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WO2015091287A1 - Dosage formulation comprising salmeterol and fluticasone propionate - Google Patents

Dosage formulation comprising salmeterol and fluticasone propionate Download PDF

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Publication number
WO2015091287A1
WO2015091287A1 PCT/EP2014/077621 EP2014077621W WO2015091287A1 WO 2015091287 A1 WO2015091287 A1 WO 2015091287A1 EP 2014077621 W EP2014077621 W EP 2014077621W WO 2015091287 A1 WO2015091287 A1 WO 2015091287A1
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WO
WIPO (PCT)
Prior art keywords
salmeterol
pharmaceutical composition
fluticasone propionate
dose
dry powder
Prior art date
Application number
PCT/EP2014/077621
Other languages
French (fr)
Inventor
Nathalie Blandine IVANOFF
Montserrat VIVES BLAZQUEZ
Matthias Arlt
Original Assignee
Almirall S.A.
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Filing date
Publication date
Application filed by Almirall S.A. filed Critical Almirall S.A.
Publication of WO2015091287A1 publication Critical patent/WO2015091287A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • This invention relates to a novel dosage for the fixed-dose combination of salmeterol and fluticasone propionate and to novel methods and formulations for the treatment of respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD), using said fixed-dose combination.
  • respiratory diseases especially asthma and chronic obstructive pulmonary disease (COPD)
  • Asthma is a chronic disease of the airways characterized by bronchoconstriction, inflammation and remodeling. The disease is estimated to affect 300 million people of all ages worldwide, placing a considerable burden on healthcare systems. Treatment options include reliever (i.e. used as required with a fast onset of action) and controller (i.e. taken daily to maintain asthma control) medication.
  • the most effective controller medications available currently are inhaled corticosteroids (ICS) (such as fluticasone propionate), which achieve control primarily via their anti-inflammatory effects. If adequate control is not achieved, other controller medications may be indicated including combinations of long- acting p2-adrenoceptor agonists (LABAs) and ICS.
  • ICS corticosteroids
  • the dry powder formulation is delivered via the Accuhaler® / Diskus® inhaler and is registered under the trade name Seretide® in most of European countries and under Advair® in the US.
  • This fixed-dose combination is available in three different dosage strengths (50/100, 50/250 and 50/500, expressed as metered doses) containing 50 micrograms of salmeterol (in form of salmeterol xinafoate) and 100, 250 or 500 micrograms of fluticasone propionate, respectively.
  • Patients should be given the strength of Seretide® containing the appropriate fluticasone propionate dosage for the severity of their disease.
  • the dose of the salmeterol/fluticasone propionate combination should be titrated to the lowest dose possible at which effective control of symptoms is maintained.
  • the highest strength is indicated (50/500 micrograms in Europa and 50/250 micrograms in US).
  • the clinical efficacy and safety of this fixed-dose combination has been extensively investigated in clinical studies in asthmatics and COPD patients. Although the benefits of this combination outweigh the associated risks, some safety issues still remain due to the intrinsic adverse effects associated with these classes of compounds.
  • Salmeterol is a long-acting p2-adrenoceptor agonist (LABA), which causes bronchodilation by a direct action on causing airways smooth muscle relaxation and inhibition of the release of hypersensitivity mediators from mast cells.
  • LPA p2-adrenoceptor agonist
  • One problem associated with the use of p2-adrenergic agonists in the treatment of respiratory diseases is the risk of side effects related to systemic ⁇ -adrenergic receptor agonism. These can include, for example, increased heart rate (tachycardia), palpitations, insomnia, anxiety, nausea and tremor.
  • Fluticasone propionate is a corticosteroid. In common with all compounds of this class it suppresses chronic airway inflammation via modulation of multiple gene transcription factors leading to the .inhibition of multiple inflammatory pathways. This results in the inhibition of production (or secretion) of inflammatory mediators and inflammatory cell recruitment and function (e.g. eosinophils, mast cells, lymphocytes, basophils,
  • fluticasone propionate administration is associated with local adverse effects in the oral cavity, pharynx and larynx and also with an increased risk of pneumonia.
  • a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier (e.g. lactose), providing a delivered dose of salmeterol equivalent to about 16 micrograms and a delivered dose of fluticasone propionate equivalent to about 280 or 140 micrograms, respectively, has the same efficacy as the commercially available Seretide® combination having a delivered dose of salmeterol/fluticasone equivalent to 47/460 micrograms or 47/231 micrograms, respectively, while showing reduced side effects.
  • a pharmaceutically acceptable dry powder carrier e.g. lactose
  • the invention provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/280 micrograms.
  • the invention further provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/140 micrograms.
  • a method of treating a respiratory disorder, particularly asthma and COPD, in a patient in need of such treatment, comprising administering a dose, typically a twice daily dose, of this salmeterol/fluticasone propionate combination providing a delivered dose equivalent to about 16/280 micrograms or 16/140 micrograms is also provided.
  • the invention further provides the use of these salmeterol/fluticasone propionate combinations in the manufacture of a medicament, e.g., as described in the preceding paragraph, for use in such a method.
  • a pharmaceutical composition as described above for use in the treatment of a respiratory condition selected from asthma and chronic obstructive pulmonary disease is also provided.
