WO2022146257A1 - A process for the preparation of dry powder compositions for inhalation - Google Patents

A process for the preparation of dry powder compositions for inhalation Download PDF

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Publication number
WO2022146257A1
WO2022146257A1 PCT/TR2020/051467 TR2020051467W WO2022146257A1 WO 2022146257 A1 WO2022146257 A1 WO 2022146257A1 TR 2020051467 W TR2020051467 W TR 2020051467W WO 2022146257 A1 WO2022146257 A1 WO 2022146257A1
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WO
WIPO (PCT)
Prior art keywords
process according
acting
lactose
agonists
minutes
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Application number
PCT/TR2020/051467
Other languages
French (fr)
Inventor
Emine Yilmaz
Devrim Celik
Fatih CAN
Original Assignee
Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
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Priority to PCT/TR2020/051467 priority Critical patent/WO2022146257A1/en
Publication of WO2022146257A1 publication Critical patent/WO2022146257A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the invention relates to a process for the preparation of dry powder pharmaceutical compositions in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • COPD chronic obstructive pulmonary disease
  • DPIs dry powder inhalers
  • 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).
  • COPD chronic obstructive pulmonary disease
  • 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.
  • LAMA long acting muscarinic antagonists
  • LABA long acting beta agonists
  • SABA short acting beta-2 agonists
  • corticosteroids corticosteroids
  • Inhaled corticosteroids are medications used to treat chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • Ultra long-acting p2 agonists are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • ultra 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 24 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.
  • Vilanterol is a selective ultra 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.
  • a ultra 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, anti-allergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
  • 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.
  • 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.
  • 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.
  • 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.
  • blending parameters such as blending speed and blending volume are just as important as carrier selection to achieve both homogeneity and uniformity of the composition.
  • the patent application numbered USRE38912E relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler.
  • an excipient mixture is prepared with coarse lactose (about 30 portions) and fine lactose (about 30 portions), and this excipient mixture is divided into about 30 portions, one layer of excipient and one layer of the active substance are stacked on top of each other, it is understood that then they started the mixing process.
  • the disadvantage here is; because the cohesive strengths of active agents are so high, they can tend to compress under a load and form hard agglomerates. Especially, active agents can be pressed more because the lower part of the layers will have more pressure than the upper parts. This is an important issue to not provide the powder from mixing homogeneously.
  • the main object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.
  • Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation with increased stability, enhanced fine particle dose (FPD) and fine particle fraction (FPF).
  • FPD enhanced fine particle dose
  • FPF fine particle fraction
  • Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation with enhanced uniformity and homogeneity.
  • Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which decreases the required blending duration to provide a homogeneous composition and the risk of caking accordingly.
  • Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which eliminates the requirement of using a sieving, saves time and provides a one-pot manufacturing accordingly.
  • Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation in which the active agent(s) minimizes the load on active agents.
  • Another object of the present invention is to obtain dry powder inhalation compositions provided by the above-mentioned process comprising at least two active agent selected from the group comprising long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA), long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids.
  • LABA long-acting beta2-adrenergic agonists
  • SABA short acting beta-2 agonists
  • LAMAs long-acting muscarinic antagonists
  • non-selective dopamine agonist and corticosteroids non-selective dopamine agonist and corticosteroids.
  • a further object of the present invention is to obtain dry powder inhalation compositions comprising combinations of ultra long-acting p2 agonists and corticosteroids.
  • Another object of the present invention is to obtain inhalation compositions comprising combinations of vilanterol or a pharmaceutically acceptable salt thereof and fluticasone or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring content uniformity and dosage accuracy in each blister or capsule.
  • Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring that effective doses of active agents reach the alveoli.
  • a further object of the present invention is to obtain inhalation compositions which can be administered in blister pack or in capsule using an inhaler.
  • a further object of the present invention is to obtain a blister pack filled with the above- mentioned dry powder inhalation combinations.
  • a further object of the present invention is to obtain a capsule filled with the above-mentioned dry powder inhalation combinations.
  • a further object of the present invention is to obtain an inhaler which is applicable with the above-mentioned blister pack or the above-mentioned capsule.
  • the invention is related to a process by which is obtain a homogeneous mixture without accumulating load on the active substances.
  • Cohesive forces of active substances are very high. Therefore, they can tend to get stuck under a load and form hard agglomerates.
