine Hl-receptor antagonist and it is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis. The compound may be administered in a solid oral dosage form or as an ophthalmic solution. The scientific name of olopatadine hydrochloride is ([(Z)-3- (dimethylamino)propylidene]-6,U-dihydrodibenz[b,e]oxepin-2- acetic acid hydrochloride).
Olopatadine hydrochloride was first disclosed in US Patent No. 5, 1 16,863. Olopatadine is stated to be an effective treatment for symptoms of allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion), as well as in the treatment of various skin diseases, such as eczema and dermatitis. Currently, olopatadine hydrochloride is commercially available from Alcon under the trademark PATANASE® which is in the form of aqueous nasal spray solution.
It is also known that the combination therapy of anti-histamine agent and corticosteroid is the preferred treatment due to diverse symptoms associated with inflammatory conditions for example, in allergic rhinitis.
Thus, it would be highly desirable, however, to provide a treatment that combines the olopatadine (effects of anti-histamine treatments) and fluticasone (effects of corticosteroid treatments), in a pharmaceutically acceptable formulation, which is tolerated in situ, without significantly disrupting the potency of the constituent pharmaceuticals. The administration of combination of intranasal fluticasone and intranasal olopatadine results in superior relief of seasonal allergic rhinitis symptoms compared with monotherapy (Allergy Asthma Proc. Mar 2010; 31 (2): 132-40).
European Patent Application No. EP 0780127 A discloses a of glucocorticoid and a leukotriene inhibiting antihistamine with an intranasal carrier.
European Patent No. EP 1227812 B discloses use of desloratadine in the manufacture of medicament for treating rhinitis by a combination therapy comprising topical application of desloratadine and mometasone furoate.
US Patent Application No. 2009136430 discloses topically administrable formulation for the sustained remission of atopical dermatitis consisting essentially of at least one antihistamine and at least one compound selected from corticosteroids and glucocorticosteroids dissolved in a pharmacologically acceptable carrier.
European Patent No. EP 1519731 B discloses a pharmaceutical formulation which comprises azelastine or a salt, solvate or physiologically functional derivatives thereof, and fluticasone or a pharmaceutically acceptable ester thereof.
International (PCT) Publication No. WO 2006/058022 discloses compositions comprising azelastine or pharmaceutically acceptable salts or esters thereof. The patent application also discloses compositions of azelastine and fluticasone or pharmaceutically acceptable salts or esters thereof.
International (PCT) Publication No. WO 97/01337 discloses nasal spray or nasal drops for the treatment of allergic rhinitis are comprising an effective amount of a topical antihistamine; an effective amount of a topical nasal steroid to reduce inflammation and sterile water.
For developing suitable nasal formulation of drugs having limited aqueous solubility, such as Fluticasone furoate, it is usually developed in the form of suspension product. Currently fluticasone furoate is commercially available from Glaxosmithkline under the trademark VERAMYST® which is in the form of nasal spray containing aqueous suspension. Fluticasone furoate is also known to possess low systemic bioavailability due to a combination of low aqueous solubility and limited mucosal contact time (Clinical Therapeutics
Volume 29, Issue 7, July 2007, Pp: 1415- 1420).
Moreover, because suspension product has limitations of systemic absorption, bioavailability, poor physical stability, dose variation with each administration and need of dispersing or shaking the product before dose administration to avail dose homogeny. Also, there are more issues in scaling up suspension products as compared to the solution products. It is also challenging to devise an aqueous formulation of fluticasone furoate in the form of solution which also renders stability to the formulation over the storage period.
Hence, there exists a need to develop a stable ready to deliver aqueous nasal composition of fluticasone and olopatadine.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.
In another general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants, wherein the solution retains at least 80% potency of fluticasone and olopatadine or pharmaceutically acceptable salts thereof after storage for three months at 40°C and 75% relative humidity.
