Dry powder formulations for inhalation in form of soft pellets

Abstract

The present invention relates to a dry powder formulation for inhalation in form of soft pellets and to a process for its preparation. The present invention also relates a dry powder formulation for inhalation in form of soft pellets for the treatment of respiratory diseases and to the use of the formulation in the manufacture of a medicament for the treatment of a respiratory disease.

Description

[0001] DRY POWDER FORMULATIONS FOR INHALATION IN FORM OF SOFT PELLETS

[0002] TECHNICAL FIELD

[0003] The present invention relates to a dry powder formulation for inhalation in form of soft pellets and to a process for its preparation. The present invention also relates a dry powder formulation for inhalation in form of soft pellets for the treatment of respiratory diseases and to the use of the formulation in the manufacture of a medicament for the treatment of a respiratory disease.

[0004] BACKGROUND OF THE INVENTION

[0005] Drugs intended for the treatment of lung diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD) are currently administered through pulmonary delivery by suitable devices which relies on inhalation of an aerosol through the mouth and throat so that the drug substance can reach the whole respiratory tract.

[0006] Currently, there are several recommended classes of drugs for the management of asthma and COPD of which bronchodilators such as beta-2 -agonists, anticholinergics and inhaled corticosteroids as well combinations thereof are the most widely used.

[0007] Another class of therapeutic agents which are under investigation in view of its antiinflammatory effects for the treatment of inflammatory respiratory diseases such as asthma and COPD is represented by the inhibitors of the phosphodiesterase enzymes type 4 (hereinafter referred to as PDE4 inhibitors).

[0008] On the other hand, it is known that the density of the beta-adrenergic receptors is higher in the distal tract of the bronchioles (Bames P et al Am Rev Respir Dis 1983, 127, 758-762), a region which is better reached by smaller particles. Moreover, inflammation in asthma in not merely confined to the large central airways but also extends to small peripheral airways. The eosinophilic inflammation process which has been seen to be associated to asthma concerns both the bronchial and the alveolar districts (Wang S J Immunol 2001, 166, 2741-2749).

[0009] Martin R in J Allergy Clin Immunol 2002, 109 (Suppl 2), 447-460 reported that distal lung diseases appear to increase the risk of recurrent asthma exacerbation, while disease-related anatomic changes in the small airways of the distal lung are prominent in fatal asthma.

[0010] In view of the above, the administration of drug with particles of a diameter equal to or lesser than 2 micron (referred as “extrafine” particles) could be advantageous. The clinical significance of distal lung disease makes this region an important therapeutic target so particles able to reach and deposit into such region could better contribute to the management of the disease.

[0011] Further lung diseases could benefit from the administration of drugs as extrafine particles, for example chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), bronchiolitis and bronchiectasis.

[0012] Pressurized metered dose inhalers (pMDIs) are well known devices for administering pharmaceutical products to the respiratory tract by inhalation. The pMDI devices typically use a propellant to expel droplets containing the pharmaceutical products to the respiratory tract as anaerosol. Depending on the active ingredients and on additional components, a pMDI formulation may be in the form of a solution or a suspension.

[0013] When the formulation is in the form of suspension, the particle size of the cloud is dominated by the particle size of the suspended drug, defined by the milling / micronization process. On the contrary, when the formulation is in the form of solution, the volumetric contribution of suspended drug particles is absent and much finer liquid droplets clouds, are generated. Therefore, pMDI solution formulations are more adapted to generate extrafine particles, so they are more suitable for the managing of therapeutic lung diseases wherein the distal tract of the respiratory tract is significantly involved, hence improving small airways outcomes and associated control.

[0014] Dry powder inhalers (DPIs) are a valid alternative to MDIs for the administration of drugs to airways and lung. However, drugs intended for inhalation as dry powders should be used in the form of micronised particles: their volumetric contribution could hence represent an obstacle to design particles for extrafine administration.

[0015] To obviate to the poor flowability of the fine particles, dry powder forms are typically formulated by mixing the drug in micronised form with coarse carrier particles, giving rise to ordered mixture where the micronised active particles adhere to the surface of the carrier particles whilst in the inhaler device.

[0016] The carrier makes the micronised powder less cohesive and improves its flowability, making easier handling the powder during the manufacturing process (pouring, filling etc.).