  • the active ingredients can be pressed more, since the lower part of the layers will have more pressure than the upper parts. In this case, it is difficult to obtain a homogeneous mixture as the mixture cannot be mixing easily.
  • Inventors have been developed a novel process for preparing dry powder compositions for inhalation in which the active agent(s) minimizes the load on active agents.
  • mixing vessel-1 has a small volume.
  • Mixing vessel-1 has preferably the volume of 2 litre.
  • first active agent, second carrier, second active agent, and first carrier are added to the mixing vessel-1 and layers are created.
  • the number of layers created in mixing vessel-1 is ⁇ 5.
  • the purpose of having 5 or less than 5 layers here is to ensure that no charge accumulates on the active agents.
  • the active agents and carriers added to the mixing vessel-1 are pre-mixed for at least 5 minutes.
  • the obtaining mixture is transferred to the mixing vessel-2.
  • Mixing vessel-2 has large volume and has preferably the volume of 60 litre.
  • the mixtures created by repeating the processes in the mixing vessel-1 are transferred to the mixing vessel-2 separately.
  • A-number of mixes are obtained in the mixing vessel-2.
  • A is an integer and 2 ⁇ A.
  • the mixture obtained in the end of the processes are mixed with a suitable mixer. If the low shear mixer is selected, the duration of mixing is at least 60 minutes. If the high shear mixer is selected, the duration of mixing is at least 10 minutes.
  • the process in accordance with the present invention is used for the preparation of the dry powder formulation comprising at least two active agents and a pharmaceutically acceptable carrier.
  • a process for preparing dry powder inhalation compositions comprising the following steps: i. plastering the inner wall of the mixing vessel-1 with the first carrier ii. adding first active agent, second carrier second active agent, and first carrier to the mixing vessel-1 and mixing the composition with the mixer iii. obtaining A-number of mixtures by repeating the processes in the step number (i) and (ii). iv. transferring A-number of mixtures to the mixing vessel-2 separately. v. mixing A-number of mixtures with the mixer wherein said A is an integer and 2 ⁇ A.
  • the said mixer in the step number (ii) and (v) are selected from low shear mixer or high shear mixer. If the high shear mixer is selected, the rotational speed of the high shear mixer in the step numbered (ii) and (v) are 75-1000 rpm, preferably 100-800 rpm, more preferably 200-600 rpm. If the low shear mixer is selected, the rotational speed of the low shear mixer in the step numbered (ii) and (v) are 10-75 rpm, preferably 15-45 rpm, more preferably 20-40 rpm.
  • duration of the step number (i) is at least 1 minutes, preferably at least 3 minutes.
  • duration of the step number (ii) is at least 3 minutes, preferably at least 5 minutes.
  • duration of the step number (v) is at least 30 minutes, preferably at least 60 minutes.
  • duration of the step number (v) is at least 5 minutes, preferably at least 10 minutes.
  • 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, long-acting muscarinic antagonists (LAMAs) and non-selective dopamine agonist or pharmaceutically acceptable salt thereof in combination.
  • SABAs short-acting p2 agonists
  • CLAs long-acting p2 agonists
  • LAMAs long-acting muscarinic antagonists
  • non-selective dopamine agonist or pharmaceutically acceptable salt thereof in combination non-selective dopamine agonist or pharmaceutically acceptable salt thereof in combination.
  • said short-acting p2 agonists 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.
  • SABAs short-acting p2 agonists
  • said long-acting p2 agonists 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.
  • 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.
  • said long-acting muscarinic antagonists 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 second active agent is selected from a group comprising corticosteroid or pharmaceutically acceptable salt thereof in combination.
  • said corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.
  • said ultra long-acting p2 agonists is vilanterol.
  • said vilanterol salt is vilanterol trifenatate.
  • said corticosteroids is fluticasone.
  • said fluticasone salt is fluticasone furoate.
  • the active substance has to be diluted with suitable carriers to prepare dry powder formulation for inhalation.
  • Carrier particles are used to improve active substance flowability, thus improving dosing accuracy, minimizing the dose variability compared with active substance alone and making them easier to handle during manufacturing operations. Additionally, with the use of carrier particles, active substance particles are emitted from the medicament compartments (capsule, blister, etc.) more readily, hence, complete discharge of the medicament compartments by the inspiratory air during inhalation can be achieved and the inhalation efficiency in terms of emitted dose and fine particle fraction (FPF) increases.
