WO2022045994A1

WO2022045994A1 - A process for the preparation of dry powder compositions for inhalation

Info

Publication number: WO2022045994A1
Application number: PCT/TR2020/050779
Authority: WO
Inventors: Fatih CAN; Devrim CELIK SAKIZCI; Emine Yilmaz
Original assignee: Arven Ilac Sanayi ve Ticaret AS
Current assignee: Arven Ilac Sanayi ve Ticaret AS
Priority date: 2020-08-28
Filing date: 2020-08-28
Publication date: 2022-03-03
Anticipated expiration: 2023-02-28

Abstract

The invention relates to a process for the preparation of dry powder pharmaceutical compositions and compositions obtained by said process which are used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Description

PROCESS FOR MANUFACTURING DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

The invention relates to processes for the preparation of dry powder pharmaceutical compositions and compositions obtained by said process which are used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Background of the Invention

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). 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. These goals can be achieved primarily with a homogenous and stable powder formulation.

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.

Corticosteroids are a class of drug that lowers inflammation in the body. They also reduce immune system activity. 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. On the other hand, long-acting beta2-agonists are bronchodilators taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief. These medications may take longer to begin working but relieve airway constriction for up to 12 hours. They are used in combination with a corticosteroid to treat asthma 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.

Salmeterol is a selective long-acting beta2-adrenergic agonist (LABA) used in the maintenance and prevention of asthma symptoms and maintenance of chronic obstructive pulmonary disease (COPD) symptoms. Symptoms of bronchospasm include shortness of breath, wheezing, coughing and chest tightness. It is also used to prevent breathing difficulties during exercise.

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 effects 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 agglomeration 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 recognizable 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.

It is potentially desirable that inhalation device delivers sufficient amount of the medicament to the patient for inhalation. The homogeneity of the discharge is basically dependent on the agglomeration tendency of the dry powder in the capsule or in the blister and the agglomeration tendency is related to both the content of the formulation (such as selected carriers and their hygroscopicity etc.) and the particle size distribution (the ratio of fine particles and coarse particles) of this content. Fine-particle dose (FPD) is defined as the dose of the aerosolized drug particles with an aerodynamic diameter < 5 microm and fine particle fraction (FPF) is the ratio of FPD to the total recovered dose. FPF is an essential factor which directly effects the amount of the drug which reaches to the lungs of the patient.

Drug particles less than 5 pm have the greatest probability of deposition in the lung, whereas those less than 2 pm tend to be concentrated in the alveoli. The dose emitted from an inhaled product contains a large proportion of particles within the 2-5 pm range ensuring a fairly even distribution throughout the lungs. Selection of the carrier and optionally other excipients is one the main approaches to adjust FPF. On the other hand, the preparation process of the dry powder composition is as important as the carrier selection to maintain FPF at a desirable range. The process can comprise several steps such as mixing/blending, sieving and filling the powder mixture into capsules or blisters.

Blending is the step in which distinct bulk material particles are brought into close contact to produce a homogenous powder mixture. A mixture can be defined as homogeneous if every sample of the mixture has the same composition and properties as any other. The phenomena of particle segregation and agglomeration present a challenge in developing a reproducible blending process. For dry particle blending, the cohesive and adhesive forces acting between particles depend on molecular forces. Therefore, blending parameters such as blending speed and blending volume are just as important as carrier selection to achieve both homogeneity and uniformity of the composition.

At this point, the duration of blending is also important to assure stability of the composition since the longer blending lasts, the greater the dry powder absorbs atmospheric moisture. Moisture is the primary cause of agglomeration; thus, it is preferable to keep the blending time short but enough to assure uniformity.

In the state of art, blending step is performed via shaker mixers with low speed which require long blending times to achieve a desirable uniformity. For instance, the patent application numbered WO2018206618 (A1) relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler. In this document, it is emphasized that low shear mixer (Turbula mixer) with a rotation speed of 11 to 45 rpm is used to provide a homogenous composition. It is also said that the rotation speed is preferably 16 to 32 rpm for a period of 60 to 300 minutes.

This long duration of blending, while providing homogeneity, is also increasing the risk of moisture which causes caking and affects FPD negatively. This technical challenge also decreases the stability of the final product since it poses a risk of a nonhomogeneous powder mixture in terms of particle size and in terms of carrier-active agent distribution. Another problem can be microbial contamination, which is often assisted by the undesirable presence of excess moisture. However, in the state of art, for example in the patent document numbered EP1292510 (B1 ), these challenges are tried to be overcome by the inclusion of a desiccant in the body of the inhaler or the walls of the medicament carrier. Furthermore, storage of the inhaler or medicament carrier within a sealed package incorporating a desiccant is also considered as a solution.

It can be seen that the prior art has not put enough emphasis on alternative solutions for these challenges. Thus, there is still a need for innovative processes which will provide a standardized method for fast and clean production of stable inhalation compositions with enhanced FPF.

