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WO2005065650A2 - Formulations - Google Patents

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Publication number
WO2005065650A2
WO2005065650A2 PCT/GB2004/004241 GB2004004241W WO2005065650A2 WO 2005065650 A2 WO2005065650 A2 WO 2005065650A2 GB 2004004241 W GB2004004241 W GB 2004004241W WO 2005065650 A2 WO2005065650 A2 WO 2005065650A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical aerosol
oxy
hydroxy
aerosol formulation
surfactant
Prior art date
Application number
PCT/GB2004/004241
Other languages
English (en)
Other versions
WO2005065650A3 (fr
Inventor
Craig Davies-Cutting
Tristan Fairbrother
Alexander J. M. Munro
Trevor Riley
Renata Zofia Williams
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP2006530593A priority Critical patent/JP2007508283A/ja
Priority to EP04820961A priority patent/EP1684721A2/fr
Publication of WO2005065650A2 publication Critical patent/WO2005065650A2/fr
Publication of WO2005065650A3 publication Critical patent/WO2005065650A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to novel pharmaceutical formulations of particulate medicaments such as beta-agonists and/or anti-inflammatory steroids in hydrofluoroalkane propellants such as 1 ,1 ,1 ,2-tetrafluoroethane (134a) and/or 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane (227) with the carboxyclic acid surfactant compound [(7,7,8,8,8-pentafluorooctyl)oxy]acetic acid, a process for the preparation of said formulations and their use in therapy.
  • the invention also relates to the use of said surfactant in such suspension formulations to enhance the emitted dose, in reducing the variability in the content uniformity of formulations or in providing enhanced Fine Particle Mass (FPM) and / or improved FPM stability.
  • Such aerosols generally comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a co-solvent, such as ethanol.
  • a surfactant or a co-solvent such as ethanol.
  • a co-solvent such as ethanol.
  • propellant 11 CCI3F
  • propellant 114 CF2CICF2CI
  • propellant 12 CI2F2
  • these propellants are now believed to provoke the degradation of stratospheric ozone and there is thus a need to provide aerosol formulations for medicaments which employ so called “ozone-friendly" propellants.
  • a class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise fluorocarbons and hydrogen- containing chlorofluorocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP0372777, WO91/04011 , WO91/11173, WO91/11495 and WO91/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared.
  • the applications all 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.
  • 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.
  • WO92/00061 discloses non-fluorinated surfactants for use with fluorocarbon propellants.
  • fluorinated surfactants may be used to stabilise micronised drug suspensions in fluorocarbon propellants such as 134a or 227, see for example US4352789, US5126123, US5376359, US application 09/580008, WO91/11173, WO91/14422, WO92/00062 and WO96/09816.
  • the problem of aggregation of the particulate d rug may be manifest as a drop in fine particle mass (FPM) after storage.
  • FPM fine particle mass
  • the FPM is a measure of the dose dispensed which has the potential to reach the therapeutic portion of the lung.
  • a drop in FPM means the therapeutically effective amount of drug available to the patient is reduced which is undesirable and may ultimately be dangerous.
  • This problem is particularly acute when the dose due to be dispensed is low, which is the case for certain potent drugs such as long acting beta agonists.
  • MMAD mass median aerodynamic diameter
  • Suspension formulations which are not adequately stabilised result in high levels of drug deposition, for example, on the canister walls or on components of the metered dose inhaler, such as the valve components including the metering chamber, seals or the like.
  • This deposition may not only result in drug loss thereby reducing the total drug content of the canister available to patient but can also adversely affect the functioning of the device, resulting in the valve sticking, orifices becoming blocked, caking of drug which may work free at a latter point and increase the dose given to the patient in an unpredictable way.
  • expensive modifications to the canister and/or valve may be required to deal with this deposition.
  • compositions comprising:
  • R a represents C ⁇ -6 alkyl or C 1-6 haloalkyl
  • R c represents hydrogen, methyl (which may be in either the ⁇ or ⁇ configuration) or methylene; R d and R e are the same or different and each represents hydrogen or halogen; and represents a single or a double bond
  • m is an integer of from 2 to 8; n is an integer of from 3 to 11 ; with the proviso that m + n is 5 to 19; R is -XSO 2 NR 6 R 7 wherein X is -(CH 2 ) P - or C 2- 6 alkenylene;
  • R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl,
  • R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 3 - 6 cycloalkyl, phenyl, and phenyl (C 1-4 alkyl)-; and p is an integer of from 0 to 6;
  • R 2 and R 3 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl, and C 1-6 haloalkyl;
  • R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4; (ii) a propellant selected from the group comprising 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heterofluoro-n-propane and mixtures thereof; and
  • the surfactant compound of the present invention has good surfactant properties, such as reducing the mean length weighted diameter of suspension formulations, stabilising FPM and/or giving good content uniformity performance, of formulations of the above medicaments in 134a and/or 227 whilst avoiding toxic effects observed for certain perfluorinated surfactant compounds.
  • the best surfactants in 134a and 227 are perfluorinated compounds with a large number of perfluorinated carbon atoms, which unfortunately have a tendency to bioaccumulate.
  • the present invention is advantageous in terms of improving the stability of the aerosol formulation by reducing drug deposition, increasing shelf life and the like.
  • the invention provides a pharmaceutical aerosol formulation wherein the particulate medicament comprises 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl) phenyljethyl ⁇ amino)hexyl]oxy ⁇ butyl) benzenesulfonamide or 3-(3- ⁇ [7- ( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl ⁇ amino)heptyl]oxy ⁇ propyl) benzenesulfonamide.
  • the invention provides a pharmaceutical aerosol formulation wherein the particulate medicament comprises 6 , 9 ⁇ -difluoro-17 -[(2-furanylcarbonyl)oxy]-11 ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester or 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3- oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • the present invention provides a pharmaceutical aerosol formulation wherein the particulate medicament comprises 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl) phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl) benzenesulfonamide and (in combination with) 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester or 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ - hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • the present invention provides a pharmaceutical aerosol f ormulation wherein the particulate medicament comprises 3-(3- ⁇ [7-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3- hydroxymethyl)phenyl]ethyl ⁇ amino)heptyl]oxy ⁇ propyl) benzenesulfonamide and (in combination with) 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester or 6 ⁇ ,9 -difluoro-11 ⁇ - hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • the s pecific compounds d escribed i n t he a bove e mbodiments of the p resent i nvention above can be in the form of salts, solvates and physiologically functional derivatives thereof.
  • the medicament employed is or includes 3-(4- ⁇ [6-( ⁇ (2 c ?)-2-hydroxy-2-[4- hydroxy-3-(hydroxymethyl) phenyljethyl ⁇ amino)hexyl]oxy ⁇ butyl) benzenesulfonamide, preferably it is employed as the cinnamate salt.
  • the invention also extends to formulations comprising [(7,7,8,8,8- pentafluorooctyl)oxy]acetic acid, a propellant such as 134a and/or 227 and a particulate drug selected from the group comprising:
  • the surfactant [(7,7,8,8,8-Pentafluorooctyl)oxy]acetic acid can be prepared by methods as described in WO03/013610.
  • the amount of the surfactant employed is desirably in the range of 0.05% to 20% w/w, particularly 0.5% to 10% w/w relative to the medicament.
  • the particle size of the particulate (e.g. micronised) medicament should be such as to permit inhalation of substantially all of the medicament into the lungs or nasal cavity upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably will have a MMAD in the range 1-10 microns, e.g. 1-5 microns.
  • a single propellant is employed, for example, 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane, especially 1 ,1 ,1 ,2-tetrafluoroethane.
  • the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone.
  • the formulations are substantially free of chlorofluorocarbons such as CCI3F, CCI2F2 and CF3CCI3.
  • the propellant may additionally contain a volatile adjuvant such as a saturated hydrocarbon, for example, propane, n -butane, isobutane, pentane a nd isopentane o r a dialkyl ether, for example, dimethyl ether.
  • a volatile adjuvant such as a saturated hydrocarbon, for example, propane, n -butane, isobutane, pentane a nd isopentane o r a dialkyl ether, for example, dimethyl ether.
  • up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w.
  • formulations which are substantially free of volatile adjuvants are preferred.
  • Polar adjuvants which may if desired, be incorporated into the formulations according to the present invention include, for example, C 2-6 aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol and mixtures thereof. Preferably ethanol will be employed. In general only small quantities (e.g. 0.05 to 3.0% w/w) of polar adjuvants are required and the use of quantities in excess of 5% w/w may disadvantageously tend to dissolve the medicament. Formulations preferably contain less than 1% w/w, for example, about 0.1% w/w of polar adjuvant. Most preferably the formulations according to the invention are substantially free of polar adjuvant. Polarity may be determined, for example, by the method described in European Patent Application Publication No. 0327777.
  • the formulations according to the present invention may optionally contain one or more further ingredients conventionally used in the art of pharmaceutical aerosol formulation.
  • optional ingredients include, but are not limited to, taste masking agents, sugars, buffers, antioxidants, water and chemical stabilisers.
  • a particularly preferred embodiment of the invention provides a pharmaceutical aerosol formulation consisting essentially of one or more particulate medicament(s) of formula (I) and/or formula (II), or other medicament disclosed in this specification or combination thereof, one or more of said propellants and [(7,7,8,8,8-pentafluorooctyl)oxy]acetic acid.
  • the invention also extends to formulations as described already which "consist of rather than comprise or consist essentially of said elements.
  • a further embodiment of the invention is a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid, such as a metered dose inhaler, containing therein one of the aerosol formulation as described above.
  • metered dose inhaler or MDI means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap.
  • MDI system includes a suitable channelling device. Suitable channelling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
  • MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (e.g. incorporated herein by reference WO96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve.
  • the cap may be secured onto the can via ultrasonic welding, screw fitting or crimping.
  • MDIs taught herein may be prepared by methods of the art (e.g., see Byron, above and WO96/32099).
  • the canister is fitted with a cap assembly, wherein a drug metering valve is situated in the cap, and said cap is crimped in place.
  • compositions according to the present invention may obviate the need for the additional processing of the canisters and/or component by, for example, coating which ultimately leads to cost saving, especially when manufacturing in bulk.
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a g asket t o prevent leakage of propellant t hrough t he valve.
  • the g asket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
  • Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60),
  • the formulations of the invention may be prepared by dispersal of a compound of formula
  • the surfactant compound may be prespiked into an empty canister before the cap and valve are secured in place.
  • a further aspect of this invention comprises a process for filling the said formulation into MDIs.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the particulate medicament is added to a charge vessel and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel, together with liquefied propellant containing the surfactant.
  • the drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