  • FPF fine particle fraction
  • the said carriers comprises fine carrier particles and coarse carrier particles.
  • Said carriers are selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.
  • said excipients are lactose having fine particle and lactose having coarse particle.
  • a coarse carrier particle such as lactose monohydrate
  • lactose monohydrate is applied to de-agglomerate the drug particles and optimize the deposition of the drug in the lung.
  • the particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention.
  • Lactose comprises lactose having coarse particle size and lactose having fine particle size.
  • Lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35- 100 pm.
  • lactose 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 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.
  • 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.
  • the D50 value is the size in microns that splits the distribution with half above and half below this diameter.
  • 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. QI- 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.
  • 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, fluidity, content uniformity and dosage accuracy.
  • the pharmaceutical compositions subjected to the invention are prepared by these steps: i. plastering the inner wall of the mixing vessel-1 with lactose having coarse particle ii. adding vilanterol, lactose having fine particle fluticasone, and lactose having coarse particle to the mixing vessel-1 and mixing the composition with the mixer iii. obtaining A-number of mixtures by repeating the processes in the step number (i) and (ii). iv. transferring A-number of mixtures to the mixing vessel-2 separately. v. mixing A-number of mixtures with the mixer wherein said A is an integer and 2 ⁇ A.
  • the invention also defines dry powder inhalation compositions obtained by the process subjected to the invention.
  • the dry powder composition comprises combinations of ultra long-acting p2 agonists and corticosteroids.
  • the dry powder composition comprises combinations of vilanterol or a pharmaceutically acceptable salt thereof and fluticasone or a pharmaceutically acceptable salt thereof.
  • the amount of vilanterol trifenatate is between 0.10-0.50%, preferably 0.20-0.40%, more preferably 0.25-0.35% by weight of the total composition.
  • the amount of fluticasone is between 0.50-2.00 %, preferably 0.60-1.90%, more preferably 0.70-1 .80% by weight of the total composition.
  • the amount of total lactose is between 97.50-99.40%, preferably 97.70-99.20%, more preferably 97.85-99.05% by weight of the total composition.
  • the total amount of lactose having fine particle size which is added into the mixing vessel in step (iii) is between 0-20%, preferably 0.5-8%, more preferably 1-6% by weight of the total composition.
  • process for the dry powder composition subjected to the invention comprises;
  • Example 1 Dry powder composition for inhalation
  • Example 2 Dry powder composition for inhalation
  • Example 3 Dry powder composition for inhalation
  • 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.
  • the dry powder composition is administered once a day by the said inhaler.
  • the dry powder composition is administered twice a day by the said inhaler.

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Abstract

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

Description

A PROCESS FOR THE PREPARATION OF DRY POWDER COMPOSITIONS FOR INHALATION
Technical Field
The invention relates to a process for the preparation of dry powder pharmaceutical compositions in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.
Background of the Invention
Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD.
Drugs combines pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected form them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action. For the dry powder inhalers (DPIs), these goals can be met with a suitable powder formulation, an efficient metering system, and a carefully selected device. Dry powder inhalers are well known devices for administering pharmaceutically active agents to the respiratory tract to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
Pharmaceutical compositions for inhalation used in the treatment of obstructive airway diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and corticosteroids.
Inhaled corticosteroids are medications used to treat chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases. Inhaled corticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe. They are taken by using an inhaler. This medication should be taken consistently so that it decreases inflammation in the airways of your lungs and prevents chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases flare-ups. Inhaled corticosteroids are considered the most effective long-term usage medication for control and management of asthma.
The clinical benefits of inhaled corticosteroids in other obstructive airway diseases include a decrease in airway hyperresponsiveness, an improvement in lung function and a reduction in severity of symptoms, frequency of exacerbations, the need for rescue medication, and an increase in symptom-free days.
Fluticasone is the most commonly used corticosteroid in the dry powder formulations for inhalation. Fluticasone furoate, which is a salt of fluticasone, is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Fluticasone furoate is available as a combination product with vilanterol, under the tradename Breo Ellipta®. Its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema.
Ultra long-acting p2 agonists are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD).
On the other hand, ultra 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 24 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.
