WO2022146254A1

WO2022146254A1 - A process for the preparation of dry powder compositions for inhalation

Info

Publication number: WO2022146254A1
Application number: PCT/TR2020/051463
Authority: WO
Inventors: Emine Yilmaz; Devrim Celik; Fatih CAN
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2022-07-07

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

A PROCESS FOR THE PREPARATION OF DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

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

Background of the Invention

Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD.

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 are medications used to treat chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases. 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. They are taken by using an inhaler. This medication should be taken consistently so that it decreases inflammation in the airways of your lungs and prevents chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases flare-ups. Inhaled corticosteroids are considered the most effective long-term usage medication for control and management of asthma.

The clinical benefits of inhaled corticosteroids in other obstructive airway diseases include a decrease in airway hyperresponsiveness, an improvement in lung function and a reduction in severity of symptoms, frequency of exacerbations, the need for rescue medication, and an increase in symptom-free days.

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 adrenoceptor agonists (LABAs, more specifically, long-acting 2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD).

On the other hand, long-acting p2-adrenergic 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. The combination of a long-acting p2-agonist (LABA) and an inhaled corticosteroid is more efficacious in asthma and chronic obstructive pulmonary disease (COPD) than other combination therapies or than either alone.

Inhalers are well known devices for administering pharmaceutically active materials to the respiratory tract by inhalation. Such active materials commonly delivered by inhalation include bronchodilators such as P2 agonists and anticholinergics, corticosteroids, antiallergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.

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 micron 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.

In the state of art, the patent application numbered USRE38912E relates to a new process for producing powdered preparations for inhalation. In this document, it is emphasized that in the mixing bowl, all of the active ingredient and excipient are mixed after being added to the process to form a layer in a certain order. Also, layers are formed horizontally. If the layers are prepared horizontally, effective mixing may not be achieved because the horizontal cross-sections of the layers will not be equal or there will not be a standard section height. If an effective mixture cannot be achieved, it will negatively affect the quality profile of the product.

It can be seen that the prior art has not put enough emphasis on alternative solutions for this problem. Thus, there is still a need for innovative processes that will solve the homogeneity problem, and which will provide a standardized method for the fast 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 preparing dry powder inhalation compositions 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 preparing dry powder inhalation compositions with increased uniformity and homogeneity, 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 minimized the agglomeration of active agents on excipients.

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 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), shortacting beta-2 agonists (SABA), ultra-long-acting beta2-adrenergic agonist 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 that is applicable to the above- mentioned blister pack or the above-mentioned capsule.

Brief Description Of Figures

FIG. 1 is a perspective view of the piece with wings according to the present invention.

FIG. 2 is another perspective view of the piece with wings according to the present invention.

FIG. 3 a perspective view of the container according to the present invention Reference Numbers in Figures

1. The piece with wings

2. The container

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 a process for preparing dry powder inhalation compositions, comprising the following steps: i. weighing the excipients and at least one active ingredients to be included in the formulation ii. placing the piece with wings (1) into the container (2) iii. adding the excipients and the active ingredients to spaces between the piece with wings (1) in separately portions iv. removing the piece with wings (1) from a container (2) v. mixing the excipients and the active ingredients wherein said a piece with wings (1) is located vertically in the step numbered (ii).

The active agents and excipients used in DPI products are not in standard sizes and shapes due to their structures. Therefore, when all ingredients with different particle values come together, the layer may be thick or thin in some areas in cross-section. Therefore, when all ingredients with different particle values come together, the layer may be thick or thin in some areas in cross-section. This situation may negatively affect the repeatability of each production. With said a piece with wings (1) as in Figure 1 , the production process in vertical sections is standardized. This minimizes the possibility that the horizontal layers will not form equal cross-sections. Also, the process is optimized as it has a standardized wingspan.

According to one embodiment, said the piece with wings (1) is used for portioning active agents. The portions take place vertically in our process. When the container (2) is filled with active agents and excipients, a piece with wings (1) ensures that the materials stand vertically in equal portions. As the portions are separated from each other with a piece with wings, not manually, the portion amounts entering the process are fixed. This provides a homogeneous mixture in the process and reduces the variation in subsequent DCU and FPD analysis results targeted to the lung.

According to one embodiment, the piece with wings (1) is used for adding and mixing all active ingredients and excipients in one go. The most important thing of the present invention that said the piece with wings (1) is located vertically in the step numbered (ii).

