WO2019098969A2

WO2019098969A2 - Dry powder compositions for inhalation

Info

Publication number: WO2019098969A2
Application number: PCT/TR2018/050437
Authority: WO
Inventors: Ali TÜRKYILMAZ; Devrim Celik
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2017-08-21
Filing date: 2018-08-17
Publication date: 2019-05-23
Also published as: WO2019098969A3; EP3672574A2; TR201712424A2

Abstract

The invention relates to dry powder pharmaceutical compositions and their administration by means of inhalers in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Description

DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

The invention relates to dry powder pharmaceutical compositions and inhalers comprising them which are used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Background of the Invention

Drugs combines pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected form them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action. For the dry powder inhalers (DPIs), these goals can be met with a suitable powder formulation, an efficient metering system, and a carefully selected device. Dry powder inhalers are well known devices for administering pharmaceutically active agents to the respiratory tract to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

Pharmaceutical compositions for inhalation used in the treatment of obstructive airway diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and corticosteroids.

Inhaled corticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.

Fluticasone is the most commonly used corticosteroid in the dry powder formulations for inhalation. Fluticasone furoate, which is a salt of fluticasone, is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Fluticasone furoate is available as a combination product with vilanterol, under the tradename Breo Ellipta®. Its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema.

Long-acting beta2-agonists are used only in combination with a corticosteroid to treat asthma. They are used in a metered-dose or dry powder inhaler. They relax the smooth muscles lining the airways that carry air to the lungs (bronchial tubes). This allows the tubes to stay open longer and makes breathing easier.

Vilanterol is a selective long-acting beta2-adrenergic agonist (LABA) with inherent 24-hour activity for once daily treatment of COPD and asthma. Vilanterol is also approved for use in combination with umeclidinium bromide as Anoro Ellipta®. It is indicated for the long term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Long-acting muscarinic antagonists, formerly known as anticholinergics, cause bronchodilation with a duration of action of over 24 hours and are used once daily.

Umeclidinium, which is a long-acting muscarinic antagonist (LAMA), blocks the M3 muscarinic receptor which is highly expressed in airway smooth muscle of the lungs, inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction. Its use has been shown to provide clinically significant, sustained improvements in lung function.

Most DPI formulations consist of micronized drug blended with larger carrier particles, which enhance flow, reduce aggregation, and aid in dispersion. A combination of intrinsic physicochemical properties, particle size, shape, surface area, and morphology affects the forces of interaction and aerodynamic properties, which in turn determine fluidization, dispersion, delivery to the lungs, and deposition in the peripheral airways.

Small drug particles are likely to agglomerate. Said coagulation can be prevented by employing suitable carrier or carrier mixtures. It also assists in controlling the fluidity of the drug coming out of the carrier device and ensuring that the active ingredient reaching to lungs is accurate and consistent.

Changes in the particle size of the powder, is known to significantly affect its deposition to the lungs and therefore, affect the efficacy. The drug particles and carrier particles are entrained in this air stream together, but only the fine drug particles enter the deep recesses of the lung (which is the site of action of the drug). The inert excipient is deposited either in the mouth or in the upper region of the lungs. Likewise, the cohesive forces between drug and carrier particles play a significant role in this delivery process. If the cohesion is too strong, the shear of the airflow may not be sufficient to separate the drug from the carrier particles, which results in low deposition efficiency. On the other hand, if the cohesion is undesirably weak, a considerable amount of drug particles inherently may stick within the mouth or within the upper lungs, which also causes low deposition efficiency.

Thus, difference of the particle sizes between the carrier and the drug is important in order to optimize the cohesive forces and also to ensure the content uniformity.

The modern era of drug delivery to the lungs using DPIs essentially began in the 1940's with the appearance of the first approved commercial DPI product, namely the Abbott Aerohaler®. This product was used to deliver penicillin and norethisderone and contains many features which would be recognisable today, in that it uses a small capsule reservoir (also described as a‘sifter’) containing a lactose based formulation, designed to be used in a device which utilizes the patient generated inspiratory airflow to disperse the therapeutic particles in an airstream.

