TW201605432A - Novel dosage and formulation - Google Patents

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 delivered dose of salmeterol/fluticasone propionate equivalent to about 16/280 micrograms or to 16/140 micrograms.

Description

Novel dosages and formulations

The present invention relates to a novel dosage for a fixed dose combination of salmeterol and fluticasone propionate, and a novel method and formulation for treating respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), using the fixed dose combination .

Asthma is a chronic airway disease characterized by bronchoconstriction, inflammation and remodeling. It is estimated that the disease affects 300 million people of all ages worldwide, placing a considerable burden on health care systems. Treatment options include soothing (i.e., having a rapid onset of action as needed) and control (i.e., daily administration to maintain control of asthma) drug therapy. The most effective controlled drug therapy currently available is inhaled corticosteroids (ICS) (such as fluticasone propionate), which are primarily controlled via anti-inflammatory effects. If adequate control is not achieved, other controlled drug therapies are indicated, including combinations of long-acting 2-adrenoreceptor agonists (LABA) and ICS.

A fixed-dose combination of salmeterol (long-acting 2-adrenoreceptor agonist) and fluticasone propionate (inhaled corticosteroid) is commercially available in Europe and the United States as a powder inhaler or inhaled aerosol for the treatment of asthma. With chronic obstructive pulmonary disease (COPD).

Dry powder formulation via Accuhaler®/Diskus® inhaler Delivered and registered under the trade name Seretide® in most European countries and Advair® in the United States. This fixed-dose combination is available in three different dose concentrations (50/100, 50/250, and 50/500, expressed as a fixed dose) containing 50 micrograms of salmeterol (sametrol hydroxynaphtholate) and 100, 250, respectively. Or 500 micrograms of fluticasone propionate. Seretide®, which is dosed with the appropriate dose of fluticasone propionate, should be given to the patient's disease severity.

According to the asthma guidelines, the dose of salmeterol/fluticasone propionate combination should be titrated to maintain the effective dose control as low as possible. For COPD, the highest concentration is indicated (50/500 micrograms in Europe and 50/250 micrograms in the United States).

The clinical efficacy and safety of this fixed-dose combination has been extensively explored in clinical studies of asthmatic patients and COPD patients. Although the benefits of this combination outweigh the associated risks, some safety issues remain due to the inherent adverse effects associated with these types of compounds.

Salmeterol is a long-acting 2-adrenoreceptor agonist (LABA) that causes airway smooth muscle relaxation by direct action and inhibits bronchiectasis by releasing allergic mediators from mast cells. One problem associated with the use of 2-adrenal agonist in the treatment of respiratory diseases is the risk of side effects on systemic adrenal agonist agonism. Such risks may include, for example, increased heart rate (tachycardia), palpitations, insomnia, anxiety, nausea, and tremors.

In 2005, the Food and Drug Administration presented a possible LABA hazard after the Sameter Trodo Central Asthma Research Trial (SMART), which demonstrated There was little but significant increase in asthma-related death in individuals treated with tro.

Fluticasone propionate is a corticosteroid. As with all such compounds, it inhibits chronic airway inflammation by modulating multiple gene transcription factors resulting in inhibition of multiple inflammatory airways. This results in inhibition of the production (or secretion) of inflammatory mediators and the recruitment and function of inflammatory cells (eg eosinophils, mast cells, lymphocytes, basophils, macrophages, neutrophils). As known for inhaled corticosteroids, administration of fluticasone propionate is associated with local adverse effects in the mouth, pharynx and larynx, as well as an increased risk of pneumonia.

Thus, there remains a need for novel formulations that exhibit the same efficacy as commercially available Serertide® formulations while having reduced side effects.

It has now surprisingly been found that a dry powder pharmaceutical composition for inhalation has the same efficacy as the commercially available Serertide® combination, which exhibits reduced side effects, and the dry powder pharmaceutical composition comprises salmeterol or a pharmaceutically acceptable salt thereof and C. Fluticasone ketone and a pharmaceutically acceptable dry powder carrier (e.g., lactose) provide salmeterol at a delivery dose equal to about 16 micrograms and fluticasone propionate at a delivery dose equal to about 280 or 140 micrograms, respectively, of the commercially available Serertide® combination. There is salmeterol/fluticasone at a delivery dose equal to 47/460 micrograms or 47/231 micrograms, respectively.

The present invention provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate and a pharmaceutically acceptable dry powder carrier providing an equivalent of about 16/280 micrograms The delivered dose of salmeterol / fluticasone propionate.

