[go: up one dir, main page]

EP2362766A2 - Pharmaceutical aerosol composition - Google Patents

Pharmaceutical aerosol composition

Info

Publication number
EP2362766A2
EP2362766A2 EP09753178A EP09753178A EP2362766A2 EP 2362766 A2 EP2362766 A2 EP 2362766A2 EP 09753178 A EP09753178 A EP 09753178A EP 09753178 A EP09753178 A EP 09753178A EP 2362766 A2 EP2362766 A2 EP 2362766A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical aerosol
aerosol composition
composition according
adjuvant
hfa
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP09753178A
Other languages
German (de)
French (fr)
Inventor
Amar Lulla
Geena Malhotra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
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
Priority claimed from PCT/GB2009/002575 external-priority patent/WO2010052450A1/en
Application filed by Cipla Ltd filed Critical Cipla Ltd
Publication of EP2362766A2 publication Critical patent/EP2362766A2/en
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A pharmaceutical aerosol composition comprising at least one hydrofluoroalkane propellant; at least one active agent complexed with an adjuvant; and, optionally, at least one pharmaceutically acceptable excipient.

Description

Pharmaceutical Aerosol Composition
Technical Field:
The present invention relates to a pharmaceutical aerosol composition. In particular the present invention relates to a stable pharmaceutical aerosol composition, its process of manufacturing and its use for the treatment of respiratory disorders.
Background and prior art:
Metered dose inhalers (MDIs) 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 (β-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 (CFCs) have been used extensively as propellants in drug formulations that are delivered to patients via a metered dose inhaler (MDI). However, recent scientific evidence suggests that 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. As a result, 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.
Propellant 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. However, 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.
Similarly, 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. However, 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 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.
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. However, to support the claimed invention, there is no explicit demonstration by way of examples or any stability study data.
Attempts have also been made to coat drug with only surfactants or instead, but the results have not been very satisfactory.
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.
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.
Since the 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. 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. In addition to increasing the particle size and clogging orifices, agglomeration may make the suspension physically unstable, an obviously undesirable result particularly in the case of aerosolized formulations.
Therefore there still remains a need to provide a way to solve the problem of fine drug particle aggregation and provide a stable aerosol composition utilizing hydrofluorocarbon propellants.
Object:
The object of the present invention is to provide a stable pharmaceutical aerosol composition.
Another object of the present invention is to provide a pharmaceutical aerosol composition wherein the fine drug particles do not aggregate during the storage. Yet another object of the present invention is to provide a simple process to manufacture the pharmaceutical aerosol composition according to the present invention.
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.
Summary:
According to a first aspect of the present invention; there is provided 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.
According to a second aspect of the present invention; there is provided 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.
According to a third aspect of the present invention; there is provided a process of manufacturing the said stable pharmaceutical aerosol composition.
According to a fourth aspect of the present invention; there is provided 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.
Detailed description:
As discussed earlier, there is a need to provide a novel way to solve the problem of aggregation of fine drug particles of aerosol composition and which remains stable throughout the storage. Surprisingly, the inventors have found that when the drug-adjuvant complex is used in the manufacture of aerosol composition, the aggregation of fine drug particles is significantly reduced which renders the composition stable throughout the storage period.
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. In particular it was observed that the fine particle mass does not remain same or decreases in timely manner during the storage. But , it was surprisingly found that when the drug was complexed with an adjuvant such as PVP K 25, PVP K 17 or PVP K30 etc., along with the addition of 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).
In a particularly advantageous embodiment, 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.
The term "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) and 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.
According to the present invention, 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). Preferably 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. Thus, for example, it is preferred that 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.
According to the invention, 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. methapyrilene; 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. noscapine; 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.
It will be well appreciated to a person skilled in the art that 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, according to the invention, 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.
The terms "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.
Where appropriate, the following 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, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide.
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. Preferably, 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. Preferably, 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). In a particularly preferred embodiment of the present invention, there is provided 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.
It will be appreciated by those skilled in the art that 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.
Preferably, 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.
Alternatively, the aerosol compositions may comprise a bronchodilator in combination with an antiallergic such as 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.
According to another aspect of the invention there is provided 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. Preferably the canister is made up of metal, glass or a plastics material such as polysulphone plastics for example polysulphone (PSU) and polyethersulphone (PES). Preferably 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:
(a) weighing the complexed drug particles in a suitable metal canister,