In another general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; one or more surfactants; one or more chelating agents; one or more preservatives; one or more pH adjusting agents; one or more taste masking agents and optionally one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof, olopatadine, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the pH of the composition ranges from about 3.5 to about 7.5.
Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents, and the like. In a another aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising combination of fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof and at least one active agent/s selected from the therapeutic category of corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants, antiallergic agents; and one or more pharmaceutically acceptable excipients.
Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
In another general aspect, there is provided a process for preparing a stable aqueous nasal spray solution for topical administration comprising preparing solution of fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof using one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a process for preparing a stable aqueous nasal spray solution for topical administration comprising preparing solution of fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof using one or more water soluble polymers and one or more surfactants and optionally with one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a process for preparing a stable aqueous nasal spray solution for topical administration comprising fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts the process comprising the steps of-
(a) preparing a solution of polymers;
(b) dispersing surfactant with fluticasone or pharmaceutically acceptable salts thereof and adding to the solution of step (a);
(c) preparing the solution of other pharmaceutically acceptable excipients by sequentially dissolving in water;
(d) adding the solution of step (c) into solution of step (b);
(e) preparing a solution of olopatadine or pharmaceutically acceptable salts thereof in water; (f) providing the solution of preservative in water;
(g) adding the solution of step (f) to solution of step (e);
(h) adding the solution of step (g) to the solution of step (d)
(h) Filling the solution of step (h) into suitable containers.
Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
In another general aspect, there is provided a method for treating an allergic and/or inflammatory symptom or disorder in a subject in need thereof, comprising nasally administering said subject a nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.
Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have surprisingly found that it is possible to develop a stable aqueous nasal spray solution of fluticasone and olopatadine combination by using judicial combination of pharmaceutically acceptable excipients.
In particular, the present inventors have found that a stable pharmaceutical aqueous composition of fluticasone and olopatadine combination can be obtained by using pharmaceutically acceptable excipients comprising one or more water soluble polymer. Further, the inventors of the present invention have found that that the resulting pharmaceutical aqueous composition of fluticasone and olopatadine may remain stable when subjected to storage at accelerated stability conditions. Thus, present invention provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
The present invention further provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof can be obtained by using one or more water soluble polymers. Further the inventors of the present invention have found that that the resulting pharmaceutical aqueous solution may remain stable for at least one month when stored at accelerated stability conditions (e.g. 40°C, 75% relative humidity or 60°C or greater).
Thus, present invention provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
The present invention further provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; at least one water soluble polymer with one or more pharmaceutically acceptable excipients.
In an embodiment, the ratio of the amount of the drug combination to the amount of water soluble polymer present in the aqueous nasal spray solution ranges from about 1 :2 to about 1 :80.
It will be appreciated that fluticasone and olopatadine, for the purpose of the present invention, may be provided as the free base, or in the form of an appropriate pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically acceptable ' ester, a pharmaceutically acceptable enantiomer, a pharmaceutically acceptable derivative, a pharmaceutically acceptable polymorph or a pharmaceutically acceptable prodrug thereof. Particularly preferred ester of fluticasone is its furoate ester, and particularly preferred salt of olopatadine is its hydrochloride salt.
The present invention in particular, provides a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; optionally one or more surfactants and one or more pharmaceutically acceptable excipients.
In an embodiment, the ratio of amount of surfactant to the amount of water soluble polymer in the aqueous solution of fluticasone and olopatadine ranges from about 1 :0.01 to about 1 :6.
The solvent present in the aqueous nasal spray solution is preferably water or aqueous based solvent. Further solvent constituents that may be present are all solvents which are suitable for nasal administration, in particular alcohols, such as, for example, ethanol, propanol, propanediol or glycerol. The aqueous nasal spray solution preferably comprises water or ethanol/water mixtures as solvent, the solvent more preferably consists of water.