The present invention provides a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate and a pharmaceutically acceptable dry powder carrier to provide a delivery dose equal to about 16/140 micrograms. Salmeterol / fluticasone propionate.

Also provided is a method of treating a respiratory condition in a patient in need of such treatment, which is specifically referred to as asthma and COPD, the method comprising administering a combination of the salmeterol/fluticasone propionate at a dose that is generally twice daily. A delivery dose equal to about 16/280 micrograms or 16/140 micrograms is provided.

The invention further provides the use of such a combination of salmeterol/fluticasone propionate for the manufacture of a medicament for use in the method, for example as described in the preceding paragraph.

A pharmaceutical composition for treating a respiratory disorder selected from the group consisting of asthma and chronic obstructive pulmonary disease as described above is also provided.

The salmeterol/fluticasone propionate formulation of the present invention may be in combination with two active ingredients or with an additional anti-inflammatory agent such as a muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor, and/or a PI3K inhibitor. / or a combination of the three components of the bronchodilator.

Salmeterol is an international non-proprietary name for (±)-2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol Weighing (INN). Usually, salmeterol is administered in the form of salmeterol hydroxynaphthoate, and its chemical formula is shown below.

In the present application, the delivered dose of salmeterol is expressed as 16 micrograms. This amount corresponds to 23 micrograms of salmeterol hydroxynaphthoate.

The chemical name of fluticasone propionate is 6,9-difluoro-11β, 17-dihydroxy-16-methyl-3-oxo-androst-1,4-diene-17-thioformic acid S- (fluorocarbon) The ester 17-propionate has the chemical formula shown below.

The salmeterol/fluticasone combination is preferably administered in dry powder form with a suitable carrier such as lactose powder (i.e., lactose granules) suitable for inhalation. In a preferred embodiment, the lactose is alpha-lactose monohydrate, preferably in the form of crystalline alpha-lactose monohydrate.

Respiratory diseases or conditions to be treated by the formulations and methods of the invention are generally asthma, chronic obstructive pulmonary disease (COPD), including acute or chronic bronchitis and emphysema, bronchial hyperreactivity, bronchiectasis or rhinitis, Especially asthma and/or chronic obstructive pulmonary disease (COPD).

Based on a review of the characteristics of Seretide® products, since this product contains salmeterol and fluticasone propionate, the same type and severity of adverse effects associated with each of these compounds can be expected. Adverse events associated with salmeterol/fluticasone propionate are provided in Table 1, listed by system organ type and frequency. Frequency is defined as: very common ( 1/10), common ( 1/100 and <1/10), not common ( 1/1000 and <1/100), rare ( 1/10000 to <1/1000) and unknown (uncommended from available data).

Due to the lower delivery dose of the pharmaceutical composition of the present invention, the following adverse events are likely to decrease:

● mouth and throat candidiasis

● hypokalemia

●hyperglycemia

●tremor

● Heart conditions (such as palpitations, tachycardia, arrhythmia, atrial tremor and angina)

● throat stimulation

● hoarse voice / difficulty in pronunciation

For the avoidance of doubt, the delivered dose means the amount of drug that can be used in the mouth for inhalation (the dose that is ejected from the mouthpiece of the inhaler device each time). The delivered dose can be measured using standard techniques known to those skilled in the art.

In the context of a dose of the active agent, "about" as used herein means within the normal limits of an acceptable change of +/- 35% as defined by the European and US Pharmacopoeia. Preferably, the term "about" means within the normal limits of +/- 25% of the acceptable change defined by the US FDA Guideline for MDI and DPI drugs. More preferably, the term "about" means within a normal limit of +/- 15% acceptable change according to the CHMP guidelines for the medical quality of inhaled and nasal products, and optimally for a dispensing system such as +/- 10% within the fixed dose accuracy.

Thus, the delivery dose of "about 16 μg salmeterol" means that the target dose of 16 μg salmeterol varies within the normal acceptance limits for the dispensing system, such as 10.4-21.6 μg salmeterol (+/- 35%) or Preferably 12-20 μg salmeterol (+/- 25%), or better 13.6-18.4 μg salmeterol (+/- 15%) or optimal 14.4-17.6 μg salmeterol (+/- 10%) .

The delivery dose of "about 280 μg fluticasone propionate" means that the target dose of 280 μg fluticasone propionate varies within the normal acceptance limits for the dispensing system, for example 182-378 μg fluticasone propionate (+/- 35%) or preferably 210 - 350 μg fluticasone propionate (+/- 25%), or better 238-322 μg fluticasone propionate (+/- 15%) or optimal 252-308 μg fluticasone propionate (+/- 10%).

The delivery dose of "about 140 μg of fluticasone propionate" means that the target dose of 140 μg of fluticasone propionate is in the normal connection to the dispensing system. Subject to variations, such as 91-189 μg fluticasone propionate (+/-35%) or preferably 105-175 μg fluticasone propionate (+/-25%), or better 119-161 μg fluticasone propionate (+/-) 15%) or optimal 126-154 μg fluticasone propionate (+/- 10%).

In a preferred embodiment, the present invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof, preferably salmeterol hydroxynaphthoate, and fluticasone propionate and lactose A powder, preferably alpha-lactose monohydrate, provides salmeterol/fluticasone equal to a delivery dose of about 16/280 micrograms.

In another preferred embodiment, the present invention is directed to a dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof, preferably salmeterol hydroxynaphthoate, and fluticasone propionate and A lactose powder, preferably alpha-lactose monohydrate, provides salmeterol/fluticasone at a delivery dose equal to about 16/140 micrograms.

The package of the formulation may be adapted for a single unit dose, multiple unit doses (administered by the manufacturer to pre-measure to individual doses in the blister, disc, pit, tube and strip) or multiple dose delivery ( The dose from the powder reservoir is measured, preferably by multiple dose delivery. Dry powder inhalers are therefore divided into three groups: (a) single dose, (b) multiple unit doses, and (c) multiple dose devices.

Formulations typically contain a powder mixture of the compound of the present invention and a suitable powder base (carrier material such as lactose) for inhalation. Each capsule or cartridge may typically contain from 2 [mu]g to 500 [mu]g of each therapeutic active ingredient. Alternatively, the active ingredient can be presented without excipients.

For single dose inhalers, a single dose has been weighed by the manufacturer into small containers that are small reservoirs, cartridges or mostly hard gelatin capsules. The capsule must be removed from the separate box or container and inserted into the receiving area of the inhaler. Secondly, the capsule must be opened or opened with a needle or cutting blade to allow a portion of the breathing gas stream to pass through the capsule to entrain the powder or to vent the powder from the capsule through the apertures during inhalation by means of centrifugal force. After inhalation, empty capsules must be removed from the inhaler again. Most of all, the inhaler must be disassembled to insert and remove the capsule, which may be difficult and burdensome for some patients. Other disadvantages associated with the use of hard gelatin capsules for inhalation of powders are (a) prevention of poor moisture absorption from ambient air, (b) problems with openings or openings that can cause breakage after the capsule has been previously exposed to extreme relative humidity. Or dents and (c) may inhale capsule fragments. Furthermore, for many capsule inhalers, incomplete drainage has been reported.

As described in WO 92/03175, some capsule inhalers have slots from which individual capsules can be transferred to a receiving chamber where opening and emptying occurs. Other capsule inhalers have a rotating slot with a capsule chamber that is lined up with an air duct for dose discharge (e.g., WO 91/02558 and GB 2242134). The capsule inhalers comprise a multi-unit dose inhaler of this type and a blister inhaler having a limited number of unit supply doses on the disc or strip. The blister inhaler provides better moisture protection than the capsule inhaler. The passage to the powder is obtained by opening the cover and the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disc, the number of doses can be increased, but the patient replaces the empty strip Inconvenient. Thus such devices having incorporated dosage systems are generally disposable, including techniques for transporting the strips and opening the blister pockets.

Multi-dose inhalers do not contain pre-measured powder formulations. It consists of a relatively large container and a dose measurement principle that must be operated by the patient. The container is provided with multiple doses which are individually separated from most of the powder depending on the volumetric displacement. There are a variety of dosimetry principles, including rotatable membranes (eg, EP0069715) or discs (eg, GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (eg, EP 0166294; GB 2165159 and WO 92/09322) and Rotatable frustums (eg WO 92/00771), all with cavities that must be filled with powder from the container. Other multi-dose devices have measuring sliders (for example US 5201308 and WO 97/00703) or measuring plungers having partial or circumferential recesses to move a volume of powder from the container to a delivery chamber or air duct, for example EP 0505321, WO 92/04068 and WO 92/04928. Reproducible dose measurements are one of the primary concerns regarding multi-dose inhaler devices. Since the filled dose measuring cup or chamber is primarily under the influence of gravity, the powder formulation must exhibit good and stable flow. Multi-dose inhalers, on the other hand, can contain a much higher number of doses, while the number of treatments for the loading dose is generally lower.

