WO2020070599A1 - Nebulization composition of mometasone - Google Patents

Nebulization composition of mometasone

Info

Publication number
WO2020070599A1
WO2020070599A1 PCT/IB2019/058212 IB2019058212W WO2020070599A1 WO 2020070599 A1 WO2020070599 A1 WO 2020070599A1 IB 2019058212 W IB2019058212 W IB 2019058212W WO 2020070599 A1 WO2020070599 A1 WO 2020070599A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
mometasone furoate
nebulization
mometasone
composition
Prior art date
Application number
PCT/IB2019/058212
Other languages
French (fr)
Inventor
Ramprasad MURUGAN
Ulhas Dhuppad
Sagar Rase
Original Assignee
Glenmark Specialty S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Specialty S.A. filed Critical Glenmark Specialty S.A.
Publication of WO2020070599A1 publication Critical patent/WO2020070599A1/en

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Classifications

    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to a sterile pharmaceutical composition comprising mometasone or a pharmaceutically acceptable salt or ester thereof, for inhalation via nebulization to a subject.
  • the invention also relates to a process of preparing the pharmaceutical composition and its use in the treatment of respiratory diseases in a subject.
  • Respiratory disorders include a number of airway diseases. Asthma and chronic obstructive airway disease (COPD) are among the most prevalent and life threatening conditions.
  • COPD chronic obstructive airway disease
  • COPD chronic disorder that is characterized by loss of elasticity of the airways and air sacs, destruction of alveolar walls, inflammation of airways, and high mucus production in the airways. All of these effects lead to clogging of the airways making it difficult for the patient to breathe.
  • Asthma is a chronic disease involving airways of the lung that is characterized by coughing, wheezing, and shortness of breath.
  • Inhalation route is the most preferred form for the treatment of respiratory disorders.
  • a number of medications delivered by the inhalation route include corticosteroids, beta agonists, anticholinergic agents, and expectorants.
  • There are different dosage forms available such as nebulization, dry powder inhalers, and metered dose inhalers.
  • Nebulization is the preferred mode of delivery as it can be used to deliver medications across all age groups especially pediatric and geriatric population.
  • the nebulization dosage form unlike the dry powder and the metered dose inhalers does not require synchronization with the user breathing pattern to maximize the delivery.
  • Corticosteroids have always demonstrated efficacy in the treatment of respiratory disorders when administered by the inhalation route. However, it has been observed that these agents have been delivered by the dry powder or the metered dose inhaler formulations, owing, to the limited aqueous solubility. Nebulization of corticosteroids necessitate formulation of aqueous suspensions of these agents. It is an extreme challenge to maintain the physical stability of the corticosteroid suspensions.
  • the present invention provides a nebulization composition comprising mometasone or its pharmaceutically acceptable salts thereof.
  • the present invention relates to a sterile pharmaceutical composition for inhalation via nebulization to a subject.
  • the nebulization composition comprises mometasone or its salt (e.g., a pharmaceutically acceptable salt) and water.
  • the pharmaceutical composition may be a suspension.
  • the nebulization composition may be contained within a pre-filled container.
  • the nebulization composition may be administered to relieve a subject suffering from asthma.
  • a sterile pharmaceutical composition is a unit dose nebulizable pharmaceutical suspension for inhalation comprising mometasone or its salt.
  • the pharmaceutical suspension may be administered in nebulized form to relieve bronchospasm in a subject, such as a subject suffering from asthma.
  • the nebulization composition comprising mometasone or its pharmaceutically acceptable salt thereof is free, or substantially free, of preservative.
  • the mometasone salt in the nebulization composition described herein is mometasone furoate, such as mometasone furoate monohydrate ;9,2l- Dichloro- 1 I b, 17-dihydroxy- 16a-methylpregna- 1 ,4-diene-3,20-dione 17-(2 furoate) monohydrate.
  • the nebulization composition contains micronized mometasone furoate monohydrate.
  • the nebulization composition contains sterile mometasone furoate monohydrate.
  • the nebulization composition contains sterile, micronized mometasone furoate monohydrate.
  • the nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • One embodiment is a 0.2 ml to 6 ml nebulization composition, such as an aqueous suspension comprising mometasone or its pharmaceutically acceptable salt thereof; such as mometasone furoate monohydrate.
  • the nebulization composition contains micronized mometasone or its pharmaceutically acceptable salt thereof.
  • the mometasone or its pharmaceutically acceptable salt has a mean particle size of about 0.1 micron to about 5 microns.
  • the mometasone or its pharmaceutically acceptable salt thereof has a D90 of NMT 10 microns.
  • the nebulization composition comprises
  • pH of the nebulization composition is between 2 and 8.
  • the nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage.
  • the nebulization composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of mometasone or its salt in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 25. degree. C. when stored in a suitable low density polyethylene (LDPE) container.
  • LDPE low density polyethylene
  • the osmolality of the nebulization composition may be from about 200 to about 500 mOsm/kg. In other embodiments of the present invention, the osmolality may be between about 275 and about 325 mOsm/kg.
  • nebulization composition is a ready-to-use dosage form which does not require any mixing or dilution by the subject prior to administration.
  • the nebulization composition may be administered for the relief of bronchospasm in a subject suffering from asthma.
  • each container comprises a single unit dose of a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt for the treatment of asthma.
  • each container includes a sterile, premixed, premeasured, aqueous suspension comprising a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt in a single container.
  • Yet another embodiment is a method of administering mometasone or its pharmaceutically acceptable salt thereof comprising administering by inhalation to a subject a nebulization composition of the present invention.
  • One embodiment is method of administering by inhalation to a subject a nebulization composition comprising mometasone or its pharmaceutically acceptable salt thereof atleast once daily or twice daily.
  • the total daily dose of mometasone furoate administered as per the invention can range from 10 to 5000 mcg/day in single or divided doses.
  • Yet another embodiment is a method of relieving bronchospasm (such as that associated with asthma) comprising administering by inhalation to a subject in need thereof a nebulization composition of the present invention.
  • Another embodiment is a method of providing a faster onset of relief from bronchospasms (such as that associated with asthma) by administering a nebulization composition of the present invention.
  • One embodiment is a method of increasing the FEV1 values by administering a nebulization composition of the present invention.
  • kits and/or systems for administering a bronchodilator to relieve bronchospasm, for instance, bronchospasm associated with asthma.
  • the kit and/or system may comprise a nebulization composition of the present invention.
  • the kit and/or system comprises a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of asthma.
  • the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a nebulization composition of the present invention containing a therapeutically effective amount of mometasone for the treatment of bronchospasm (such as that associated with asthma), and instructions for using the same.