In a further embodiment, there is provided a stable aqueous nasal spray solution comprising fluticasone, or pharmaceutically acceptable salts thereof; olopatadine, or pharmaceutically acceptable salts thereof; one or more water soluble polymers; one or more surfactants; one or more chelating agents; one or more preservatives; one or more pH adjusting agents; one or more sweetener/taste masking agents and optionally with one or more pharmaceutically acceptable excipients.
Examples of suitable water soluble polymers which can be employed in the aqueous nasal spray solution 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- 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 hydroxylpropyl 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. In a preferred embodiment, combination of water soluble polymers may be used to achieve stable aqueous solution of the present invention. Examples of combination of water soluble polymers include hydroxypropyl methylcellulose - propylene glycol mixture, and polyethylene glycol - propylene glycol mixture.
Suitable "surfactants" which can be used for preparing aqueous nasal spray solution may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.
Examples of suitable surfactants which can be employed in the aqueous nasal spray solution 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.
The amount of surfactant may range from about 1% to about 20% w/w relative to the total weight of the solution.
In an embodiment, the HLB value of the surfactant employed in the aqueous nasal spray solution is approximately 10 or greater.
In order to improve the ability of the aqueous nasal spray solution to be tolerated on administration to the nasal mucous membrane, it is advantageous to formulate it as isotonic solution. The osmolality can be set by variation of the amounts of the dissolved substances present in the aqueous nasal spray solution besides fluticasone, olopatadine and any further substances present, and/or by addition of an isotonicity agent, preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.
In an embodiment, the aqueous nasal spray solution of fluticasone and olopatadine has an osmolality of about less than 350 mOsm kg.
Examples suitable of the preservatives which can be employed in the aqueous nasal spray solution 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. The amount of the preservative present in the aqueous nasal spray solution may range from about 0.005 to about 0.2% w/w relative to the total weight of the solution. Preferably, the preservative is present at a concentration of about 0.01% relative to the final weight of the solution.
Examples of suitable antioxidants which can be employed in the aqueous nasal spray solution may be selected from, but not limited to ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione and the like. The amount of the antioxidant present in the aqueous nasal spray solution may ranges from about 0.0002 to about 0.5% w/w relative to the total weight of the solution.
Examples of suitable chelating agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA. The amount of the chelating agent present in the aqueous nasal spray solution of the present invention may range from about 0.0002 to about 0.5% w/w relative to the total weight of the solution.
Examples of suitable pH adjusting agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphate salts, or combinations thereof.
The solution of the present invention comprises an amount of a pH adjusting agent sufficient to adjust the pH of the composition to from about 4 to about 7, preferably from about 4.5 to about 6.5 and more preferably from about 3.5 to about 6.5. Preferably, the amount of pH adjusting agent ranges from about 0.005% to about 1% w/w relative to the total weight of the solution.
Examples of suitable sweetener/taste masking agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to sucralose, thaumatin (e.g., Talin(R)) sucrose, saccharin (including the salt forms: sodium, calcium, etc.), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents. Particularly preferred taste masking agent is sucralose. The amount of the sweetener/taste masking agent present in the aqueous nasal spray solution may range from about 0.05 to about 0.1% w/w relative to the total weight of the solution.
Alternatively, the aqueous nasal spray solution further may include a crystallization inhibitor. Examples of suitable crystallization inhibitors that can be used may include, but not limited to hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, poly(2-propenoic acid), and other cellulose derivatives, and combinations of these cellulose derivatives with low viscosity grades. The amount of crystallization inhibitor that can be used may ranges from about 0.01% to about 10.0% w/w relative to the total weight of the solution.
It will also be appreciated to the skilled artisan that in order to improve the physical properties, appearances, or smells of the composition of the present invention, one or more further pharmaceutically acceptable excipients may be added as desired.
The stable aqueous nasal spray solution of fluticasone and olopatadine may comprise one or more additional pharmaceutical active agent/s selected from the therapeutic category of, but not limited to, corticosteroids, non- steroidal antiinflammatory agents, antihistaminic agents, decongestants, antiallergic agents and the like.
