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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• the present invention relates to a pharmaceutical aerosol composition.
• the present invention relates to a stable pharmaceutical aerosol composition, its process of manufacturing and its use for the treatment of respiratory disorders.
• Metered dose inhalers are, at present, the most efficient and best-accepted means for accurately delivering drugs in small doses to the human respiratory tract.
• Therapeutic agents commonly delivered by the inhalation route include bronchodilators ( ⁇ -2 agonists and anticholinergics), corticosteroids, and anti-allergies. Inhalation may also be a viable route for anti-infective, vaccinating, systemically acting and diagnostic agents, as well as anti- leukotrienes, and anti-proteases.
• MDIs comprise a pressure resistant container typically filled with a product such as a drug dissolved in a liquified propellant or micronized particles suspended in a liquified propellant where the container is fitted with a metering valve. Actuation of the metering valve allows a small portion of the spray product to be released whereby the pressure of the liquified propellant carries the dissolved or micronized drug particles out of the container to the patient.
• the valve actuator is used to direct the aerosol spray into the patient's oropharynx.
• Chlorofluorocarbons have been used extensively as propellants in drug formulations that are delivered to patients via a metered dose inhaler (MDI).
• MDI metered dose inhaler
• CFCs damage the Earth's ozone layer. It is believed that ozone blocks harmful ultraviolet rays and that depletion of the ozone layer will result in the incidence of skin cancer.
• CFCs are now gradually being replaced by hydro fluorocarbons or HFAs (the names will be used interchangeably herein), (e.g. HFA 134a & HFA 227) as the preferred MDI propellants.
• HFA 134a or 1,1,1,2-tetrafluoroethane (the names will be used interchangeably herein) is non-flammable, has low toxicity and has vapor pressure suitable for use in aerosols.
• HFA 134a is a very poor solvent which fails to dissolve or adequately disperse commonly used surfactants such as sorbitan trioleate, sorbitan monooleate, lecithins and oleic acid in useful concentrations without the aid of a co-solvent.
• propellant HFA 227 or 1,1,1,2,3,3,3-heptafluropropane (the names will be used interchangeably herein) is non-flammable, has low toxicity and has a vapor pressure suitable for use in aerosols.
• the polarity and solubility of HFA 227 differ from those of commonly used CFC propellants, and many commonly used surfactants are not soluble or are poorly dispersible in HFA 227.
• US5182097 relates to aerosol formulations consisting of 1,1,1,2-tetrafluoroethane, a drug and oleic acid as a surfactant to aid in dispersing the drug in the propellant.
• US5612053 relates to respirable dry powder formulations comprising controlled release particles of a cohesive composite of a drug and a carrier, wherein the carrier is a natural polysaccharide gum added as a filler.
• EP0384371 discloses aerosols in which 1,1,1,2,3,3,3-heptafluoropropane or its mixture with propane, butane, isobutane, dimethyl ether, or 1,1, difluoroethane serves as the propellant. The application does not, however, disclose suspension aerosols or pharmaceutical aerosol formulation.
• WO93/11747 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof
• a pharmaceutical suspension formulation suitable for aerosol administration consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof
• the application specifically discloses formulations of Formoterol Fumarate in HFA 134a, HFA 227 and 1:1 mixtures of HFA 134a and HFA 227.
• the formulations do not contain surfactants or ethanol. It is stated that mixtures of HFA 134a and HFA 227 may be adjusted for density matching with the drug.
• WO93/11745 discloses pharmaceutical aerosol formulations, substantially free of surfactant containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and up to 5% of a polar co-solvent.
• Preferred propellants are HFA 134a and HFA 227 which are preferably used alone.
• the preferred polar co-solvent is ethanol and it is stated that in general only small quantities e.g. 0.05 to 3.0% w/w of polar co-solvent are required to improve the dispersion and the use of quantities in excess of 5% w/w may disadvantageous ⁇ tend to dissolve the medicament.
• a number of medicinal aerosol formulations using HFA propellant systems are disclosed in, for example, EP0372777, WO91/11173, and WO91/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments. All applications propose the addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants in small amounts intended to minimise potential ozone damage, but have not been able to establish any unexpected advantage.
• adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants in small amounts intended to minimise potential ozone damage, but have not been able to establish any unexpected advantage.