Nowadays, many commercialized DPI products have been developed based on using a single excipient in the formulation. The vast majority of these products contain lactose monohydrate which is used as carrier to aid the dosing of the drug and to modify the cohesive nature of micronized drug substances.

On the other hand, the use of a single excipient may not be capable of achieving the required performance efficiency, manufacturability. The use of multiple excipients in DPI products has been realised with the approval of Exubera®, and more recently, TOBI®Podhaler®, but perhaps the most notable and more broadly applied new excipient platform strategy for the development of DPIs used to date is the‘dual excipient platform’ (DEP) where lactose monohydrate is used in conjunction with a second excipient, namely magnesium stearate.

Recently, mannitol is also suggested as carrier instead of lactose. For instance, the patent application numbered EP2682097A2 reveals disadvantages rising with the excess use of lactose in inhalation formulations and highlights the use of a carrier other than lactose, namely mannitol. It is a known fact that lactose cannot be used for compounds that interact with the reducing sugar function of the lactose. Such drugs are the ones having amine groups, as described above, especially the ones having primary or secondary amine. Besides, it can be inconvenient for patients with lactose intolerance, since its ratio in the formulation can reach to over 99% by weight. Considering these facts, the use of mannitol seems reasonable; however, mannitol also has its own disadvantages in case of misuse or overuse.

Scientific observations show that mannitol can increase tendency of the dry powder for inhalation to agglomerate due to its micronized particle size and the moisture in the air. Thus, its ratio in the formulation and its particle size are two essential points to be considered in order to eliminate these risky cases. The prior art does not mention this agglomeration problem caused by mannitol use, accordingly it does not give any clue about the technical solution.

Scientific literature claiming that the addition of tertiary materials, such as magnesium stearate, has been elaborating the fine particle dose performance characteristics of DPI formulations ( Brambilla et at., 2003; Chiesi et at., 2001; Musa et at., 2003; Staniforth, 1997; Zhou and Moreton, 2012). Thus, many patent applications have appeared describing the use of excipient combinations, with these applications typically describing formulations containing dual excipient mixtures of carrier and a tertiary material, including magnesium stearate. It has been reported that the presence of magnesium stearate in DPI formulations results in not only the generation of a higher, but more stable fine particle mass, which was explained in terms of the functional ability of magnesium stearate to protect the formulation from moisture, representing yet another possible stabilizing role for tertiary materials in DPI products ( Guchardi et a!., 2008; Keller and Muller-Walz, 2001).

In another patent application numbered EP2682108A2, the use of a tertiary material such as magnesium stearate, stearic acid, sodium lauryl sulphate, sodium stearyl fumarate, stearyl alcohol, sodium benzoate or their mixtures to provide stability; especially magnesium stearate is suggested to improve the moisture resistance of the powder formulation.

Moisture in the air is one of the challenges while improving DPIs since it causes the dry powder to clump together and clog the inhaler. This is a potential problem especially for capsule and blister based DPI products, where any moisture ingress occurring during storage may change the chemical behavior and influence the long-term performance of the product. It can also lead to other crucial problems such as the failure in the dosage accuracy present in each cavity or capsule and the decrease in the stability and in the effectiveness of the treatment.

Nevertheless, magnesium stearate use shouldn’t be the first solution come to mind considering its toxic effect for the lungs. The selection of the active agents, suitable carriers and probable other excipients for these active agents, and also their ratios in the formulation has a significant effect on the hygroscopic behavior of the total powder mixture. However, the prior art has not put any emphasis on these alternative solutions.

Thus, there is still a need for a DPI formulation, comprising a ternary combination of active agents selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), which is free of magnesium stearate and which also ensure high stability, fluidity, content uniformity and dosage accuracy.