Suitable corticosteroid, may be selected from, but not limited to beclomethasone, flunisolide, triamcinolone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof. Other corticosteroids may be also be selected from aldosterone, beclomethasone, betamethasone, ciclesonide, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, tixocortol or pharmaceutically-acceptable salts, optically active racemates and mixtures thereof.
Suitable non-steroidal anti-inflammatory agents may be selected from, but not limited to acetaminophen, acetylsalicylic acid, ibuprofen, etodolac, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, oxaprozin, sulindac, etodolac, droxicam, lornoxicam, licofelone pharmaceutically-acceptable salts thereof, optically active racemates thereof and mixtures thereof.
Suitable antihistaminic agents may be selected from, but not limited to drug belonging from class of piperazines, phenothiazines, piperidines such as azelastine, cetirizine, loratadine, azelastine, chlorpheniramine, fexofenadine, desloratadine, loratadine, astemizole, cyclizine, bepotastine, promethazine, diphenhydramine, dimenhydrinate, pheniramine, ebastine, levocetirizine, quetiapine, meclizine, ciproxifan, clobenpropit, thioperamide pharmaceutically acceptable salts or mixtures thereof
Suitable decongestants may be selected from, but not limited to pseudoephedrine, desoxyephedrine, propylhexedrine, phenylpropanolamine, xylometazoline, phenylephrine, tetrahydrozoline, naphazoline, oxymetazoline, tramazoline and pharmaceutically acceptable salts or mixtures thereof.
Suitable antiallergic agents, may be selected from but not limited to cromolyn, ketotifen, N-allyl-(dichloro-3, 4-benzyl)-2-methylamino-2-propanol-l, Andolast, oxatamide, nedocromil, emedastine, pyrilamine, levocabastine, and pharmaceutically- acceptable salts or mixtures thereof.
The aqueous nasal spray solution can be administered as a drop or any other form suitable for topical administration.. The composition may also be administered using a nasal tampon or a nasal sponge.
In a preferred embodiment, the aqueous nasal spray solution is provided in the form of nasal spray.
Other means for delivering the nasal spray, such as inhalation via a metered dose inhaler (MDI), may also be used. Several types of MDIs are regularly used for administration by inhalation. These types of devices can include breath-actuated MDI, spacer/holding chambers in combination with MDI, and nebulizers. The term "MDI" as used herein refers to an inhalation delivery system comprising, for example, a canister containing mixture of active agent and a propellant optionally with one or more excipients, a metered dose valve, an actuator, and a mouthpiece. The canister is usually filled with a solution of an active agent, such as the nasal spray composition, and a propellant, such as one or more hydrofluoroalkanes [e.g. 1 , 1 , 1 ,2-tetrafluoroethane (HFA-134a) and 1, 1, 1 ,2,3,3,3-heptafluoropropane (HFA-227)]; chlorofluorocarbons; and alcohols such as ethanol, isopropanol, butanol, propanol or mixtures thereof. When the actuator is depressed a metered dose of the solution is aerosolized for inhalation. Particles comprising the active agent are propelled towards the mouthpiece where they may then be inhaled by a subject.
The amount of fluticasone and olopatadine or pharmaceutically acceptable salt thereof is a therapeutically effective amount and can be determined depending on the type and the degree of the disease, the age and the weight of the patient, and the like.
However, it will be appreciated that the above dosing regime should be tailored according to the individual patient's age, body weight and/or symptom severity.
The invention further provides a process of preparing the stable aqueous nasal spray solution comprising preparing solution of fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
In an embodiment, the process of preparing the stable aqueous nasal spray solution comprises steps of preparing solution of fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof with one or more water soluble polymers and further addition of one or more pharmaceutically acceptable excipients to the said solution.