Because the flow of breathing in a multi-dose device typically passes directly through the dose measurement chamber, and because the large volume and rigid dose measurement system of the multi-dose inhaler cannot be agitated by the flow of breath, only the powder material is entrained from the chamber and Very little deagglomeration is obtained during discharge.

Therefore, a separate disintegration member is required. However, actually, It is part of the design of the inhaler. Because of the high number of doses in a multi-dose device, the adhesion of the powder to the inner wall of the air tube must be minimized, and/or such components must be cleaned periodically without affecting the residual dose in the device. Some disposable drug containers for multi-dose inhalers can be replaced after a prescribed number of doses have been taken (e.g., WO 97/000703). These semi-permanent multi-dose inhalers with disposable drug containers are even more rigorously required to prevent drug accumulation.

In a preferred embodiment, the salmeterol/fluticasone propionate combination of the present invention is administered via a breath-actuated multi-dose dry powder inhaler that delivers up to 200 doses from a non-movable cartridge. A particularly 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 content is incorporated herein by reference. Genuair® is also described in H. Chrystyn et al. Int J Clin Pract (2012) 66, 3, 309-317; and H. Magnussen et al. Respiratory Medicine (2009) 103, 1832-1837. Another breath-actuated multi-dose dry powder inhaler suitable for administration in combination with the salmeterol/fluticasone propionate of the present invention is Novolizer®, 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 invention may also be administered via a single dose dry powder inhaler, such as the device described in WO 2005/113042 or EP 1270034.

The agent used for injecting by inhalation requires control Grain size. The optimum particle size for inhalation into the bronchial system is usually from 1 to 10 μm, preferably from 2 to 5 μm. Particles larger than 20 μm are usually too large to reach a small air passage when inhaled. To achieve such particle sizes, the particles of the active ingredient so produced can be reduced in size by conventional means, for example by micronisation or supercritical fluid techniques. The desired portion can be separated by wind grading or sieving. Preferably, the particles will be crystalline.

Because of the poor flowability and extreme cohesion of micronized powders, it is difficult to achieve high dose reproducibility with such powders. To improve the efficiency of the dry powder composition, the particles should be large in the inhaler but should be small when discharged into the respiratory tract. Therefore, excipients such as lactose are usually employed. The particle size of the excipient is generally much greater than the inhaled medicament of the present invention. When the excipient is lactose, it is generally present in the form of lactose particles, preferably crystalline alpha-lactose monohydrate, which has, for example, an average particle size range of from 20 to 1000 μm, preferably from 90 to 150 μm. The median particle size roughly corresponds to the average value and is 50% by mass of the particles having a larger equivalent diameter and the other 50% by mass having a smaller equivalent diameter. Thus, the average particle size is generally referred to in the art as the equivalent d50. The surrounding particle size distribution can affect fluidity, bulk density, and the like. Since the particle size diameter is to be characterized, other equivalent diameters other than d50, such as d10 and d90, can be used. D10 is an equivalent diameter of 10% by mass of the particles having a smaller diameter (and thus the remaining 90% by mass is thicker). The d90 is 90% by mass of the particles having an equivalent diameter of a smaller diameter. In one embodiment, the lactose particles used in the formulation of the invention have a d10 of from 90 to 160 μm, a d50 of from 170 to 270 μm and a d90 of 290-400 μm.

Suitable lactose materials for use in the present invention are commercially available, for example, from DFE Pharma (Respitose® ML001, Respitose® ML006, Respitose® SV003, Respitose® SV010, Lactohale® 100, Lactohale® 200, Lactohale® 201, Lactohale ® 300) or Meggle (Inhalac® 70, Inhalac® 120, Inhalac® 230, Inhalac® 250, Inhalac® 400, PrismaLac® 40, Capsulac® 60, Capsulac® 60 INH, SacheLac® 80, SpheroLac® 100) or Sheffield Bio -Science (monohydrate inhaler 120M, monohydrate inhaler 80M, monohydrate inhalant 40M, anhydrous inhalant 40M, monohydrate inhaler 120MS, anhydrous inhalant 120MS).

The weight ratio between the lactose particles and fluticasone propionate depends on the inhaler device used, but is typically, for example, from 5:1 to 100:1, such as from 25:1 to 75:1, preferably from 30:1 to 60:1. Better 35:1 to 45:1.