Objects and Brief Description of the Invention

The main object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which eliminate all aforesaid problems and bring additional advantages to the relevant prior art. Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation with increased stability, enhanced fine particle dose (FPD) and fine particle fraction (FPF).

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation with enhanced uniformity and homogeneity.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which decreases the required blending duration to provide a homogeneous composition and the risk of caking accordingly.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which eliminates the requirement of using a sieving, saves time and provides a one-pot manufacturing accordingly.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation in which the active agent(s) and carrier are added in more than one portions together or separately.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which decrease contamination in the powder mixture depending on the process time and steps.

Another object of the present invention is to obtain dry powder inhalation compositions provided by the above-mentioned process comprising at least one active agent selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs).

A further object of the present invention is to obtain dry powder inhalation compositions comprising a corticosteroid and a selective long-acting beta2-adrenergic agonist (LABA) in combination.

Another object of the present invention is to obtain inhalation compositions comprising fluticasone or a pharmaceutically acceptable salt thereof and salmeterol or a pharmaceutically acceptable salt thereof. Another object of the present invention is to obtain inhalation compositions 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 compositions 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 compositions which can be administered in blister pack or in capsule using an inhaler.

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 process for manufacturing dry powder compositions for inhalation wherein a first active agent with lower amount in mass and at least one second active agent with greater amount in mass comparing with the first active agent each separately selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs) comprising the steps of adding the first active agent and the second active agent with at least one carrier are in a high shear mixer and mixing with an impeller of the mixer with a rotational speed of 75-1000 rpm wherein each of the first active agent and the second active agent with carrier is added to the mixer in separate steps and each adding step of the first active agent and the second active agent with the carrier into the mixer is followed by at least one blending step for a duration of is at least 3 minutes. The present invention relates to a process for manufacturing dry powder compositions for inhalation in which at least one active agent and at least one carrier are added in a mixer comprising an impeller with a rotational speed of 75-1000 rpm, together or separately in more than one portions.

According to the preferred embodiment, said mixer is a high shear mixer.

According to the preferred embodiment, the process is carried out by dry granulation and free of any liquid.

According to the preferred embodiment, the process is free of sieving and time-saving accordingly.

According to the preferred embodiment, in the case of presence of more than one active agent, each active agent is added in separate portions.

According to one embodiment, carrier addition per portion is performed only with at least one active agent.

According to the preferred embodiment, the rotational speed of said impeller is in the range of 100-1500 rpm, more preferably in the range of 150-800 rpm.

According to the preferred embodiment, each addition of active agent and/or carrier into the mixer is followed by at least one blending step. Preferably, the duration of said blending step is at least 3 minutes.

According to the preferred embodiment, the addition of active agent and/or carrier is repeated 10 times at most.

According to preferred embodiment, the process is carried out for 10-120 minutes, more preferably 15-60 minutes. This duration is far shorter than the duration required in the prior art.

According to one embodiment, said impeller is bottom-driven.

Said impeller comprises at least one blade, preferably three blades. According to one embodiment, said mixer further comprises a chopper located on the internal side wall of the mixer with a rotational speed of 1-2200 rpm, preferably 50-1000 rpm, more preferably 100-500 rpm.

According to one embodiment, said chopper is in the form of a hook.

According to one embodiment, said active agent is selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs).

According to the preferred embodiment, the dry powder composition comprises a corticosteroid or pharmaceutically acceptable salt thereof and a selective long-acting beta2- adrenergic agonist (LABA) or pharmaceutically acceptable salt thereof in combination.

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

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, said long-acting beta-2-adrenergic agonist is salmeterol. According to this preferred embodiment, said salmeterol salt is salmeterol xinafoate.

According to one embodiment, said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. According to the preferred embodiment, said carrier is lactose monohydrate. Particle size distribution of the carrier plays 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.

According to the preferred embodiment, the process comprises the use of coarse lactose of which d50 value in the range 25-250 pm. According to one embodiment, the process further comprises the use of fine lactose of which d50 value is in the range of 0-25 pm.

Coarse carrier 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 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. This preferred selection of carrier and its particle size distribution eliminates agglomeration of active agent particles and assures the enhanced stability, moisture resistance, fluidity, content uniformity and dosage accuracy.

According to one embodiment, the process comprises the following procedural steps: i. plastering the inner wall of the mixer with coarse lactose by blending for at least 3 minutes

II. adding salmeterol xinafoate and blending for at least 5 minutes ill. adding fluticasone propionate, fine lactose and coarse lactose and blending for at least 10 minutes

According to one embodiment, coarse lactose mentioned in step (i) and (iii) have a d50 value in the range 25-250 pm, preferably in the range of 30-80 pm.

It has been surprisingly seen that these steps considerably enhance the uniformity and homogeneity of the final composition even though it takes at least 18 minutes in total.

The invention also defines dry powder inhalation compositions obtained by the process mentioned above.

According to one embodiment, the amount of fluticasone propionate is between 0.1-10%, preferably 0.3-8%, more preferably 0.5-5% by weight of the total composition.

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

According to one embodiment, the amount of total lactose is between 85-99.89%, preferably 89-99.65%, more preferably 93-99.4% by weight of the total composition.