  • the salmeterol/fluticasone propionate formulations of this invention may be administered as a combination of two active ingredients, or as a triple combination with one additional anti-inflammatory and/or bronchodilating agents, e.g., M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors and/or PI3K inhibitors.
  • additional anti-inflammatory and/or bronchodilating agents e.g., M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors and/or PI3K inhibitors.
  • Salmeterol is the International Non-proprietary Name (INN) for ( ⁇ )-2- (Hydroxymethyl)-4-[1 -hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol.
  • INN International Non-proprietary Name
  • salmeterol is administered in the form of a salmeterol xinafoate, the chemical formula of which is shown below.
  • the delivered dose for salmeterol is expressed micrograms. This amount corresponds to 23 micrograms of salmeterol xinafoate.
  • Fluticasone propionate's chemical name is 6a,9-Difluoro-1 1 beta,17-dihydroxy-16a- methyl-3-oxoandrosta-1 ,4-diene-17p-carbothioic acid S-(fluoromethyl) ester 17-propionate and has the chemical formula shown below.
  • the salmeterol/fluticasone combination is preferably administered in the form of a dry powder in admixture with a suitable carrier, e.g., lactose powder (i.e. lactose particles), suitable for inhalation.
  • a suitable carrier e.g., lactose powder (i.e. lactose particles)
  • lactose powder i.e. lactose particles
  • the lactose is in the form of alpha-lactose monohydrate, preferably crystalline alpha-lactose monohydrate.
  • the respiratory disease or condition to be treated with the formulations and methods of the present invention are typically asthma, chronic obstructive pulmonary disease (COPD) including acute or chronic bronchitis and emphysema, bronchial hyperreactivity, bronchiectasis or rhinitis, in particular asthma and/or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Cardiac disorders such as palpitations, tachycardia, cardiac arrhythmias, atrial fibrillation and angina pectoris
  • delivered dose it is meant the amount of the drug which is available at the mouth for inhalation (dose emitted from the mouthpiece of the inhaler device per actuation).
  • the delivered dose can be measured using standard techniques known to those skilled in the art.
  • a delivered dose of "about 16 ⁇ g salmeterol” it is meant a target dose of 16 ⁇ g salmeterol subject to variation within the normal limits of acceptance for the dispensing system, e.g. 10.4-21 .6 ⁇ g salmeterol (plus/minus 35%) or preferably 12-20 ⁇ g salmeterol (plus/minus 25%), or more preferably 13.6-18.4 salmeterol (plus/minus 15%) or most preferably 14.4-17.6 salmeterol (plus/minus 10%).
  • a delivered dose of "about 280 ⁇ g fluticasone propionate” it is meant a target dose of 280 ⁇ g fluticasone propionate subject to variation within the normal limits of acceptance for the dispensing system, e.g. 182-378 ⁇ g fluticasone propionate (plus/minus 35%) or preferably 210-350 ⁇ g fluticasone propionate (plus/minus 25%), or more preferably 238-322 ⁇ g fluticasone propionate (plus/minus 15%) or most preferably 252-308 ⁇ g fluticasone propionate (plus/minus 10%).
  • a delivered dose of "about 140 ⁇ g fluticasone propionate” it is meant a target dose of 140 ⁇ g fluticasone propionate subject to variation within the normal limits of acceptance for the dispensing system, e.g. 91 -189 ⁇ g fluticasone propionate (plus/minus 35%) or preferably 105-175 ⁇ g fluticasone propionate (plus/minus 25%), or more preferably 1 19-161 ⁇ g fluticasone propionate (plus/minus 15%) or most preferably 126-154 ⁇ g fluticasone propionate (plus/minus 10%).
  • the invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or pharmaceutically acceptable salt, preferably salmeterol xinafoate, and fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/280 micrograms.
  • salmeterol or pharmaceutically acceptable salt preferably salmeterol xinafoate
  • fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/280 micrograms.
  • the invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or pharmaceutically acceptable salt, preferably salmeterol xinafoate, and fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/140 micrograms.
  • a dry powder pharmaceutical composition for inhalation comprising salmeterol or pharmaceutically acceptable salt, preferably salmeterol xinafoate, and fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/140 micrograms.
  • Packaging of the formulation may be suitable for single unit dose, multi-unit dose
  • Dry powder inhalers are thus classified into three groups: (a) single-dose, (b) multiple-unit dose and (c) multi-dose devices.
  • Formulations generally contain a powder mix for inhalation of the compounds of the invention and a suitable powder base (carrier substance) such as lactose.
  • a suitable powder base such as lactose.
  • Each capsule or cartridge may generally contain between 2 ⁇ g and 500 ⁇ g of each therapeutically active ingredient.
  • the active ingredient (s) may be presented without excipients.
  • single doses have been weighed by the manufacturer into small containers, which are small reservoirs, cartridges or mostly hard gelatine capsules.
  • a capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler.
  • the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation.
  • the emptied capsule has to be removed from the inhaler again.
  • Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175.
  • Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g.
  • WO91/02558 and GB 2242134 comprise the type of multiple-unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
  • Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement.
  • WO 92/00771 all having cavities which have to be filled with powder from the container.