The weight ratio between the lactose particles and salmeterol hydroxynaphtholate depends on the inhaler device used, but is typically, for example, from 100:1 to 1000:1, such as from 250:1 to 750:1, preferably from 350:1 to 650:1, better 450:1 to 550:1.

In a more preferred embodiment, the salmeterol/fluticasone propionate formulation of the present invention is administered as a dry powder formulation of salmeterol/fluticasone propionate and lactose, preferably alpha-lactose monohydrate, suitable for administration via a dry powder formulation of lactose, preferably alpha-lactose monohydrate The weight ratio of fluticasone propionate to lactose administered by a dry powder inhaler is from 1:30 to 1:60, preferably from 1:35 to 1:45 and/or the weight ratio of salmeterol to lactose is 1:350. To 1:650, preferably 1:450 to 1:550, wherein fluticasone propionate and The salmeterol hydroxynaphthoate particles have an average particle size of 2 to 5 μm in diameter, for example, a diameter of less than 3 μm, and the d10 of the lactose particles is 90-160 μm, the d50 is 170-270 μm, and the d90 is 290-400 μm.

Additional active agents such as M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, egfr-kinase inhibitors, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors or NK1 receptor agonists can be used in this Inventive methods and formulations. For example, the invention provides a salmeterol/fluticasone propionate formulation as described herein, further comprising an effective amount of one or more of such additional active agents, for example further comprising an effective amount of an M3 muscarinic antagonist, PDE4 inhibitor, JAK inhibitor and/or PI3K inhibitor. The invention also provides a method for treating a respiratory condition, such as asthma or COPD, as described above, comprising administering a salmeterol/fluticasone propionate formulation as described herein, and further comprising one of the concurrently effective amounts Or a plurality of such additional active agents, for example, further comprising an effective amount of an 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 and an M3 muscarinic antagonist as defined above. The most preferred M3 muscarinic antagonist is selected from the group consisting of adenia, tiotropium bromide, glycopyrrolate, indole bromide and GSK-1160724, preferably adenia and most preferably adiponium bromide.

The invention also provides a pharmaceutical composition comprising salmeterol and fluticasone and a PDE4 inhibitor as defined above. The preferred PDE4 inhibitor is selected from the group consisting of roflumilast, tetomilast, ibistast, revastat, RPL-554 and CHF-6001, preferably roflumilast.

Combinations of these three components are suitable for one or two daily doses.

The following examples are provided to enable those skilled in the art to clarify the invention in a sufficiently clear and complete manner, but are not to be construed as limiting the basic aspects of the subject matter set forth in the foregoing part of the specification.

Instance

Example 1

Medicinal composition for inhalation comprising salmeterol hydroxynaphtholate and fluticasone propionate

A pharmaceutical composition having a batch size of 8 kg was prepared, which contained salmeterol hydroxynaphtholate, fluticasone propionate, and α-lactose monohydrate having a d10 of 90-160 μm, a d50 of 170-270 μm, and a d90 of 290-400 μm.

Fluticasone propionate (186.7 g) and alpha-lactose monohydrate (7798 g) were blended in a Bohle blender, the mixture was sieved through a sieve Bohle BTS and finally the mixture was blended in a Bohle blender.

Salmeterol hydroxynaphtholate (15.33 g) was added to the mixture and blended in a Bohle mixer, this mixture was sieved through a sieve Bohle BTS and finally, the mixture was blended in a Bohle blender.

A mixture of salmeterol hydroxynaphthylate and fluticasone propionate and lactose monohydrate was prepared by alternate blending and sieving steps to ensure uniformity and to comminute possible cohesive mass.

Genuair® (H. Chrystyn et al. (2009)) cartridges contain this composition. The cartridges were calibrated to provide 60 dosing doses. Every time The Genuair® provides a 12 mg dose of the above composition.

Delivery dose measurement

According to the European Pharmacopoeia, 7th edition (7.0), Chapter 2.9.18 and the United States Pharmacopoeia USP36-NF31, Chapter 601; measuring the pharmaceutical composition described in Example 1 using the "Collection Tube" device (CT) The delivered dose (the amount of drug used for inhalation in the mouth). For this purpose, via the adapter Genuair® collection tube is fitted to the inhaler, the pressing _pin Genuair® dose inhaler _(key) and releases, 2L or 4L then sucked into the air through the inhaler (expiratory flow rate flowing through the inhaler in 4KPa The pressure drop is about 65 L/min) and the collection tube. Subsequently, the inhalation powder delivered to the collection tube was extracted with a solvent and analyzed using a high performance liquid chromatography apparatus (HPLC).