Objects and Brief Description of the Invention

The main object of the present invention is to obtain dry powder inhalation combinations applicable in obstructive airway diseases, comprising active agents selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.

Another object of the present invention is to obtain inhalation combinations comprising active agents which are hygroscopically convenient.

Another object of the present invention is to obtain inhalation combinations comprising fluticasone or a pharmaceutically acceptable salt thereof, vilanterol or a pharmaceutically acceptable salt thereof and umeclidinium or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to obtain inhalation combinations comprising two types of carrier.

Another object of the present invention is to obtain inhalation combinations comprising lactose and mannitol as carriers. Another object of the present invention is to obtain inhalation combinations comprising lactose having fine particles and mannitol having coarse particles as carriers.

Another object of the present invention is to obtain inhalation combinations free of stearates and amino acids.

Another object of the present invention is to obtain inhalation combinations having appropriate carrier particle size ratios and carrier weight ratios ensuring improved moisture resistance, high stability and high fluidity.

Another object of the present invention is to obtain inhalation combinations facilitating filling process into the blister pack or the capsule and accordingly enhancing filling rate.

Another object of the present invention is to obtain inhalation combinations having appropriate particle size and ratios of both carriers and active agents ensuring content uniformity and dosage accuracy in each blister or capsule.

Another object of the present invention is to obtain inhalation combinations having appropriate particle size and ratios of both carriers and active agents ensuring that effective doses of active agents reach the alveoli.

A further object of the present invention is to obtain inhalation combinations which can be administered in blister pack or in capsule with an inhaler (inhalation device).

A further object of the present invention is to obtain a blister pack filled with the above mentioned dry powder inhalation combinations.

A further object of the present invention is to obtain a capsule filled with the above mentioned dry powder inhalation combinations.

A further object of the present invention is to obtain an inhaler which is applicable with the above-mentioned blister pack or the above-mentioned capsule. Detailed Description of Invention

In accordance with the objects outlined above, detailed features of the present invention are given herein.

The present invention relates to dry powder compositions for inhalation, which are used in the treatment of chronic obstructive pulmonary disease and asthma in mammals especially in humans, comprising a corticosteroid or pharmaceutically acceptable salt thereof, a long-acting beta2-adrenergic agonist (LABA) or pharmaceutically acceptable salt thereof and a long-acting muscarinic antagonist (LAMA) or pharmaceutically acceptable salt thereof in combination.

In a preferred embodiment of the invention, said corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.

According to the preferred embodiment, the said corticosteroid is fluticasone. According to this preferred embodiment, the said fluticasone salt is fluticasone furoate.

In a preferred embodiment of the invention, the said long-acting beta-2-adrenergic agonist is selected from the group comprising salmeterol, formoterol, arformoterol, salbutamol, indacaterol, terbutaline, metaproterenol, vilanterol, carmoterol, olodaterol, bambuterol, clenbuterol or mixtures thereof.

According to the preferred embodiment, the said long-acting beta-2-adrenergic agonist is vilanterol. According to this preferred embodiment, the said vilanterol salt is vilanterol trifenatate.

In a preferred embodiment of the invention, the said long-acting muscarinic antagonist is selected from the group comprising tiotropium, aclidinium, darotropium, umeclidinium, glycopyronium, ipratropium or mixtures thereof. According to the preferred embodiment, the said long-acting muscarinic antagonist is umeclidinium. According to this preferred embodiment, the said umeclidinium salt is umeclidinium bromide.

According to a preferred embodiment, the dry powder composition comprises;

- fluticasone furoate

- vilanterol trifenatate

- umeclidinium bromide

These ternary active agent combination is not randomly formulated; on the contrary, they are specifically selected considering their hygroscopic behaviors. They are all non- hygroscopic powders which is essential for the composition subjected to the invention to provide high moisture resistance and stability, fluidity, content uniformity, accordingly.

According to the preferred embodiment, fluticasone furoate is present in an amount of 0.01 to 1 mg, more preferably 0.05 to 0.5 mg in the total composition.