Vilanterol is a selective ultra 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 ultra 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, anti-allergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
Most DPI formulations consist of micronized drug blended with larger carrier particles, which enhance flow, reduce aggregation, and aid in dispersion. A combination of intrinsic physicochemical properties, particle size, shape, surface area, and morphology effects the forces of interaction and aerodynamic properties, which in turn determine fluidization, dispersion, delivery to the lungs, and deposition in the peripheral airways.
Small drug particles are likely to agglomerate. Said agglomeration can be prevented by employing suitable carrier or carrier mixtures. It also assists in controlling the fluidity of the drug coming out of the carrier device and ensuring that the active ingredient reaching to lungs is accurate and consistent.
Changes in the particle size of the powder, is known to significantly affect its deposition to the lungs and therefore, affect the efficacy. The drug particles and carrier particles are entrained in this air stream together, but only the fine drug particles enter the deep recesses of the lung (which is the site of action of the drug). The inert excipient is deposited either in the mouth or in the upper region of the lungs. Likewise, the cohesive forces between drug and carrier particles play a significant role in this delivery process. If the cohesion is too strong, the shear of the airflow may not be sufficient to separate the drug from the carrier particles, which results in low deposition efficiency. On the other hand, if the cohesion is undesirably weak, a considerable amount of drug particles inherently may stick within the mouth or within the upper lungs, which also causes low deposition efficiency.
Thus, difference of the particle sizes between the carrier and the drug is important in order to optimize the cohesive forces and also to ensure the content uniformity.
The modern era of drug delivery to the lungs using DPIs essentially began in the 1940's with the appearance of the first approved commercial DPI product, namely the Abbott Aerohaler®. This product was used to deliver penicillin and norethisderone and contains many features which would be recognizable today, in that it uses a small capsule reservoir (also described as a ‘sifter’) containing a lactose-based formulation, designed to be used in a device which utilizes the patient generated inspiratory airflow to disperse the therapeutic particles in an airstream.
It is potentially desirable that inhalation device delivers sufficient amount of the medicament to the patient for inhalation. The homogeneity of the discharge is basically dependent on the agglomeration tendency of the dry powder in the capsule or in the blister and the agglomeration tendency is related to both the content of the formulation (such as selected carriers and their hygroscopicity etc.) and the particle size distribution (the ratio of fine particles and coarse particles) of this content. Fine-particle dose (FPD) is defined as the dose of the aerosolized drug particles with an aerodynamic diameter < 5 micron and fine particle fraction (FPF) is the ratio of FPD to the total recovered dose. FPF is an essential factor which directly effects the amount of the drug which reaches to the lungs of the patient.
Drug particles less than 5 pm have the greatest probability of deposition in the lung, whereas those less than 2 pm tend to be concentrated in the alveoli. The dose emitted from an inhaled product contains a large proportion of particles within the 2-5 pm range ensuring a fairly even distribution throughout the lungs. Selection of the carrier and optionally other excipients is one the main approaches to adjust FPF. On the other hand, the preparation process of the dry powder composition is as important as the carrier selection to maintain FPF at a desirable range. The process can comprise several steps such as mixing/blending, sieving and filling the powder mixture into capsules or blisters.
Blending is the step in which distinct bulk material particles are brought into close contact to produce a homogenous powder mixture. A mixture can be defined as homogeneous if every sample of the mixture has the same composition and properties as any other. The phenomena of particle segregation and agglomeration present a challenge in developing a reproducible blending process. For dry particle blending, the cohesive and adhesive forces acting between particles depend on molecular forces. Therefore, blending parameters such as blending speed and blending volume are just as important as carrier selection to achieve both homogeneity and uniformity of the composition.
In the state of art, the patent application numbered USRE38912E relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler. When the examples in the patent are examined, an excipient mixture is prepared with coarse lactose (about 30 portions) and fine lactose (about 30 portions), and this excipient mixture is divided into about 30 portions, one layer of excipient and one layer of the active substance are stacked on top of each other, it is understood that then they started the mixing process. The disadvantage here is; because the cohesive strengths of active agents are so high, they can tend to compress under a load and form hard agglomerates. Especially, active agents can be pressed more because the lower part of the layers will have more pressure than the upper parts. This is an important issue to not provide the powder from mixing homogeneously.
On the other hand, this document does not include any mention of a process that minimizes the load on active ingredients.
It can be seen that the prior art has not put enough emphasis on alternative solutions for this problem. Thus, there is still a need for innovative processes that will solve the homogeneity problem, and which will provide a standardized method for the fast production of stable inhalation compositions with enhanced FPF.