[0017] During inhalation, the drug particles separate from the surface of carrier particles and penetrate the lower lungs, while the larger carrier particles are mostly deposited in the oropharyngeal cavity.

[0018] The re-dispersion of drug particles from the carrier surface is regarded as the most critical factor which governs the availability of the medicament to the lungs. This will depend on the mechanical stability of the powder mix and the way this is influenced by the adhesion characteristics between the drug and the carrier particles and the external forces required to break up the non-covalent bonds formed between adhering particles. Too strong bonds between adhering particles may prevent indeed the separation of the micronized drug particles from the surface of carrier particles.

[0019] Different approaches aimed at modulating the adhesion have been proposed in the art to promote the release of the drug particles from the carrier particles and, hence, to increase the respirable fraction.

[0020] For instance, it has been suggested to add fine particles of an excipient and / or ternary agents with lubricant or anti-adherent properties.

[0021] Examples of said approaches are reported in EP 663815 WO 96 / 02231, WO 96 / 23485, WO 00 / 33789, WO 01 / 78693, and US 2015 / 017248.

[0022] An alternative method to formulate dry powders for inhalation with improved flowability is to agglomerate, in a controlled manner, the micronised particles to form spheres of relatively high density and compactness. The process is termed spheronisation and when, before spheronisation, the active ingredient is mixed with a plurality of fine particles of one or more excipient, the resulting product has also beentermed as soft pellets.

[0023] Examples are reported in WO 95 / 24889, WO 98 / 31350, WO 98 / 31351, WO 01 / 89491 and WO 01 / 89492.

[0024] Soft pellet generally refers to the formation of agglomerates composed by fine particles of either active ingredient or active ingredient and excipients that are kept altogether by weak interparticulate forces. Instead, the term Hard Pellet is linked to the presence of coarse particles (e.g. lactose monohydrate) onto which fine particles are prone to adhere.

[0025] In WO 01 / 89491 and WO 01 / 89492, it is generically envisioned the possibility of adding coarse carrier particles having a mean particle size greater than 25 micrometers.

[0026] In WO 2021 / 058454 as well, formulations made of coarse carrier particles and soft pellets are disclosed.

[0027] However, soft pellets, made of active ingredient and excipients particles only, may reach a so high internal cohesion as to compromise their breaking up into the original small particles during inhalation: such drawback could be regarded as a critical step when medium-high or high-resistance dry powder inhalers are used. With said inhalers, lesser energy is indeed available for breaking up the pellets into the small primary particles of the active ingredient.

[0028] Therefore, it would be advantageous to provide a platform technology for the administration of active ingredients in form of powder formulations by inhalation with aerosol performances, in particular with good extrafine particle fraction.

[0029] On the other hand, said platform shall also provide formulations physically and chemically stable, endowed with good technological characteristics, especially optimal flowability properties, good machine handling, such as powder filling. Said platform could turn out to be particularly effective for the treatment of diseases affecting the distal and peripheral part of the lungs.

[0030] SUMMARY OF THE INVENTION

[0031] In a first aspect, the invention is directed to a dry powder pharmaceutical formulation for inhalation in form of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles. As ternary agents, lubricant and anti-adherent excipients are particularly advantageous due to their effect on reducing the cohesiveness and adhesiveness of fine particles.

[0032] In a second aspect, the invention is directed to a dry powder pharmaceutical formulation for inhalation in form of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles, and wherein said pellets are obtainable by a process comprising the steps of:

[0033] i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;

[0034] iii) co-milling the obtained mixture;

[0035] iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers.In a third aspect, the invention is directed to a dry powder pharmaceutical formulation consisting of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles, and wherein said pellets are obtained by a process comprising the steps of:

[0036] i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;

[0037] iii) co-milling the obtained mixture;

[0038] iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers. In a fourth aspect, the invention concerns a dry powder inhaler filled with the aforementioned dry powder pharmaceutical composition.

[0039] In a fifth aspect, the invention concerns a process for preparing the aforementioned pharmaceutical composition comprising the steps of:

[0040] i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;

[0041] iii) co-milling the obtained mixture;

[0042] iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers. In a sixth aspect, the invention is also directed to a package comprising a dry powder pharmaceutical formulation according to the invention and a dry powder inhaler.