According to this embodiment, the amount of fluticasone furoate is between 0.1 -10%, preferably 0.2-5%, more preferably 0.3-3% by weight of the total composition.

According to the preferred embodiment, vilanterol trifenatate is present in an amount of 0.005 to 0.5 mg, more preferably 0.01 to 0.1 mg in the total composition.

According to this embodiment, the amount of vilanterol trifenatate is between 0.01 -5%, preferably 0.05-3%, more preferably 0.1 -2% by weight of the total composition.

According to the preferred embodiment, umeclidinium bromide is present in an amount of 0.005 to 0.5 mg, more preferably 0.01 to 0.15 mg in the total composition.

According to an embodiment, the amount of umeclidinium bromide is between 0.05-10%, preferably 0.1 -5%, more preferably 0.2-3% by weight of the total composition.

In a preferred embodiment, the dry powder composition further comprises at least one carrier selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol to provide the fluidity of the composition coming out of an inhaler device and to ensure that the active ingredients accurately and consistently reaches the lungs.

According to an embodiment, the composition comprises two different carriers in specified ratios. Preferably, these two carriers are lactose and mannitol.

According to the most preferred embodiment, the composition is free of all types of amino acids such as leucine and all types of stearates such as magnesium stearate. It means that required moisture resistance, stability, fluidity, content uniformity and dosage accuracy are ensured even in absence of a further excipient apart from carrier. It is significantly important considering the prior art and scientific observations in which the use of an amino acid or stearate, especially magnesium stearate, is shown as indispensable to ensure these qualifications.

In this invention, surprisingly high stability and fluidity are provided by the synergistic effect of selectively combined non-hygroscopic active agents, specified weight ratio and specified particle size ratio of selected two carriers which are lactose and mannitol.

Particle size distributions of these carriers play a crucial role for the qualification of the composition subjected to the invention. As used herein,‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).

Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.

According to this measuring method, the d50 value is the size in microns that splits the distribution with half above and half below this diameter. Similarly, 90% of the distribution lies below the D90 value, and 10% of the distribution lies below the D10 value.

In the preferred embodiment of the invention, lactose is present in the composition as the carrier having fine particle size, which means the mean particle size (d50 value) of lactose is in the range of 2-10 pm. In this preferred embodiment, mannitol is present in the composition as the carrier having coarse particle size, which means the mean particle size (d50 value) of mannitol is in the range of 75-200 pm.

Coarse carrier particles, namely mannitol particles, are used to prevent agglomeration of the active agent particles having mean particle size lower than 10 pm. During inhalation, as the active agent and the carrier particles need to be separated from each other, shape and surface roughness of the carrier particles are especially important. Particles having smooth surface will be separated much easier from the active agents compared to the particles in the same size but having high porosity.

Active agent particles will tend to concentrate on the regions having higher energy as the surface energy does not dissipate on the coarse carrier particles evenly. This might prevent separation of the active agent particles from the coarse carrier after pulmonary administration, especially in low dose formulations. In this sense, fine carrier particles, namely lactose particles, are used to help the active agents to reach to the lungs easier and in high doses. As the high-energy regions of coarse carrier particles will be covered by fine carrier particles, the active agent particles will be attaching to low energy regions; thus, the amount of active agent particles detached from the coarse carrier particles will potentially increase.

According to the preferred embodiment, the amount of the lactose with fine particles is in the range of 1 -15%, more preferably 3-10% by weight of the total composition.

According to this preferred embodiment, the amount of the mannitol with coarse particles is in the range of 85-99%, more preferably 90-97% by weight of the total composition.

In the most preferred embodiment of the invention, d50 value of lactose particles is ranging between 4 and 7 pm.

According to this preferred embodiment, d10 value of lactose particles is in the range of 0.5-5 pm, preferably 1 -4 pm.