  • kits comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the nebulization compositions of the present invention.
  • the time taken for administering the nebulization composition of the present invention may be from about 1 minute to about 10 minutes.
  • kits for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
  • a nebulizer (i) a nebulizer; (ii) a nebulization composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
  • One embodiment of the present invention is the process of preparing the nebulization composition of the present invention, the process comprising the steps of:
  • step (v) Aseptically mixing the aqueous phase of step (iv) to step (ii).
  • Another embodiment of the invention relates to a device comprising mometasone or its pharmaceutically acceptable salt thereof, for example, for use in relieving the symptoms of asthma.
  • Yet another embodiment is a method for improving user compliance and/or quality of life as compared to conventional treatments for asthma.
  • the method comprises initiating treatment with the nebulization composition of the present invention, or a container, kit, or system of the present invention.
  • the present invention provides convenient, fast and reliable treatment for asthma that represents an improvement over traditional asthma treatments.
  • the present invention relates to a sterile pharmaceutical composition for inhalation via nebulization to a subject.
  • the nebulization composition comprises mometasone or its salt (e.g., a pharmaceutically acceptable salt) and water.
  • the pharmaceutical composition may be a suspension.
  • the nebulization composition may be contained within a pre -filled container.
  • the nebulization composition may be administered to relieve a subject suffering from asthma.
  • the term "mometasone" as used herein, include acids, salts, esters, hydrates, polymorphs, hemihydrates, solvates, and derivatives thereof.
  • the mometasone is in the form of mometasone furoate monohydrate.
  • the mometasone is in the form of anhydrous mometasone furoate.
  • Mometasone furoate can be either crystalline or amorphous form.
  • the mometasone is in the form of anhydrous amorphous mometasone furoate.
  • Mometasone furoate monohydrate is a corticosteroid and is a white powder having molecular weight 539.45.
  • the IUPAC name is 9,21 -Dichloro- 1 I b, 17-dihydroxy- l6a-methylpregna-l,4-diene-3,20-dionel7-(2 furoate) monohydrate with the structure:
  • Mometasone furoate monohydrate is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran.
  • mometasone or its pharmaceutically acceptable salt thereof may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or hydroalcoholic mixture or any other aqueous vehicle comprising a pharmaceutically acceptable amount of an osmotic agent.
  • an "effective amount" of a therapeutic agent will be recognized by clinicians and persons of ordinary skill in the art, and includes an amount effective to treat, reduce, alleviate, ameliorate, eliminate or prevent one or more symptoms of the condition sought to be treated, or alternately, the condition sought to be avoided, or to otherwise produce a clinically recognizable favorable change in the condition or its effects.
  • the nebulizable composition of the present invention may be provided in sterile unit dose treatments.
  • the nebulization composition comprises an aqueous suspension comprising mometasone furoate monohydrate and wherein the composition is free of any other pharmaceutically acceptable excipients.
  • the nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the volume of the nebulization composition is about 0.2 ml to about 6 ml.
  • the nebulization composition of the present invention may contain mometasone furoate monohydrate in micronized form. Suitable micronization techniques like Microfluidizer, High pressure homogenizer, Ball mill, Sonication and other such techniques commonly known in the art can be employed to effectively size reduce the mometasone or its pharmaceutically acceptable salt thereof.
  • the particle size of mometasone or its pharmaceutically acceptable salt thereof desired for effective nebulization of the compositions of the present invention can range from about 0.1 micron to about 5 micron.
  • the nebulization compositions contain mometasone or its pharmaceutically acceptable salt thereof having a D90 of NMT 10 microns.
  • the nebulization composition of the present invention have a pH of about 2 to about 8.
  • the pH may be adjusted by the addition of one or more pharmaceutically acceptable acids.
  • suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and combinations thereof.
  • suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid.
  • the pH is adjusted with 1N hydrochloric acid or 1N sulfuric acid.
  • the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid.
  • a preferred organic acid is citric acid.
  • mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as for example citric acid or ascorbic acid.
  • the nebulization composition may contain 0.0001% to 0.53% w/v of citric acid, or 0.0001% to 2.20% w/v of sodium citrate, or 0.00937% to 9.5% w/v of monosodium phosphate dehydrate, or 0.0017% to 1.7% w/v of Dibasic sodium phosphate anhydrous.
  • the nebulization composition of the present invention may optionally include a buffer.
  • General and biological buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate -phosphate -borate (Teorell-Stanhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS- TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers.
  • the osmolality of the nebulization composition may be from about 200 to about 500 mOsm/kg. Preferably, the osmolality may be from about 275 to about 325 mOsm/kg.
  • the nebulization compositions of the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt.
  • Suitable tonicity adjusting agents may include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium bi
  • Suitable osmotic adjusting agents include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof.
  • Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, dextrose and mixtures thereof.
  • any cosolvent that is suitable for inhalation and capable of dissolving or dispersing the mometasone or its pharmaceutically acceptable salt thereof in the mixture of cosolvent and water can be used.
  • suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons.
  • the cosolvent is a short chain polar alcohol. More preferably, the cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. The most preferred cosolvent is ethanol.
  • suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes.
  • Suitable ethers include dimethyl ether and diethyl ether.
  • suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane .
  • Suitable nonionic surfactants include all substances of this type that can normally be used in agrochemical compositions.
  • polyethylene glycol ethers of linear alcohols reaction products of fatty acids with ethylene oxide and/or propylene oxide
  • polyvinyl alcohol polyvinylpyrrolidone
  • copolymers of polyvinyl alcohol and polyvinylpyrrolidone polyethylene oxide -polypropylene oxide block copolymers and also copolymers of (meth)acrylic acid and (meth)acrylic esters, and also alkyl ethoxylates and alkylaryl ethoxylates, which optionally may be phosphated and optionally may be neutralized with bases, it being possible for mention to be made, by way of example, of sorbitol ethoxylates.
  • Suitable anionic surfactants include all substances of this type that can normally be used in agrochemical compositions. Preference is given to alkali metal salts and alkaline earth metal salts of alkylsulphonic acids or alkylarylsulphonic acids.
  • suitable cationic surfactants include but are not limited to ammnonium bromides; nonionic surfactants include but are not limited to alkyl ethoxylates, alkyl gluccosides and alkyl phenol ethoxylates; and amphoteric surfactants include but are not limited to betaines, amphoacetates, and amphodiacetates.
  • a preferred anionic surfactant is sodium dodecyl sulfate (SDS) and a preferred cationic surfactant is dodecyl trimethyl ammonium bromide; SDS is most preferred for the methods of the present invention. Also possible is the incorporation of amphoteric surfactants, such as alkyl betaines, alkyl ami do betaines, and alkyl amphoacetates.