• US6303103 discloses a pharmaceutical aerosol formulation which comprises particulate salbutamol and an anticholinergic medicament or physiologically acceptable salts and solvates thereof, a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant and substantially free of or containing less than 0.0001% of surfactant by weight of the medicament.
• a pharmaceutical aerosol formulation which comprises particulate salbutamol and an anticholinergic medicament or physiologically acceptable salts and solvates thereof, a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant and substantially free of or containing less than 0.0001% of surfactant by weight of the medicament.
• WO91/04011 describes a self-propelling powder aerosol composition containing finely- divided, pre-micronized solid drug coated with a single non-perfluorinated surface-active dispersing agent suspended in an aerosol propellant in which the dispersing agent is substantially insoluble.
• PCT/GB2008/002029 describes a formulation comprising tiotropium bromide coated with polyvinylpyrrolidone.
• This coating approach suffers from the disadvantage that it requires multiple processing steps and may cause difficulties in scale-up due to overspray and lack of uniformity.
• the disclosure of all these patents and patent applications are herein incorporated by reference.
• surfactants Most of the above prior art suggests the use of surfactants. However, the use of surfactants may not be feasible for all drugs because considerable difficulties have been encountered in finding suitable suspending agents or surfactants which are soluble in hydrofluoroalkanes and capable of stabilizing medicament suspensions. Also, with additional incorporation of excipients along with the surfactants may destabilize the formulation.
• HFAs are more polar and more hygroscopic than CFCs
• water ingress is more significantly found in HFA MDIs, and which also worsened by use of polar, water miscible cosolvents, such as alcohol.
• polar, water miscible cosolvents such as alcohol.
• the above phenomenon could also be influenced by nature of the drug substance or other excipients present in the formulation.
• Ambient moisture diffuses into MDIs through the valve gaskets and adversely affects the physical stability of MDI formulation by promoting drug particle growth and aggregation.
• the aggregation of drug particles may clog the valve orifice of the aerosol container rendering the dispensing device inoperative, or if a metering valve is employed, it may be render inaccurate dosing which, in the case of highly potent drugs, may lead to undesirable results.
• agglomeration may make the suspension physically unstable, an obviously undesirable result particularly in the case of aerosolized formulations.
• the object of the present invention is to provide a stable pharmaceutical aerosol composition.
• Still another object of the present invention is to provide a pharmaceutical aerosol composition with dose uniformity throughout the life of the can.
• a further object of the present invention is to provide a pharmaceutical aerosol composition for use in the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment of respiratory disorders.
• a stable pharmaceutical aerosol composition comprising one or more HFA propellants and at least one active complexed with an adjuvant; and, optionally, one or more pharmaceutically acceptable excipient.
• a stable pharmaceutical aerosol composition comprising at least one active complexed with an adjuvant; one or more HFA propellants; and at least one other pharmaceutically acceptable excipient, such as at least one bulking agent and/or co-solvent.
• a pharmaceutical aerosol composition for use in the treatment of mild, moderate or severe acute or chronic symptoms, or for prophylactic treatment, of respiratory disorders such as asthma.
• the inventors further observed that the dispersion of surfactant in the pharmaceutical aerosol composition with other pharmaceutically acceptable excipients rendered the composition unstable during the storage.
• the fine particle mass does not remain same or decreases in timely manner during the storage.
• an adjuvant such as PVP K 25, PVP K 17 or PVP K30 etc.
• propellant(s) or optionally with one or more bulking agent and/or co-solvent(s) aggregation of fine drug particles was reduced significantly and hence keeping the composition stable during the storage period. It was also found that the composition continued to exhibit uniform delivered dose characteristics throughout the life of the MDI.
• the present invention provides a pharmaceutical aerosol composition. More specifically, the pharmaceutical aerosol composition comprises at least one pharmaceutical active agent complexed with an adjuvant, at least one hydrofluoroalkane (HFA) propellant and optionally other suitable excipients such as one or more bulking agent(s) and/or co-solvent(s).
• HFA hydrofluoroalkane
• the adjuvant is a polymer, preferably a polyvinylpyrrolidone (PVP and other commercially available grades such as PVP Kl 2, PVP K15. PVP K17, PVP K25, PVP K30, PVP K60, PVP K90), preferably having a molecular weight ranging from PVP 2500 to PVP 1,200,000, preferably PVP 2500 to PVP 1,000,000. It has been found that when such polymers are complexed with drugs, they yield good quality pharmaceutical aerosol suspensions.