Objects and Brief Description of the Invention
The main object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.
Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation with increased stability, enhanced fine particle dose (FPD) and fine particle fraction (FPF).
Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation with enhanced uniformity and homogeneity.
Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which decreases the required blending duration to provide a homogeneous composition and the risk of caking accordingly.
Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation which eliminates the requirement of using a sieving, saves time and provides a one-pot manufacturing accordingly.
Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation in which the active agent(s) minimizes the load on active agents. Another object of the present invention is to obtain dry powder inhalation compositions provided by the above-mentioned process comprising at least two active agent selected from the group comprising long-acting beta2-adrenergic agonists (LABAs), short acting beta-2 agonists (SABA), long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids.
A further object of the present invention is to obtain dry powder inhalation compositions comprising combinations of ultra long-acting p2 agonists and corticosteroids.
Another object of the present invention is to obtain inhalation compositions comprising combinations of vilanterol or a pharmaceutically acceptable salt thereof and fluticasone or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring content uniformity and dosage accuracy in each blister or capsule.
Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring that effective doses of active agents reach the alveoli.
A further object of the present invention is to obtain inhalation compositions which can be administered in blister pack or in capsule using an inhaler.
A further object of the present invention is to obtain a blister pack filled with the above- mentioned dry powder inhalation combinations.
A further object of the present invention is to obtain a capsule filled with the above-mentioned dry powder inhalation combinations.
A further object of the present invention is to obtain an inhaler which is applicable with the above-mentioned blister pack or the above-mentioned capsule. Detailed Description of Invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
The invention is related to a process by which is obtain a homogeneous mixture without accumulating load on the active substances.
Cohesive forces of active substances are very high. Therefore, they can tend to get stuck under a load and form hard agglomerates. In particular, the active ingredients can be pressed more, since the lower part of the layers will have more pressure than the upper parts. In this case, it is difficult to obtain a homogeneous mixture as the mixture cannot be mixing easily. Inventors have been developed a novel process for preparing dry powder compositions for inhalation in which the active agent(s) minimizes the load on active agents.
There are two separate mixing vessels in the mentioned process. The first of these mixing vessels which is mixing vessel-1 has a small volume. Mixing vessel-1 has preferably the volume of 2 litre. After plastering the inner wall of the mixing vessel-1 with the first carrier for at least 3 minutes; first active agent, second carrier, second active agent, and first carrier are added to the mixing vessel-1 and layers are created. The number of layers created in mixing vessel-1 is < 5. The purpose of having 5 or less than 5 layers here is to ensure that no charge accumulates on the active agents. The active agents and carriers added to the mixing vessel-1 are pre-mixed for at least 5 minutes. The obtaining mixture is transferred to the mixing vessel-2. Mixing vessel-2 has large volume and has preferably the volume of 60 litre. The mixtures created by repeating the processes in the mixing vessel-1 are transferred to the mixing vessel-2 separately. A-number of mixes are obtained in the mixing vessel-2. A is an integer and 2<A. The mixture obtained in the end of the processes are mixed with a suitable mixer. If the low shear mixer is selected, the duration of mixing is at least 60 minutes. If the high shear mixer is selected, the duration of mixing is at least 10 minutes.
The process in accordance with the present invention is used for the preparation of the dry powder formulation comprising at least two active agents and a pharmaceutically acceptable carrier.
A process for preparing dry powder inhalation compositions, comprising the following steps: i. plastering the inner wall of the mixing vessel-1 with the first carrier ii. adding first active agent, second carrier second active agent, and first carrier to the mixing vessel-1 and mixing the composition with the mixer iii. obtaining A-number of mixtures by repeating the processes in the step number (i) and (ii). iv. transferring A-number of mixtures to the mixing vessel-2 separately. v. mixing A-number of mixtures with the mixer wherein said A is an integer and 2<A.
As explained above, performing two separate processes in two separate mixing vessels is one of the most important aspects of the invention. Surprisingly, it has been found that the mixture formed is more homogeneous and stable product with low variation at the end of the process by after a pre-mixing process and then mixing it again in a separate mixing vessel.
