FOR INHALATION

TECHNICAL FIELD

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.

BACKGROUND OF THE INVENTION

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

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

Corticosteroids are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Inhaled corticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.

Fluticasone is the most commonly used corticosteroid in the dry powder formulations for inhalation. Fluticasone furoate, which is a salt of fluticasone, is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Fluticasone furoate is available as a combination product with vilanterol, under the tradename Breo Ellipta®. Its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. On the other hand, long-acting beta2-agonists are bronchodilators taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief. These medications may take longer to begin working but relieve airway constriction for up to 12 hours. They are used in combination with a corticosteroid to treat asthma in a metered-dose or dry powder inhaler. They relax the smooth muscles lining the airways that carry air to the lungs (bronchial tubes). This allows the tubes to stay open longer and makes breathing easier.

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

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

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

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

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

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

Drug particles less than 5 μm have the greatest probability of deposition in the lung, whereas those less than 2 μm tend to be concentrated in the alveoli. The dose emitted from an inhaled product contains a large proportion of particles within the 2-5 μm 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.

The process can comprise several steps such as mixing, sieving and filling the powder mixture into capsules or blisters. At this point, the duration of the process gain significance since the longer the process lasts, the greater the dry powder absorbs atmospheric moisture. Moisture is the primary cause of agglomeration. Another issue to consider is the number of the steps which are performed during the process. Intervention to the powder, especially manual contact, is known to increase the risk of microbial reproduction so it is preferable for the process to have fewer steps and to last shorter. However, in the prior art, processes to prepare dry powder compositions for inhalation comprise several sieving steps which are repeated after a mixing step. For instance, the patent application numbered WO2019098969 reveals pharmaceutical compositions for inhalation used in the treatment of obstructive airway diseases which comprise long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and corticosteroids. The preparation method of the composition is specified as comprising several mixing steps and more than one sieving step which is performed by manual sieves with 500 mesh.

The physical and dynamic properties of the sieves used in the process are also crucial to have an optimized fine particle fraction. During these processes manual sieves which only provide simple mechanic filtration are used and therefore mesh blinding is one the biggest problem encountered in the prior art. Mesh blinding/blockage and agglomeration shall cause a vicious circle by leading each other and eventually decrease the fine particle fraction of the drug. In addition, it requires mesh cleaning following every single sieving step. It means more manual contact, more steps and more labor which lead an increase in the cost and impurities. This technical challenge also decreases the stability of the final product since it poses a risk of a nonhomogeneous powder mixture in terms of particle size and in terms of carrier-active agent distribution. 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 which will solve the agglomeration problem, and which will provide a standardized method for fast and clean production of stable inhalation compositions with enhanced FPF. OBJECTS AND BRIEF DESCRIPTION OF THE INVENTION

The main object of the present invention is to provide a novel process for 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 stability, enhanced fine particle dose (FPD) and fine particle fraction (FPF).

Another object of the present invention is to provide a novel process for preparing dry powder inhalation compositions comprising ultrasonic sieving and vibrasonic screen deblending technology which ensures a clean mesh screen and a consistent flow rate through the screen. Another object of the present invention is to provide a novel process for preparing dry powder inhalation compositions eliminating the need of mesh cleaning steps to achieve a required particle size distribution.

Another object of the present invention is to provide a novel process for preparing dry powder inhalation compositions which increase production output and reduced cost.

Another object of the present invention is to provide a novel process for preparing dry powder inhalation compositions which decrease impurities in the powder mixture.

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

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

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

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

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

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

Another object of the present invention is to obtain inhalation combinations having appropriate particle size and ratios of both carriers and active agents ensuring that effective doses of active agents reach the alveoli. A further object of the present invention is to obtain inhalation combinations which can be administered in blister pack or in capsule with an inhaler (inhalation device).

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

A further object of the present invention is to obtain a capsule filled with the above-mentioned dry powder inhalation combinations. A further object of the present invention is to obtain an inhaler which is applicable with the above-mentioned blister pack or the above-mentioned capsule.

DETAILED DESCRIPTION OF INVENTION

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

The present invention relates to a process for preparing dry powder inhalation compositions, comprising ultrasonic sieving and vibratory screen deblending which ensure a clean mesh screen and a consistent flow rate through the screen.

According to one embodiment, ultrasonic sieving and vibratory screen deblending are performed coordinately or consecutively. In the preferred embodiment, ultrasonic sieving and vibratory screen deblending are performed coordinately. According to the preferred embodiment, said vibration is provided by an electrical motor and said ultrasonic sieving is performed by a probe providing ultrasonic frequency. Most preferably, said probe is centrally positioned on the sieve.

According to the preferred embodiment, said process is free of mesh cleaning step.

According to one embodiment, the process comprises the following procedural steps: i. plastering the inner wall of the mixing vessel with a carrier having coarse particle size of which the D50 value is in the range of 50-150 μm ii. adding an active agent and a carrier having fine particle size of which the D50 value is in the range of 0.01-10 μm and mixing iii. repeating the previous step for each active agent in case of the presence of more than one active agent iv. adding carrier having coarse particle size and mixing v. repeating the previous step at least 2 times vi. sieving the mixture through a sieve having a 100-500 μm mesh size and providing ultrasonic frequency and automatic vibration vii. washing the screen with the carrier having coarse particle size viii. mixing the sieved mixture ix. sieving the mixture through a sieve having a 100-315 μm mesh size and providing ultrasonic frequency and automatic vibration x. washing the screen with the carrier having coarse particle size xi. mixing the final mixture

According to one embodiment, mixing mentioned in the steps numbered (ii), (iv) and (viii) is continued for at least 10 minutes. According to one embodiment, mixing mentioned in the step numbered (xi) is continued for at least 90 minutes.