  • Other multi-dose devices have measuring slides (e. g.US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit e. g. EP 0505321 , WO 92/04068 and WO 92/04928.
  • Reproducible dose measuring is one of the major concerns for multi-dose inhaler devices.
  • the powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
  • Multi-dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
  • the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi-dose inhalers cannot be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge.
  • the salmeterol/fluticasone propionate combination of the present invention is administered via a breath-activated, multi-dose, dry powder inhaler, which delivers up to 200 metered doses from a non-removable cartridge.
  • a breath-activated, multi-dose, dry powder inhaler which delivers up to 200 metered doses from a non-removable cartridge.
  • An especially preferred multi-dose inhaler device for this purpose is Genuair®, (formerly known as Novolizer SD2FL), or as described in WO 97/00703, WO 03/000325 or WO 2006/008027 the contents of which applications are incorporated herein by reference. Genuair® is also described in H. Chrystyn et al. Int J Clin Pract (2012) 66, 3, 309-317; and in H. Magnussen et al.
  • the salmeterol/fluticasone propionate combination of the present invention can also be administered via single-dose dry powder inhalers such as the devices described in WO 2005/1 13042 or in EP1270034.
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1 -10 ⁇ , preferably 2-5 ⁇ . Particles having a size above 20 ⁇ are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient as produced may be size reduced by conventional means e.g. by micronisation or supercritical fluid techniques.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • an excipient for example lactose is generally employed.
  • the particle size of the excipient will usually be much greater than the inhaled medicament within the present invention.
  • lactose it will typically be present as lactose particles, preferably crystalline alpha-lactose monohydrate, e.g., having an average particle size range of 20-1000 ⁇ , preferably in the range of 90-150 ⁇ .
  • the median particle size approximately corresponds to the average and is the diameter where 50 mass-% of the particles have a larger equivalent diameter, and the other 50 mass-% have a smaller equivalent diameter.
  • the average particle size is generally referred to in the art as equivalent d50.
  • the distribution of particle size around may affect flow properties, bulk density, etc.
  • other equivalent diameters can be used in addition to d50, such as d10 and d90.
  • d10 is the equivalent diameter where 10 mass-% of the particles have a smaller diameter (and hence the remaining 90% is coarser).
  • d90 is the equivalent diameter where 90 mass-% of the particles have a smaller diameter.
  • the lactose particles for use in formulations of the invention have a d10 of 90 - 160 ⁇ , a d50 of 170 - 270 ⁇ , and d90 of 290 - 400 ⁇ .
  • Suitable lactose materials for use in the present invention are commercially available, e.g., from DFE Pharma (Respitose® ML001 , Respitose® ML006, Respitose® SV003,
  • Respitose® SV010 Lactohale® 100, Lactohale® 200, Lactohale® 201 , Lactohale® 300
  • Meggle lnhalac® 70, lnhalac® 120, lnhalac® 230, lnhalac® 250, lnhalac® 400,
  • PrismaLac® 40 Capsulac® 60, Capsulac® 60 INH, SacheLac® 80, SpheroLac® 100) or Sheffield Bio-Science (Monohydrate inhalation 120 M, Monohydrate inhalation 80 M, Monohydrate inhalation 40 M, Anhydrous inhalation 40 M, Monohydrate inhalation 120 MS, Anhydrous inhalation 120 MS).
  • the ratio between the lactose particles and the fluticasone propionate by weight will depend on the inhaler device used, but is typically, e.g., 5:1 to 100:1 , for example 25:1 to 75:1 , preferably 30:1 to 60:1 , more preferably 35:1 to 45:1.
  • the ratio between the lactose particles and the salmeterol xinafoate by weight will depend on the inhaler device used, but is typically, e.g., 100:1 to 1000:1 , for example 250:1 to 750:1 , preferably 350:1 to 650:1 , more preferably 450:1 to 550:1.
  • the salmeterol/fluticasone propionate formulation of this invention is administered in the form of a dry powder formulation of salmeterol/fluticasone propionate in admixture with lactose, preferably alpha-lactose monohydrate, in a ratio by weight of fluticasone propionate to lactose of 1 :30 to 1 :60, preferably 1 :35 to 1 :45 and/or a ratio by weight of salmeterol xinafoate to lactose of 1 :350 to 1 :650, preferably 1 :450 to 1 :550, suitable for administration via a dry powder inhaler, wherein the fluticasone propionate and salmeterol xinafoate particles have an average particle size of from 2 to 5 ⁇ in diameter, e.g., less than 3 ⁇ in diameter, and the lactose particles have a d10 of 90 - 160 ⁇ - ⁇ , a d50 of 170
  • Additional active agents such as M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, inhibitors of egfr-kinase, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors or NK1 receptor agonists may be utilized in the methods and formulations of the inventions.
  • the invention provides salmeterol/fluticasone propionate formulations as described herein further comprising an effective amount of one or more such additional active agents, e.g. further comprising an effective amount of a M3 muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor and/or a PI3K inhibitor.
  • the invention also provides methods for treating respiratory conditions as herein before described, e.g., asthma or COPD, comprising administering a salmeterol/fluticasone propionate formulation as described herein and further comprising administering simultaneously an effective amount of one or more such additional active agents, e.g. further comprising an effective amount of a M3 muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor and/or a PI3K inhibitor.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising salmeterol and fluticasone as defined above and a M3 muscarinic antagonist.
  • M3 muscarinic antagonists are selected from aclidinium, tiotropium, glycopyrrolate, umeclidinium and GSK- 1 160724, preferably aclidinium and most preferably, aclidinium bromide.
  • the invention also provides a pharmaceutical composition comprising salmeterol and fluticasone as defined above and a PDE4 inhibitor.
  • PDE4 inhibitors are selected from roflumilast, tetomilast, elbimilast, revamilast, RPL-554 and CHF-6001 , preferably roflumilast.
  • composition for inhalation comprising salmeterol xinafoate and fluticasone propionate
  • a pharmaceutical composition in a batch size of 8 kg comprising salmeterol xinafoate, fluticasone propionate and alpha-lactose monohydrate having a d10 of 90-160 ⁇ , a d50 of 170-270 m and a d90 of 290-400 ⁇ , was prepared.
  • Salmeterol xinafoate (15.33 g) was added to the mixture and blended in a Bohle blender, this mixture was sieved through a sieving-machine Bohle BTS and finally, the mixture was blended in a Bohle blender.
  • the mixture of salmeterol xinafoate and fluticasone propionate and a-lactose monohydrate is prepared by alternate blending and sieving steps to guarantee homogeneity and to break up possible agglomerates.
  • Genuair® (H. Chrystyn et al. (2009)) cartridges were filled with the composition. The cartridges were calibrated to provide 60 metered doses. Each actuation of the Genuair® provided a metered dose of 12 mg of the composition described above. Measurement of the delivered dose
  • the measurement of the delivered dose (amount of the drug which is available at the mouth for inhalation) of the pharmaceutical composition described in example 1 is carried out based on European Pharmacopoiea 7th Edition (7.0), Chapter 2.9.18 and US
  • the mean delivered dose per actuation (per inhalation) was 16 ⁇ g of salmeterol which corresponds to 23 ⁇ g salmeterol xinafoate, and 280 ⁇ g of fluticasone propionate.

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Abstract

A dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivereddoseof salmeterol/fluticasone propionate equivalent to about 16/280 microgramsor to 16/140 micrograms.

Description

DOSAGE FORMULATION COMPRISING SALMETEROL AND FLUTICASONE
PROPIONATE
This invention relates to a novel dosage for the fixed-dose combination of salmeterol and fluticasone propionate and to novel methods and formulations for the treatment of respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD), using said fixed-dose combination.
BACKGROUND
Asthma is a chronic disease of the airways characterized by bronchoconstriction, inflammation and remodeling. The disease is estimated to affect 300 million people of all ages worldwide, placing a considerable burden on healthcare systems. Treatment options include reliever (i.e. used as required with a fast onset of action) and controller (i.e. taken daily to maintain asthma control) medication. The most effective controller medications available currently are inhaled corticosteroids (ICS) (such as fluticasone propionate), which achieve control primarily via their anti-inflammatory effects. If adequate control is not achieved, other controller medications may be indicated including combinations of long- acting p2-adrenoceptor agonists (LABAs) and ICS.
The fixed-dose combination of salmeterol (a long-acting p2-adrenoceptor agonist) and fluticasone propionate (an inhaled corticosteroid) is commercially available in Europe and US for the treatment of asthma and chronic obstructive pulmonary disease (COPD) as a powder inhalation or as an inhalation aerosol.
The dry powder formulation is delivered via the Accuhaler® / Diskus® inhaler and is registered under the trade name Seretide® in most of European countries and under Advair® in the US. This fixed-dose combination is available in three different dosage strengths (50/100, 50/250 and 50/500, expressed as metered doses) containing 50 micrograms of salmeterol (in form of salmeterol xinafoate) and 100, 250 or 500 micrograms of fluticasone propionate, respectively. Patients should be given the strength of Seretide® containing the appropriate fluticasone propionate dosage for the severity of their disease.
According to asthma guidelines, the dose of the salmeterol/fluticasone propionate combination should be titrated to the lowest dose possible at which effective control of symptoms is maintained. For COPD, the highest strength is indicated (50/500 micrograms in Europa and 50/250 micrograms in US). The clinical efficacy and safety of this fixed-dose combination has been extensively investigated in clinical studies in asthmatics and COPD patients. Although the benefits of this combination outweigh the associated risks, some safety issues still remain due to the intrinsic adverse effects associated with these classes of compounds.
Salmeterol is a long-acting p2-adrenoceptor agonist (LABA), which causes bronchodilation by a direct action on causing airways smooth muscle relaxation and inhibition of the release of hypersensitivity mediators from mast cells. One problem associated with the use of p2-adrenergic agonists in the treatment of respiratory diseases is the risk of side effects related to systemic β-adrenergic receptor agonism. These can include, for example, increased heart rate (tachycardia), palpitations, insomnia, anxiety, nausea and tremor.
In 2005, the Food and Drug Administration addressed the possible danger of LABAs after the Salmeterol Multi-Center Asthma Research Trial (SMART), which showed a small but significant increase in asthma-related deaths on subjects being treated with salmeterol.