[0043] In a seventh aspect, the invention refers to the claimed formulations for use in the treatment of a respiratory disease, such as an inflammatory and / or obstructive airways disease, in particular chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), bronchiolitis and bronchiectasis.

[0044] In an eight aspect, the invention refers to a method of treatment of a respiratory disease, such as an inflammatory and / or obstructive airways disease, in particular chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), bronchiolitis and bronchiectasis.

[0045] In a ninth aspect, the invention refers to the use of the claimed formulations in the manufacture of a medicament for the treatment of a respiratory disease, such as an inflammatory and / or obstructive airways disease, in particular chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), bronchiolitis and bronchiectasis.

[0046] DEFINITIONS

[0047] The term “micron”, “pm” and “micrometers” are used as synonymous.

[0048] By the term “physiologically acceptable” it is meant a safe, pharmacologically-inert substance. By the term “excipient” it is meant a physiologically acceptable and pharmacologically-inert substance.

[0049] By the term “ternary agent” it is meant a substance with lubricant or anti -adherent properties. The term “surface coating” refers to the covering of the surface of the fine excipient particles by forming a film or a discontinuous layer of the ternary agent around said particles.The term “soft pellets” refer to spheronized particles having a diameter typically comprised between 100 and 800 micrometers as measured by sieve separation procedure. Particles smaller than 100 pm passed through the pores of the 100 pm sieve and the larger than 800 pm were retained by the 800 pm sieve.

[0050] By the term “fine particles” it is meant particles having a size typically lower than 25 microns, up to few tens of microns.

[0051] By the term “micronized” it is meant a substance having a size of few microns, typically comprised between 1 and 15 micron.

[0052] By the term “coarse” it is meant particles having a size of higher than 30 micron, typically of one or few hundred microns.

[0053] In general terms, the particle size of particles is quantified by measuring a characteristic equivalent sphere diameter, known as volume diameter, by laser diffraction.

[0054] The particle size can also be quantified by measuring the mass diameter by means of suitable known instrument such as, for instance, the sieve analyser.

[0055] The volume diameter (VD) is related to the mass diameter (MD) by the density of the particles (assuming a size independent density for the particles).

[0056] In the present application, the particle size of the active ingredients is expressed in terms of volume diameter, while that of the excipient is expressed in terms of mass diameter.

[0057] The particles have a normal (Gaussian) distribution which is defined in terms of the volume or mass median diameter (VMD or MMD) which corresponds to the volume or mass diameter of 50 percent by weight of the particles, and, optionally, in terms of volume or mass diameter of 10% and 90% of the particles, respectively.

[0058] Another common approach to define the particle size distribution is the utilization of three values: i) the volume median diameter Dv(50) which is the volume diameter where 50% of the distribution is above and 50% is below; ii) Dv(90), where 90% of the volume distribution is below this value; iii) Dv(10), where 10% of the volume distribution is below this value. The span is the width of the distribution based on the 10%, 50% and 90% quantile and is calculated according to the formula:

[0059] D[v,0.9]~ D[V,0.1]

[0060] Span =

[0061] D[v,0.5]

[0062] As used herein, the term “spheronised” refers to the term used in the art to indicate soft-pellets as for instance disclosed in WO 98 / 31351.

[0063] The term “spheronisation” refers to a process to make spheronised agglomerates of microparticles and includes different processes such as tumbling and vibration.

[0064] The term “good flowability” refers to a formulation that is easy handled during the manufacturing process and can ensure an accurate and reproducible delivering of the therapeutically effective dose.

[0065] Flow characteristics can be evaluated by different tests such as dynamic repose angle, Carr’s index, Hausner ratio or flow rate through an orifice. A Carr’s index of less than 25 is usually taken to indicate good flow characteristics.

[0066] In the context of the present application the flow properties were determined by the dynamic reposeangle method described in the European Pharmacopeia (Eur. Ph.) 11.8, 11thEdition, chapter 2.9.36 “powder flow” (pp 5834-5836) or by angle of repose according to the USP-NF 2024, 1174.

[0067] The expression “physically stable” refers to a formulation wherein the active particles do not substantially segregate and / or detach from the surface of the carrier particles both during manufacturing of the dry powder and in the delivery device before use. The tendency to segregate can be evaluated according to Staniforth et al. J. Pharm. Pharmacol. 34,700-706, 1982 and it is considered acceptable if the distribution of the active ingredient in the powder formulation after the test, expressed as relative standard deviation (RSD), does not change significantly with respect to that of the formulation before the test.

