WO2023128918A1

WO2023128918A1 - A process including a feeding gas system for preparing dry powder inhalation compositions

Info

Publication number: WO2023128918A1
Application number: PCT/TR2021/051672
Authority: WO
Inventors: Fatih CAN; Devrim Celik; Emine Yilmaz
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2023-07-06

Abstract

The invention relates to a process including feeding gas system for preparing dry powder inhalation compositions in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Description

A PROCESS INCLUDING A FEEDING GAS SYSTEM FOR PREPARING POWDER COMPOSITIONS

Technical Field

The invention relates to a process including a feeding gas system for preparing powder compositions especially dry powders for inhalation 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.

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 force 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.

In the literature, there are various methods for including active pharmaceutical ingredients (active agents) or low amounts of excipients into solid product formulations. For example, for solid formulations, there are methods such as mixing the active agents and excipients in the process sequentially, forming and mixing layers of active agents and excipients, sieving and mixing the active agents onto the excipient mixture.

One of the biggest problems encountered while preparing dry powder compositions: The active substance and excipient to be included in the formulation are scattered around while adding to the process. Therefore, losses are experienced in active agents and excipients. It is an important step in terms of ensuring that the drug quality is sustainable and unchanged without the loss of effective and fine particulate excipients. In the literature, it seems that there is not enough reference to the processes that prevent the powdering of the active agents or excipients and add them to the process without dispersing. There is a need for innovative developments that allow the active agent or excipients to be added directly to the process without worrying about loss.

In addition, the inhalable active agents can be cohesive in nature. Mixing equipment used in the preparation of dry powder compositions may not be sufficient to homogeneously disperse agglomerated active agents and excipients with cohesive properties. The fine particle d(90) value used in dry powder inhalation compositions to optimize the dose amount of fine particles is below 30 microns and has a cohesive structure. Fine particles with small dimensions are mostly cohesive and are easily collected by applying pressure on them. Dry granulation uses its cohesive properties to form larger granules without using any binders. The 'fluidization' of fine cohesive particles has been considered a difficult process but is also known to form agglomerates.

It may be necessary to mix for a long time in order to obtain a homogeneous mixture during the addition of the active agent or cohesive auxiliary substances with a D50 value below 30 pm to the process. This may cause heating in the mixture and an increase in the amount of impurities. When an effective mixture cannot be achieved, the required quality profile of the product cannot be achieved because the formulation mixture is not homogeneous. It can be seen in the literature that there is not enough auger to reduce cohesive loads.

There is a need for innovative developments that provide a great advantage in terms of homogeneity in the powder mixture obtained with the active agent and excipients, which reduce the cohesive loads and break the agglomerated structures, allowing them to be added to the process.

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 including feeding gas system 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 including feeding gas system 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 including feeding gas system for preparing dry powder inhalation compositions with minimized the agglomeration of active agents on excipients.

Another object of the present invention is to provide a novel process including feeding gas system for preparing dry powder inhalation compositions 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, non-selective dopamine agonist long-acting beta2- adrenergic agonists (LABAs), short-acting 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 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.

The present invention relates to a novel process including feeding gas system for preparing dry powder inhalation compositions.

The inhalable active agents can be cohesive in nature. In addition, the fine particle d(90) value used to optimize the fine particle dose amount of inhalation products is below 30 microns and has a cohesive structure. Active agents and excipients with cohesive properties can be taken into the process by reducing their cohesive loads and breaking their agglomerated structures, proses including feeding gas system.

A great advantage is provided in terms of homogeneity in the powder mixture obtained with these active and excipients, whose cohesive loads are reduced and their agglomerated structures can be broken down. In addition, mixing equipment may not be sufficient to homogeneously disperse agglomerated active and auxiliary materials with cohesive properties. This problem can be avoided with the process including feeding gas system mentioned in the invention.

The invention describes a process that provides fast and easy transfer of active agents and fine particulate excipients without loss in the formulation. It is an important step in terms of ensuring that the drug quality is sustainable and unchanged without the loss of effective and fine particulate excipients. Thanks to the process including feeding gas system, the active agents with cohesive loads and the addition of fine particulate excipients to the process ensure homogeneity and also aim to keep the product stable. Low variation product is obtained.

While the active agents and excipients to be included in the formulation are added to the process, they are scattered around. Therefore, losses are experienced in active agents and excipients. One of the other features of the invention is the active agent and excipients to be included in the formulation can be included in the process including feeding gas system without scattering. It is to prevent the dusting of the active agents or excipients with a process including feeding gas system and to ensure that they are included in the process without dispersing. Thus, it is ensured that the active agents or excipients are directly added to the process including feeding gas system without worrying about loss. In addition, with the application of the invention, easy transfer of the active agents and excipients to the process is ensured, the process becomes faster and more reliable.