According to these preferred embodiment, d90 value of lactose particles is in the range of 5-30 pm, preferably 7-15 pm. In the most preferred embodiment of the invention, d50 value of mannitol particles is ranging between 100 and 150 pm.

According to this preferred embodiment, d10 value of mannitol particles is in the range of 2-30 pm, preferably 3-25 pm.

According to these preferred embodiment, d90 value of mannitol particles is in the range of 100-400 pm, preferably 150-350 pm.

The d10 value ratio of lactose particles to mannitol particles is in the range of 1 :15 to 1 :100, preferably 1 :20 to 1 :50.

The d50 value ratio of lactose particles to mannitol particles is in the range of 1 : 10 to 1 :50, preferably 1 : 15 to 1 :40.

The d90 value ratio of lactose particles to mannitol particles is in the range of 1 : 10 to 1 :50, preferably 1 :10 to 1 :30.

The weight ratio of lactose to mannitol is in the range of 1 :5 to 1 :100 and preferably 1 :10 to 1 :50. In the most preferred embodiment, this range is 1 :15 to 1 :25.

This preferred selection of carriers and their ranges eliminates agglomeration of active agent particles and assures the enhanced stability, moisture resistance, fluidity, content uniformity and dosage accuracy.

According to one preferred embodiment, the dry powder composition subjected to the invention comprises;

- 0.1 -10% by weight of fluticasone furoate,

- 0.01 -5% by weight of vilanterol trifenatate,

- 0.05-10% by weight of umeclidinium bromide,

- 1 -15% by weight of lactose

- 85-99% by weight of mannitol

According to all these embodiments, the below given formulations can be used for the dry powder composition subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.

Example 1 : Dry powder composition for inhalation

Example 2: Dry powder composition for inhalation

Example 3: Dry powder composition for inhalation

Example 4: Dry powder composition for inhalation

The pharmaceutical compositions subjected to the invention are prepared by these steps:

- Plastering the inner wall of a container with one fifth of mannitol

- Adding fluticasone furoate, vilanterol trifenatate, umeclidinium bromide and lactose into the plastered container and mixing them to prepare a powder mixture

- Adding one fifth of mannitol to the powder mixture and mixing

- Repeating the previous step for 2 times more

- Sieving the mixture through a 500 pm mesh

- Washing the sieved mixture with one fifth of mannitol to compose a final powder mixture

- Mixing and sieving the final powder mixture through a 500 pm mesh

The dry powder composition subjected to the invention is suitable for administration in dosage forms such as capsules, cartridges or blister packs. The one unit dose of the composition in the dosage form is ranging between 2 to 50 mg.

In an embodiment, the dry powder composition is presented in one dose capsule. The said capsule may be a gelatin or a natural or synthetic pharmaceutically acceptable polymer such as hydroxypropyl methylcellulose and it is arranged for use in a dry powder inhaler and the composition is configured to be delivered to the lungs by the respiratory flow of the patient via the said inhaler. In a preferred embodiment, one dose capsule contains 25 mg dry powder composition. In another preferred embodiment, one dose capsule contains 12.5 mg dry powder composition.

In the preferred embodiment, the dry powder composition subjected is suitable for administration in a multi-dose system, more preferably in a multi-dose blister pack which has more than one blister with air and moisture barrier property. The said blister pack comprises an aluminum material covering them to prevent moisture intake. Each blister is further encapsulated with a material resistant to moisture. By this means, blisters prevent water penetration and moisture intake from outside into the composition.

Each blister contains the same amount of active agent and carrier which is provided via content uniformity and dosage accuracy of the composition. For this invention, it is ensured by the specific selection of carriers, their amounts and their mean particle sizes. In a preferred embodiment, a blister contains 5 mg dry powder composition.

In the most preferred embodiment, the said blister pack is arranged to be loaded in a dry powder inhaler and the composition subjected to the invention is configured to be delivered to the lungs via the said inhaler. The inhaler has means to open the blister and to provide respective delivery of each unit dose.