According to the preferred embodiment, the said mixer in the step number (ii) and (v) are selected from low shear mixer or high shear mixer. If the high shear mixer is selected, the rotational speed of the high shear mixer in the step numbered (ii) and (v) are 75-1000 rpm, preferably 100-800 rpm, more preferably 200-600 rpm. If the low shear mixer is selected, the rotational speed of the low shear mixer in the step numbered (ii) and (v) are 10-75 rpm, preferably 15-45 rpm, more preferably 20-40 rpm.
According to the preferred embodiment, duration of the step number (i) is at least 1 minutes, preferably at least 3 minutes.
According to the preferred embodiment, duration of the step number (ii) is at least 3 minutes, preferably at least 5 minutes.
According to the preferred embodiment, if the low shear mixer is selected, duration of the step number (v) is at least 30 minutes, preferably at least 60 minutes.
According to the preferred embodiment, if the high shear mixer is selected, duration of the step number (v) is at least 5 minutes, preferably at least 10 minutes.
According to the preferred embodiment, 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, long-acting muscarinic antagonists (LAMAs) and non-selective dopamine agonist 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, the second active agent is selected from a group comprising corticosteroid or pharmaceutically acceptable salt thereof in combination.
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 ultra long-acting p2 agonists is vilanterol. According to this preferred embodiment, said vilanterol salt is vilanterol trifenatate.
According to the preferred embodiment, said corticosteroids is fluticasone. According to this preferred embodiment, said fluticasone salt is fluticasone furoate. The active substance has to be diluted with suitable carriers to prepare dry powder formulation for inhalation. Carrier particles are used to improve active substance flowability, thus improving dosing accuracy, minimizing the dose variability compared with active substance alone and making them easier to handle during manufacturing operations. Additionally, with the use of carrier particles, active substance particles are emitted from the medicament compartments (capsule, blister, etc.) more readily, hence, complete discharge of the medicament compartments by the inspiratory air during inhalation can be achieved and the inhalation efficiency in terms of emitted dose and fine particle fraction (FPF) increases.
According to the preferred embodiment, the said carriers comprises fine carrier particles and coarse carrier particles. Said carriers are selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. Most preferably, said excipients are lactose having fine particle and lactose having coarse particle.
According to the preferred embodiment, a coarse carrier particle, such as lactose monohydrate, is applied to de-agglomerate the drug particles and optimize the deposition of the drug in the lung. The particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention. Lactose comprises lactose having coarse particle size and lactose having fine particle size. Lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35- 100 pm.
According to the preferred embodiment, lactose having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm.
According to one embodiment, the choice of carrier is essential in ensuring that the device works correctly and delivers the right amount of active to the patient. Therefore, to use lactose as a carrier in two different particle sizes (fine and coarse) is essential.
Particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention. As used herein, ‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).
Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.
According to this measuring method, the D50 value is the size in microns that splits the distribution with half above and half below this diameter.
In the preferred embodiment of the invention, said lactose monohydrate is present in the composition in two parts. One of these parts is lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0. QI- 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, fluidity, content uniformity and dosage accuracy.
According to one embodiment, the pharmaceutical compositions subjected to the invention are prepared by these steps: i. plastering the inner wall of the mixing vessel-1 with lactose having coarse particle ii. adding vilanterol, lactose having fine particle fluticasone, and lactose having coarse particle to the mixing vessel-1 and mixing the composition with the mixer iii. obtaining A-number of mixtures by repeating the processes in the step number (i) and (ii). iv. transferring A-number of mixtures to the mixing vessel-2 separately. v. mixing A-number of mixtures with the mixer wherein said A is an integer and 2<A.
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 combinations of ultra long-acting p2 agonists and corticosteroids.
According to a preferred embodiment, the dry powder composition comprises combinations of vilanterol or a pharmaceutically acceptable salt thereof and fluticasone or a pharmaceutically acceptable salt thereof.
According to one embodiment, the amount of vilanterol trifenatate is between 0.10-0.50%, preferably 0.20-0.40%, more preferably 0.25-0.35% by weight of the total composition.
According to one embodiment, the amount of fluticasone is between 0.50-2.00 %, preferably 0.60-1.90%, more preferably 0.70-1 .80% by weight of the total composition.
According to one embodiment, the amount of total lactose is between 97.50-99.40%, preferably 97.70-99.20%, more preferably 97.85-99.05% 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 step (iii) is between 0-20%, preferably 0.5-8%, more preferably 1-6% by weight of the total composition.