The most important feature of the invention is that active agent or cohesive excipients with a D50 value of less than 30 pm are added to the composition mixture in a closed environment with the feeding gas system in order to include them in solid product compositions.

In the invention, when the active agent and excipients that make up the formulation mixture are sprayed into the mixer container at pressure, the active agent or the cohesive excipient parts with a D50 value below 30 pm are in motion, so they fall homogeneously to different parts of the mixture, not to a specific part. Then, when the mixing process is applied, the active agent or cohesive excipient particles with a D50 value below 30 pm, which are attached to different areas in the mixing bowl, are homogeneously dispersed in the formulation.

The invention describes a process that homogenizes a low amount of active agents or excipients in the formulation. Homogeneity is one of the first and most important parameters for drug formulations to be delivered accurately and reliably to the patient.

The flow rate of the gas to be used for spraying the active agent or cohesive excipient parts with a D50 value below 30 pm can be applied as low or fast according to its properties to fluidize the materials in the formulation.

According to the one embodiment, the process for preparing dry powder inhalation compositions wherein the addition of active agents and excipient to the process including feeding gas system.

According to the preferred embodiment, said feeding gas system is selected from the group comprising nitrogen (N2), helium (He), argon (Ar).

According to the preferred embodiment, pressure of said feeding gas system is between 1.2- 3.0 bar, preferably 1.5-2.9 bar, more preferably 1.8-2.8 bar. The inventors have surprisingly found that the cohesive loads of the active agent and excipients are minimized, the agglomerations are reduced in this way, and the pressure of the feeding gas system is between 1.8-2.8 bar. When this range is exceeded, the desired quality profile is not achieved.

The inventors have been found that when using a pressure below the given range active agent or cohesive excipient of spraying difficulties were encountered. Also, when using a pressure above the given range agglomerations of active ingredient and excipient have been observed.

The present invention relates to a process for preparing dry powder inhalation compositions including feeding gas system according to any one of the preceding claims, comprising the following steps: i. plastering the inner wall of the mixing vessel with first fraction of the first carrier and mixing with the mixer ii. adding at least one active agent into the plastered mixing vessel and mixing with the mixer iii. adding second carrier and second fraction of first carrier into the plastered mixing vessel and mixing with the mixer wherein the pressure of said feding gas system is between 1.2-3.0 bar, preferably 1.5-2.9 bar, more preferably 1.8-2.8 bar.

According to the preferred embodiment, the pressure of said feeding gas system is performed in the step numbered (ii) and (iii).

According to the preferred embodiment, the impeller speed of mixer in the step numbered (i) and (ii) is 200-700, preferably 250-650 rpm, more preferably 300-600 rpm and the impeller speed in the step numbered (iii) is 100-500 rpm, preferably 125-475 rpm, more preferably 150-450 rpm.

According to the preferred embodiment, the impeller speed in the step numbered (i) and (ii) of the process and the impeller speed in the step numbered (iii) of the process is the important aspects of the invention. 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), non-selective dopamine agonist 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 the preferred embodiment, said non-selective dopamine agonist is apomorfin or a pharmaceutically acceptable salt or ester thereof.

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 active agent have a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm.

According to the preferred embodiment, excipient is selected from the group comprising carriers, lubricants/glidants or mixtures thereof.

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

According to the preferred embodiment, the said first carrier is lactose having coarse particle.

According to the preferred embodiment, the said second carrier is lactose having fine 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 comprises coarse lactose and fine lactose. Lactose monohydrate comprises coarse lactose of which the mean particle size (D50 value) is between 25-250 pm, preferably 35-100 pm.

According to the preferred embodiment, lactose monohydrate comprises fine lactose of which the mean particle size D50 value) is between 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.

In a preferred embodiment, lubricants/glidants are selected from the group comprising magnesium stearate, sodium stearate, calcium stearate, zinc stearate, lithium stereate, sodium stearyl fumarate, silicon dioxide, talc, colloidal silicon dioxide, corn, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulfate, behenic acid, erucic acid, lauric acid, oleic acid, palmitic acid, glyceryl behenate, aluminum dioxide, starch, titanium dioxide, sodium stearoyl lactylate, dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI), phosphatidylglycerol (PG), lecithin, soya lecithin, laxiric acid, triglycerides, hydrogenated castor oil waxy powder, l-leucine, isoleucine, trileucine, lysine, methionine, phenylalanine, valine, aspartame, and acesulfame potassium or mixtures thereof.

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 a process including feeding gas system for preparing dry powder inhalation compositions. 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 process including feeding gas system for preparing dry powder inhalation compositions eliminates agglomeration of active agent particles and assures 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 at least one active agent which 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), non-selective dopamine agonist or corticosteroids or a pharmaceutically acceptable salt thereof in combination.

According to a preferred embodiment, the dry powder composition comprises umeclidinium, preferably umeclidinium bromide.