In a further another embodiment, there is provided a process of preparing the stable aqueous nasal spray solution comprising fluticasone or pharmaceutically acceptable salts thereof and olopatadine or pharmaceutically acceptable salts thereof comprises steps of-
(a) preparing the of solution of polymers;
(b) dispersing surfactant with fluticasone or pharmaceutically acceptable salts thereof and adding to the solution of step (a);
(c) preparing the solution of other pharmaceutically acceptable excipients by sequentially dissolving in water;
(d) adding the solution of step (c) into solution of step (b); (e) preparing a solution of olopatadine or pharmaceutically acceptable salts thereof in water;
(f) providing the solution of preservative in water;
(g) adding the solution of step (f) to solution of step (e);
(h) adding the solution of step (g) to the solution of step (d)
(h) Filling the solution of step (h) into suitable containers.
The clear solution formulations are filled in to commercially available bottles and fit with metered dose pumps for nasal delivery of the drug products.
The aqueous solution can, for nasal administration, be applied in all medicament forms which are suitable for nasal administration, such as, for example, nasal drops by means of dispensing devices suitable for this purpose, such as bottles with drop device or nasal spray pumps.
In an embodiment, the invention further provides a stable aqueous nasal spray solution comprising combination of fluticasone or pharmaceutically acceptable salts thereof and fluticasone or pharmaceutically acceptable salts thereof for use in the preparation of a medicament for treatment of inflammatory disorders comprising administering the said composition to the patient in need thereof.
In a further embodiment, the invention provides a method for treating an allergic and/inflammatory symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a stable aqueous nasal spray solution comprising a therapeutically effective amount of combination of fluticasone or pharmaceutically acceptable salts thereof and fluticasone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1
Table 1
Sr. No. Ingredients Qty (%w/w)
1 Olopatadine Hydrochloride 0.475
2 Fluticasone Furoate 0.010 3 Benzalkonium chloride Solution (50%) 0.020
4 Citric Acid 0.050
5 Disodium Edetate 0.050
6 Hydroxyprbpyl methylcellulose 0.050
7 Polysorbate 80 5.000
8 Propylene Glycol 14.000
9 Sodium Citrate 0.300
10 Sucralose 0.150
1 1 Purified Water Q.S. to 100%
Procedure:
A solution of hydroxypropyl methylcellulose was prepared with water. Separately, fluticasone furoate and polysorbate 80 were dispersed and added to the above glycol solution to prepare Fluticasone furoate solution. A bulk solution containing edetate disodium, citric acid monohydrate, sodium Citrate dihydrate and sucralose was prepared with purified water and added to the hydroxypropyl methylcellulose solution followed by addition of fluticasone furoate solution. Olopatadine solution was prepared separately by adding olopatadine hydrochloride to water. A solution of benzalkonium chloride was also prepared separately and added to the olopatadine solution which was then added to the bulk solution containing fluticasone furoate. Finally, the solution was filled into suitable containers.
Example 2
Table 2
Figure imgf000016_0001
Procedure:
A solution of propylene Glycol and polyethylene glycol was prepared to make glycol solution. Separately, fluticasone furoate and polysorbate 80 were dispersed and added to the above glycol solution to prepare fluticasone furoate solution. A bulk solution containing edetate disodium, citric acid monohydrate, sodium citrate dihydrate and sucralose was prepared with purified water and added to the solution of fluticasone furoate. Olopatadine solution was prepared separately by adding olopatadine hydrochloride to water. A solution of benzalkonium chloride was also prepared separately and added to the olopatadine solution which was then added to the bulk solution containing Fluticasone furoate. Finally, the solution was filled into suitable containers.
Example 3: Stability study
Stability study of the aqueous nasal spray solution of the present invention was carried out at accelerated stability conditions (40°C, 75% relative humidity (RH) and 60°C) placing containers both in upright (Up) and inverted (Inv) positions. The result indicates that the solution of the present invention remains stable and retains at least 80% potency of fluticasone furoate and olopatadine hydrochloride over the storage period.