  • an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure formulation does not vaporise, and then a metering valve crimped onto the canister.
  • each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler system for administration of the medicament into the lungs or nasal cavity of a patient.
  • the chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art.
  • the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product.
  • Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
  • twin impinger assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C.
  • Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff", for example, in the range of 1 to 5000 micrograms of medicament per puff.
  • the present invention also provides for a method of treatment or prophylaxis of respiratory disorders which comprises administering to a patient in need thereof a pharmaceutical aerosol formulation according to the present invention.
  • the present invention provides for the use of a pharmaceutical aerosol formulation according to the present invention for the manufacture of a medicament for administration by inhalation for the treatment of respiratory disorders.
  • Suitable examples of respiratory disorders include, but are not limited to, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis.
  • COPD chronic obstructive pulmonary disease
  • the respiratory disorder is asthma or COPD, in particular asthma.
  • Administration of medicament may be indicated for the treatment of mild, moderate, severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example, from 1 to 8 times per day, giving for example 1 , 2, 3 or 4 puffs each time.
  • the present invention also provides for the use of the surfactant [(7,7,8,8,8- pentafluorooctyl)oxy]acetic acid to enhance the F PM and / or improve FPM stability of pharmaceutical aerosol formulations comprising of one or more particulate medicament(s) of formula (I) and/or formula (II), or other medicament disclosed in this specification or combination thereof and one or more of said propellants.
  • the surfactant [(7,7,8,8,8- pentafluorooctyl)oxy]acetic acid to enhance the F PM and / or improve FPM stability of pharmaceutical aerosol formulations comprising of one or more particulate medicament(s) of formula (I) and/or formula (II), or other medicament disclosed in this specification or combination thereof and one or more of said propellants.
  • the present invention also provides for the use of the surfactant [(7,7,8,8,8- pentafluorooctyl)oxy]acetic acid to reduce the variability in the content uniformity, for example, by reducing the relative standard deviation (RSD) of pharmaceutical aerosol formulations comprising of one or more particulate medicament(s) of formula (I) and/or formula (II), or other medicament disclosed in this specification or combination thereof and one or more of said propellants.
  • RSD relative standard deviation
  • Example 2 Standard 8 mL MDI cans, coated with a polymer blend of PTFE and polyether sulfone, were pre-spiked with 0.6 mg of [(7,7,8,8,8-pentafluorooctyl)oxy]acetic acid, the valves crimped in place, and a suspension of about 6 mg of 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (DRUG 2) in about 12 g of P134a was filled through the valve. A corresponding surfactant free control was also prepared (CONTROL 2).
  • Mean length weighted equivalent diameter of suspensions was determined by image analysis (Galai CIS-100 image analyser) . It represents the diameter a circle of equivalent area to the object under analysis (weighted by particle diameter in the distribution).
  • Table 1 shows mean particle size data determined by image analysis using a Galai CIS- 100 particle size analyser for sample formulations prepared as described above. In this measurement, particle size is represented as the equivalent diameter of a circle of equal area to the object. The mean is the average of 4 determinations. The particle size measurement was obtained by transferring the suspensions to a pressurised cell, and video-imaging the sample under shear via a microscope objective.
  • the equivalent diameter is defined as the diameter of a circle of equal area to the object.
  • Area Equivalent Diameter ⁇
  • the mean equivalent diameter can be weighted by number, length or volume, e.g. For three particles with equivalent diameters of x, y and z: Mean Number weighted
  • Table 2 shows data relating to the FPM (the sum of stages 3 to 5) obtained using an Anderson Cascade Impactor stack. Data were obtained at the beginning of use of the device. Controls were prepared corresponding to each of the samples but omitting the surfactant. The analysis of aerosol formulations using such stacks is well known to person skilled in the art. The data is shown as absolute FPM in ⁇ g and percentage FPM (in brackets) which expresses absolute FPM as a percentage of the total ex-valve emitted dose. This data is given for an initial timepoint and then after storage for 12 weeks at 40°C and 75% relative humidity.
  • Table 2 shows samples containing surfactant show an increase in the absolute value of the FPM fraction in most cases. This indicates that a greater proportion of the dose will be available to reach the therapeutic target of in the lung, which is desirable. Furthermore, it can be seen that the FPM for Example 2 is stabilised by the presence of the surfactant.
  • the data shows that the percentage of the target dose is increased in the formulations of the present invention. Furthermore, the variability of the dose dispensed (at the end of use) for the formulations of the invention which contain a surfactant is reduced as can be seen by the reduction in the percentage relative standard deviation.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
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  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne de nouvelles formulations pharmaceutiques de médicaments se présentant sous forme de particules, tels que des agonistes bêta et/ou des stéroïdes anti-inflammatoires dans des agents propulseurs d'hydrofluoroalcane comprenant un tensioactif d'acide carboxylique.
PCT/GB2004/004241 2003-10-09 2004-10-06 Formulations WO2005065650A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2006530593A JP2007508283A (ja) 2003-10-09 2004-10-06 カルボン酸界面活性剤を含むエアロゾル製剤
EP04820961A EP1684721A2 (fr) 2003-10-09 2004-10-06 Formulations d'aerosol comprenant un tensio actif d'un acide carboxylique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0323701.3 2003-10-09
GBGB0323701.3A GB0323701D0 (en) 2003-10-09 2003-10-09 Formulations