According to this embodiment, the amount of coarse lactose is between 90-100%, preferably 96-99% by weight of the total lactose.

According to this embodiment, the amount of fine lactose is between 0-20%, preferably 1-10 % by weight of the total lactose.

According to another embodiment, the process comprises the following procedural steps: a. plastering the inner wall of the mixer with coarse lactose by blending for at least 3 minutes b. adding salmeterol xinafoate and blending for at least 5 minutes c. adding salmeterol xinafoate and coarse lactose and blending for at least 5 minutes d. adding fluticasone propionate and coarse lactose and blending for at least 10 minutes

According to one embodiment, coarse lactose mentioned in step (a) has a d50 value in the range 25-250 pm, preferably in the range of 30-80 pm.

According to one embodiment, the amount of coarse lactose mentioned in step (a) is 20-40% by weight of the coarse lactose in the final dry powder composition. According to this embodiment, the amount of coarse lactose mentioned in step (c) is 20-40% by weight of the coarse lactose in the final dry powder composition. And accordingly, the amount of coarse lactose mentioned in step (d) is 30-50% by weight of the coarse lactose in the final dry powder composition.

According to one embodiment, the amount of salmeterol xinafoate mentioned in step (b) is half by weight of the salmeterol xinafoate in the final dry powder composition. According to this embodiment, the amount of salmeterol xinafoate mentioned in step (c) is the other half by weight of the salmeterol xinafoate in the final dry powder composition.

It has been surprisingly seen that these steps considerably enhance the uniformity and homogeneity of the final composition even though it takes at least 23 minutes in total.

According to one embodiment, the amount of coarse lactose is between 85-99.89%, preferably 89-99.65%, more preferably 93-99.4% by weight of the total composition. According to one preferred embodiment, the dry powder composition subjected to the invention comprises;

- 0.1 -10% by weight of fluticasone propionate

- 0.01-5% by weight of salmeterol xinafoate

- 85-99.89% by weight of lactose monohydrate

According to 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

Unlike processes in the art in which sieving is essential to assure stable and uniform dry powder compositions, these suggested processes don’t require any sieving step to provide such compositions. The process subjected to the invention only requires a mixer defined as in any embodiment above.

Although the process time is shortened, uniformity and FPD value are enhanced by the coordinated effect of the selected blending speed range and the addition of the components by portioning. The increase in stability also leads the extension of the shelf life of the final composition. As FPD and FDP values are enhanced, the accurate and consistent transport of the active agents to the lungs is guaranteed.

On the other hand, as the process subjected to the invention eliminates sieving procedures required labor and production cost are considerably reduced, thus an increased production output it provided.

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.

The dry powder compositions 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 100 to 500 mcg for fluticasone propionate and 10 to 100 mcg for salmeterol xinafoate.

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 13 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 13 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.

According to a preferred embodiment, dry powder composition subjected to the invention is used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases.

Claims

1. A process for manufacturing dry powder compositions for inhalation wherein a first active agent with lower amount in mass and at least one second active agent with greater amount in mass comparing with the first active agent each separately selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs) comprising the steps of adding the first active agent and the second active agent with at least one carrier are in a high shear mixer and mixing with an impeller of the mixer with a rotational speed of 75-1000 rpm wherein each of the first active agent and the second active agent with carrier is added to the mixer in separate steps and each adding step of the first active agent and the second active agent with the carrier into the mixer is followed by at least one blending step for a duration of is at least 3 minutes.

2. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein, the process is free of sieving step.

3. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein, the rotational speed of said impeller is in the range of 100- 1500 rpm, more preferably in the range of 150-800 rpm.

4. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein, the addition of active agent and/or carrier is repeated 10 times at most.

5. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein the process is carried out for 10-120 minutes, more preferably 15-60 minutes.

6. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein the impeller is bottom-driven and having at least one blade, preferably three blades.

7. A process for manufacturing dry powder compositions according to any one of the preceding claims, the mixer further comprises a chopper located on the internal side wall of the mixer with a rotational speed of 1-2200 rpm, preferably 50-100 rpm, more preferably 100-500 rpm. A process for manufacturing dry powder compositions according to any one of the preceding claims, the first active agent is selected from a group comprising short-acting P2 agonists (SABAs), long-acting P2 agonists (LABAs), ultra-long acting P2 agonists or long-acting muscarinic antagonists (LAMAs) or pharmaceutically acceptable salt thereof in combination. A process for manufacturing dry powder compositions according to claim 8, wherein said long-acting beta-2-adrenergic agonist is salmeterol. A process for manufacturing dry powder compositions according to claim 8-9, wherein wherein the second active agent is a corticosteroid or pharmaceutically acceptable salt thereof. A process for manufacturing dry powder compositions according to claim 10, wherein 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. A process for manufacturing dry powder compositions according to claim 11 , wherein, said corticosteroid is fluticasone. A process for manufacturing dry powder compositions according to any one of the preceding claims, wherein said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.