Fluticasone propionate is a corticosteroid. In common with all compounds of this class it suppresses chronic airway inflammation via modulation of multiple gene transcription factors leading to the .inhibition of multiple inflammatory pathways. This results in the inhibition of production (or secretion) of inflammatory mediators and inflammatory cell recruitment and function (e.g. eosinophils, mast cells, lymphocytes, basophils,
macrophages, neutrophils). As known for inhaled corticosteroids, fluticasone propionate administration is associated with local adverse effects in the oral cavity, pharynx and larynx and also with an increased risk of pneumonia.
Thus, there is still a need for new formulations showing the same efficacy as currently available Serertide® formulation, while having reduced side effects.
SUMMARY OF THE INVENTION
It has now surprisingly been found that a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier (e.g. lactose), providing a delivered dose of salmeterol equivalent to about 16 micrograms and a delivered dose of fluticasone propionate equivalent to about 280 or 140 micrograms, respectively, has the same efficacy as the commercially available Seretide® combination having a delivered dose of salmeterol/fluticasone equivalent to 47/460 micrograms or 47/231 micrograms, respectively, while showing reduced side effects.
The invention provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/280 micrograms.
The invention further provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/140 micrograms.
A method of treating a respiratory disorder, particularly asthma and COPD, in a patient in need of such treatment, comprising administering a dose, typically a twice daily dose, of this salmeterol/fluticasone propionate combination providing a delivered dose equivalent to about 16/280 micrograms or 16/140 micrograms is also provided.
The invention further provides the use of these salmeterol/fluticasone propionate combinations in the manufacture of a medicament, e.g., as described in the preceding paragraph, for use in such a method. The pharmaceutical composition as described above for use in the treatment of a respiratory condition selected from asthma and chronic obstructive pulmonary disease is also provided.
The salmeterol/fluticasone propionate formulations of this invention may be administered as a combination of two active ingredients, or as a triple combination with one additional anti-inflammatory and/or bronchodilating agents, e.g., M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors and/or PI3K inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Salmeterol is the International Non-proprietary Name (INN) for (±)-2- (Hydroxymethyl)-4-[1 -hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol. Typically, salmeterol is administered in the form of a salmeterol xinafoate, the chemical formula of which is shown below.
Figure imgf000005_0001
Throughout this application, the delivered dose for salmeterol is expressed micrograms. This amount corresponds to 23 micrograms of salmeterol xinafoate.
Fluticasone propionate's chemical name is 6a,9-Difluoro-1 1 beta,17-dihydroxy-16a- methyl-3-oxoandrosta-1 ,4-diene-17p-carbothioic acid S-(fluoromethyl) ester 17-propionate and has the chemical formula shown below.
Figure imgf000005_0002
The salmeterol/fluticasone combination is preferably administered in the form of a dry powder in admixture with a suitable carrier, e.g., lactose powder (i.e. lactose particles), suitable for inhalation. In a preferred embodiment, the lactose is in the form of alpha-lactose monohydrate, preferably crystalline alpha-lactose monohydrate.
The respiratory disease or condition to be treated with the formulations and methods of the present invention are typically asthma, chronic obstructive pulmonary disease (COPD) including acute or chronic bronchitis and emphysema, bronchial hyperreactivity, bronchiectasis or rhinitis, in particular asthma and/or chronic obstructive pulmonary disease (COPD).
According to the Summary of Product Characteristics of Seretide®, as this product contains salmeterol and fluticasone propionate, the same type and severity of adverse reactions associated with each of the compounds may be expected. Adverse events which have been associated with salmeterol/fluticasone propionate are given in Table 1 , listed by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and <1/10), uncommon (≥ 1/1000 and <1/100), rare (≥ 1/10000 to <1/1000) and not known (cannot be estimated from the available data).
Table 1 :
Figure imgf000006_0001
Paradoxical bronchospasm Rare
Skin and subcutaneous tissue
Contusions Common disorders
Muscle cramps Common
Musculoskeletal & Connective Traumatic fractures Common Tissue Disorders Arthralgia Common
Myalgia Common
Due to the lower delivered dose of the pharmaceutical compositions of the present invention, the following adverse events are potentially reduced:
• Candidiasis of the mouth and throat
· Hypokalaemia
• Hyperglycaemia
• Tremor
• Cardiac disorders (such as palpitations, tachycardia, cardiac arrhythmias, atrial fibrillation and angina pectoris)
· Throat irritation
• Hoarseness/dysphonia
For the avoidance of doubt, by delivered dose it is meant the amount of the drug which is available at the mouth for inhalation (dose emitted from the mouthpiece of the inhaler device per actuation). The delivered dose can be measured using standard techniques known to those skilled in the art.
In the context of dosage of an active agent, "about" as used herein means within the normal limits of acceptable variations of plus/minus 35% as defined by the European and US Pharmacopeia. Preferably, the term "about" means within the normal limits of acceptable variations of plus/minus 25% as defined by the US FDA draft guidance for MDI and DPI Drug products. More preferably the term "about" means within the normal limits of acceptable variations of plus/minus 15% according to the CHMP Guideline on the
Pharmaceutical Quality of Inhalation and Nasal Products, and most preferably within the metered dosing accuracy for the dispensing system e.g. plus/minus 10%.
Thus, by a delivered dose of "about 16 μg salmeterol" it is meant a target dose of 16 μg salmeterol subject to variation within the normal limits of acceptance for the dispensing system, e.g. 10.4-21 .6 μg salmeterol (plus/minus 35%) or preferably 12-20 μg salmeterol (plus/minus 25%), or more preferably 13.6-18.4 salmeterol (plus/minus 15%) or most preferably 14.4-17.6 salmeterol (plus/minus 10%).
By a delivered dose of "about 280 μg fluticasone propionate" it is meant a target dose of 280 μg fluticasone propionate subject to variation within the normal limits of acceptance for the dispensing system, e.g. 182-378 μg fluticasone propionate (plus/minus 35%) or preferably 210-350 μg fluticasone propionate (plus/minus 25%), or more preferably 238-322 μg fluticasone propionate (plus/minus 15%) or most preferably 252-308 μg fluticasone propionate (plus/minus 10%).
By a delivered dose of "about 140 μg fluticasone propionate" it is meant a target dose of 140 μg fluticasone propionate subject to variation within the normal limits of acceptance for the dispensing system, e.g. 91 -189 μg fluticasone propionate (plus/minus 35%) or preferably 105-175 μg fluticasone propionate (plus/minus 25%), or more preferably 1 19-161 μg fluticasone propionate (plus/minus 15%) or most preferably 126-154 μg fluticasone propionate (plus/minus 10%).
In a preferred embodiment, the invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or pharmaceutically acceptable salt, preferably salmeterol xinafoate, and fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/280 micrograms.
In another preferred embodiment, the invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or pharmaceutically acceptable salt, preferably salmeterol xinafoate, and fluticasone propionate in admixture with lactose powder, preferably alpha-lactose monohydrate, providing a delivered dose of salmeterol/fluticasone equivalent to about 16/140 micrograms. Packaging of the formulation may be suitable for single unit dose, multi-unit dose
(dispersing individual doses which are pre-metered into blisters, disks, dimples, tubes and strip by the manufacturers) or multi-dose delivery (measuring the dose from a powder reservoir), preferably by multi-dose delivery. Dry powder inhalers are thus classified into three groups: (a) single-dose, (b) multiple-unit dose and (c) multi-dose devices.
Formulations generally contain a powder mix for inhalation of the compounds of the invention and a suitable powder base (carrier substance) such as lactose. Each capsule or cartridge may generally contain between 2 μg and 500 μg of each therapeutically active ingredient. Alternatively, the active ingredient (s) may be presented without excipients.
For single-dose inhalers, single doses have been weighed by the manufacturer into small containers, which are small reservoirs, cartridges or mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler. Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients. Other drawbacks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection against moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indentation, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported.
Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g.
WO91/02558 and GB 2242134). They comprise the type of multiple-unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (e. g. EP0069715) or disks (e. g. GB
2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (e. g. EP
0166294; GB 2165159 and WO 92/09322) and rotatable frustums (e. g. WO 92/00771 ), all having cavities which have to be filled with powder from the container. Other multi-dose devices have measuring slides (e. g.US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit e. g. EP 0505321 , WO 92/04068 and WO 92/04928. Reproducible dose measuring is one of the major concerns for multi-dose inhaler devices. The powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity. Multi-dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi-dose inhalers cannot be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge.
Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi-dose devices, powder adhesion onto the inner walls of the air conduits and the de-agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi-dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (e. g. WO 97/000703). For such semi-permanent multi-dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even stricter.
In a preferred embodiment, the salmeterol/fluticasone propionate combination of the present invention is administered via a breath-activated, multi-dose, dry powder inhaler, which delivers up to 200 metered doses from a non-removable cartridge. An especially preferred multi-dose inhaler device for this purpose is Genuair®, (formerly known as Novolizer SD2FL), or as described in WO 97/00703, WO 03/000325 or WO 2006/008027 the contents of which applications are incorporated herein by reference. Genuair® is also described in H. Chrystyn et al. Int J Clin Pract (2012) 66, 3, 309-317; and in H. Magnussen et al. Respiratory Medicine (2009) 103, 1832-1837. Another breath-activated, multi-dose, dry powder inhaler suitable for the administration of the salmeterol/fluticasone propionate combination of the present invention is Novolizer®, which is described in C. Fenton et al., Drugs (2003); 63, 22,: 2437-2445; and D. Kohler, Respiratory Medicine (2004) Supplement A, S17-S21.
In another embodiment, the salmeterol/fluticasone propionate combination of the present invention can also be administered via single-dose dry powder inhalers such as the devices described in WO 2005/1 13042 or in EP1270034.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1 -10 μηη, preferably 2-5 μηι. Particles having a size above 20 μηι are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means e.g. by micronisation or supercritical fluid techniques. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.