According to the preferred embodiment, ultrasonic frequency mentioned in the steps numbered (vi) and (ix) is performed in 10-40 kHz, preferably in 25 kHz. Additionally, automatic vibration mentioned in the steps numbered (vi) and (ix) is provided by an electrical motor and ensures deblinding for the blocked meshes. Manual contacts are eliminated by this automatic mechanism.

According to the preferred embodiment, active agents mentioned in the steps numbered (ii) and (iii) are selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs).

According to the preferred embodiment, carrier mentioned in the steps numbered (i), (iv), (vii) and (x) is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.

According to the preferred embodiment, carrier mentioned in the step numbered (ii) is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. Unlike processes in the art in which manual meshes are used, the process subjected to the invention does not require mesh cleaning to eliminate mesh blockage. Therefore, manual contact, microbial reproduction and impurities are decreased. 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.

On the other hand, the process subjected to the invention eliminates downtime to clean the meshes as screens stay clear from blockage and accordingly required labor and production cost are considerably reduced, thus an increased production output it provided.

The invention also defines dry powder inhalation compositions obtained by the process subjected to the invention. According to one embodiment, said composition comprises active agents which are selected from the group comprising corticosteroids, long-acting beta2-adrenergic agonists (LA BAs), short acting beta-2 agonists (SABA) and long-acting muscarinic antagonists (LAMAs).

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

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

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

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

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

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

This combination is not randomly formulated; on the contrary, they are specifically selected considering their hygroscopic behaviors. They are non-hygroscopic powders which fight against agglomeration and which enhance moisture resistance and stability, fluidity, content uniformity.

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.

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

According to an embodiment, the composition comprises lactose monohydrate as the carrier. The amount of lactose monohydrate is between 85-99.89%, preferably 90-99%, more preferably 94-99% by weight of the total composition.

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. Similarly, 90% of the distribution lies below the D90 value, and 10% of the distribution lies below the D10 value.

In the preferred embodiment of the invention, 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 0.01-10 μm, preferably 0.01-5 μm. The other part is monohydrate having coarse particle size which means the mean particle size (D50 value) is in the range of 50-150 μm, preferably 50-75 μm.

According to the preferred embodiment, the weight ratio of lactose monohydrate having fine particles to lactose monohydrate having coarse particles is in the range of 1:1 to 1:100, preferably 1:20 to 1:75, more preferably 1:30 to 1:50. In this invention, surprisingly high stability and fluidity are provided by the synergistic effect of selectively combined non-hygroscopic active agents, specified weight ratio and specified particle size ratio of selected carrier.

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.

Coarse carrier particles are used to prevent agglomeration of the active agent particles having mean particle size lower than 10 μm. 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 preferred embodiment, the dry powder composition subjected to the invention comprises;

- 0.1-10% by weight of fluticasone propionate

- 0.01-5% by weight of salmeterol xinafoate

- 85-99.89% by weight of lactose monohydrate

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

Example 1: Dry powder composition for inhalation Example 2: Dry powder composition for inhalation

The pharmaceutical compositions subjected to the invention are prepared by these steps: i. plastering the inner wall of the mixing vessel with lactose having coarse particle size of which the D50 value is in the range of 50-150 μm ii. adding salmeterol xinafoate and lactose having fine particle size of which the D50 value is in the range of 0.01-10 μm and mixing iii. adding fluticasone propionate and lactose having fine particle size of which the D50 value is in the range of 0.01-10 μm and mixing iv. adding lactose having coarse particle size and mixing v. repeating the previous step at least 2 times vi. sieving the mixture through a sieve having a 100-500 μm mesh size and providing ultrasonic frequency and automatic vibration vii. washing the screen with lactose having coarse particle size viii. mixing the sieved mixture ix. sieving the mixture through a sieve having a 100-315 μm mesh size and providing ultrasonic frequency and automatic vibration x. washing the screen with lactose having coarse particle size xi. mixing the final mixture

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), (iv), (v), (vii) and (x) is between 80-95%, preferably 85-94%, more preferably 90-94% by weight of the total composition.

According to the preferred embodiment, the total amount of lactose having fine particle size which is added into the mixing vessel in steps numbered (ii) and (iii) is between 4-5%, preferably 4.5-4.95%, more preferably 4.7-4.95% by weight of the total composition. According to the preferred embodiment, mixing mentioned in the steps numbered (ii), (iv) and (viii) is continued for at least 10 minutes. According to the preferred embodiment, sieving mentioned in the step numbered (vi) is performed by a sieve having 125-315 μm, more preferably 125-250 mesh size.

According to the preferred embodiment, sieving mentioned in the step numbered (ix) is performed by a sieve having 100-250 μm, more preferably 100-125 mesh size.

According to the preferred embodiment, mixing mentioned in the step numbered (xi) is continued for at least 90 minutes.

According to the preferred embodiment, ultrasonic frequency mentioned in the steps numbered (vi) and (ix) is performed in 10-40 kHz, preferably 25 kHz. Additionally, automatic vibration mentioned in the steps numbered (vi) and (ix) is provided by an electrical motor and ensures deblinding for the blocked meshes. Manual contacts are eliminated by this automatic mechanism.

Analyses have shown that fine particle dose value of salmeterol xinafoate is increased by %14 and fine particle dose value of fluticasone propionate is increased by %19 for dry powder compositions obtained by the above-mentioned process subjected to the invention.

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 100 to 500 meg for fluticasone propionate and 10 to 100 meg 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.