According to one preferred embodiment, process for the dry powder composition subjected to the invention comprises;
0.10-0.50% by weight of vilanterol trifenatate
0.50-2.00 % by weight of fluticasone furoate - 0-20% by weight of lactose monohydrate having fine particle size
- 97.50-99.40% by weight of lactose monohydrate
According to all these embodiments, the below given formulations can be used a process for preparing dry powder inhalation compositions subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure. Example 1 : Dry powder composition for inhalation
Figure imgf000014_0001
Example 2: Dry powder composition for inhalation
Figure imgf000014_0002
Example 3: Dry powder composition for inhalation
Figure imgf000014_0003
According to a preferred embodiment, dry powder composition subjected to the invention is used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases. In an embodiment of the invention, the dry powder composition is administered once a day by the said inhaler.
In another embodiment of the invention, the dry powder composition is administered twice a day by the said inhaler.

Claims

1. A process for preparing dry powder inhalation compositions, comprising the following steps:
1. plastering the inner wall of the mixing vessel-1 with the first carrier ii. adding first active agent, second carrier second active agent, and first carrier to the mixing vessel-1 and mixing the composition with the mixer iii. obtaining A-number of mixtures by repeating the processes in the step number (i) and (ii). iv. transferring A-number of mixtures to the mixing vessel-2 separately. v. mixing A-number of mixtures with the mixer wherein said A is an integer and 2<A.
2. The process 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, long-acting muscarinic antagonists (LAMAs) and non- selective dopamine agonist or pharmaceutically acceptable salt thereof in combination.
3. The process according to claim 2, said short-acting p2 agonists (SABAs) is selected from the group comprising bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.
4. The process according to claim 2, said long-acting p2 agonists (LABAs) is selected from the group comprising arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.
5. The process according to claim 2, said ultra long-acting p2 agonists is selected from the group comprising abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.
6. The process according to claim 2, said long-acting muscarinic antagonists (LAMAs) is selected from the group comprising aclidinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.
7. The process according to claim 2 or claim 5, wherein said ultra long-acting p2 agonists is vilanterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof.
8. The process according to claim 1, wherein said the second active agent is selected from corticosteroid or pharmaceutically acceptable salt thereof in combination.
9. The process according to claim 8, 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 process according to claim 9, wherein said corticosteroid is fluticasone or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof.
11. The process according to claim 1, wherein said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol.
12. The process according to any one of the preceding claims, wherein said carrier are preferably lactose and more preferably lactose monohydrate.
13. The process according to any one of the preceding claims, wherein said lactose comprises lactose having coarse particle size and lactose having fine particle size.
14. The process according to any one of the preceding claims, wherein said lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 pm. 17
15. The process according to any one of the preceding claims, wherein lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm.
16. The process according to claim 1 , wherein said mixer in the step number (v) is low shear mixer (Turbula mixer) or high shear mixer.
17. The process according to claim 16, wherein said high shear mixer is with rotation speed from 75-1000 rpm, preferably 100-800 rpm, more preferably 200-600 rpm.
18. The process according to claim 16, wherein said low shear mixer is with rotation speed from 10-75 rpm, preferably 15-45 rpm, more preferably 20-40 rpm.
19. The process according to claim 1 , wherein duration of the step number (i) is at least 1 minutes, preferably 3 minutes.
20. The process according to claim 1 , wherein duration of the step number (ii) is at least 3 minutes, preferably 5 minutes.
21. The process according to claim 17, wherein duration of the step number (v) is at least 5 minutes, preferably 10 minutes.
22. The process according to claim 18, wherein duration of the step number (v) is at least 30 minutes, preferably 60 minutes.
PCT/TR2020/051467 2020-12-31 2020-12-31 A process for the preparation of dry powder compositions for inhalation WO2022146257A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110319371A1 (en) * 2009-02-26 2011-12-29 Glaxo Group Limited Pharmaceutical formulations comprising 4-hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
EP2957552A1 (en) * 2014-06-16 2015-12-23 Arven Ilac Sanayi Ve Ticaret A.S. Vilanterol formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110319371A1 (en) * 2009-02-26 2011-12-29 Glaxo Group Limited Pharmaceutical formulations comprising 4-hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
EP2957552A1 (en) * 2014-06-16 2015-12-23 Arven Ilac Sanayi Ve Ticaret A.S. Vilanterol formulations

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