• PVP polyvinylpyrrolidone
• adjuvant is used throughout the description in broad sense to include not only polyvinylpyrrolidone (PVP) and its other commercially available grades such as PVP Kl 2, PVP K15. PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, but also suitable water soluble and water insoluble polymers or their mixtures, cyclodextrins, polyethylene glycols (e.g.
• PEG 4000 and PEG 6000 surfactants such as sorbitan trioleate, sorbitan monooleate, tweens, e.g., tween 20, 40, 60, 80, 120, lipids, lecithin, oleic acid, citric acid, and polyoxyethylene-lauryl ether (e.g. Brij 30).
• surfactants such as sorbitan trioleate, sorbitan monooleate, tweens, e.g., tween 20, 40, 60, 80, 120, lipids, lecithin, oleic acid, citric acid, and polyoxyethylene-lauryl ether (e.g. Brij 30).
• the water soluble polymers that can be used as an adjuvant, according to the present invention comprise homopolymers and co-polymers of N-vinyl lactams, especially homopolymers and co-polymers of N-vinyl pyrrolidone e.g.
• polyvinylpyrrolidone PVP
• copolymers of PVP and vinyl acetate co-polymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate
• dextrins such as grades of maltodextrin, cellulose esters and cellulose ethers
• high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide and propylene oxide and the like.
• the water insoluble polymers that can be used as an adjuvant, according to the present invention comprise acrylic copolymers e.g. Eudragit ElOO or Eudragit EPO; Eudragit L30D- 55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze; polyvinylacetate, for example, Kollicoat SR 3OD; cellulose derivatives such as ethylcellulose, cellulose acetate and the like.
• acrylic copolymers e.g. Eudragit ElOO or Eudragit EPO
• Eudragit L30D- 55 Eudragit FS30D
• Eudragit RL30D Eudragit RS30D
• Eudragit NE30D Eudragit NE30D
• Acryl-Eze polyvinylacetate
• polyvinylacetate for example, Kollicoat SR 3OD
• cellulose derivatives such as ethylcellulose, cellulose acetate and the like
• the amount of adjuvant in the drug-adjuvant complex ranges from 0.5% to 500% by weight of the drug, preferably from 0.5% to 100% by weight of the drug. Suitable amounts of the adjuvant are 0.5%, 1%, 2%, 10%, 50% and 100% by weight of the drug.
• the drug-adjuvant is in particulate (micronised form).
• the particle size is such as to permit substantially all of the particles to be potentially available for inhalation into the lungs upon administration of the aerosol composition.
• at least 90%, more preferably at least 95% by weight of the particles have a diameter of less than 15 micrometers, preferably from 0.5 to 15 micrometers, more preferably from 0.5 to 10 micrometers, and most preferably from 0.5 to 5 micrometers.
• Most preferably at least 95% by weight of the particles have a diameter from 0.5 to 5 micrometers.
• drugs which may be complexed in aerosol compositions include any drug useful in inhalation therapy known to a person skilled in the art which comprises one or more of the following for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti -infectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.
• analgesics e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine
• anginal preparations e.g. diltiazem
• antiallergics e.g. cromoglycate, keto
• anti-inflammatories e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone
• corticosteroids e.g. budesonide, ciclesonide, fluticasone, betamethasone, beclomethasone, tixocortol, formocortal, rimexolone, prednisolone, methylprednisolone, deflazacort, prednisone, cortisone, dexamethasone, hyderocortisone
• antitussives e.g.
• bronchodilators e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2- pyridinyl)ethoxy]hexyl]amino]me thyl]benzenemethanol; diuretics, e.g.
• amiloride anticholinergics e.g. tiotropium, ipratropium, aclidinium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon or pharmaceutically acceptable salts thereof.
• anticholinergics e.g. tiotropium, ipratropium, aclidinium, atropine or oxitropium
• hormones e.g. cortisone, hydrocortisone or prednisolone
• xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline
• therapeutic proteins and peptides e.g
• the drugs may be used in the form of their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs thereof to optimize the activity and/or stability of the composition.
• Particularly preferred drugs for complexation in aerosol composition include antiallergics, anticholinergics, bronchodilators and corticosteroids for example salbutamol, beclomethasone, ipratropium, formoterol, tiotropium, aclidinium, salmeterol, fluticasone, budesonide, fenoterol, ciclesonide, mometasone, or their pharmaceutically acceptable salts are especially preferred.