Table 3
Figure imgf000017_0001
While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

We Claim:
1. A stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.
2. The stable aqueous nasal spray solution as claimed in claim 1, wherein the water soluble polymer comprises one or more of glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4- pentanediol, 1,2,6-hexanetriol, thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, pectin, low methoxyl pectin, guar gum, gum arabic, carrageenan, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
3. The stable aqueous nasal spray solution as claimed in claim 1, wherein the ratio of the amount of fluticasone or pharmaceutically acceptable salt thereof and olopatadine or pharmaceutically acceptable salt thereof to the amount of water soluble polymer is in the range of from about 1 :2 to about 1 :80.
4. The stable aqueous nasal spray solution as claimed in claim 1, wherein the surfactant comprises one or more of anionic, cationic, non-ionic, and amphophilic surfactants.
5. The stable aqueous nasal spray solution as claimed in claim 1, wherein the surfactant comprises one or more of non-ionic surfactants.
6. The stable aqueous nasal spray solution as claimed in claim 5, wherein the non-ionic surfactant is a polyethoxylated sorbitan derivative.
7. The stable aqueous nasal spray solution as claimed in claim 1, wherein the ratio of the amount of surfactant to the amount of water soluble polymer is in the range of from about 1 :0.01 to about 1 :6.
8. The stable aqueous nasal spray solution as claimed in claim 1 , further comprising one or more pharmaceutically acceptable excipients comprising one or more chelating agents, preservatives, pH adjusting agents, and taste masking agents.
9. The stable aqueous nasal spray solution as claimed in claim 8, wherein the chelating agent comprises one or more of edetate disodium, edetate trisodium, edetate tetrasodium, and diethyleneamine pentaacetate.
10. The stable aqueous nasal spray solution as claimed in claim 8, wherein the preservative comprises one or more of benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, and disodium edetate.
1 1. The stable aqueous nasal spray solution as claimed in claim 8, wherein the pH adjusting agent comprises one or more of citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and phosphate salts.
12. The stable aqueous nasal spray solution as claimed in claim 8, wherein the taste masking agent comprises one or more of sucralose, thaumatin, sucrose, saccharin, fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, and camphor.
13. The stable aqueous nasal spray solution as claimed in claim 1 , wherein pH of the solution ranges from about 3.5 to about 7.5.
14. The stable aqueous nasal spray solution as claimed in claim 1, wherein the osmolality of the solution is less than about 350 mOsm/kg.
15. The stable aqueous nasal spray solution as claimed in claim 1 , further comprising at least one active agent selected from corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants and antiallergic agents.
16. A stable aqueous nasal spray solution for topical administration comprising: (a) fluticasone, or pharmaceutically acceptable salts thereof;
(b) olopatadine, or pharmaceutically acceptable salts thereof;
(c) about 0.005% to about 0.2% w/w of one or more preservative/s;
(d) about 0.005% to about 1% w/w of one or more pH adjusting agent/s;
(e) about 0.0002% to about 0.5% w/w of one or more chelating agent/s;
(f) about 0.001% to about 30% w/w of one or more water soluble polymer/s;
(g) about 1% to about 20% w/w of one or more surfactant/s; and
(h) water in quantity sufficient to make volume.
17. The stable aqueous nasal spray solution as claimed in claim 16, further comprising about 0.05% to 0.1% w/w of one or more sweetening agent/s.
18. A stable aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants; wherein the solution retains at least 80% potency of fluticasone and olopatadine or pharmaceutically acceptable salts thereof after storage for three months at 40°C and 75% relative humidity.
19. A process for preparing a stable aqueous nasal spray solution for topical administration, the process comprising preparing the solution of fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof using one or more water soluble polymer, one or more surfactants and optionally one or more pharmaceutically acceptable excipients.
20. A method for treating an allergic and/or inflammatory symptom or disorder in a subject in need thereof, comprising nasally administering to the subject an aqueous nasal spray solution for topical administration comprising fluticasone, or pharmaceutically acceptable salts thereof and olopatadine, or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally with one or more surfactants.
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