The average delivered dose per actuation (per inhalation) was 16 μg salmeterol, which corresponds to 23 μg salmeterol hydroxy naphthylate and 280 μg fluticasone propionate.

Example 2

In a Phase I, randomized, open-label, two-way, fully crossover, single-dose clinical trial, salmeterol (hydroxynaphthoate form) / fluticasone propionate fixed-dose combination (FDC) was administered via Genuair® and ccuhaler ^TM Healthy volunteers were evaluated for pharmacokinetics of the two formulations.

This study demonstrates the bioequivalence of salmeterol (hydroxynaphthoate form)/fluticasone propionate 16/280 μg fixed dose combination (FDC) administered via Genuair® and Seretide® Accuhaler® 50/500 μg.

Improvements that do not affect, alter, alter or modify the basic aspects of the pharmaceutical composition are included within the scope of the invention.

Claims (18)

A dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate and a pharmaceutically acceptable dry powder carrier providing salmeterol at a delivery dose equal to about 16 micrograms And a delivery dose equal to about 280 or 140 micrograms of fluticasone propionate. A dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate and a pharmaceutically acceptable dry powder carrier providing a saliva equivalent to a delivery dose of about 16/280 micrograms Tropy/fluticasone propionate. A dry powder pharmaceutical composition for inhalation comprising salmeterol or a pharmaceutically acceptable salt thereof and fluticasone propionate and a pharmaceutically acceptable dry powder carrier providing a saliva equivalent to a delivery dose of about 16/140 micrograms Tropy/fluticasone propionate. The dry powder pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of salmeterol is salmeterol hydroxynaphthylate. The dry powder pharmaceutical composition according to any of the preceding claims, wherein the dry powder carrier is lactose. The dry powder pharmaceutical composition according to claim 5, wherein the lactose is in the form of α-lactose monohydrate. The dry powder pharmaceutical composition according to any one of the preceding claims, wherein the lactose particles have a d10 of from 90 to 160 μm, a d50 of from 170 to 270 μm and a d90 of from 290 to 400 μm. A dry powder pharmaceutical composition according to any of the preceding claims, which is for use A multi-dose dry powder formulation is administered in a multi-dose dry powder inhaler device. The dry powder pharmaceutical composition according to any one of the preceding claims, wherein the weight ratio of salmeterol hydroxynaphthoate to lactose is from 1:350 to 1:650, preferably from 1:450 to 1:550 and/or C. The weight ratio of fluticasone to lactose is from 1:30 to 1:60, preferably from 1:35 to 1:45. The dry powder pharmaceutical composition according to any one of the preceding claims, wherein the salidene hydroxynaphthoate and/or fluticasone propionate have an average particle diameter in the range of 2 to 5 μm. The dry powder pharmaceutical composition according to any of the preceding claims, further comprising an effective amount of one or more additional active agents selected from the group consisting of M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists An egfr-kinase inhibitor, a p38 kinase inhibitor, a JAK inhibitor, a PI3K inhibitor, and an NK1 receptor agonist, preferably an M3 muscarinic antagonist, a PDE4 inhibitor, a JAK inhibitor, or a PI3K inhibitor. The dry powder pharmaceutical composition of claim 11, wherein the additional active agent is selected from the group consisting of M3 muscarinic antagonists. The dry powder pharmaceutical composition of claim 12, wherein the additional active agent is Adenia or a pharmaceutically acceptable salt thereof. A method of treating a respiratory condition in a patient in need of such treatment, the respiratory condition being selected from the group consisting of asthma and chronic obstructive pulmonary disease, the method comprising administering a dry powder pharmaceutical composition according to any one of the preceding claims, administered twice daily. Things. The method of claim 14, further comprising administering an effective amount of one or more additional active agents selected from the group consisting of M3 muscarinic antagonists, PDE4 inhibitors, leukotriene D4 antagonists, egfr-kinase inhibition Agents, p38 kinase inhibitors, JAK inhibitors, PI3K inhibitors and NK1 receptor agonists, preferably M3 muscarinic antagonists, PDE4 inhibitors, JAK inhibitors or PI3K inhibitors. The method of claim 15, wherein the additional active agent is Adenia or a pharmaceutically acceptable salt thereof. A dry powder pharmaceutical composition according to any one of claims 1 to 13 for use in the treatment of a respiratory condition selected from the group consisting of asthma and chronic obstructive pulmonary disease. Use of a pharmaceutical composition according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of a respiratory condition selected from the group consisting of asthma and chronic obstructive pulmonary disease.