In a preferred embodiment, the said dry powder inhaler further comprises a lid and a lock mechanism connected to the lid which is arranged to maintain the inhaler locked in both positions in which it is ready for inhalation and the lid is closed. According to this embodiment, the inhaler also ensures to be automatically re-set once the lid is closed.

Subsequent to opening of the device cap, a force is exerted to the device cock by the user. Afterwards, the cock is bolted by being guided by the tracks within the body of the device and the tracks on itself. Mechanism is assured to function via this action. In the end of bolting, cock is locked upon clamping and single dose drug come out of the blister is enabled to be administered. Pushing of the cock by the user completely until the locking position ensures the blister to be completely peeled off and the dosage amount to be accurately administered. As a result of this locking cock is immobilized and is disabled for a short time. This pushing action further causes the spring inside the mechanism to be compressed between the cock and the inner body of the device. Said device becomes ready to re-use following the closing of the cap by the user after the administration of the powder composition, without needing to be set again, thanks to the mechanism involved.

According to a preferred embodiment, pharmaceutical compositions subjected to the invention are used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases. In an embodiment of the invention, the dry powder composition is administered once a day by the said inhaler. In another embodiment of the invention, the dry powder composition is administered twice a day by the said inhaler.

Claims

1. A dry powder composition for inhalation comprising;

- a corticosteroid or pharmaceutically acceptable salt thereof,

- a long-acting beta2-adrenergic agonist or pharmaceutically acceptable salt thereof,

- a long-acting muscarinic antagonist (LAMA) or pharmaceutically acceptable salt thereof;

wherein the composition is free of all types of amino acids and stearates.

2. The dry powder composition for inhalation according to claim 1 , wherein the said corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole and triamcynolondane or mixtures thereof.

3. The dry powder composition for inhalation according to claim 2, wherein the said corticosteroid is fluticasone.

4. The dry powder composition for inhalation according to claim 3, wherein the said corticosteroid salt is fluticasone furoate.

5. The dry powder composition for inhalation according to claim 1 , wherein the said long- acting beta-2-adrenergic agonist is selected from the group comprising salmeterol, formoterol, arformoterol, salbutamol, indacaterol, terbutaline, metaproterenol, vilanterol, carmoterol, olodaterol, bambuterol, clenbuterol or mixtures thereof.

6. The dry powder composition for inhalation according to claim 5, wherein the said long- acting beta-2-adrenergic agonist is vilanterol.

7. The dry powder composition for inhalation according to claim 6, wherein the said long- acting beta-2-adrenergic agonist salt is vilanterol trifenatate.

8. The dry powder composition for inhalation according to claim 1 , wherein the said long- acting muscarinic antagonist is selected from the group comprising tiotropium, aclidinium, darotropium, umeclidinium, glycopyronium, ipratropium or mixtures thereof.

9. The dry powder composition for inhalation according to claim 8, wherein the said long- acting muscarinic antagonist is umeclidinium.

10. The dry powder composition for inhalation according to claim 9, wherein the said long- acting muscarinic antagonist salt is umeclidinium bromide.

11. The dry powder composition for inhalation according to any one of the preceding claims, wherein the composition further comprises at least one carrier selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.

12. The dry powder composition for inhalation according to claim 1 1 , wherein the composition comprises two carriers which are lactose and mannitol.

13. The dry powder composition for inhalation according to claim 12, wherein the mean particle size (d50) of lactose is in the range of 2-10 pm.

14. The dry powder composition for inhalation according to claim 13, wherein the mean particle size (d50) of lactose is in the range of 4-7 pm.

15. The dry powder composition for inhalation according to claim 12, wherein the mean particle size (d50) of mannitol is in the range of 75-200 pm.

16. The dry powder composition for inhalation according to claim 15, wherein the mean particle size (d50) of mannitol is in the range of 100 and150 pm.

17. The dry powder composition for inhalation according to claim 12, wherein the d10 value of lactose particles is in the range of 0.5-5 pm.