• bronchodilators or “corticosteroids” and the like are used in broad sense to include not only the beta-agonists or anticholinergic agents or corticosteroids per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs.
• salts of the drugs mentioned above may be used; acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate diphosphate, polygalacturonate, salicylate, stearate,
• Betamimetic agents useful in the composition of the present invention include, but are not limited to, salbutamol, formoterol, levalbuterol, carmoterol, pirbuterol and salmeterol.
• Suitable pharmaceutically acceptable salts of the betamimetics include, but are not limited to the hydrochloride, sulfate, maleate, tartrate, and citrate salts.
• the betamimetic agent is selected from salbutamol, salbutamol sulfate, levosalbutamol, levosalbutamol sulphate or levosalbutamol tartarate.
• Anticholinergic agents useful in the composition of the present invention include, but are not limited to, oxitropium, ipratropium, aclidinium and tiotropium.
• Suitable pharmaceutically acceptable salts of the anticholinergic agents include, but are not limited to, the halide salts such as bromide, chloride or iodide.
• the anticholinergic agent is tiotropium or tiotropium bromide or tiotropium bromide monohydrate.
• a preferred pharmaceutical aerosol composition in accordance with the present invention comprises: (a) an effective amount of at least one drug complexed with an adjuvant; (b) at least one hydro fluorocarbon propellant; and (c) optionally, at least one pharmaceutically acceptable excipient including one or more bulking agent(s) and/or co-solvent(s).
• a stable pharmaceutical aerosol composition comprising: (a) an effective amount of at least one pharmaceutical active selected from tiotropium, aclidinium, ipratropium, levosalbutamol or a pharmaceutically acceptable salt thereof complexed with PVP Kl 7 or PVP K30; (b) at least one hydrofluorocarbon propellant; and (c) optionally at least one bulking agent(s) such as lactose and/or co-solvent(s) such as polyethylene glycol 400 (PEG 400) with other pharmaceutically acceptable excipients.
• the aerosol composition according to the present invention may, if desired, comprise combination of two or more drugs. Accordingly, the present invention further provides aerosol composition comprising two or more drugs, wherein at least one of the drug is complexed with the adjuvant along with one or more optional pharmaceutically acceptable excipients.
• the pharmaceutical aerosol composition comprises bronchodilators such as tiotropium (e.g. as the bromide salt), salbutamol (e.g. as the free base or as the sulphate salt), levosalbutamol (e.g. as the sulphate salt), salmeterol (e.g. as the xinafoate salt), aclidinium, isoprenaline or their pharmaceutically acceptable salts or bronchodilator(s) in combination with one or more corticosteroid(s) such as a beclomethasone ester (e.g. the diproprionate), budesonide or a fluticasone ester (e.g. the propionate) or their other pharmaceutically acceptable salts, wherein at least one of the drug is complexed with the adjuvant.
• bronchodilators such as tiotropium (e.g. as the bromide salt), salbutamol (e.g. as the free base or as the
• the aerosol compositions may comprise a bronchodilator in combination with an antiallergic such as cromoglycate (e.g. the sodium salt).
• cromoglycate e.g. the sodium salt
• examples of such combinations include isoprenaline and sodium cromoglycate; salmeterol and fluticasone propionate; or salbutamol and beclomethasone dipropionate and the like.
• a pharmaceutical aerosol dispenser comprising a canister having a chamber containing a pharmaceutical aerosol composition according to the present invention; an outlet for delivering the pharmaceutical aerosol composition to a patient in need thereof; and a valve for controlling flow of the pharmaceutical aerosol composition from the chamber to the outlet.
• the canister is made up of metal, glass or a plastics material such as polysulphone plastics for example polysulphone (PSU) and polyethersulphone (PES).
• PSU polysulphone
• PES polyethersulphone
• the pharmaceutical aerosol device is a MDI.
• the present invention further provides a process of manufacturing a pharmaceutical aerosol dispenser for delivering the aerosol pharmaceutical formulation to a patient in need thereof, comprising:
• the present invention provides a process of manufacturing a complex of an active agent and an adjuvant comprising:
• step (b) heating the mixture from step (a) to a suitable temperature and adding water to form a clear solution;
• step (c) adding the adjuvant to the above solution from step (b);
• step (f) drying (for example at suitable temperature, or preferably 50 0 C) the washed residue from step (e) to form a drug-adjuvant complex.