  • Polysorbates and Sorbitans may be used as surfactants in the nebulizable composition.
  • the nebulization composition may contain 0.002 % to 0.40% w/v Polysorbate 80, or 0.0006 to 9.00% w/v Polysorbate 20, or 0.00075 to 1.25% w/v Sorbitan Laurate.
  • Suitable antioxidants include, but are not limited to, ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro-vitamins occurring in the human body.
  • the nebulization composition may also contain a complexing agent, examples include but not limited to EDTA and salts thereof, such as edetate disodium.
  • a complexing agent examples include but not limited to EDTA and salts thereof, such as edetate disodium.
  • the nebulization composition composition contain 0.0001 to 0.75% w/v Edetate disodium.
  • the nebulization composition comprising a complexing agent provides an improved stability with reduced levels of impurities and degradation products.
  • the nebulization composition of the present invention may comprise
  • pH of the nebulization composition is between 2 and 8.
  • the nebulization composition may be contained in a unit-dose, low-density polyethylene (LDPE) container, polypropylene container, or a cyclic polyolefin container.
  • LDPE low-density polyethylene
  • Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain 2 or more unit-dose containers.
  • Each foil pouch containing the unit dose container may be disposed in a shelf carton.
  • the nebulization composition comprises a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof.
  • Such system and/or kit may provide such containers in prepackaged form.
  • top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand.
  • the TWIST-FLEX.TM. top is advantageous in that it allows for easy dispensing of the nebulization composition, prevents spillage and eliminates the need to open the container or tearing by cutting or tearing off the top, or the like, thereby reducing cross-contamination.
  • One or more of the semi-permeable single unit dose containers may be prepackaged in aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and light as it helps to improves the shelf-life and stability of the nebulization composition.
  • Dispensing vials may include, but are not limited to, any container comprising glass, low density polyethylene, polypropylene, cyclic polyolefins or any other material capable of preventing the nebulization composition from leaking out of the container.
  • the vial may be enclosed by any conventional means including, but not limited to, screw cap, heat seal, snap-on top, flip-top, twist-off stopper, peel away top, and the like.
  • the nebulization compositions provided herein is a prepackaged, sterile, premixed, premeasured mometasone furoate aqueous suspension.
  • the nebulization composition is a ready-to-use dosage form which does not require any mixing or dilution by the subject prior to administration.
  • the nebulization composition may be administered for the relief of bronchospasm in a subject suffering from asthma.
  • One or more prefilled containers containing a nebulization composition of the present invention can also be provided.
  • Each container comprises a single unit dose of a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt for the treatment of asthma.
  • Each such container includes a sterile, premixed, premeasured, aqueous suspension comprising a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt in a single container.
  • the nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage.
  • the nebulization composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of mometasone or its salt in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 25. degree. C. when stored in a suitable low density polyethylene (LDPE) container.
  • LDPE low density polyethylene
  • the nebulization composition of the present invention can be prepared by a process comprising the steps of:
  • step (v) Aseptically mixing the aqueous phase of step (iv) to step (ii).
  • the nebulization composition of the present invention may be administered by a suitable nebulizer.
  • suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.
  • the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow.
  • the nebulizer being equipped with a mouthpiece or suitable face mask.
  • the nebulization compositions may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR.TM. Ultrasonic Nebulizer.
  • nebulizers may also include those manufactured, designed, or sold by Aerogen. Additionally, the formulations described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers or by breath actuated jet nebulizers.
  • the nebulization composition of the present invention demonstrate a fine particle fraction which is NET 5%.
  • a Geometric standard deviation (GSD) of about 0.5 to 5 may be observed when the nebulization composition of the present invention is administered through a nebulizer.
  • the nebulization composition of the present invention demonstrate a mass mean aerodynamic diameter of about 5 to 10 micron when administered through a nebulizer device.
  • the present invention relates to a method of administering mometasone or its pharmaceutically acceptable salt thereof comprising administering by inhalation to a subject a nebulization composition of the present invention.
  • the nebulization compositions comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily.
  • the nebulization composition of the present invention comprises mometasone furoate monohydrate.
  • the nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the present invention also relates to a method of relieving bronchospasm (such as that associated with asthma) comprising administering by inhalation to a subject in need thereof a nebulization composition of the present invention.
  • a nebulization composition of the present invention comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily.
  • the nebulization composition of the present invention comprises mometasone furoate monohydrate.
  • the nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition of the present invention also provide a faster onset of relief from bronchospasms (such as that associated with asthma).
  • the present invention relates to a method of increasing the FEV1 values by administering a nebulization composition of the present invention.
  • the total daily dose of mometasone furoate administered as per the invention can range from 10 to 5000 mcg/day in single or divided doses.
  • the nebulization composition of the present invention can be supplied as a part of a kit and/or system for administering a bronchodilator to relieve bronchospasm, for instance, bronchospasm associated with asthma.
  • the kit and/or system may comprise a nebulization composition of the present invention.
  • the kit and/or system comprises a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of asthma.
  • the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a nebulization composition of the present invention containing a therapeutically effective amount of mometasone for the treatment of bronchospasm (such as that associated with asthma), and instructions for using the same.
  • the nebulization composition can also be supplied as a part of a kit, said kit comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the nebulization compositions of the present invention.
  • the time taken for administering the nebulization composition of the present invention may be from about 1 minute to about 10 minutes.
  • the nebulization compositions comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily.
  • the nebulization composition of the present invention comprises mometasone furoate monohydrate.
  • the nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
  • the present invention relates to a kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
  • a nebulization composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
  • the present invention relates to a device comprising mometasone or its pharmaceutically acceptable salt thereof, for example, for use in relieving the symptoms of asthma.
  • a method for improving user compliance and/or quality of life as compared to conventional treatments for asthma is an aspect of the present invention.
  • the method comprises initiating treatment with the nebulization composition of the present invention, or a container, kit, or system of the present invention.
  • the present invention provides convenient, fast and reliable treatment for asthma that represents an improvement over traditional asthma treatments.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 6 Filter the solution of step 6 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 5 add and dissolve batch quantity of edetate disodium.
  • step 7 Filter the solution of step 7 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 5 add and dissolve batch quantity of edetate disodium.
  • step 7 Filter the solution of step 7 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 6 Filter the solution of step 6 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 5 add and dissolve batch quantity of edetate disodium.
  • step 7 Filter the solution of step 7 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 6 Filter the solution of step 6 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 4 add and dissolve batch quantity of edetate disodium.
  • step 7 Filter the solution of step 7 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of sodium chloride.
  • step 6 Filter the solution of step 6 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of Sodium chloride.