According to the preferred embodiment, the active agents is selected from a group comprising short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultra-long acting p2 agonists, long-acting muscarinic antagonists (LAMAs) and corticosteroids or pharmaceutically acceptable salt thereof in combination.

According to the preferred embodiment, said short-acting p2 agonists (SABAs) is selected from the group comprising bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said long-acting p2 agonists (LABAs) is selected from the group comprising arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said ultra long-acting p2 agonists is selected from the group comprising abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said long-acting muscarinic antagonists (LAMAs) is selected from the group comprising aclidinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to this preferred embodiment, said long-acting p2 agonists (LABAs) is salmeterol salt. According to this preferred embodiment, said salmeterol salt is salmeterol xinafoate.

According to the preferred embodiment, 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.

According to the preferred embodiment, the said excipients comprises fine carrier particles and coarse carrier particles. Said excipients are selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. Most preferably, said excipients are lactose having fine particle and lactose having coarse particle.

According to the preferred embodiment, a coarse carrier particle, such as lactose monohydrate, is applied to de-agglomerate the drug particles and optimize the deposition of the drug in the lung. The particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention. Lactose comprises lactose having coarse particle size and lactose having fine particle size. Lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35- 100 pm.

According to the preferred embodiment, lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm.

According to one embodiment, the choice of carrier is essential in ensuring that the device works correctly and delivers the right amount of active to the patient. Therefore, to use lactose as a carrier in two different particle sizes (fine and coarse) is essential.

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.

In the preferred embodiment of the invention, said lactose monohydrate is present in the composition in two parts. One of these parts is lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm. The other part is lactose monohydrate having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 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. In this invention, surprisingly high uniformity and homogeneity are provided by the piece with wings (1). Accordingly, homogeneity and stability are increased which means shelf life of the final product is extended. Besides, fine particle fraction and particle size distribution of the final powder mixture are enhanced which means the accurate and consistent transport of the active agents to the lungs is guaranteed.

This the piece with wings (1) and its particle size distribution eliminates agglomeration of active agent particles and assures the enhanced homogeneity, stability, moisture resistance, fluidity, content uniformity and dosage accuracy.

The invention also defines dry powder inhalation compositions obtained by the process subjected to the invention.

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.

According to a preferred embodiment, the dry powder composition comprises fluticasone propionate and salmeterol xinafoate.

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 the preferred embodiment, the total amount of lactose having coarse particle size which is added into the mixing vessel in steps numbered (i) and (iii) is between 80-97%, preferably 85-96%, more preferably 90-95% 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 the preferred embodiment, the total amount of lactose having fine particle size which is added into the mixing vessel in step (iii) is between 0-20%, preferably 0.5-8%, more preferably 1-6% by weight of the total composition.

According to one preferred embodiment, process for 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 all these embodiments, the below given formulations can be used a process for preparing dry powder inhalation compositions 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

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 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 50 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.

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, 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. 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 process for preparing dry powder inhalation compositions, comprising the following steps: i . weighing the excipients and at least one active ingredients to be included in the formulation ii . placing the piece with wings (1) into the container (2) iii . adding the excipients and the active ingredients to spaces between the piece with wings (1) in separately portions iv . removing the piece with wings (1) from a container (2) v . mixing the excipients and the active ingredients wherein said a piece with wings (1) is located vertically in the step numbered (ii).

2. The process according to claim 1, wherein the active agent is selected from a group comprising short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultralong acting p2 agonists, long-acting muscarinic antagonists (LAMAs) or corticosteroids or pharmaceutically acceptable salt thereof in combination.

3. The process according to claim 2, said short-acting p2 agonists (SABAs) is selected from the group comprising bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

4. The process according to claim 2, said long-acting p2 agonists (LABAs) is selected from the group comprising arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

5. The process according to claim 2, said ultra long-acting p2 agonists is selected from the group comprising abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

6. The process according to claim 2, said long-acting muscarinic antagonists (LAMAs) is selected from the group comprising aclidinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

7. The process according to claim 2, wherein said long-acting beta-2-adrenergic agonist is salmeterol.

8. The process according to claim 2, 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.

9. The process according to claim 2, wherein said corticosteroid is fluticasone.

10. The process according to claim 1 , wherein said excipients is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.

11. The process according to claim 10, wherein said excipients are preferably lactose and more preferably lactose monohydrate.

12. The process according to claim 10 or claim 11 , wherein said lactose comprises lactose having coarse particle size and lactose having fine particle size.

13. The process according to claim 12, wherein said lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 pm.

14. The process according to claim 12, wherein lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm.