WO2022045993A1

WO2022045993A1 - A production method of dry powder compositions for inhalation

Info

Publication number: WO2022045993A1
Application number: PCT/TR2020/050778
Authority: WO
Inventors: Fatih CAN; Devrim CELIK SAKIZCI; Emine Yilmaz; Serkan ACAR; Fulden KUS; Yasemin LEVENT; Irem KOSE
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2020-08-28
Filing date: 2020-08-28
Publication date: 2022-03-03

Abstract

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

Description

A PRODUCTION METHOD OF DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

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 (filling volume of mixer) 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 EP3277265A1 discloses relates to processes for dry powder blending of pharmaceutical and non-pharmaceutical solid particulates. In particular, the present invention relates to a process of preparing a dry microparticulate powder blend comprising one or more micronized active pharmaceutical ingredient(s) (API) and optionally, one or more micronized or non-micronized pharmaceutically acceptable carrier(s) and/or excipient(s), wherein the process comprises the steps of 'pulsating blending' of the micronized active pharmaceutical ingredient(s) and the pharmaceutically acceptable carrier(s) and/or excipient(s).

On the other hand, these invention do not mention any motivation of a production method with specific mass density, specific filling volume values and specific ratio of active agent particles.

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 production method for preparing dry powder inhalation compositions which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.

The main object of the present invention is to provide a production method of dry powder compositions with improved flow properties for use in the prevention, treatment, or in the alleviation of the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.

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

Another object of the present invention is to provide a production method 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 obtain inhalation combinations having high homogeneity and uniformity with an appropriate ratio of rotation speed. Another object of the present invention is to obtain inhalation combinations having high homogeneity and uniformity with an appropriate ratio of active agents and appropriate bulk density.

Another object of the present invention is to provide a production method for dry powder compositions for inhalation which eliminates the requirement of sieving and saves time accordingly.

Another object of the present invention is to provide a production method for dry powder compositions for inhalation which eliminates the requirement of using a sieve and provides one-pot manufacturing accordingly.

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.

Detailed Description of Invention

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

In order to gain benefit from drug particles used in inhalation therapy, the drug particles should be delivered to the lungs in an inhalable size. Since drug particles of an inhalable size are quite cohesive, they tend to agglomerate and have poor flow properties. Because of these features they possessed, they are produced and filled into inhaler blisters, capsules or reservoirs with difficulty. Therefore, micronized drug particles are diluted using carrier agents to improve the flow properties of the drug particles and to uniformly fill the drug particles into blisters, capsules, or reservoirs. Additionally, since the amount of the carrier particles are substantially higher than that of the drug particles, the properties of dry powder formulations are greatly influenced by the properties of the carrier particles.

Accordingly, the present invention provides a dry powder composition comprising the first active agent is selected from a group of 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 and corticosteroid particles and carrier particles suitable for use in dry powder inhalers for the treatment of respiratory diseases.

The flow properties of the dry powder formulation according to the present invention comprising micronized drug particles and carrier particles was surprisingly found to have a signification improvement when the formulation was formulated to have a poured bulk density between 0.50 g/ml - 0.75 g/ml. By improving the flowability of said dry powder formulation formulated to have a poured bulk density in the range indicated above, the formulation can be uniformly portioned into blisters, capsules or reservoirs suitably used in dry powder inhalers, and thus, any dose inhaled by a patient from the respective blister, capsule, or reservoir during inhalation can be delivered with a high dose accuracy. Having said that, the dry powder formulation with good flow properties contributes to an almost complete discharge of the powder from the inhaler during inhalation.

The poured bulk density of the dry powder composition according to the present invention is set between 0.50 g/ml and 0.75 g/ml.

The poured bulk density according to the present invention is measured using a known method as described in "Powder testing guide: Methods of measuring the physical properties of Bulk powders," L.Svarovsky, Elsevier Applied Science 1987, pp. 84-86. In general terms, this method is based on calculating the poured bulk density of a previously weighed powder by passing it through a funnel into a graduated container. After all of the powder is poured into the container, the amount of powder is divided by the volume of the container, and thus the poured bulk density is obtained.

Depending on the bulk density and mixing ratio of the selected carrier, the bulk density of the product has emerged. This bulk density value range was effective in determining the optimum filling volume of the mixer. When all these factors were combined, it showed a synergistic effect in the homogeneous mixing of the dry powder.

Depending on the properties of the powder forming the formulation, the filling volume of the mixer causes the powder not to mix homogeneously. Also, depending on the homogeneous mixing of the powder, the content uniformity of each dose and the dose uniformity given to the patient during the delivery of the product with the medical device and the fine particle dose amount reaching the lungs are affected. Active agent particles in the dry powder mixture with small particles adhere to the walls of the mixer when the filling volume of mixer is low. In cases where the filling volume of mixer is high, active agent particles do not distribute homogeneously between the carrier particles and agglomerate. Inventors were surprisingly found that the mixture of composition was more homogeneous when the filling volume of the mixer was between 45-75%. The filling volume of mixer according to the present invention is between 45-75%.

Based on the bulk density of the product and use of the optimum filling volume of the mixer, the homogeneity of the formulation mixture has been achieved. Besides these features, the present invention relates to a production method of dry powder composition 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.

The present invention relates to a production method of dry powder formulation comprising a first active agent and a corticosteroid wherein the first active agent is selected from a group of 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 wherein the ratio of the first active agent which is small in mass to corticosteroid which is large in mass in the composition is selected between 0,1-0, 5 and the total amount of API is between 1-12% comprising the steps of adding the first active agent and corticosteroid with at least one carrier are in the mixer wherein each of the first active agent and corticosteroid with carrier is added to the mixer in separate steps and each adding step of the first active agent and corticosteroid with the carrier into the mixer is followed by at least one blending step until poured bulk density of the mixed dry powder is set between 0.50 g/ml - 0.75 g/ml and the filling volume of mixer is selected between %45-75 of the total volume.

According to the preferred embodiment, the said mixer is high shear mixer with a rotational speed of 75-1000 rpm.

According to the preferred embodiment, first active agents which is small in mass 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.

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.

In a preferred embodiment of the invention, said corticosteroid which is large in mass 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 which is large in mass is fluticasone. According to this preferred embodiment, said fluticasone salt is fluticasone propionate.

According to the more preferred embodiment, the dry powder composition comprises a fluticasone or pharmaceutically acceptable salt thereof and salmeterol or pharmaceutically acceptable salt thereof in combination.

According to one embodiment, the ratio of the first active agent which is small in mass to corticosteroid which is large in mass in the composition is selected between 0,1 -0,5 and the total amount of API is between 1-5%.

Besides the salmeterol xinafoate and fluticasone propionate particles, the dry powder formulation according to the present invention comprises the carrier agent to dilute and carry the drug particles. 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.

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 with fine carrier particles and coarse carrier particles.

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.

According to one embodiment, a production method of dry powder formulation comprising a first active agent and a corticosteroid wherein the first active agent is selected from a group of 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 wherein the ratio of the first active agent which is small in mass to corticosteroid which is large in mass in the composition is selected between 0,1-0, 5 and the total amount of API is between 1-12% comprising the steps of adding the first active agent and corticosteroid with at least one carrier are in the mixer wherein each of the first active agent and corticosteroid with carrier is added to the mixer in separate steps and each adding step of the first active agent and corticosteroid with the carrier into the mixer is followed by at least one blending step until poured bulk density of the mixed dry powder is set between 0.50 g/ml - 0.75 g/ml and the filling volume of mixer is selected between %45-75 of the total volume.

According to the preferred embodiment, the said mixer is a high shear mixer with a rotational speed of 75-1000 rpm.

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.

The invention also defines dry powder inhalation compositions obtained by the production method mentioned above. 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 0.1-20%, preferably 0.3-15%, more preferably 0.5-12% 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 ratio of salmeterol which is small in mass to fluticasone which is large in mass in the composition is selected between 0,1-0, 5.

According to one embodiment, API comprises salmeterol xinafoate and fluticasone propionate and the total amount of API is between 1-12%.

According to one embodiment, the amount of total lactose is between 75-99.89 %, preferably 82-99.65%, more preferably 86-99.4% by weight of the total composition.

According to the preferred embodiment, the total amount of lactose having fine particle size which is between 0-20%, preferably 0.5-10%, more preferably 1-6% by weight of the total composition.

According to one preferred embodiment, the weight ratio of lactose having fine particle size to lactose having coarse particle size is between 0-25%, preferably 0.5-12%, more preferably 1-7%.

According to one preferred embodiment, a production method for the dry powder composition subjected to the invention comprises;

- 0.5-12 % by weight of fluticasone propionate

- 0.01-2% by weight of salmeterol xinafoate

- 86-99.4% by weight of lactose monohydrate

According to all these embodiments, the below given formulations can be used a production method of dry powder 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

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.

The uniformity and FPD value are enhanced by the coordinated effect of the selected blending speed range. 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 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 production method of dry powder formulation comprising a first active agent and a corticosteroid wherein the first active agent is selected from a group of 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 wherein the ratio of the first active agent which is small in mass to corticosteroid which is large in mass in the composition is selected between 0,1 -0,5 and the total amount of API is between 1-12% comprising the steps of adding the first active agent and corticosteroid with at least one carrier are in the mixer wherein each of the first active agent and corticosteroid with carrier is added to the mixer in separate steps and each adding step of the first active agent and corticosteroid with the carrier into the mixer is followed by at least one blending step until poured bulk density of the mixed dry powder is set between 0.50 g/ml - 0.75 g/ml and the filling volume of mixer is selected between %45-75 of the total volume.

2. The production method according to claim 1 , wherein the said mixer is a high shear mixer with a rotational speed of 75-1000 rpm.

3. The production method according to claim 1 , wherein 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.

4. The production method according to claim 3, 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.

5. The production method according to claim 3, 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.

6. The production method according to claim 3, 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.

7. The production method according to claim 3, 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.

8. The production method according to claim 3, wherein said long-acting beta-2- adrenergic agonist is salmeterol.

9. The production method according to claim 1 , 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.

10. The production method according to claim 9, wherein said corticosteroid is fluticasone.

11. The production method according to claim 1 , wherein said carrier is selected from the group comprising coarse carrier particles, fine carrier particles or mixtures thereof.

12. The production method according to claim 11 , said carrier particles is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.

13. The production method according to claim 11 , wherein said the fine carrier particles and the coarse carrier particles are preferably lactose and more preferably lactose monohydrate.