Achieving a high dose reproducibility with micronised powders is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient, for example lactose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as lactose particles, preferably crystalline alpha-lactose monohydrate, e.g., having an average particle size range of 20-1000 μηη, preferably in the range of 90-150 μηη. The median particle size approximately corresponds to the average and is the diameter where 50 mass-% of the particles have a larger equivalent diameter, and the other 50 mass-% have a smaller equivalent diameter. Hence the average particle size is generally referred to in the art as equivalent d50. The distribution of particle size around may affect flow properties, bulk density, etc. Hence to characterize a particle size diameter, other equivalent diameters can be used in addition to d50, such as d10 and d90. d10 is the equivalent diameter where 10 mass-% of the particles have a smaller diameter (and hence the remaining 90% is coarser). d90 is the equivalent diameter where 90 mass-% of the particles have a smaller diameter. In one embodiment, the lactose particles for use in formulations of the invention have a d10 of 90 - 160 μπι, a d50 of 170 - 270 μπι, and d90 of 290 - 400 μπι.
Suitable lactose materials for use in the present invention are commercially available, e.g., from DFE Pharma (Respitose® ML001 , Respitose® ML006, Respitose® SV003,
Respitose® SV010, Lactohale® 100, Lactohale® 200, Lactohale® 201 , Lactohale® 300) or Meggle (lnhalac® 70, lnhalac® 120, lnhalac® 230, lnhalac® 250, lnhalac® 400,
PrismaLac® 40, Capsulac® 60, Capsulac® 60 INH, SacheLac® 80, SpheroLac® 100) or Sheffield Bio-Science (Monohydrate inhalation 120 M, Monohydrate inhalation 80 M, Monohydrate inhalation 40 M, Anhydrous inhalation 40 M, Monohydrate inhalation 120 MS, Anhydrous inhalation 120 MS).
The ratio between the lactose particles and the fluticasone propionate by weight will depend on the inhaler device used, but is typically, e.g., 5:1 to 100:1 , for example 25:1 to 75:1 , preferably 30:1 to 60:1 , more preferably 35:1 to 45:1. The ratio between the lactose particles and the salmeterol xinafoate by weight will depend on the inhaler device used, but is typically, e.g., 100:1 to 1000:1 , for example 250:1 to 750:1 , preferably 350:1 to 650:1 , more preferably 450:1 to 550:1. In a preferred embodiment, the salmeterol/fluticasone propionate formulation of this invention is administered in the form of a dry powder formulation of salmeterol/fluticasone propionate in admixture with lactose, preferably alpha-lactose monohydrate, in a ratio by weight of fluticasone propionate to lactose of 1 :30 to 1 :60, preferably 1 :35 to 1 :45 and/or a ratio by weight of salmeterol xinafoate to lactose of 1 :350 to 1 :650, preferably 1 :450 to 1 :550, suitable for administration via a dry powder inhaler, wherein the fluticasone propionate and salmeterol xinafoate particles have an average particle size of from 2 to 5 μπΊ in diameter, e.g., less than 3 μηη in diameter, and the lactose particles have a d10 of 90 - 160 μη-ι, a d50 of 170 - 270 μπι, and d90 of 290 - 400 μπι.
Additional active agents such as M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, inhibitors of egfr-kinase, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors or NK1 receptor agonists may be utilized in the methods and formulations of the inventions. For example, the invention provides salmeterol/fluticasone propionate formulations as described herein further comprising an effective amount of one or more such additional active agents, e.g. further comprising an effective amount of a M3 muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor and/or a PI3K inhibitor. The invention also provides methods for treating respiratory conditions as herein before described, e.g., asthma or COPD, comprising administering a salmeterol/fluticasone propionate formulation as described herein and further comprising administering simultaneously an effective amount of one or more such additional active agents, e.g. further comprising an effective amount of a M3 muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor and/or a PI3K inhibitor.
The invention also provides a pharmaceutical composition comprising salmeterol and fluticasone as defined above and a M3 muscarinic antagonist. Most preferred M3 muscarinic antagonists are selected from aclidinium, tiotropium, glycopyrrolate, umeclidinium and GSK- 1 160724, preferably aclidinium and most preferably, aclidinium bromide.
The invention also provides a pharmaceutical composition comprising salmeterol and fluticasone as defined above and a PDE4 inhibitor. Most preferred PDE4 inhibitors are selected from roflumilast, tetomilast, elbimilast, revamilast, RPL-554 and CHF-6001 , preferably roflumilast.
These triple combinations are suitable for administration once or twice a day. The following examples are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.
EXAMPLES Example 1
Pharmaceutical composition for inhalation comprising salmeterol xinafoate and fluticasone propionate
A pharmaceutical composition in a batch size of 8 kg comprising salmeterol xinafoate, fluticasone propionate and alpha-lactose monohydrate having a d10 of 90-160 μηη, a d50 of 170-270 m and a d90 of 290-400 μηι, was prepared.
Fluticasone propionate (186.7 g), and alpha-lactose monohydrate (7798 g) were blended in a Bohle blender, the mixture was sieved through a sieving-machine Bohle BTS and finally, the mixture was blended in a Bohle blender.
Salmeterol xinafoate (15.33 g) was added to the mixture and blended in a Bohle blender, this mixture was sieved through a sieving-machine Bohle BTS and finally, the mixture was blended in a Bohle blender.
The mixture of salmeterol xinafoate and fluticasone propionate and a-lactose monohydrate is prepared by alternate blending and sieving steps to guarantee homogeneity and to break up possible agglomerates.
