NOVEL CARRIER PARTICLES FOR DRY POWDER INHALATION FORMULATIONS

Abstract

The present invention relates to carrier particles for dry powder formulations for inhalation and a process for preparing the same.

Description

NOVEL CARRIER PARTICLES FOR DRY POWDER INHALATION FORMULATIONS FIELD OF INVENTION The present invention relates to carrier particles for dry powder formulations for inhalation and to a process for preparing them. BACKGROUND OF THE INVENTION Drug therapy using dry powder inhalation (DPI) has been used for many years to treat respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. Compared to oral medications, only relatively small doses are needed for effective therapy because first-pass metabolism is significantly reduced. These small doses minimize the body's exposure to the drug and reduce side effects. Systemic adverse effects are also reduced because topical pulmonary delivery carries the drug directly to the site of action. Lower dosage regimens can also provide considerable cost savings, particularly with expensive therapeutic agents. Dry powder forms are typically formulated to Ref. 332318 mix the drug in micronized form with coarse carrier particles, resulting in an ordered mixture where the micronized active particles adhere to the surface of the carrier particles while in the inhaler device. The carrier makes the micronized powder less cohesive and improves its flowability, making it easier to handle the powder during the manufacturing process (pouring, filling, etc.). During inhalation, drug particles detach from the surface of carrier particles and penetrate the lower part of the lungs, while larger carrier particles are deposited mainly in the oropharyngeal cavity. The redispersion of drug particles from the carrier surface is considered the most crucial factor governing drug availability to the lungs. This depends on the mechanical stability of the powder mixture and how this stability is influenced by the adhesion characteristics between the drug and the carrier, as well as the external forces required to break the non-covalent bonds formed between the adhering particles. Very strong bonds between the adhering particles can actually prevent the separation of the micronized drug particles from the surface of the carrier particles. Different approaches aimed at modulating adhesion have been proposed in the technique to promote the release of drug particles from carrier particles and, therefore, to increase the respirable fraction. For example, it has been suggested to add fine particles of an excipient and / or ternary agents with lubricating or non-stick properties. Examples of the approaches are reported in documents EP 663815, WO 96 / 02231, WO 96 / 23485, WO 00 / 33789, WO 01 / 78693 and US 2015 / 017248. An alternative method for formulating dry inhalation powders with improved flowability is to agglomerate micronized particles in a controlled manner to form spheres of relatively high density and compactability. This process is called spheronization, and when, prior to spheronization, the active ingredient is mixed with a plurality of fine particles of one or more excipients, the resulting product has also been referred to as soft pellets. Examples are reported in documents WO 95 / 24889, WO 98 / 31350, WO 98 / 31351 and WO 01 / 89491 and WO 01 / 89492. ! 7.W(\ / N77.(\7JW In documents WO 01 / 89491 and WO 01 / 89492, the possibility of adding a coarse carrier having an average particle size greater than 25 micrometers is generically considered. However, soft pellets can achieve such a high level of internal coherence that it compromises their breakup into small particles during inhalation; this disadvantage could be considered a crucial step when using medium-high or high strength dry powder inhalers. With inhalers, less available energy is needed to break the pellets into small primary particles of the active ingredient. Furthermore, ternary agents are inhaled by patients and therefore add a regulatory burden when seeking product approval. Therefore, it would be advantageous to provide a platform technology for the administration of active ingredients in powder form by means of inhalation with improved aerosol yields without the use of ternary agents. BRIEF DESCRIPTION OF THE INVENTION The invention relates to a dry powder formulation for administration by means of a dry powder inhaler (DPI) comprising: a fraction of spheronized particles having a bulk diameter between 100 and 800 micrometers comprising micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient in an appropriate weight ratio; ) a coarse particle fraction comprising a physiologically acceptable excipient having a bulk diameter between 150 and 400 micrometers, wherein the ratio between fraction a) and fraction b) is between 5:95 and 50:50 percent by weight. In a second aspect, the invention relates to a process for preparing the claimed formulation, the process comprising the following steps: i) prepare a fraction of micronized particles of the active ingredient and the physiologically acceptable excipient; ii) optionally condition the resulting mixture; iii) subject the mixture to agglomeration and spheronization to obtain the spheronized particles; iv) optionally sieve to isolate the fraction that has the desired diameter; v) add the coarse particle fraction b); vi) combine the mixture obtained. In one embodiment, the fraction of step i) is prepared by mixing micronized particles of the active ingredient and 25 micronized particles of the physiologically acceptable excipient. In an alternative embodiment, the fraction of step i) is prepared by co-micronizing together the particles of the active ingredient and the particles of the physiologically acceptable excipient, then mixing. A fourth aspect relates to a dry powder formulation for administration by means of a dry powder inhaler (DPI) comprising: a) a fraction of spheronized particles having a bulk diameter between 100 and 800 micrometers comprising micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient in a suitable weight ratio; b) a coarse particle fraction comprising a physiologically acceptable excipient having a bulk diameter between 150 and 400 micrometers, wherein the ratio between fraction a) and fraction b) is between 5:95 and 50:50 percent by weight, the formulation can be obtained by a process comprising the following steps: i) prepare a fraction of micronized particles of the active ingredient and the physiologically acceptable excipient; ii) optionally condition the resulting mixture; iii) subject the mixture to agglomeration and spheronization to obtain spheronized particles; iv) optionally sieve to isolate the fraction that has the desired diameter; v) add the coarse particle fraction b) and vi) combine the resulting mixture. A fifth aspect relates to a dry powder formulation for administration by means of a dry powder inhaler (DPI) comprising: a) a fraction of spheronized particles having a bulk diameter between 100 and 800 micrometers comprising micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient in a suitable weight ratio; b) a coarse particle fraction comprising a physiologically acceptable excipient having a bulk diameter between 150 and 400 micrometers, wherein the ratio between fraction a) and fraction b) is between 5:95 and 50:50 percent by weight, the formulation being obtained by a process comprising the following steps: i) prepare a fraction of micronized particles of the active ingredient and the physiologically acceptable excipient; ii) optionally condition the resulting mixture; iii) subject the mixture to agglomeration and spheronization to obtain spheronized particles; iv) optionally sieve to isolate the fraction that has the desired diameter; v) add the coarse particle fraction b); and vi) combine the resulting mixture. In a sixth aspect, the invention relates to a dry powder inhaler filled with the claimed dry powder pharmaceutical formulation. In a seventh aspect, the invention relates to a package comprising a dry powder pharmaceutical formulation according to the invention and a dry powder inhaler. In an additional aspect, the invention relates to the formulation as described above for use as a medicament, preferably for the prevention and / or treatment of a respiratory disease, most preferably selected from asthma and COPD. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The terms mine and micrometers are used as synonyms. The term physiologically acceptable is understood to mean a pharmacologically inert, safe substance. The therapeutically effective daily dose refers to the amount of active ingredient administered by inhalation after the inhaler is activated. The daily dose can be delivered in one or more actuations (shots or inhalations) of the inhaler. The term fine particles refers to particles that are up to a few tenths of a millimeter in size. The term micronized refers to a substance that has a size of a few microns, typically between 1 and 15 microns. The term coarse refers to particles that are larger than 30 microns, typically from one to a few hundred microns. In general terms, the particle size of particles is quantified by measuring a characteristic equivalent sphere diameter, known as the volume diameter, by means of laser beam diffraction. Particle size can also be quantified by measuring the mass diameter using a suitable known instrument such as, for example, a sieve analyzer. The volume diameter (VD) is related to the mass diameter (MD) by the particle density (assuming a size-independent density for the particles). ) 7.W(\ / N77.(\7JW In this application, the particle size of the active ingredients is expressed in terms of diameter in volume, while that of the excipient is expressed in terms of diameter in mass. The particles have a normal (Gaussian) distribution which is defined in terms of the volume mean diameter (VMD or MMD) which corresponds to the volume mean diameter of 50 percent by weight of the particles and, optionally, in terms of the volume mean diameter of 10% and 90% of the particles, respectively. Another common approach to defining the particle size distribution is to use three values: i) the volume mean diameter d(v,0.5), which is the volume diameter where 50% of the distribution is above and 50% is below; ii) d(v,0.9), where 90% of the volume distribution is below this value; iii) d(v,0.1), where 10% of the volume distribution is below this value. The interval is the width of the distribution based on the 10%, 50%, and 90% quartiles and is calculated according to the formula. After aerosolization, particle size is expressed as mass aerodynamic diameter (MAD), and particle size distribution as mass median aerodynamic diameter (MMAD). MAD indicates the ability of particles to be carried suspended in an airstream. MMAD corresponds to the mass aerodynamic diameter of 50 percent of the particles by weight. As used in this document, the term spheronized refers to the term used in the field to indicate soft pellets as disclosed for example in document WO 98 / 31351. The term spheronization refers to a process for making spheronized particles and includes different processes such as mixing and vibration. This process is carried out before adding the coarse excipient particles. In stark contrast, in documents WO 01 / 78693 and WO 2013 / 110632, the term was used to describe the process of rounding the coarse excipient particles at the end of the final formulation preparation. Spheronized particles do not form during this process when the amount of fine particles is less than 20% by weight of the final formulation. The term loading capacity refers to the ability of coarse excipient particles to have space on their surface for a certain amount of fine particles of either the excipient and / or the active ingredient. In the context of the present invention, it refers to the ability of coarse excipient particles to have space, without powder segregation, for a quantity of spheronized particles higher than 20% but lower than 60%, preferably approximately 30-40%. The term good flowability refers to a formulation that is easily handled during the manufacturing process and can ensure an accurate and reproducible delivery of the therapeutically effective dose. Flow characteristics can be evaluated by means of different tests such as angle of repose, Carr index, Hausner ratio or flow rate through an orifice. In the context of this application, the flow properties were tested by measuring the flow rate through an orifice according to the method described in the European Pharmacopoeia (Eur. Ph.) 7.3, 7th Edition or by means of the angle of repose according to the United States Pharmacopeia, 1174. The expression "good homogeneity" refers to a formulation where, after mixing, the uniformity of distribution of the active ingredient, expressed as the coefficient of variation (CV), also known as the relative standard deviation (RSD), is less than 2.5%, preferably equal to or less than 1.5%. The term "physically stable in the device before use" refers to a formulation in which the active particles do not segregate and / or substantially separate from the surface of the carrier particles, both during the manufacture of the dry powder and in the dispensing device before use. The tendency to segregate can be assessed according to Staniforth et al. J. Pharm. Pharmacol. 34,700-706, 1982 and is considered acceptable if the distribution of the active ingredient in the powder formulation after testing, expressed as relative standard deviation (RSD), does not change significantly from that of the formulation before testing. The expression respirable fraction refers to an index of the percentage of active particles that would reach the deep part of the lungs in a patient. The respirable fraction, also called the fine particulate fraction (FPF), is assessed by means of a suitable in vitro apparatus such as the Andersen Cascade Impactor (ACI), Multi-Stage Liquid Impactor (MLSI) or Next Generation Impactor (NGI), preferably by means of AGI, according to procedures reported in common Pharmacopoeias, in particular the European Pharmacopoeia (Eur. Ph.) 7.3, 7th Edition. It is calculated by means of the percentage relationship between the mass of fine particles (formerly fine particle dose) and the dose supplied. The delivered dose is calculated from the cumulative deposition in the device, while the mass of fine particles is calculated from the deposition of particles that have a diameter < 5.0 microns. The term prevention means an approach to reducing the risk of the onset of a disease. The term treatment means an approach to achieving beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, the relief or improvement of one or more symptoms or conditions, a decrease in the severity of the disease, a stable (i.e., non-worsening) state of the disease, prevention of disease spread, a delay or slowing of disease progression, improvement or palliation of the disease state, or remission (whether partial or complete), whether detectable or undetectable. The term may also mean the prolongation of survival compared to the expected survival without treatment. ! 7.W(\ / N77.(\7JW The term therapeutically amount means the amount of active ingredient that, when delivered to the lungs via a dry powder formulation as described herein, provides the desired biological effect. The term surface coating refers to the covering of the surface of the excipient particles by forming a thin film of ternary agent around the particles. The term dry powder inhaler (DPI) refers to a device that delivers medication to the lungs in the form of a dry powder. DPIs can be divided into two basic types: i) single-dose inhalers, for the administration of pre-subdivided individual doses of the active compound; ii) multiple-dose dry powder inhalers (MDPIs), either with pre-subdivided individual doses or pre-filled with sufficient quantities of active ingredient for multiple doses; each dose is created by a measuring unit within the inhaler. Based on the required inspiratory flow rates (L / min), which in turn are strictly dependent on their design and mechanical elements, DPIs are also divided into: i) low resistance devices (> 90 1 / min); ii) intermediate resistance devices (approximately 60-90 rpm); iii) intermediate-high resistance devices (approximately 50-60 rpm); iv) high resistance devices (less than 30 1 / min). The reported classification is generated with respect to the flow rates required to produce a pressure drop of 4 KPa (KiloPascals) according to the European Pharmacopoeia (Eur Ph). A high individual dose is understood to mean a dose equal to or higher than 1 mg. The invention relates to a dry powder formulation for use in a dry powder inhaler (DPI) comprising: a) a fraction of spheronized particles having a diameter of 100 to 800 micrometers comprising micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient in a suitable weight ratio; b) a coarse particle fraction consisting of a physiologically acceptable excipient having a mass diameter between 150 and 400 micrometers, in ! 7.W(\ / N77.(\7JW where the ratio between fraction a) and fraction b) is between 5:95 and 50:50 percent by weight. In fact, it has been discovered that if fine excipient particles are pre-spheronized together with active ingredient particles and then combined with coarse excipient particles, it is possible to achieve a high respirable fraction after administration by inhalation, thus avoiding the use of ternary agents. Spheronized particles with a selected diameter allow for good uniformity of distribution of the active ingredient(s) as well as minimal variation in drug dosage, or in other words, adequate accuracy of the delivered doses. The rounded shape of the spheronized particles also improves the flowability of the powder formulation, as defined in detail in this document. In fact, formulations comprising pre-spheronized particles according to the invention exhibit better flow properties than corresponding formulations comprising non-spheronized fine particles. Dilution of spheronized particles with a coarse carrier made of particles that are resistant to shear stress and compaction, allows division into capsules or DPI devices by means of, for example, a filling technology usually suitable for a carrier-based powder formulation and not suitable for pure soft pellets. The particles also proved particularly well-suited to the cup size of depot-based multi-dose inhalers. Advantageously, the particles have been found to substantially reduce powder loss during loading into the metering chamber. The desired particle size can be obtained by sieving according to known methods. Additionally, another advantage of the invention is that the presence of coarse excipient particles, with a well-defined, selected particle size, favors the disintegration of the spheronized particles into small particles during inhalation, making the technology of the invention particularly useful for the administration of active ingredients with intermediate-high or high strength dry powder inhalers. By exposing the platform technology of the invention, i.e., by combining the spheronized particles and coarse particles in the claimed ratios, it is also possible to achieve good powder flowability and adequate physical stability in the device prior to use. Advantageously, the micronized and coarse excipient particles can be made of any physiologically acceptable material or a combination thereof; suitable for use by inhalation, so that the preparation of the present formulation results in a convenient and versatile process. For example, the particles may be made up of one or more materials selected from polyols, for example, sorbitol, mannitol and xylitol, and crystalline sugars, including monosaccharides and disaccharides; inorganic salts such as sodium chloride and calcium carbonate; organic salts such as sodium lactate; and other organic compounds such as urea, polysaccharides, for example, starch and its derivatives; oligosaccharides, for example, cyclodextrins and dextrins. Preferably, the particles are made of a crystalline sugar, even more preferably selected from: a monosaccharide such as glucose or arabinose or a disaccharide such as maltose, sucrose, dextrose or lactose. Preferably, the particles are made of lactose, more preferably of alpha-lactose monohydrate since the excipient is chemically and physically stable after storage and easy to handle. Advantageously, the spheronized particles have a bulk diameter between 100 and 800 micrometers. More advantageously, their diameter is between 200 and 800 micrometers, preferably between 300 and 700 micrometers. It has been found, in fact, that particles having a starting diameter of 200 micrometers possess particularly desirable flow properties. In a particular preferred embodiment of the invention, the spheronized particles have a bulk diameter between 200 and 350 micrometers. In one embodiment, the micronized particles of both the excipient and the active ingredient have a mass mean diameter equal to or less than 15 micrometers, preferably equal to or less than 10 micrometers, more preferably from 1 to 6 micrometers. This latter particle size is particularly suitable for active ingredients that are useful for the prevention and / or treatment of a respiratory disease. In one particular embodiment, at least 90% of the particles of both the excipient and the active ingredient have a diameter less than 6 µm, and more preferably less than 5 µm. More preferably, they could have a mean median diameter of 2–4 µm. According to the present invention, one or more active ingredients are present in the spheronized particles in a total percentage between 0.5 and 100% by weight, the remaining portion being fine excipient particles and optionally additive particles. In some embodiments, the percentage of one or more active ingredients is between 1.0 and 99.5%, preferably between 2.0 and 95%, while in other embodiments, the percentage is between 10 and 90% by weight or between 20 and 30% by weight. In one embodiment, the spheronized particles are made up of one or more active ingredients and fine particles of only one physiologically acceptable excipient. In one embodiment of the invention, the coarse carrier particles of fraction b) have a bulk diameter (MD) between 150 and 400 microns, with a medium bulk diameter (MMD) preferably greater than 175 microns, preferably an MD between 200 and 380 microns, and more preferably the MD may be between 210 and 355 microns. The desired particle size can be obtained by sieving according to known methods. When its MD is between 210 and 355 microns, the coarse carrier particles may have a relatively highly fissured surface, i.e., one in which there are cracks and valleys and other concave regions, collectively referred to in this document as fissures. As further explained, when using percentages of the active ingredient higher than 20%, the presence of the cracks allows the spheronized particles to form spontaneously during mixing. Additionally, although spheronized particles have better flow properties than fine particles, when using percentages of the active ingredient higher than 20%, the presence of fissures on the surface of the coarse excipient particles still allows for improvement in the flowability of the final formulation. Relatively highly cracked coarse particles could be defined in terms of crack index or roughness coefficient as described for example in documents WO 01 / 78695 and WO 01 / 78693, incorporated herein by reference and can be characterized according to the description reported therein. Coarse carrier particles can also be characterized in terms of compaction density or total intrusion volume as measured, as reported for example in document WO 01 / 78695. The compaction density of the coarse carrier particles is advantageously less than 0.8 g / cm3, preferably between 0.8 and 0.5 g / cm3. According to a preferred embodiment, to prevent their segregation from the dust, the spheroidized particles and the coarse carrier particles should have substantially similar bulk diameters. For example, if coarse carrier particles with a bulk diameter of 210–355 microns are used, the spheroidized particles should preferably have a bulk diameter between 200 and 350 microns. According to a preferred embodiment, fraction a) consists solely of micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient. In an additional embodiment, the formulation of the invention may also comprise a ternary agent. When present, the ternary agent is preferably included in the spheronized particles. The ternary agent can be an amino acid, preferably selected from the group consisting of leucine, isoleucine, lysine, valine, methionine, and phenylalanine. Alternatively, the ternary agent may include or consist of one or more water-soluble surfactant materials, e.g., lecithin. In certain embodiments, the ternary agent may include or consist of one or more lubricants selected from the group consisting of stearic acid and salts thereof such as magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate. Advantageously, the particles of the ternary agent have a mass median diameter equal to or less than 15 micrometers, equal to or less than 10 micrometers, more preferably from 1 to 6 micrometers. The optimal amount of additive material will depend on the chemical composition and other properties of the additive material. In general, the amount of additive should not exceed 10% by weight, based on the total weight of the formulation. However, it is thought that for most ternary agents, their quantity should not be greater than 5%, preferably no greater than 2% based on the total weight of the formulation. When magnesium stearate is used as the ternary agent, its amount is generally between 0.01 and 2%, advantageously between 0.02 and 1%, and more advantageously between 0.1% and 0.5% by weight based on the total weight of the formulation. Depending, for example, on its quantity and mixing time, magnesium stearate can coat the surface of the fine excipient particles in such a way that the degree of molecular surface coating is at least 5%, preferably more than 10%, more preferably more than 15%, and even more preferably equal to or greater than 25%. When using active ingredients with a relatively low dosage potency such as beta2 agonists, antimuscarinic drugs and corticosteroids, a quantity of magnesium stearate between 0.1% and 0.5% by weight is preferred, with a degree of molecular surface coating higher than 15%. The degree of molecular surface coating, which indicates the percentage of the total surface of the excipient particles coated by magnesium stearate, can be determined by measuring the water contact angle, as reported in the literature, for example, in document WO 2011 / 120779. In one embodiment, the ratio between fraction a) and fraction b) is between 5:99 and 50:50 percent by weight, more preferably between 10:90 and 30:70 percent by weight. In a further preferred embodiment, the ratio is between 10:90 and 15:85 percent by weight. In a particular embodiment, the ratio is 10:90 percent by weight. The ratio between fraction a) and fraction b) is preferably 10:90 when using active ingredients with a relatively low dosage potency such as beta2-agonists, antimuscarinic drugs and corticosteroids. In another aspect, the invention also relates to a process for preparing the formulation of the invention; the process comprises the following steps: i) prepare a fraction of micronized particles of the active ingredient and the physiologically acceptable excipient; ii) optionally condition the resulting mixture; ii) subject the mixture to agglomeration and spheronization to obtain the spheronized particles; iv) optionally sieving to isolate the fraction having a diameter between 100 and 800 micrometers; v) adding a fraction of coarse particles comprising a physiologically acceptable excipient having a bulk diameter between 150 and 400 micrometers; and vi) combining the resulting mixture. In one embodiment, the fraction of step i) is prepared by mixing micronized particles of the active ingredient and micronized particles of the physiologically acceptable excipient. The mixing can be carried out in any suitable mixer, such as the TurbulaMR mixer, for an appropriate time until a homogeneous distribution is achieved. Typically, when using the TurbulaMR mixer, the mixing time may vary from 30 minutes to 2 hours, depending, for example, on the amount of the active ingredient and the excipient, and the experimental conditions. In an alternative embodiment, the fraction of step i) is prepared by co-micronizing together the particles of the active ingredient and the particles of the physiologically acceptable excipient, preferably by means of milling, then mixing. This would allow avoiding the usual problem encountered during the mixing of fine powders, namely the inability of mixers to disintegrate powder agglomerates, which requires an additional re-micronization step as disclosed for example in document WO 98 / 31350. The grinding could be carried out according to methods known in the field, for example, by using a ball mill or a jet mill for a sufficient time to achieve the desired particle size. In step ii), the particle fraction a) may optionally be subjected to a conditioning step, according to the conditions known in the field, as disclosed for example in document WO 2011 / 131663. The spheronization of step iii) can be carried out in accordance with methods reported in the field, for example, in documents WO 98 / 31351 or WO 95 / 24889 or alternative methods based on mixing and vibration. Typically, a commercially available vibrating screen, such as the AS 200MR vibrating screen from Retsch GmbH, Germany, could be used. A skilled person in the field will need to select the method for adjusting the processing time and other parameters to obtain the desired spheroidal particles. In fact, the vibration time and amplitude impact the overall particle quality and can be fine-tuned to adjust particle size, sphericity, and to minimize irregularities in shape. Typically, the time to achieve spherization is less than 5 minutes or even less. In a preferred embodiment of the invention, the spheronization of step iii) is carried out in a vibrating screen apparatus operating at a vibration frequency of 50 Hz, a vibration amplitude of 0.2-1.2 mm and a vibration time of 60-200 seconds. By adopting the parameters, it is possible to obtain spheronized particles with a diameter between 200 and 350 microns. The presence and complete formation of spheronized particles can be detected by microscopic analysis, for example, by scanning electron microscopy (SEM), using methods known to a skilled person. Any commercially available microscope can be used appropriately, for example, the JSM-F100 (Jeol Ltd, Tokyo, Japan). If necessary, the spheronized particles obtained are sieved according to methods known to the expert person to improve the target particle size. Step vi) which consists of mixing the coarse particles of excipient b) and the fine particles a) is typically carried out in a suitable mixer, e.g. drum mixers such as TurbulaMR (Willy A. Bachofen AG Switzerland), or other mixers for at least 30 minutes, preferably for no more than four hours, more preferably for three hours. In general, the person skilled in the technique should adjust the mixing time and the rotation speed of the mixer to obtain a homogeneous mixture, but to avoid the destruction of the spheronized particles. In a preferred embodiment of the invention, step vi) of mixing is carried out in a TurbulaMR mixer operating at a rotational speed of 72 rpm. It has actually been found that, if spheronized particles with a well-defined particle size are desired, operating at a lower speed tends to increase the size with the mixing time. In an alternative process, the spheronized particles are formed in situ during the mixing of all components for at least 3 hours, preferably four hours. It was discovered that when the percentage of the active ingredient is higher than 20%, preferably equal to or higher than 25%, and more preferably higher than 30% by weight of the formulation, and coarse fissured particles are used, spheronized particles form spontaneously during mixing. Therefore, in this case, the powder of the invention could be advantageously prepared by mixing together all the coarse excipient particles, the fine excipient particles, and the active ingredient(s). This will result in time savings and possibly increase the industrial feasibility of manufacturing the present formulation. In particular, this approach is less time-consuming than one that involves pre-preparing the spheronized particles. Furthermore, forming spheronized particles by direct mixing with a coarse carrier, as described herein, allows for better control and consistency of their size, thereby improving the reproducibility and reliability of the preparation process. As mentioned earlier, the resulting mixture can be optionally sieved. Sieving might be appropriate when a predetermined particle size needs to be used. The active ingredient can be any pharmaceutically active compound that can be administered by inhalation in dry powder form. By way of example, these may be selected from short-acting and long-acting beta2-agonists such as terbutaline, reproterol, salbutamol, salmeterol, formoterol, carmoterol, milveterol, abediterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambuterol, broxaterol, isoprenaline or hexoprenaline or stereoisomers, salts and / or solvate forms thereof; short-acting and long-acting antimuscarinic antagonists such as tiotropium, ipratropium, oxitropium, oxybutynin, aclidinium, trospium, glycopyrronium, in the form of salts and / or solvate forms thereof; short-acting and long-acting corticosteroids such as butixocart, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its ester, i.e. furoate, fluticasone and its ester, i.e. propionate and furoate, beclomethasone and its ester, i.e. propionate, loteprednol or triamcinolone acetonide and solvate forms thereof;leukotriene antagonists, such as andolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; phosphodiesterase inhibitors, such as filaminast, piclamilast or roflumilast; neutrophil elastase (HNE) inhibitors, such as those disclosed in WO 2013 / 037809 and WO 2014 / 095700; and phosphoinositide 3-kinase inhibitors, such as those disclosed in WO 2015 / 091685. To the extent that any of these compounds possess chiral centers, the compounds can be used in an optically pure form or can be presented as diastereomeric mixtures or racemic mixtures. The formulations comprising a long beta2-agonist, an anti-muscarinic antagonist and / or an inhalation corticosteroid, alone or in any combination thereof, constitute particular embodiments of the invention. Advantageously, the muscarinic antagonist is an aclidinium salt, preferably as a bromide salt, darifenacin, preferably a hydrobromide, a darotropium salt, preferably as a bromide, a fesoterodine salt, preferably as a fumarate, a glycopyrronium salt, preferably as a bromide, an oxitropium salt, preferably as a bromide, oxybutynin, preferably as a hydrochloride or hydrobromide, a salt of ! 7.W(\ / N77.(\7JW solifenacin, preferably as succinate, a salt of tiotropium, preferably as bromide, a salt of tolterodine, preferably as tartrate, a salt of trospium, preferably as chloride and a salt of umeclidinium, preferably as bromide. Glycopyrronium bromide in the form of the (3R,2R') enantiomer or a racemic mixture of (3S,2R') and (3R,2S') is more preferred, and tiotropium bromide, the racemic mixture of (3S,2R') and (3R,2S') of glycopyrronium bromide (hereinafter referred to as rac-glycopyrronium bromide) is even more preferred. The long-acting beta2-agonist, which may be present in a particular salt and / or solvate form, is preferably formoterol fumarate dihydrate, salmeterol xinafoate, milveterol hydrochloride, olodaterol hydrochloride, tulobuterol hydrochloride, and vilanterol trifenatate. Formoterol fumarate dihydrate is the most preferred. Inhaled corticosteroids, which may be present in a particular ester and / or solvate form, include, for example, beclomethasone dipropionate or its monohydrate form, fluticasone propionate, fluticasone furoate, ciclesonide, flunisolide or its hemihydrate form, mometasone furoate, and triamcinolone acetonide. Budesonide is preferred, and beclomethasone dipropionate is preferred even more. In one modality, formulations comprising the formoterol fumarate dihydrate form and its combinations with inhalation corticosteroids and / or muscarinic antagonists, particularly with beclometasone dipropionate and / or rac-glycopyrronium bromide, are preferred. In another embodiment of the invention, the dry powder formulation of the invention is useful for administering active ingredients that are delivered in individual doses by actuating the inhaler of 1 mg or higher, i.e., 2 mg, 5 mg or more, hereinafter referred to as high-dose active ingredients. It is known that powder formulations comprising high-dosage active ingredients such as antibiotics, for example Tobi PodiHalerMR, are currently on the market. Therefore, examples of high-dose active ingredients are antibiotics such as ciprofloxacin, levofloxacin and colistin, tobramycin, amikacin and gentamicin; proteins such as insulin and allantitrypsin; antiviral drugs such as zanamivir and ribavirin; antifungal agents such as itraconazole and phosphodiesterase (PDE)-5 inhibitors such as sildenafil and tadalafil. The concentration of the active ingredient in the powder formulation will depend on several aspects, such as the weight of the shot of the formulation delivered after the inhaler is activated. For example, considering an expected individual dose of 1 mg, if the actuation weight of the formulation delivered after pressing the inhaler is 10 mg, this would correspond to an active ingredient concentration of 10% w / w. Similarly, for an actuation weight of 5 mg, the active ingredient concentration would be 20% w / w, while for an actuation weight of 20 mg, the active ingredient concentration would be 5% w / w. Therefore, the formulation of the invention could be particularly useful for the administration of active ingredients that are present in a high concentration, for example, from 4 to 30%, preferably from 10 to 25% w / w. According to one aspect, the present invention relates to the formulation as described in detail herein for use as a medicament, more preferably for the treatment of respiratory diseases. In preferred embodiments, the respiratory diseases are selected from asthma and COPD. This formulation is also useful for the preparation of a drug for use in the treatment of respiratory diseases, preferably asthma and COPD. The dry powder inhalation formulation of the invention can be used with any dry powder inhaler currently known to the skilled person. In this respect, dry powder inhalers can generally be divided into: i) single-dose (unit-dose) inhalers, for the administration of individual subdivided doses of the active compound; ii) pre-measured multi-dose inhalers or depot inhalers pre-loaded with sufficient quantities of active ingredients for longer treatment cycles. Dry powder formulations can be presented in a unit dosage form. Dry powder compositions for topical delivery to the lungs by inhalation may be presented, for example, in capsules and cartridges of, for example, gelatin, or bubble-type packaging of, for example, thin sheet of laminated aluminum metal, for use in an inhaler or insufflator. The dry powder formulation for inhalation according to the invention is particularly suitable for multi-dose dry powder inhalers comprising a reservoir from which individual therapeutic doses can be withdrawn on demand by means of actuating the device. A preferred multi-dose device is the inhaler described in WO 2004 / 012801 and WO 2016 / 000983. Other multi-dose devices that can be used include, for example, the DISKUSMR from GlaxoSmithKline, TURBOHALERMR from AstraZeneca, TWISTHALERMR from Schering, EASYHALERMR from Orion, SPIROMAXMR and AIRMAXMR from Teva, and CLICKHALERMR from Innovata. Examples of commercially available single-dose devices include the ROTOHALERMR from GlaxoSmithKline, the HANDIHALERMR from Boehringer Ingelheim, and the RS01MR from Plastiape. The following examples illustrate the invention in detail. EXAMPLES Example 1 A powder formulation was prepared that had the unit composition, i.e., the composition per actuation of the inhaler, reported in Table 1. Approximately 300 g of micronized beclometasone dipropionate (BDP) and 100 g of micronized lactose monohydrate were mixed for 2 minutes in a vibrating sieve apparatus at a frequency of 50 Hz and an oscillation amplitude of 0.2 mm. The powder mixture was collected on the bottom plate after passing through a 100 µm cascade. The collected spheronized pellets were gently sieved through an 800 µm sieve. The resulting spheronized particles were mixed with approximately 600 g of coarse cracked alpha-lactose monohydrate particles having a mass diameter between 212-355 microns, to obtain a ratio of 40:60 percent by weight. The mixing was carried out in a TurbulaMR mixer for 2 hours at 2-3 rpm. Table 1 Components Amounts Per Inhaler Actuation Single Dose mg % mg Spheronized particles 4 40 beclomethasone dipropionate 3 3000 alpha-lactose monohydrate 1 Alpha-lactose monohydrate 212-355 pm 6 60 Total weight 10 100 The formulation was poured into the multi-dose dry powder inhaler (DPI) described in WO 2016 / 000983. The evaluation of aerosol yields was carried out using a Proxima Impactor Generation (NGI) according to the conditions reported in the European Pharmacopoeia 8.5aEd 2015, paragraph 2.9.18, pages 309-320. After aerosolization of 3 doses from the inhaler device, the NGI apparatus was disassembled and the amounts of drug deposited in the stages were recovered by washing with a mixture of water:acetonitrile 50:50 v / v and then quantified by High Performance Liquid Chromatography (HPLC). The following parameters were calculated: i) the delivered dose, which is the amount of drug delivered from the device recovered in all parts of the impactor; i) the mass of fine particles (FPM), which is the amount of delivered dose that has a particle size equal to or lower than 5.0 microns; iii) the fraction of fine particles (FPF), which is the ratio between the mass of fine particles and the delivered dose; iv) the MMAD. The results (mean value ± SD) are reported in Table 2. Table 2 / 7Wt\ñl77f\7IVrY BDP (active ingredient) Delivered Dose [pg] 2.16 Mass of Fine Particles [pg] 0.87 Fraction of Fine Particles [%] 38.5 MMAD [pm] 2.26 As can be seen, an FPF of almost 40% was achieved. Based on additional data collected by the applicant, it has been found that similar results are obtained if the total weight per actuation of the inhaler is 20 mg. In the prior art, for example, in WO 01 / 78693, powder formulations comprising a carrier consisting of only coarse excipient particles and fine excipient particles not in the form of soft pellets, as disclosed in Example 5, resulted in lower aerosol yields, with an FPF rarely higher than 20%. In stark contrast, the formulation prepared according to the teaching of the present invention surprisingly yields good aerosol performance, and in particular, an FPF of almost 40% is achieved. Example 2 A powder formulation can be prepared that has the unit composition, i.e., the composition per actuation of the inhaler, reported in Table 3. Appropriate amounts of micronized formoterol fumarate dihydrate (approximately 0.3 g), micronized beclometasone dipropionate (approximately 5 g), and micronized lactose monohydrate (approximately 144.7 g) are combined in a TurbulaMR mixer to give the ratio within the spheronized particles reported in Table 3. The mixture is subjected to conditioning at a temperature of 22 ± 1°C and 75% relative humidity for one hour, then it is spheronized to agglomerates at room temperature at a controlled relative humidity of less than 50%. The resulting spheronized particles are sieved to isolate the fraction having a mass diameter between 200 and 800 microns, then mixed with approximately 350 g of coarse cracked alpha-lactose monohydrate particles having a mass diameter between 212-355 microns, in a ratio of 30:70 percent by weight. Table 3 Components Amounts Per Inhaler Actuation Single Dose mg % g Spheronized particles 3 30 Formate fumarate dihydrate 0.006 6 Beclomethasone dipropionate 0.100 100 Alpha-lactose monohydrate 2.894 Alpha-lactose monohydrate 212-355 pm 7 70 Total weight 10 100 The formulation is poured into the multi-dose dry powder inhaler described in document WO 2016 / 000983. Example 3 Analogously to Example 2, another powder formulation can be prepared that has the unit composition, i.e., the composition per actuation of the inhaler, reported in Table 4. Appropriate amounts of micronized formoterol fumarate dihydrate (approximately 0.1 g), micronized beclometasone dipropionate (approximately 1.67 g), micronized glycopyrronium bromide (0.21 g), and micronized lactose monohydrate (approximately 48.02 g) are combined in a TurbulaMR mixer to provide the ratio within the spheronized particles reported in Table 4. The mixture is subjected to conditioning at a temperature of 22 ± 1°C and 75% relative humidity for one hour, then it is spheronized to agglomerates at room temperature at a controlled relative humidity of less than 50%. The resulting spheronized particles are sieved to isolate the fraction having a diameter between 200 and 800 microns, then mixed with approximately 450 g of coarse cracked alpha-lactose monohydrate particles having a mass diameter between 212-355 microns, in a ratio of 10:90 percent by weight. Table 4 Components Amounts Per Inhaler Actuation Single Dose mg % mg Spheronized particles 3 30 Formoterol fumarate dihydrate 0.006 6 Beclomethasone dipropionate 0.100 100 Glycopyrronium bromide 0.0125 12.5 Alpha-lactose monohydrate 2.8815 Alpha-lactose monohydrate 212-355 pm 7 70 Total weight 10 100 The formulation is poured into the multi-dose dry powder inhaler described in document WO 2016 / 000983. Example 4 Another powder formulation was prepared by using the Human Neutrophilic Elastase (HNE) inhibitor disclosed in WO 2014 / 095700 as an active ingredient and hereafter referred to as CHE 6333. Approximately 800 g of micronized material as CHF 6333 was added to approximately 3.2 kg of a carrier prepared according to WO 01 / 78693. The combination was mixed for 3 hours in a TurbulaMR mixer and sieved through a 600 pm sieve. The resulting mixture contains a formulation according to the invention having the unit composition reported in Table 5. The presence and complete formation of spheronized particles were detected by scanning electron microscopy. Table 5 Components Amounts Per Inhaler Actuation Single Dose mg % Mg Spheronized particles 5.6 28 CHF 6333 micronized 4 2000 Magnesium stearate 0.032 Micronized alpha-lactose monohydrate 1.568 Alpha-lactose monohydrate 212-355 pm 14.4 72 Total weight 20 100 The formulation was poured into the multi-dose dry powder inhaler described in WO document 2016 / 000983 or in the RS01MR single-dose dry powder inhaler from Plastiape SpA (Italy). The evaluation of aerosol yields was performed as reported in Example 1. The results (mean ± SD) are reported in Table 6. Table 6 CHF 6333 Multi-Dose DPI Single-Dose DPI Delivered Dose [pg] 1.92 1.53 Fine Particle Mass [pg] 0.80 1.18 Fine Particle Fraction [%] 41.7 77.1 MMAD [pm] 2.09 1.88 As can be seen, good performance is achieved in terms of FPF, particularly with a single-dose DPI. Based on additional data collected by the applicant, it has been found that similar results are obtained if the total weight per actuation of the inhaler is 20 mg. Example 5 Two analogous formulations comprising CHF 6333 as the active ingredient were prepared as reported in Example 4, but for the delivery of single doses of 1 mg and 4 mg. The formulations were poured into the RS01MR single-dose dry powder inhaler from Plastiape SpA (Italy). The evaluation of aerosol yields was performed as reported in Example 1. The results (mean ± SD) are reported in Table 7. ! 7.W(\ / N77.(\7JW Table 7 CHF 6333 1 mg 4 mg Delivered Dose [pg] 0.81 2.88 Mass of Fine Particles [pg] 0.58 2.13 Fraction of Fine Particles [%] 71.6 73.9 MMAD [pm] 2.16 1.85 Example 6 An additional powder formulation was prepared that had the unit composition reported in Table 1, but with spheronized particles having a bulk diameter between 200 and 350 microns. Approximately 300 g of micronized beclometasone dipropionate (BDP) and 100 g of micronized lactose monohydrate were pre-mixed for 2 minutes. The mixture was then poured into an AS 200MR vibrating screen apparatus from Retsch GmbH, Germany. The system of two sieves and a collection plate was prepared on the vibrating pad. The top sieve (size > 350 pm) is supposed to break up any large agglomeration or large-scale heterogeneity that is initially present in the powder sample. The lower sieve (350 µm > size > 250 µm) establishes the desired spheroidal particle characteristics. The bottom collection plate contains the spheroidal material. The micronized powder was poured onto the top plate and the vibrating systems were activated to operate at a vibration frequency of 50 Hz, a vibration amplitude of 0.2-1.2 mm and a vibration time of 60-200 seconds. The resulting spheronized particles were mixed with approximately 600 g of coarse cracked alpha-lactose monohydrate particles having a mass diameter between 212-355 microns, to obtain a ratio of 40:60 percent by weight. The mixing was carried out in a TurbulaMR mixer for 3 hours at 7.5 rpm. The formulation was poured into the multi-dose dry powder inhaler (DPI) described in WO 2016 / 000983. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

Having described the invention as above, the following claims are claimed as property:

1. A dry powder formulation for administration by means of a dry powder inhaler (DPI), characterized in that it comprises: a) a spheronized particle fraction having a bulk diameter between 100 and 800 micrometers comprising micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient in a suitable weight ratio; b) a coarse particle fraction comprising a physiologically acceptable excipient having a bulk diameter between 150 and 400 micrometers; wherein the ratio between fraction a) and fraction b) is between 5:95 and 50:50 percent by weight.

2. The dry powder formulation according to claim 1, characterized in that the spheronized particles have a bulk diameter between 200 and 800 micrometers.

3. The dry powder formulation according to claim 1 or 2, characterized in that the spheronized particles of fraction a) consist solely of micronized particles of one or more active ingredients and micronized particles of a physiologically acceptable excipient.

4. The dry powder formulation according to any of claims 1 to 3, characterized in that the ratio between fraction a) and fraction b) is between 10:90 and 30:70 percent by weight.

5. The dry powder formulation according to any of claims 1 to 4, characterized in that one or more active ingredients are present in the spheronized particles a) in a total percentage between 0.5 and 100% by weight.

6. The dry powder formulation according to claim 5, characterized in that the percentage of one or more active ingredients is between 1.0 and 99.5% by weight.

7. The dry powder formulation according to any of the preceding claims, characterized in that the physiologically acceptable excipient is alpha-lactose monohydrate.

8. The dry powder formulation according to any of the preceding claims, characterized in that the bulk diameter of the coarse particles of fraction b) is between 210 and 355 50 micrometers.

9. The dry powder formulation according to any of the preceding claims, characterized in that the bulk diameter of the spheronized particles of fraction a) is between 200 and 350 micrometers and the bulk diameter of the coarse particles of fraction b) is between 210 and 355 micrometers.

10. The dry powder formulation according to any one of claims 1 to 9, characterized in that the active ingredient is selected from the group consisting of beta2-agonists and / or anti-muscarinics and / or inhaled corticosteroids.

11. The dry powder formulation according to claim 10, characterized in that the beta2 agonist is formoterol fumarate dihydrate.

12. The dry powder formulation according to claim 10, characterized in that the inhalation corticosteroid is beclomethasone dipropionate (BDP).

13. The dry powder formulation according to claim 10, characterized in that the muscarinic antagonist is glycopyrronium bromide.

14. The dry powder formulation according to claim 10, characterized in that the 51 active ingredients are a combination of formoterol fumarate dihydrate, beclometasone dipropionate, and glycopyrronium bromide.

15. A process for preparing the powder formulation according to claim 1, characterized in that it comprises the steps of: (i) preparing a fraction of micronized particles of the active ingredient and the physiologically acceptable excipient; (ii) optionally conditioning the resulting mixture; (iii) subjecting the mixture to agglomeration and spheronization to obtain the spheronized particles; (iv) optionally sieving to isolate the fraction having the desired diameter; (v) adding the coarse particle fraction (b); (vi) combining the resulting mixture.

16. The process according to claim 15, characterized in that the fraction of step i) is prepared by mixing micronized particles of the active ingredient and micronized particles of the physiologically acceptable excipient.

17. The process according to claim 15, characterized in that the fraction of step i) is prepared by co-micronizing the particles of the active ingredient and the particles of the physiologically acceptable excipient, then mixing.

18. A dry powder inhaler, characterized in that it is filled with the dry powder pharmaceutical formulation in accordance with any of claims 1 to 14.