18. The dry powder composition for inhalation according to claim 17, wherein the d10 value of lactose particles is in the range of 1 -4 pm.

19. The dry powder composition for inhalation according to claim 12, wherein the d90 value of lactose particles is in the range of 5-30 pm.

20. The dry powder composition for inhalation according to claim 19, wherein the d90 value of lactose particles is in the range of 7-15 pm.

21. The dry powder composition for inhalation according to claim 12, wherein the d10 value of mannitol particles is in the range of 2-30 pm.

22. The dry powder composition for inhalation according to claim 21 , wherein the d10 value of mannitol particles is in the range of 3-25 pm.

23. The dry powder composition for inhalation according to claim 12, wherein the d90 value of mannitol particles is in the range of 100-400 pm.

24. The dry powder composition for inhalation according to claim 23, wherein the d90 value of mannitol particles is in the range of 150-350 pm.

25. The dry powder composition for inhalation according to claim 12, wherein the d10 value ratio of lactose particles to mannitol particles is in the range of 1 : 15 to 1 :100.

26. The dry powder composition for inhalation according to claim 25, wherein the d10 value ratio of lactose particles to mannitol particles is in the range of 1 :20 to 1 :50.

27. The dry powder composition for inhalation according to claim 12, wherein the d50 value ratio of lactose particles to mannitol particles is in the range of 1 : 10 to 1 :50.

28. The dry powder composition for inhalation according to claim 27, wherein the d50 value ratio of lactose particles to mannitol particles is in the range of 1 : 15 to 1 :40.

29. The dry powder composition for inhalation according to claim 12, wherein the d90 value ratio of lactose particles to mannitol particles is in the range of 1 : 10 to 1 :50.

30. The dry powder composition for inhalation according to claim 29, wherein the d90 value ratio of lactose particles to mannitol particles is in the range of 1 : 10 to 1 :30.

31. The dry powder composition for inhalation according to claim 12, wherein the weight ratio of lactose to mannitol is in the range of 1 :5 to 1 :100.

32. The dry powder composition for inhalation according to claim 31 , wherein the weight ratio of lactose to mannitol is in the range of 1 : 10 to 1 :50.

33. The dry powder composition for inhalation according to claim 32, wherein the weight ratio of lactose to mannitol is in the range of 1 : 15 to 1 :25.

34. The dry powder composition for inhalation according to any preceding claims, wherein the composition comprises;

- 0.1 -10% by weight of fluticasone furoate,

- 0.01 -5% by weight of vilanterol trifenatate,

- 0.05-10% by weight of umeclidinium bromide,

- 1 -15% by weight of lactose

- 85-99% by weight of mannitol

35. A process for preparing the dry powder composition for inhalation according to claim 34, comprising the following steps:

- Plastering the inner wall of the container with one fifth of mannitol

- Adding one fifth of mannitol to the powder mixture and mixing

- Repeating the previous step for 2 times more

- Sieving the mixture

- Mixing and sieving the final powder mixture

36. A dosage form for administration of the dry powder composition according to any one of the claims 1 to 34; wherein the dosage form is capsule, catridge or blister pack.

37. A dosage form according to claim 36; wherein one-unit dose of the dry powder composition in the dosage form is ranging between 2 to 50 mg.

38. A dosage form according to claim 36; wherein the dosage form is a multi-dose blister pack.

39. Use of a multi-dose blister pack according to claim 38 in a dry powder inhaler; wherein the blister pack comprises more than one unit-dose blister having moisture barrier property.

40. A dry powder inhaler according to claim 39, wherein the dry powder inhaler comprises means to open a blister and to enable respective delivery of each unit dose.

41. A dry powder inhaler according to claim 40 for use in the treatment of obstructive airway diseases.

42. A dry powder inhaler according to claim 41 wherein administered once a day.

43. Use of a dry powder inhaler according to claim 41 wherein administered twice a day.