Genuair® (H. Chrystyn et al. (2009)) cartridges were filled with the composition. The cartridges were calibrated to provide 60 metered doses. Each actuation of the Genuair® provided a metered dose of 12 mg of the composition described above. Measurement of the delivered dose
The measurement of the delivered dose (amount of the drug which is available at the mouth for inhalation) of the pharmaceutical composition described in example 1 is carried out based on European Pharmacopoiea 7th Edition (7.0), Chapter 2.9.18 and US
Pharmacopoiea USP36-NF31 , Chapter 601 ; using a "Collection Tube" apparatus (CT). For this, the Genuair® inhaler is fitted to the Collection Tube via an adapter, the dosage key of the Genuair® inhaler is pressed and released and then 2L or 4L of air are sucked through the inhaler (inspiratory flow rate through the inhaler was approx. 65 L/min at a pressure drop of 4 KPa) and the Collection Tube. Subsequently, the inhalation powder delivered to the Collection Tube is extracted with solvent and analyzed using High Performance Liquid chromatography equipment (HPLC).
The mean delivered dose per actuation (per inhalation) was 16 μg of salmeterol which corresponds to 23 μg salmeterol xinafoate, and 280 μg of fluticasone propionate.
Example 2
In a phase I, randomised, open label, 2-way complete cross-over, single dose clinical trial, salmeterol (as xinafoate)/fluticasone propionate Fixed Dose Combination (FDC) was administered to healthy volunteers via Genuair® and via Accuhaler™ in order to assess the pharmacokinetics of both formulations.
This study demonstrated the bioequivalence of salmeterol (as xinafoate )/fluticasone propionate 16/280 μg fixed-dose combination (FDC) administered via Genuair® with Seretide® Accuhaler® 50/500 μg.
Modifications, which do not affect, alter, change or modify the essential aspects of the pharmaceutical compositions described, are included within the scope of the present invention.

Claims

1 . A dry powder pharmaceutical composition for inhalation comprising salmeterol or a
pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol equivalent to about 16 micrograms and a delivered dose of fluticasone propionate equivalent to about 280 or 140 micrograms.
2. A dry powder pharmaceutical composition for inhalation comprising salmeterol or a
pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/280 micrograms.
3. A dry powder pharmaceutical composition for inhalation comprising salmeterol or a
pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, providing a delivered dose of salmeterol/fluticasone propionate equivalent to about 16/140 micrograms.
4. The pharmaceutical composition according to claims 1 to 3 wherein the pharmaceutically acceptable salt of salmeterol is salmeterol xinafoate.
5. The pharmaceutical composition according to any preceding claim, wherein the dry
powder carrier is lactose.
6. The pharmaceutical composition according to claim 5 wherein the lactose is in the form of alpha-lactose monohydrate.
7. The pharmaceutical composition according to any of the preceding claims wherein the lactose particles have a d10 of 90 - 160 μπι, a d50 of 170 - 270 μπι, and d90 of 290 - 400 μηι.
8. A pharmaceutical composition according to any preceding claim, in the form of a multi- dose dry powder formulation for administration in a multi-dose dry powder inhaler device.
9. The pharmaceutical composition according to any of the preceding claims wherein the ratio by weight of salmeterol xinafoate to lactose is from 1 :350 to 1 :650, preferably from 1 :450 to 1 :550 and/or the ratio by weight of fluticasone propionate to lactose is from 1 :30 to 1 :60, preferably from 1 :35 to 1 :45.
10. The pharmaceutical composition according to any of the preceding claims wherein the average particle diameter of salmeterol xinafoate and/or fluticasone propionate is within
2-5 μηι.
1 1 . The pharmaceutical composition according to any of the preceding claims further
comprising an effective amount of one or more additional active agents selected from M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, inhibitors of egfr- kinase, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors and NK1 receptor agonists, preferably M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors or PI3K inhibitors.
12. The pharmaceutical composition according to claim 1 1 wherein the additional active agent is selected from a M3 muscarinic antagonist.
13. The pharmaceutical composition according to claim 12 wherein the additional active agent is aclidinium or a pharmaceutically acceptable salt thereof.
14. A method of treating a respiratory condition selected from asthma and chronic
obstructive pulmonary disease in a patient in need of such treatment, comprising administering a twice daily delivered dose of a dry powder pharmaceutical composition as defined in any preceding claim.
15. The method according to claim 14 further comprising administering an effective amount of one or more additional active agents selected from M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, inhibitors of egfr-kinase, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors and NK1 receptor agonists, preferably M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors or PI3K inhibitors.
16. The method of claim 15 wherein the additional active agent is aclidinium or a
pharmaceutically acceptable salt thereof.
17. The pharmaceutical composition according to any of claims 1 -13 for use in the treatment of a respiratory condition selected from asthma and chronic obstructive pulmonary disease.
8. Use of a pharmaceutical composition as defined in claims 1 to 13 in the manufacture of a medicament for use in the treatment of a respiratory condition selected from asthma and chronic obstructive disease.
9. A single dose, multiple unit dose or multi-dose inhaler containing a dry powder
pharmaceutical composition comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate in admixture with a pharmaceutically acceptable dry powder carrier, which inhaler is calibrated to deliver, upon actuation, a delivered dose of salmeterol equivalent to about 16 micrograms and a delivered dose of fluticasone propionate equivalent to about 280 or 140 micrograms.
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