(b) optionally mixing the complexed drug particles with one or more suitable excipients selected from cosolvents, bulking agents, antioxidants, lubricants and optionally with one or more surfactants or with other similarly complexed or non-complexed drugs,
(c) crimping the canister with a suitable valve and charging with HFA Propellant.
In another aspect, the present invention provides a process of manufacturing a complex of an active agent and an adjuvant comprising:
(a) mixing the active agent in an organic solvent (e.g. acetone),
(b) heating the mixture from step (a) to a suitable temperature and adding water to form a clear solution;
(c) adding the adjuvant to the above solution from step (b);
(d) concentrating the clear solution under reduced pressure, preferably under vacuum, to form a residue;
(e), washing the residue with the same solvent used in step (a); and
(f) drying (for example at suitable temperature, or preferably 500C) 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. Alternatively, 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. Such optional excipients include, but are not limited to, taste masking agents, buffers, antioxidants, water and chemical stabilizers.
Examples of 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.
Examples of cosolvents include, but are not limited to one or more of polyethylene glycol ("PEG"), propylene glycol, isopropyl myristate or glycerol. Suitably, 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. Suitably, 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.
As discussed earlier, the aerosol compositions traditionally contained CFC propellants. Due to environmental concerns, HFA propellants are now preferred over CFC propellants. As will be understood by those skilled in the art, 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). Optionally 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.
Ln a further aspect, 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.
In a preferred embodiment, 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.
In another preferred embodiment, there is provided 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.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Examples:
Process of preparing the tiotr opium bromide-PVP complex- 1) 5 g of Tiotropium bromide was introduced in a reaction vessel. Acetone was added. The reaction mixture was heated to a temperature of 50-55°C. Further water (15 ml) was added to the reaction mixture to get a clear solution. To this solution 2.5 g of PVP-K-17 was added. The solution was concentrated under vacuum to get a residue. The residue was washed with acetone (15 ml) and dried under vacuum at 50°C to get the title compound (6 g).
2) 5 g of Tiotropium bromide was introduced in a reaction vessel. Water (15 ml) was added to the reaction mixture to get a clear solution. To this solution 2.5 g of PVP-K- 17 was added. The solution was concentrated under vacuum to get a residue. The residue was washed with acetone (15 ml) and dried under vacuum at 50°C to get the title complex (6 g).
3J_Tiotropium bromide- PVP Complex Formed by Lvophilization
5 g of Tiotropium bromide and 2.5 g of polyvinylpyrrolidone (PVP) was stirred in 50 ml of water at 25-3O0C until dissolved. The solution was quick freezed in a dry ice bath. The solution was lyophilized at a condenser temperature of approximately 0°C in presence of high vacuum. The resultant title complex was obtained in the form of a solid (5.8 g).
4)_Tiotropium bromide- PVP Complex Formed by Evaporation
2.5 g of Tiotropium bromide and 1.25 g of polyvinylpyrrolidone (PVP) was stirred in 10 ml of ethanol at 25-300C until dissolved. Pour the solution into a polyethylene tray and evaporate the ethanol in a vacuum oven in presence of a nitrogen stream. The resultant dry solid title product was isolated (2.5 g).
5}_Tiotropium bromide- PVP Complex Formed by Spray Drying
2.5 g of Tiotropium bromide was dissolved in 25 ml of methanol. 1.25 g of PVP was dissolved in methanol (15 ml). Both the solutions were mixed and spray dried. Parameters used for the manufacture of the drug-adjuvant complex are as follows:
Instrument - Labultima LU-222 ADVANCE SPRAY DRYER
Temperature - 50-550C
Vacuum - 40mm WC
N2 pressure -1-2 kg
Feeding rate - 3ml/min.
The solid product was collected in a collector (2.0 g). Examples of Pharmaceutical Aerosol Composition:
Composition 1: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Composition 2: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (100%), co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG
Composition 3: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%) and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 4: Pharmaceutical aerosol composition containing Ipratropium bromide-PVP complex (0.5%) and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 5: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (100%) and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227. Composition 6: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with propellant.
Composition 7: Pharmaceutical aerosol composition containing Levosalbutamol sulphate- PVP complex (0.5%), bulking agent and HFA propellant.
Process:
(a) The active ingredient to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with propellant.
Composition 8: Pharmaceutical aerosol composition containing Levosalbutamol tartarate- PVP complex (0.5%), bulking agent and HFA propellant.
Process:
(a) The active ingredient to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with propellant.
Composition 9: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Composition 10: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Composition 11: Pharmaceutical aerosol composition containing Tiotropium-PVP complex (0.5%), bulking agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the canister.
(b) Lactose was added to (a)
(c) The canister was crimped with the metered valve and was charged with the solution of propellant and PEG.
Composition 12:
Process: (a) The active ingredients were added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 13:
Process:
(a) The active ingredient is added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 14:
Process:
(a) The active ingredients were added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 15:
Process:
(a) The active ingredients were added to the canister.
(b) The canister was crimped with the metered valve
(c) The canister was charged with HFA227.
Composition 16:
Process:
(a) The active ingredients were added to the canister.
(b) The canister was crimped with the metered valve and the canister was charged with the solution of propellant and PEG.
Stability study data of pharmaceutical aerosol composition comprising Drug-adjuvant complex and HFA:
An accelerated stability study was carried out comparing following three different set of compositions (1) drug and HFA propellant; (2) drug-adjuvant complex and HFA propellant; & (3) drug, co-solvent, surfactant, bulking agent and HFA propellant.
It was found that the aerosol composition containing drug-adjuvant complex exhibited consistent fine particle size during the study when stored at accelerated stability conditions.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants; reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

Claims

CLAIMS:
1. A pharmaceutical aerosol composition comprising at least one hydrofluoroalkane (HFA) propellant; at least one active agent complexed with an adjuvant; and, optionally, one or more pharmaceutically acceptable excipients.
2. A pharmaceutical aerosol composition according to claim 1, wherein the adjuvant is selected from polymer; cyclodextrins, polyethylene glycols, lipids, citric acid, and surfactants such as sorbitan trioleate, sorbitan monooleate, tweens, lecithin, oleic acid, polyoxyethylene- lauryl ether, or mixtures thereof.
3. A pharmaceutical aerosol composition according to claim 2, wherein the adjuvant is a polymer.
4. A pharmaceutical aerosol composition according to claim 3, wherein the polymer is a water soluble polymer, a water insoluble polymer; or a mixture thereof.
5. A pharmaceutical aerosol composition according to claim 4, wherein the water soluble polymer comprises polyvinylpyrrolidone, homopolymers and co-polymers of N-vinyl lactams such as homopolymers and co-polymers of N-vinyl pyrrolidone, co-polymers of polyvinyl pyrrolidone 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.
6. A pharmaceutical aerosol composition according to claim 4, wherein the water insoluble polymer comprises acrylic copolymers; polyvinylacetate; cellulose derivatives such as ethylcellulose, cellulose acetate.
7. A pharmaceutical aerosol composition according to claim 1 to 5, wherein the adjuvant is a polyvinylpyrrolidone.
8. A pharmaceutical aerosol composition according to claim 7, wherein the polyvinylpyrrolidone is a polyvinylpyrrolidone having a molecular weight ranging from 2500 to 1,200,000.
9. A pharmaceutical aerosol composition according to any preceding claim, wherein the amount of adjuvant in the complex of the active agent and the adjuvant ranges from 0.5% to 500% by weight of the active agent.
10. A pharmaceutical aerosol composition according to any preceding claim, wherein the complex of the active agent and the adjuvant is particulate and has a size distribution such that at least 90% of the particles have a diameter of less than or equal 15 micrometers.
11. A pharmaceutical aerosol composition according to any preceding claim, wherein the active agent is an antiallergic, an anticholinergic or a bronchodilator.
12. A pharmaceutical aerosol composition according to claim 11, wherein the active agent is selected from tiotropium, salbutamol, beclomethasone, ipratropium, formoterol, aclidinium, salmeterol, fluticasone, budesonide, fenoterol, ciclesonide, mometasone, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical aerosol composition according to claim 12, wherein the active agent is salbutamol, salbutamol sulfate, levosalbutamol, levosalbutamol sulphate, levosalbutamol tartarate, ipratropium, ipratropium bromide, tiotropium, tiotropium bromide or tiotropium bromide monohydrate.
14. A pharmaceutical aerosol composition according to any preceding claim, wherein the pharmaceutically acceptable excipients include a bulking agent, a cosolvent or both.
15. A pharmaceutical aerosol composition according to claim 14, wherein the pharmaceutically acceptable excipients further include a taste masking agent, a buffer, an antioxidant, water, and a chemical stabilizer.
16. A pharmaceutical aerosol composition according to claim 14 or 15, wherein the bulking agent includes one or more saccharides and/or one or more sugar alcohols.
17. A pharmaceutical aerosol composition according to claim 14, 15 or 16, wherein the cosolvent includes one or more of polyethylene glycol, propylene glycol, isopropyl myristate and glycerol.
18. A pharmaceutical aerosol composition according to any preceding claim, wherein the HFA propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) or a mixture thereof.
19. A pharmaceutical aerosol composition according to any preceding claim 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.
20. The use of a pharmaceutical aerosol composition according to any one of claims 1 to 18 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.
21. 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 any one of claims 1 to 18 to a patient in need thereof.
22. A pharmaceutical aerosol dispenser comprising a canister having a chamber containing a pharmaceutical aerosol composition according to any preceding claim; 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.
23. A process for manufacturing a pharmaceutical aerosol dispenser for delivering a pharmaceutical composition according to any one of claims 1 to 18, comprising: (a) placing a predetermined amount of the complex of the active agent and the adjuvant in a suitable canister,
(b) optionally mixing the complex with one or more pharmaceutically acceptable excipients;
(c) crimping the canister with a suitable valve and charging with the HFA propellant.
24. A process for manufacturing a complex of an active agent and an adjuvant, comprising:
(a) mixing the active agent in an organic solvent;
(b) heating the mixture from step (a) to a suitable temperature and adding water to form a clear solution;
(c) adding the adjuvant to the solution from step (c);
(d) concentrating the solution from step (d) under reduced pressure to form a residue;
(e) washing the residue from step (d) with the same solvent used in step (a); and
(f) drying the washed residue from step (e) to form a drug-adjuvant complex.
25. A pharmaceutical aerosol composition substantially as herein described with reference to the examples.
EP09753178A 2008-11-04 2009-11-04 Pharmaceutical aerosol composition Withdrawn EP2362766A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2351MU2008 2008-11-04
IN2402MU2008 2008-11-14
PCT/GB2009/002575 WO2010052450A1 (en) 2008-11-04 2009-10-29 Tiotropium bromide having a low degree of crystallinity
PCT/GB2009/002617 WO2010052466A2 (en) 2008-11-04 2009-11-04 Pharmaceutical aerosol composition

Publications (1)

Publication Number Publication Date
EP2362766A2 true EP2362766A2 (en) 2011-09-07

Family

ID=41630445

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09753178A Withdrawn EP2362766A2 (en) 2008-11-04 2009-11-04 Pharmaceutical aerosol composition

Country Status (12)

Country Link
EP (1) EP2362766A2 (en)
JP (1) JP2012507574A (en)
KR (1) KR20110096538A (en)
CN (1) CN102238939B (en)
AU (1) AU2009312598A1 (en)
BR (1) BRPI0916047A2 (en)
CA (1) CA2742718A1 (en)
MX (1) MX2011004730A (en)
NZ (1) NZ592861A (en)
RU (1) RU2565438C2 (en)
WO (1) WO2010052466A2 (en)
ZA (1) ZA201103347B (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2493827C1 (en) * 2012-10-03 2013-09-27 Шолекс Девелопмент Гмбх Stable combined solution of fenoterol hydrobromide and ipratropium bromide
JP2016503390A (en) * 2012-10-23 2016-02-04 シプラ・リミテッド Pharmaceutical composition
GB201306984D0 (en) * 2013-04-17 2013-05-29 Mexichem Amanco Holding Sa Composition
KR101484481B1 (en) * 2014-08-07 2015-01-20 주식회사 다림바이오텍 Manufacturing method of subligual spray composition comprising PDE-5 inhibitor, and subligual spray composition manufactured by the same
CN107320464A (en) * 2017-04-28 2017-11-07 北京北朋科技有限公司 The preparation method of the budesonide suspension of high pH value
GB2573297A (en) * 2018-04-30 2019-11-06 Mexichem Fluor Sa De Cv Pharmaceutical composition
EP3860580A4 (en) * 2018-10-01 2022-07-20 Kindeva Drug Delivery L.P. FORMULATION AND AEROSOL CANS, INHALERS AND LIKE WITH THE FORMULATION
CN114796166A (en) * 2021-01-29 2022-07-29 北京远大九和药业有限公司 Aerosol containing terpene volatile oil and preparation method thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684698A (en) * 1986-05-02 1987-08-04 Gaf Corporation Water soluble multicomplex of chlorothiazide, furosemide and poly(N-vinyl-2-pyrrolidone)
IL103238A (en) * 1991-09-25 1995-07-31 Fisons Plc Pressurised aerosol compositions
EP0655237A1 (en) * 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medicinal aerosol formulation
DE69630798T2 (en) * 1995-09-19 2004-09-23 Fujisawa Pharmaceutical Co., Ltd. AEROSOL COMPOSITIONS
DE69814428T2 (en) * 1997-09-29 2004-05-13 Nektar Therapeutics, San Carlos PREPARED, STABILIZED PREPARATIONS
DE10214031A1 (en) * 2002-03-27 2004-02-19 Pharmatech Gmbh Process for the production and application of micro- and nanoparticles by micronization
ME00349B (en) * 2003-11-03 2011-05-10 Boehringer Ingelheim Int NEW CRYSTALLINE ANHYDRATE WITH ANTICHOLINERGER EFFICACY
CA2606549A1 (en) * 2005-05-02 2006-11-09 Boehringer Ingelheim International Gmbh Crystalline forms of tiotropium bromide
CN102731494A (en) * 2005-12-19 2012-10-17 西科尔公司 Novel forms of tiotropium bromide and processes for preparation thereof
JP2010519195A (en) * 2007-02-19 2010-06-03 シプラ・リミテッド Pharmaceutical composition
GB0801876D0 (en) * 2008-02-01 2008-03-12 Vectura Group Plc Suspension formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010052466A2 *

Also Published As

Publication number Publication date
BRPI0916047A2 (en) 2015-11-10
CN102238939B (en) 2015-05-20
AU2009312598A1 (en) 2010-05-14
WO2010052466A3 (en) 2010-11-04
CN102238939A (en) 2011-11-09
MX2011004730A (en) 2011-05-30
WO2010052466A2 (en) 2010-05-14
CA2742718A1 (en) 2010-05-14
RU2011122652A (en) 2012-12-20
RU2565438C2 (en) 2015-10-20
WO2010052466A8 (en) 2011-11-24
NZ592861A (en) 2013-01-25
ZA201103347B (en) 2012-01-25
JP2012507574A (en) 2012-03-29
KR20110096538A (en) 2011-08-30

Similar Documents

Publication Publication Date Title
JP3675474B2 (en) Medicine
JP3210012B2 (en) Medicine
ES2774391T3 (en) Compositions, methods and systems for the respiratory administration of two or more active agents
JP3776124B2 (en) Medicinal aerosol comprising at least one sugar
CN102238939B (en) Pharmaceutical aerosol composition
JPH10510521A (en) Propellant mixture for aerosol formulations
PT1133277E (en) Pharmaceutical aerosol composition containing hfa 227 and hfa 134a
JP2002530156A (en) Pressurized quantitative suction device (MDI)
JP2010519195A (en) Pharmaceutical composition
CN114712338A (en) pharmaceutical composition
KR20010072621A (en) Pharmaceutical formulations for aerosols with two or more active substances
JP2019500340A (en) Pharmaceutical composition
WO2008152398A2 (en) Formulations for inhalation
CN112040930A (en) Pharmaceutical compositions comprising salbutamol
DK2501363T3 (en) inhalable
SK16062002A3 (en) Pharmaceutical formulation for administration through pressurized metered dose inhalers and method for preparation thereof
US20130160761A1 (en) Pharmaceutical Aerosol Composition
US9526790B2 (en) Pharmaceutical aerosol compositions comprising fluticasone
WO2022049382A1 (en) Pharmaceutical composition
WO2020152548A1 (en) Stable aerosol inhalation compositions of formoterol
WO2007034207A2 (en) Troventol formulation
HK1097777A1 (en) Medicinal aerosol formulation
HK1097777B (en) Medicinal aerosol formulation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110527

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MALHOTRA, GEENA

Inventor name: LULLA, AMAR

DAX Request for extension of the european patent (deleted)
RIN1 Information on inventor provided before grant (corrected)

Inventor name: GHAGARE, MARUTI

Inventor name: KANKAN, RAJENDRA, NARAYANRAO

Inventor name: RAO, DHARMARAJ, RAMACHANDRA

Inventor name: MALHOTRA, GEENA

Inventor name: LULLA, AMAR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CIPLA LIMITED

17Q First examination report despatched

Effective date: 20151007

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160218