According to one embodiment, the amount of umeclidinium bromide 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 fine lactose is between 0.5-20.0%, preferably 1.0-16.0%, more preferably 1.5-12.0% by weight of the total composition.

According to this embodiment, the amount of coarse lactose is between 70.0-99.4-%, preferably 76.0-98.7% more preferably 83.0-98.2%by weight of the total composition.

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

- 0.1-10.0% by weight of umeclidinium bromide

- 0.5-20.0% by weight of fine lactose monohydrate

- 70.0-99.4% by weight of coarse lactose monohydrate

According to another embodiment, the dry powder composition comprises umeclidinium bromide, vilanterol trifenatate and fluticasone furoate.

According to one embodiment, the amount of umeclidinium bromide 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 vilanterol trifenatate is between 0.10-8%, preferably 0.15-6%, more preferably 0.20-4% by weight of the total composition.

According to one embodiment, the amount of fluticasone furoate 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 fine lactose is between 0.5-20.0%, preferably 1.0-16.0%, more preferably 1.5-12.0% by weight of the total composition.

According to this embodiment, the amount of coarse lactose is between 52.00-99.20%, preferably 62.00-98.25%, more preferably 74.00-97.3% by weight of the total composition.

0.1-10%, % by weight of umeclidinium bromide

0.10-8%, % by weight of vilanterol trifenatate - 0.1-10%, % by weight of fluticasone furoate

- 0.5-20.0%, % by weight of fine lactose monohydrate

- 52.00-99.20%, % by weight of coarse 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.

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 wherein the addition of active agents and excipient to the process including gas feeding system.

2. The process according to claim 2, wherein said feeding gas system is selected from the group comprising nitrogen (N2), helium (He), argon (Ar).

3. The process according to any one of the preceding claims, wherein pressure of said feeding gas system is between 1.2-3.0 bar, preferably 1.5-2.9 bar, more preferably 1.8-2.8 bar.

4. A process for preparing dry powder inhalation compositions including feeding gas system according to any one of the preceding claims, comprising the following steps: i. plastering the inner wall of the mixing vessel with first fraction of the first carrier and mixing with the mixer ii. adding at least one active agent into the plastered mixing vessel and mixing with the mixer iii. adding second carrier and second fraction of first carrier into the plastered mixing vessel and mixing with the mixer the pressure of said feeding gas system is between 1.2-3.0 bar, preferably 1.5-2.9 bar, more preferably 1.8-2.8 bar.

5. The process according to any one of the preceding claims, wherein the impeller speed of mixer in the step numbered (i) and (ii) is 200-700, preferably 250-650 rpm, more preferably 300-600 rpm and the impeller speed in the step numbered (iii) is 100- 500 rpm, preferably 125-475 rpm, more preferably 150-450 rpm.

6. The process according to any one of the preceding claims, wherein said active agent have a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm.

7. The process according to any one of the preceding claims, wherein the active agent 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), non-selective dopamine agonist and corticosteroids or pharmaceutically acceptable salt thereof in combination. The process according to any one of the preceding claims, 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. The process according to any one of the preceding claims, 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. The process according to any one of the preceding claims, 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. The process according to any one of the preceding claims, 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. The process according to any one of the preceding claims, wherein said non-selective dopamine agonist is apomorfin or a pharmaceutically acceptable salt or ester thereof. The process according to any one of the preceding claims, 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, 19 hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.

14. The process according to any one of the preceding claims, wherein said excipient is selected from the group comprising carriers, lubricants/glidants or mixtures thereof.

15. The process according to any one of the proceeding claims, wherein said carriers are selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof.

16. The process according to any one of the proceeding claims, wherein said carrier is lactose, more preferably lactose monohydrate.

17. The process according to any one of the preceding claims, wherein said lactose comprises coarse lactose and fine lactose.

18. The process according to any one of the preceding claims, wherein said lactose monohydrate comprises coarse lactose of which the mean particle size is between 25-250 pm, preferably 35-100 pm.

19. The process according to any one of the preceding claims, wherein said lactose monohydrate comprises fine lactose of which the mean particle size is between 0. QI- 25 pm, preferably 0.01-20 pm.

20. The process according to any one of the preceding claims, lubricants/glidants are selected from the group comprising magnesium stearate, sodium stearate, calcium stearate, zinc stearate, lithium stereate, sodium stearyl fumarate, silicon dioxide, talc, colloidal silicon dioxide, corn, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulfate, behenic acid, erucic acid, lauric acid, oleic acid, palmitic acid, glyceryl behenate, aluminum dioxide, starch, titanium dioxide, sodium stearoyl lactylate, dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI), phosphatidylglycerol (PG), lecithin, soya lecithin, laxiric acid, triglycerides, hydrogenated castor oil waxy powder, l-leucine, isoleucine, 20 trileucine, lysine, methionine, phenylalanine, valine, aspartame, and acesulfame potassium or mixtures thereof.