  • step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate
  • step 6 To step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous.
  • step 8 Filter the solution of step 8 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of Sodium chloride.
  • step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate 7.
  • step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous.
  • step 8 Check the pH of the above bulk solution (Limit: between 2.0 and 8.0) 9. Filter the solution of step 8 aseptically.
  • step 3 homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
  • step 2 add and dissolve batch quantity of Sodium chloride. 6.
  • step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate
  • step 6 To step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous.
  • step 8 Filter the solution of step 8 aseptically.

Abstract

The present invention relates to a sterile pharmaceutical composition comprising mometasone or a pharmaceutically acceptable salt or ester thereof, for inhalation via nebulization to a subject. The invention also relates to a process of preparing the pharmaceutical composition and its use in the treatment of respiratory diseases in a subject.

Description

NEBULIZATION COMPOSITION OF MOMETASONE
PRIORITY DOCUMENTS
This patent application claims priority to Indian Provisional Patent Application number 201821037741 (filed on Oct 5, 2018) the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a sterile pharmaceutical composition comprising mometasone or a pharmaceutically acceptable salt or ester thereof, for inhalation via nebulization to a subject. The invention also relates to a process of preparing the pharmaceutical composition and its use in the treatment of respiratory diseases in a subject.
BACKGROUND OF THE INVENTION
Respiratory disorders include a number of airway diseases. Asthma and chronic obstructive airway disease (COPD) are among the most prevalent and life threatening conditions.
COPD is a chronic disorder that is characterized by loss of elasticity of the airways and air sacs, destruction of alveolar walls, inflammation of airways, and high mucus production in the airways. All of these effects lead to clogging of the airways making it difficult for the patient to breathe. Asthma, on the other hand, is a chronic disease involving airways of the lung that is characterized by coughing, wheezing, and shortness of breath.
Inhalation route is the most preferred form for the treatment of respiratory disorders. A number of medications delivered by the inhalation route include corticosteroids, beta agonists, anticholinergic agents, and expectorants. There are different dosage forms available such as nebulization, dry powder inhalers, and metered dose inhalers.
Nebulization is the preferred mode of delivery as it can be used to deliver medications across all age groups especially pediatric and geriatric population. The nebulization dosage form, unlike the dry powder and the metered dose inhalers does not require synchronization with the user breathing pattern to maximize the delivery. Corticosteroids have always demonstrated efficacy in the treatment of respiratory disorders when administered by the inhalation route. However, it has been observed that these agents have been delivered by the dry powder or the metered dose inhaler formulations, owing, to the limited aqueous solubility. Nebulization of corticosteroids necessitate formulation of aqueous suspensions of these agents. It is an extreme challenge to maintain the physical stability of the corticosteroid suspensions. Further, delivery of reproducible doses of the corticosteroids from these suspensions is a long faced challenge in the respiratory domain. Mometasone is one such corticosteroid which has proved to be extremely useful for treatment of respiratory disorders. However, nebulization dosage form of mometasone has not been available as on date.
There still exists an unmet need in the art to effectively deliver mometasone in nebulized form for the treatment of respiratory disorders. The present invention provides a nebulization composition comprising mometasone or its pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
The present invention relates to a sterile pharmaceutical composition for inhalation via nebulization to a subject. The nebulization composition comprises mometasone or its salt (e.g., a pharmaceutically acceptable salt) and water. The pharmaceutical composition may be a suspension. The nebulization composition may be contained within a pre-filled container. The nebulization composition may be administered to relieve a subject suffering from asthma.
In one embodiment, a sterile pharmaceutical composition is a unit dose nebulizable pharmaceutical suspension for inhalation comprising mometasone or its salt. The pharmaceutical suspension may be administered in nebulized form to relieve bronchospasm in a subject, such as a subject suffering from asthma.
In a preferred embodiment, the nebulization composition comprising mometasone or its pharmaceutically acceptable salt thereof is free, or substantially free, of preservative.
One embodiment is a nebulization composition comprising
(i) mometasone or its pharmaceutically acceptable salts thereof
(ii) water
wherein said composition is free of any pharmaceutically acceptable excipients thereof. In a preferred embodiment, the mometasone salt in the nebulization composition described herein is mometasone furoate, such as mometasone furoate monohydrate ;9,2l- Dichloro- 1 I b, 17-dihydroxy- 16a-methylpregna- 1 ,4-diene-3,20-dione 17-(2 furoate) monohydrate.
In an embodiment, the nebulization composition contains micronized mometasone furoate monohydrate.
In another embodiment, the nebulization composition contains sterile mometasone furoate monohydrate.
In yet another embodiment, the nebulization composition contains sterile, micronized mometasone furoate monohydrate.
The nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
In a preferred embodiment, the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
One embodiment is a 0.2 ml to 6 ml nebulization composition, such as an aqueous suspension comprising mometasone or its pharmaceutically acceptable salt thereof; such as mometasone furoate monohydrate.
In one embodiment, the nebulization composition contains micronized mometasone or its pharmaceutically acceptable salt thereof. The mometasone or its pharmaceutically acceptable salt has a mean particle size of about 0.1 micron to about 5 microns. In another embodiment, the mometasone or its pharmaceutically acceptable salt thereof has a D90 of NMT 10 microns.
In yet another embodiment, the nebulization composition comprises
(i) mometasone or its pharmaceutically acceptable salt thereof
(ii) pharmaceutically acceptable surfactant (iii) pharmaceutically acceptable isotonicity adjusting agents
(iv) a pharmaceutically acceptable buffer
(v) an agent to adjust pH
wherein pH of the nebulization composition is between 2 and 8.
In one embodiment, the nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage. The nebulization composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of mometasone or its salt in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 25. degree. C. when stored in a suitable low density polyethylene (LDPE) container.
The osmolality of the nebulization composition may be from about 200 to about 500 mOsm/kg. In other embodiments of the present invention, the osmolality may be between about 275 and about 325 mOsm/kg.
Another embodiment is a prepackaged, sterile, premixed, premeasured mometasone furoate aqueous suspension. Preferably, the nebulization composition is a ready-to-use dosage form which does not require any mixing or dilution by the subject prior to administration. The nebulization composition may be administered for the relief of bronchospasm in a subject suffering from asthma.
Yet another embodiment is one or more prefilled containers containing a nebulization composition of the present invention. In one embodiment, each container comprises a single unit dose of a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt for the treatment of asthma. In one embodiment, each container includes a sterile, premixed, premeasured, aqueous suspension comprising a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt in a single container.