Publications (2)

Publication Number Publication Date
WO2005065650A2 true WO2005065650A2 (fr) 2005-07-21
WO2005065650A3 WO2005065650A3 (fr) 2006-04-27

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PCT/GB2004/004241 WO2005065650A2 (fr) 2003-10-09 2004-10-06 Formulations

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EP (1) EP1684721A2 (fr)
JP (1) JP2007508283A (fr)
GB (1) GB0323701D0 (fr)
WO (1) WO2005065650A2 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
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WO2007121920A2 (fr) 2006-04-21 2007-11-01 Novartis Ag Composés organiques
WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
EP2206499A1 (fr) 2004-11-02 2010-07-14 Novartis AG Derives de quinuclidine et leur utilisation en tant qu'antagonistes des recépteurs muscariniques m3
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
EP2280006A1 (fr) 2005-08-08 2011-02-02 Pulmagen Therapeutics (Synergy) Limited Composition pharmaceutique pour inhalation comprenant un oxazole ou thiazole antagoniste du récepteur m3 muscarinique
EP2281813A1 (fr) 2005-08-08 2011-02-09 Pulmagen Therapeutics (Synergy) Limited Dérivés de bicyclo[2.2.1]hept-7-ylamine et leurs utilisations
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
EP2292619A1 (fr) 2004-10-22 2011-03-09 Novartis AG Derivés de purin et leurs utilisation comme agonists d'adenosin-A2A-récepteur
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
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EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
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EP2322525A1 (fr) 2006-04-21 2011-05-18 Novartis AG Derives de purine comme d'agonistes des recepteurs de l'adenosine A2A
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WO2010076553A1 (fr) 2008-12-30 2010-07-08 Dr. Reddy's Laboratories Ltd Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
WO2011051672A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
WO2011051671A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminopyridine comme inhibiteurs de la kallicréine
WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
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WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk

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WO2005065650A3 (fr) 2006-04-27

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