• the solvent used in the above process may be selected from acetonitrile, methanol, water, dimethyl formamide, acetone, tetrahydrofuran, dimethyl sulfoxide. Most preferable solvent is acetone.
• the complex of an active agent and an adjuvant can be isolated by lyophilization or by flash-evaporating the solvent using suitable techniques known in the art such as spray-drying. Flash-evaporating technique with respect to the present invention means removal of the solvent by applying heat and vacuum.
• the active agent used in the process of preparing the complex with an adjuvant according to the present invention may be in amorphous, crystalline, monohydrate or anhydrous form or a derivative or a polymorph or a prodrug thereof.
• the pharmaceutical aerosol composition according to the present invention may optionally contain one or more excipients or carriers conventionally used in the art of pharmaceutical aerosol formulation.
• excipients include, but are not limited to, taste masking agents, buffers, antioxidants, water and chemical stabilizers.
• suitable bulking agents include, but are not limited to one or more of saccharides such as monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.
• the bulking agent may be present in a concentration of 0.005- 500%, more preferably in a range of 0.005-300% by weight of the complex.
• the preferred bulking agent is Lactose.
• cosolvents include, but are not limited to one or more of polyethylene glycol ("PEG"), propylene glycol, isopropyl myristate or glycerol.
• PEG polyethylene glycol
• the cosolvent is PEG, such as PEG 200 or PEG 400.
• the cosolvent can be present in a range of about 0.05% to about 15% by weight of the composition.
• the cosolvent is present in a range of about 0.05% to about 1% or about 0.05% to about 0.3% by weight of the composition.
• the present invention may optionally comprise antioxidants like citric acid, benzalkonium chloride.
• HFA propellants are now preferred over CFC propellants.
• suitable HFA propellants for use in the present invention include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227).
• HFA-134a 1,1,1,2-tetrafluoroethane
• HFA-227 1,1,1,2,3,3,3-heptafluoropropane
• mixtures of two or more such halogen-substituted hydrocarbons may also be used.
• the invention is particularly useful in that it allows pharmaceutically acceptably stable dispersions to be attained using HFA propellant as the aerosol propellant.
• the aerosol compositions of the invention may be prepared with HFA propellant alone or a mixture of HFA propellant and another miscible adjuvant having a polarity equal to or lower than the polarity of the HFA propellant.
• the present invention provides a pharmaceutical aerosol composition according to the present invention for use in the treatment of mild, moderate or severe acute or chronic symptoms, or for prophylactic treatment, of a respiratory disorder, such as asthma.
• the present invention provides use of the pharmaceutical aerosol composition according to the present invention in the manufacture of a medicament for the treatment of mild, moderate or severe acute or chronic symptoms, or for prophylactic treatment, of a respiratory disorder, such as asthma.
• a method of treatment of mild, moderate or severe acute or chronic symptoms, or for prophylactic treatment, of a respiratory disorder, such as asthma comprising administering a therapeutically effective amount of a pharmaceutical aerosol composition according to the present invention to a patient in need thereof.
• Composition 1 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), co-solvent and HFA propellant.
• Composition 2 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (100%), co-solvent and HFA propellant.
• Composition 3 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%) and HFA propellant.
• Composition 4 Pharmaceutical aerosol composition containing Ipratropium bromide-PVP complex (0.5%) and HFA propellant.
• Composition 5 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (100%) and HFA propellant.
• composition 6 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
• Composition 7 Pharmaceutical aerosol composition containing Levosalbutamol sulphate- PVP complex (0.5%), bulking agent and HFA propellant.
• Composition 8 Pharmaceutical aerosol composition containing Levosalbutamol tartarate- PVP complex (0.5%), bulking agent and HFA propellant.
• Composition 9 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
• Composition 10 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
• Composition 11 Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
• Composition 12 is a composition of Composition 12:
• Composition 13 is a composition of Composition 13:
• composition 14 is a composition of Composition 14:
• Composition 15 is a composition of Composition 15:
• Composition 16 is a composition of Composition 16:
• aerosol composition containing drug-adjuvant complex exhibited consistent fine particle size during the study when stored at accelerated stability conditions.

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