Yet another embodiment is a method of administering mometasone or its pharmaceutically acceptable salt thereof comprising administering by inhalation to a subject a nebulization composition of the present invention. One embodiment is method of administering by inhalation to a subject a nebulization composition comprising mometasone or its pharmaceutically acceptable salt thereof atleast once daily or twice daily. The total daily dose of mometasone furoate administered as per the invention can range from 10 to 5000 mcg/day in single or divided doses.
Yet another embodiment is a method of relieving bronchospasm (such as that associated with asthma) comprising administering by inhalation to a subject in need thereof a nebulization composition of the present invention.
Another embodiment is a method of providing a faster onset of relief from bronchospasms (such as that associated with asthma) by administering a nebulization composition of the present invention.
One embodiment is a method of increasing the FEV1 values by administering a nebulization composition of the present invention.
Yet another embodiment is a kit and/or system for administering a bronchodilator to relieve bronchospasm, for instance, bronchospasm associated with asthma. The kit and/or system may comprise a nebulization composition of the present invention. In one embodiment, the kit and/or system comprises a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of asthma. In another embodiment, the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a nebulization composition of the present invention containing a therapeutically effective amount of mometasone for the treatment of bronchospasm (such as that associated with asthma), and instructions for using the same.
Another embodiment is a kit comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the nebulization compositions of the present invention. The time taken for administering the nebulization composition of the present invention may be from about 1 minute to about 10 minutes.
One embodiment is a kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
(i) a nebulizer; (ii) a nebulization composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
(a) mometasone or its pharmaceutically acceptable salt; and
(b) water.
One embodiment of the present invention is the process of preparing the nebulization composition of the present invention, the process comprising the steps of:
(i) Dispersing mometasone or its pharmaceutically acceptable salt in a aqueous solution of a surfactant
(ii) Homogenizing the suspension obtained in step (i)
(iii) Adding isotonicity adjusting agents to separate quantity of WFI.
(iv) Adjusting pH with buffers and pH adjusting agents of step (iii)
(v) Aseptically mixing the aqueous phase of step (iv) to step (ii).
(vi) Making up the weight of the suspension using WFI.
(vii) Filling in LDPE vials
Another embodiment of the invention relates to a device comprising mometasone or its pharmaceutically acceptable salt thereof, for example, for use in relieving the symptoms of asthma.
Yet another embodiment is a method for improving user compliance and/or quality of life as compared to conventional treatments for asthma. The method comprises initiating treatment with the nebulization composition of the present invention, or a container, kit, or system of the present invention. The present invention provides convenient, fast and reliable treatment for asthma that represents an improvement over traditional asthma treatments.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a sterile pharmaceutical composition for inhalation via nebulization to a subject. The nebulization composition comprises mometasone or its salt (e.g., a pharmaceutically acceptable salt) and water. The pharmaceutical composition may be a suspension. The nebulization composition may be contained within a pre -filled container. The nebulization composition may be administered to relieve a subject suffering from asthma. The term "mometasone" as used herein, include acids, salts, esters, hydrates, polymorphs, hemihydrates, solvates, and derivatives thereof. In one aspect of the invention, the mometasone is in the form of mometasone furoate monohydrate. In another aspect of the invention, the mometasone is in the form of anhydrous mometasone furoate. Mometasone furoate can be either crystalline or amorphous form. In one more aspect, the mometasone is in the form of anhydrous amorphous mometasone furoate.
Mometasone furoate monohydrate is a corticosteroid and is a white powder having molecular weight 539.45. The IUPAC name is 9,21 -Dichloro- 1 I b, 17-dihydroxy- l6a-methylpregna-l,4-diene-3,20-dionel7-(2 furoate) monohydrate with the structure:
Figure imgf000008_0001
Mometasone furoate monohydrate is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran.
In the present invention, mometasone or its pharmaceutically acceptable salt thereof may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or hydroalcoholic mixture or any other aqueous vehicle comprising a pharmaceutically acceptable amount of an osmotic agent.
To treat indications with a therapeutic agent, an "effective amount" of a therapeutic agent will be recognized by clinicians and persons of ordinary skill in the art, and includes an amount effective to treat, reduce, alleviate, ameliorate, eliminate or prevent one or more symptoms of the condition sought to be treated, or alternately, the condition sought to be avoided, or to otherwise produce a clinically recognizable favorable change in the condition or its effects. The nebulizable composition of the present invention may be provided in sterile unit dose treatments. The nebulization composition comprises an aqueous suspension comprising mometasone furoate monohydrate and wherein the composition is free of any other pharmaceutically acceptable excipients.
The nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. Preferably, the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. The volume of the nebulization composition is about 0.2 ml to about 6 ml.
The nebulization composition of the present invention may contain mometasone furoate monohydrate in micronized form. Suitable micronization techniques like Microfluidizer, High pressure homogenizer, Ball mill, Sonication and other such techniques commonly known in the art can be employed to effectively size reduce the mometasone or its pharmaceutically acceptable salt thereof. The particle size of mometasone or its pharmaceutically acceptable salt thereof desired for effective nebulization of the compositions of the present invention can range from about 0.1 micron to about 5 micron. The nebulization compositions contain mometasone or its pharmaceutically acceptable salt thereof having a D90 of NMT 10 microns.
The nebulization composition of the present invention have a pH of about 2 to about 8. The pH may be adjusted by the addition of one or more pharmaceutically acceptable acids. Examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and combinations thereof. Examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid. In one embodiment, the pH is adjusted with 1N hydrochloric acid or 1N sulfuric acid. In another embodiment, the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. A preferred organic acid is citric acid. If desired, mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as for example citric acid or ascorbic acid. The nebulization composition may contain 0.0001% to 0.53% w/v of citric acid, or 0.0001% to 2.20% w/v of sodium citrate, or 0.00937% to 9.5% w/v of monosodium phosphate dehydrate, or 0.0017% to 1.7% w/v of Dibasic sodium phosphate anhydrous.
The nebulization composition of the present invention may optionally include a buffer. General and biological buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate -phosphate -borate (Teorell-Stanhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS- TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers.
The osmolality of the nebulization composition may be from about 200 to about 500 mOsm/kg. Preferably, the osmolality may be from about 275 to about 325 mOsm/kg. The nebulization compositions of the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt.
Suitable tonicity adjusting agents may include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine, zinc sulfate, and mixtures thereof. The nebulization composition of the present invention may contain 0.0001% to 1.13% w/v of sodium chloride, preferably 0.9% w/v.
Suitable osmotic adjusting agents that may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, dextrose and mixtures thereof.
Any cosolvent that is suitable for inhalation and capable of dissolving or dispersing the mometasone or its pharmaceutically acceptable salt thereof in the mixture of cosolvent and water can be used. Examples of suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons. Preferably, the cosolvent is a short chain polar alcohol. More preferably, the cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. The most preferred cosolvent is ethanol. Examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes. Examples of suitable ethers include dimethyl ether and diethyl ether. Examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane .
Suitable nonionic surfactants include all substances of this type that can normally be used in agrochemical compositions. Preferably mention may be made of polyethylene glycol ethers of linear alcohols, reaction products of fatty acids with ethylene oxide and/or propylene oxide, and also polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinyl alcohol and polyvinylpyrrolidone, polyethylene oxide -polypropylene oxide block copolymers and also copolymers of (meth)acrylic acid and (meth)acrylic esters, and also alkyl ethoxylates and alkylaryl ethoxylates, which optionally may be phosphated and optionally may be neutralized with bases, it being possible for mention to be made, by way of example, of sorbitol ethoxylates. Suitable anionic surfactants include all substances of this type that can normally be used in agrochemical compositions. Preference is given to alkali metal salts and alkaline earth metal salts of alkylsulphonic acids or alkylarylsulphonic acids. Examples of suitable cationic surfactants include but are not limited to ammnonium bromides; nonionic surfactants include but are not limited to alkyl ethoxylates, alkyl gluccosides and alkyl phenol ethoxylates; and amphoteric surfactants include but are not limited to betaines, amphoacetates, and amphodiacetates. A preferred anionic surfactant is sodium dodecyl sulfate (SDS) and a preferred cationic surfactant is dodecyl trimethyl ammonium bromide; SDS is most preferred for the methods of the present invention. Also possible is the incorporation of amphoteric surfactants, such as alkyl betaines, alkyl ami do betaines, and alkyl amphoacetates.
Preferably, Polysorbates and Sorbitans may be used as surfactants in the nebulizable composition.
The nebulization composition may contain 0.002 % to 0.40% w/v Polysorbate 80, or 0.0006 to 9.00% w/v Polysorbate 20, or 0.00075 to 1.25% w/v Sorbitan Laurate.
Suitable antioxidants that may be used include, but are not limited to, ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro-vitamins occurring in the human body.
The nebulization composition may also contain a complexing agent, examples include but not limited to EDTA and salts thereof, such as edetate disodium. Preferably the nebulization composition composition contain 0.0001 to 0.75% w/v Edetate disodium. The nebulization composition comprising a complexing agent provides an improved stability with reduced levels of impurities and degradation products.
The nebulization composition of the present invention may comprise
(i) mometasone or its pharmaceutically acceptable salt thereof
(ii) pharmaceutically acceptable surfactant
(iii) pharmaceutically acceptable isotonicity adjusting agents
(iv) a pharmaceutically acceptable buffer
(v) an agent to adjust pH
wherein pH of the nebulization composition is between 2 and 8.
The nebulization composition may be contained in a unit-dose, low-density polyethylene (LDPE) container, polypropylene container, or a cyclic polyolefin container. Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain 2 or more unit-dose containers. Each foil pouch containing the unit dose container may be disposed in a shelf carton. The nebulization composition comprises a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof. Such system and/or kit may provide such containers in prepackaged form. The container with a TWIST-FLEX.TM. top prefer, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand. The TWIST-FLEX.TM. top is advantageous in that it allows for easy dispensing of the nebulization composition, prevents spillage and eliminates the need to open the container or tearing by cutting or tearing off the top, or the like, thereby reducing cross-contamination. One or more of the semi-permeable single unit dose containers may be prepackaged in aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and light as it helps to improves the shelf-life and stability of the nebulization composition. Dispensing vials may include, but are not limited to, any container comprising glass, low density polyethylene, polypropylene, cyclic polyolefins or any other material capable of preventing the nebulization composition from leaking out of the container. The vial may be enclosed by any conventional means including, but not limited to, screw cap, heat seal, snap-on top, flip-top, twist-off stopper, peel away top, and the like.
The nebulization compositions provided herein is a prepackaged, sterile, premixed, premeasured mometasone furoate aqueous suspension. Preferably, the nebulization composition is a ready-to-use dosage form which does not require any mixing or dilution by the subject prior to administration. The nebulization composition may be administered for the relief of bronchospasm in a subject suffering from asthma.
One or more prefilled containers containing a nebulization composition of the present invention can also be provided. Each container comprises a single unit dose of a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt for the treatment of asthma. Each such container includes a sterile, premixed, premeasured, aqueous suspension comprising a single unit dose of a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt in a single container.
The nebulization composition provided herein has a long shelf life, i.e., it is stable during long term storage. The nebulization composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of mometasone or its salt in the nebulization composition after being stored for 3 or 6 months or 1, 2 or 3 years at 25. degree. C. when stored in a suitable low density polyethylene (LDPE) container.
The nebulization composition of the present invention can be prepared by a process comprising the steps of:
(i) Dispersing mometasone or its pharmaceutically acceptable salt in a aqueous solution of a surfactant
(ii) Homogenizing the suspension obtained in step (i)
(iii) Adding isotonicity adjusting agents to separate quantity of WFI.
(iv) Adjusting pH with buffers and pH adjusting agents of step (iii)
(v) Aseptically mixing the aqueous phase of step (iv) to step (ii).
(vi) Making up the weight of the suspension using WFI.
(vii) Filling in FDPE vials
The nebulization composition of the present invention may be administered by a suitable nebulizer. Suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow. The nebulizer being equipped with a mouthpiece or suitable face mask. The nebulization compositions may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR.TM. Ultrasonic Nebulizer. Other nebulizers may also include those manufactured, designed, or sold by Aerogen. Additionally, the formulations described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers or by breath actuated jet nebulizers. The nebulization composition of the present invention demonstrate a fine particle fraction which is NET 5%. A Geometric standard deviation (GSD) of about 0.5 to 5 may be observed when the nebulization composition of the present invention is administered through a nebulizer. The nebulization composition of the present invention demonstrate a mass mean aerodynamic diameter of about 5 to 10 micron when administered through a nebulizer device.
The present invention relates to a method of administering mometasone or its pharmaceutically acceptable salt thereof comprising administering by inhalation to a subject a nebulization composition of the present invention. The nebulization compositions comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily. Preferably, the nebulization composition of the present invention comprises mometasone furoate monohydrate. The nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. Preferably, the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
The present invention also relates to a method of relieving bronchospasm (such as that associated with asthma) comprising administering by inhalation to a subject in need thereof a nebulization composition of the present invention. The nebulization compositions comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily. Preferably, the nebulization composition of the present invention comprises mometasone furoate monohydrate. The nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. Preferably, the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. The nebulization composition of the present invention also provide a faster onset of relief from bronchospasms (such as that associated with asthma).
The present invention relates to a method of increasing the FEV1 values by administering a nebulization composition of the present invention. The total daily dose of mometasone furoate administered as per the invention can range from 10 to 5000 mcg/day in single or divided doses.
The nebulization composition of the present invention can be supplied as a part of a kit and/or system for administering a bronchodilator to relieve bronchospasm, for instance, bronchospasm associated with asthma. The kit and/or system may comprise a nebulization composition of the present invention. In one instance, the kit and/or system comprises a nebulization composition of the present invention comprising a therapeutically effective amount of mometasone or its pharmaceutically acceptable salt thereof in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of asthma. In another instance, the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a nebulization composition of the present invention containing a therapeutically effective amount of mometasone for the treatment of bronchospasm (such as that associated with asthma), and instructions for using the same.
The nebulization composition can also be supplied as a part of a kit, said kit comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the nebulization compositions of the present invention. The time taken for administering the nebulization composition of the present invention may be from about 1 minute to about 10 minutes. The nebulization compositions comprising mometasone or its pharmaceutically acceptable salts thereof can be administered to a subject atleast once daily or twice daily. Preferably, the nebulization composition of the present invention comprises mometasone furoate monohydrate. The nebulization composition may include from about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate, such as from about 0.005mg/ml to about 0.01 mg/ml, from about 0.01 mg/ml to about 0.05 mg/ml, from about 0.05mg/ml to about 0.125 mg/ml, from about 0.125 mg/ml to about 0.25 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, from about 0.5 mg/ml to about 1 mg/ml, from about 1 mg/ml to about 2 mg/ml, from about 2 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate. Preferably, the nebulization composition comprises about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
The present invention relates to a kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
(i) a nebulizer;
(ii) a nebulization composition for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
(a) mometasone or its pharmaceutically acceptable salt; and
(b) water.
The present invention relates to a device comprising mometasone or its pharmaceutically acceptable salt thereof, for example, for use in relieving the symptoms of asthma. A method for improving user compliance and/or quality of life as compared to conventional treatments for asthma is an aspect of the present invention. The method comprises initiating treatment with the nebulization composition of the present invention, or a container, kit, or system of the present invention. The present invention provides convenient, fast and reliable treatment for asthma that represents an improvement over traditional asthma treatments.
The following non-limiting examples suitably illustrate the pharmaceutical compositions of the present invention.
Example 1
Figure imgf000017_0001
Figure imgf000018_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection (WFI) of total batch size in stainless steel vessel.
Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate monohydrate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with sodium citrate and / or citric acid.
7. Filter the solution of step 6 aseptically.
8. Aseptically transfer the API slurry of step 4 to filtered solution of step 7.
9. Make up the weight to 100% with previously cooled WFI of step 1.
10. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 2
Figure imgf000018_0002
Figure imgf000019_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. To step 5 add and dissolve batch quantity of edetate disodium.
7. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with citric acid and / or sodium citrate
8. Filter the solution of step 7 aseptically.
9. Aseptically transfer the API slurry of step 4 to filtered solution of step 8.
10. Make up the weight to 100% with previously cooled WFI of step 1.
11. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 3
Figure imgf000019_0002
Figure imgf000020_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. To step 5 add and dissolve batch quantity of edetate disodium.
7. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with citric acid.
8. Filter the solution of step 7 aseptically.
9. Aseptically transfer the API slurry of step 4 to filtered solution of step 8.
10. Make up the weight to 100% with previously cooled WFI of step 1.
11. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 4
Figure imgf000020_0002
Figure imgf000021_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with citric acid.
7. Filter the solution of step 6 aseptically.
8. Aseptically transfer the API slurry of step 4 to filtered solution of step 7.
9. Make up the weight to 100% with previously cooled WFI of step 1.
10. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 5
Figure imgf000021_0002
Figure imgf000022_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. To step 5 add and dissolve batch quantity of edetate disodium.
7. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with hydrochloric acid and / or sodium hydroxide
8. Filter the solution of step 7 aseptically.
9. Aseptically transfer the API slurry of step 4 to filtered solution of step 8.
10. Make up the weight to 100% with previously cooled WFI of step 1.
11. Fill in plastic ampoules (Fill volume: 0.2 mL to 5 mL) and packed in aluminium pouch and seal.
Example 6
Figure imgf000023_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate monohydrate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with hydrochloric acid and / or sodium hydroxide.
7. Filter the solution of step 6 aseptically.
8. Aseptically transfer the API slurry of step 4 to filtered solution of step 7.
9. Make up the weight to 100% with previously cooled WFI of step 1.
10. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 7
Figure imgf000024_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. To step 4 add and dissolve batch quantity of edetate disodium.
7. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with hydrochloric acid.
8. Filter the solution of step 7 aseptically.
9. Aseptically transfer the API slurry of step 4 to filtered solution of step 8.
10. Make up the weight to 100% with previously cooled WFI of step 1.
11. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal. Example 8
Figure imgf000025_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 80 and disperse the batch quantity of Mometasone furoate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of sodium chloride.
6. Check and adjust the pH of the above bulk solution between 2.0 and 8.0 with hydrochloric acid.
7. Filter the solution of step 6 aseptically.
8. Aseptically transfer the API slurry of step 4 to filtered solution of step 7.
9. Make up the weight to 100% with previously cooled WFI of step 1.
10. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal. Example 9
Figure imgf000026_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 20 and Sorbitan Laurate and disperse the batch quantity of Mometasone furoate monohydrate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of Sodium chloride.
6. To step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate
7. To step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous.
8. Check the pH of the above bulk solution (Limit: between 2.0 and 8.0)
9. Filter the solution of step 8 aseptically.
10. Aseptically transfer the API slurry of step 4 to filtered solution of step 9 under stirring. 11. Make up the weight to 100% with previously cooled WFI of step 1.
12. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal. Example 10
Figure imgf000027_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Polysorbate 20 and disperse the batch quantity of Mometasone furoate monohydrate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of Sodium chloride.
6. To step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate 7. To step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous. 8. Check the pH of the above bulk solution (Limit: between 2.0 and 8.0) 9. Filter the solution of step 8 aseptically.
10. Aseptically transfer the API slurry of step 4 to filtered solution of step 9 under stirring.
11. Make up the weight to 100% with previously cooled WFI of step 1.
12. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
Example 11
Figure imgf000028_0001
*Used as Mometasone furoate monohydrate
Manufacturing process
1. Collect 120% of water for injection of total batch size in stainless steel vessel. Purge with Nitrogen.
2. From above step, transfer 40% of water for injection of total batch size in another stainless steel vessel.
3. Collect 1 to 60% of water for injection of total batch size. To this WFI, add and dissolve batch quantity of Sorbitan Laurate and disperse the batch quantity of Mometasone furoate monohydrate under stirring to get uniform slurry.
4. If required, homogenize the above slurry of step 3 using various high pressure homogeniser or Microfluidiser or Ball Mill.
5. To step 2 add and dissolve batch quantity of Sodium chloride. 6. To step 5 add and dissolve batch quantity of Monosodium phosphate dihydrate
7. To step 6 add and dissolve batch quantity of Dibasic sodium phosphate anhydrous.
8. Check the pH of the above bulk solution (Limit: between 2.0 and 8.0)
9. Filter the solution of step 8 aseptically.
10. Aseptically transfer the API slurry of step 4 to filtered solution of step 9 under stirring.
11. Make up the weight to 100% with previously cooled WFI of step 1.
12. Fill in plastic ampoules (Fill volume: 0.2 mL to 6 mL) and packed in aluminium pouch and seal.
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

WE CLAIM:
1. A sterile pharmaceutical composition for nebulization comprising
(i) mometasone or its pharmaceutically acceptable salt or ester thereof
(ii) a pharmaceutically acceptable surfactant
(iii) a pharmaceutically acceptable isotonicity adjusting agent
(iv) a pharmaceutically acceptable buffer
(v) a complexing agent, and
(vi) water
wherein pH of the composition is between 2 to 8, and
wherein the composition is contained in a pre-filled container.
2. The pharmaceutical composition according to claim 1 , wherein the composition is a suspension.
3. The pharmaceutical composition according to claim 1, wherein the composition contains mometasone furoate monohydrate.
4. The pharmaceutical composition according to claim 1 , wherein the composition contains sterile mometasone furoate monohydrate.
5. The pharmaceutical composition according to claim 1, wherein the composition contains about 0.005 mg/ml to about 5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
6. The pharmaceutical composition according to claim 1 , wherein the composition contains about 0.5 mg/ml of mometasone furoate equivalent to mometasone furoate monohydrate.
7. The pharmaceutical composition according to claim 1, wherein the volume of said composition is between about 0.2 ml to about 6 ml.
8. The pharmaceutical composition according to claim 1, wherein said composition contains mometasone furoate monohydrate having a mean particle size of about 0.1 micron to about 5 microns.
9. The pharmaceutical composition according to claim 1, wherein said composition has an osmolality of about 200 to about 500 mOsm/kg.
10. The pharmaceutical composition according to claim 1, wherein the complexing agent is edetate disodium.
11. The pharmaceutical composition according to claim 1 , wherein the composition has a Geometric standard deviation of about 0.5 to about 5 and a mass mean aerodynamic diameter of about 5 to about 10 micron when administered by a nebulizer device.
12. The pharmaceutical composition according to claim 1, wherein said composition is a prepackaged, sterile, premixed, premeasured unit dose composition.
13. The pharmaceutical composition according to claim 1, wherein said composition is administered to relieve bronchospasm in a subject.
14. The pharmaceutical composition according to claim 1, wherein said composition is administered once daily.
15. The pharmaceutical composition according to claim 1, wherein said composition is administered twice daily.
16. The pharmaceutical composition according to claim 1, wherein total daily dose of about 10 to about 5000 meg mometasone furoate is administered from in single or divided doses.
17. A kit for the treatment, prevention or amelioration or one or more symptoms of diseases or disorders associated with bronchoconstriction which comprises:
(i) a nebulizer;
(ii) a nebulization composition as claimed in claim 1
18. A process of preparing the nebulization composition of claim 1, the process
comprising the steps of:
(i) Dispersing mometasone or its pharmaceutically acceptable salt in a aqueous solution of a surfactant
(ii) Homogenizing the suspension obtained in step (i)
(iii) Adding isotonicity adjusting agent and complexing agent to separate quantity of water for injection.
(iv) Adjusting pH with buffers and pH adjusting agents of step (iii)
(v) Aseptically mixing the aqueous phase of step (iv) to step (ii). (vi) Making up the weight of the suspension using water for injection.
(vii) Filling in LDPE vials
19. A sterile pharmaceutical composition for nebulization comprising
(i) Mometasone furoate monohydrate
(ii) Polysorbate 80
(iii) Sodium chloride
(iv) Edetate disodium
(v) Citric acid and Sodium citrate
(vi) water
20. A sterile pharmaceutical composition for nebulization comprising
(i) Mometasone furoate monohydrate
(ii) Polysorbate 80
(iii) Sodium chloride
(iv) Edetate disodium
(v) Citric acid
(vi) water
21. A sterile pharmaceutical composition for nebulization comprising
(i) Mometasone furoate monohydrate
(ii) Polysorbate 80
(iii) Sodium chloride
(iv) Edetate disodium
(v) optionally, hydrochloric acid and sodium hydroxide
(vi) water
22. A sterile pharmaceutical composition for nebulization comprising
(i) Mometasone furoate monohydrate
(ii) Polysorbate 20
(iii) Sorbitan Laurate
(iv) Sodium chloride
(v) Monosodium phosphate dihydrate
(vi) Dibasic sodium phosphate anhydrous (vii) water
23. A sterile pharmaceutical composition for nebulization comprising
(i) Mometasone furoate monohydrate
(ii) Polysorbate 20
(iii) Sodium chloride
(iv) Monosodium phosphate dihydrate
(v) Dibasic sodium phosphate anhydrous
(vi) water
24. A sterile pharmaceutical composition for nebulization comprising (i) Mometasone furoate monohydrate
(ii) Sorbitan Laurate
(iii) Sodium chloride
(iv) Monosodium phosphate dihydrate
(v) Dibasic sodium phosphate anhydrous
(vi) water
PCT/IB2019/058212 2018-10-05 2019-09-27 Nebulization composition of mometasone WO2020070599A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114767630A (en) * 2022-06-06 2022-07-22 黑龙江中医药大学 Medicine composition for treating allergic rhinitis and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033991A1 (en) * 1997-10-09 2000-09-13 Schering Corporation Mometasone furoate suspensions for nebulization
WO2015036902A1 (en) * 2013-09-13 2015-03-19 Glenmark Pharmaceuticals Ltd Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033991A1 (en) * 1997-10-09 2000-09-13 Schering Corporation Mometasone furoate suspensions for nebulization
WO2015036902A1 (en) * 2013-09-13 2015-03-19 Glenmark Pharmaceuticals Ltd Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114767630A (en) * 2022-06-06 2022-07-22 黑龙江中医药大学 Medicine composition for treating allergic rhinitis and application thereof

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