[0068] The expression “bulk density” of a powder refers to the ratio of the mass of an untapped powder sample to its volume and it could be determined by measuring the volume of a known mass of powder sample poured in a graduated cylinder.

[0069] The expression “respirable fraction” refers to an index of the percentage of active particles which would reach the deep lungs in a patient. The respirable fraction, also termed fine particle fraction (FPF), is evaluated using a suitable in vitro apparatus such as Andersen Cascade Impactor (ACI), Multistage Liquid Impinger (MLSI) or Next Generation Impactor (NGI), preferably by NGI, according to procedures reported in the European Pharmacopeia (Eur. Ph.) 11, 11thEdition.

[0070] It is calculated by the percentage ratio between the fine particle mass (formerly fine particle dose) and the delivered dose.

[0071] The expression “delivered dose” refers to the total amount of drug that is emitted by the device and is calculated from the cumulative deposition in stages of the apparatus. It is calculated from the cumulative deposition in the apparatus, while the fine particle mass is calculated from the deposition of particles having a diameter < 5.0 micron.

[0072] The expression “fine particle mass” refers to the mass of the drug that is present in particles with an aerodynamic diameter lower than 5 micron, and it is calculated as sum from all stages of the apparatus that capture particles having a diameter lower than 5 micron.

[0073] The expression “fine particle fraction” refers to the proportion of the delivered dose that has an aerodynamic diameter below 5 micron and it is calculated by the percentage ratio between the particles with a diameter lower than or equal to 5 micron (fine particle mass) and the delivered dose.

[0074] The expression “extra fine particle dose” refers to the mass of the drug that is present in particles with an aerodynamic diameter lower than 2 micron.

[0075] The “extrafine particle fraction” is calculated by the percentage ratio of particles with a diameter of less than 2 micron and the delivered dose.

[0076] The term "treatment" means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. The term can also mean prolonging survival as compared to expected survival if not receiving treatment.The term “therapeutically effective 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.

[0077] 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:

[0078] i) single dose inhalers, for the administration of pre -subdivided single doses of the active compound,

[0079] ii) multi-dose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre- loaded with quantities of active ingredient enough for multiple doses; each dose is created by a metering unit within the inhaler.

[0080] Based on the required inspiratory flow rates (1 / min) which in turn are strictly depending on their design and mechanical features, DPI's are also divided in:

[0081] i) low-resistance devices (> 901 / min);

[0082] ii) medium-resistance devices (about 60-901 / min);

[0083] iii) medium -high resistance devices (about 50-601 / min);

[0084] iv) high-resistance devices (less than 301 / min).

[0085] The reported classification is generated with respect to the flow rates required to produce a pressure drop of 4 kPa (KiloPascal) in accordance to the European Pharmacopoeia (Eur Ph) 11 , chapter 2.9.18 (369-382).

[0086] By “therapeutically effective dose” it is meant the quantity of active ingredient administered by inhalation upon actuation of the inhaler. Said dose may be delivered in one or more actuations (shots or puffs) of the inhaler.

[0087] By “high single effective dose” it is meant a dose of active ingredient as powder for inhalation equal to or higher than 500 pg.

[0088] DETAILED DESCRIPTION OF THE INVENTION

[0089] In one aspect, the invention is directed to a dry powder pharmaceutical formulation for inhalation in the form of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent. Soft pellets are typically formed from an agglomeration of micronized particles. Thus in one preferred embodiment, the active ingredient, the excipient and the ternary agent are all in the form of finely divided particles. By this it is typically meant that the soft pellets are formed from an agglomeration of micronized particles, and that the soft pellets are capable of decomposing into the micronized particles during inhalation. Thus, upon actuation of an inhaler comprising the dry powder formulation, the micronized particles separate from the soft pellets and are released into the airstream.

[0090] It has been found that the formulations of the invention are able to provide high respirable fractions, both in terms of fine particle fraction (FPF) and extrafine particle fraction (EFPF).

[0091] In fact, the formulations of the invention provide a FPF higher than 60% and an EFPF higher than 25%

[0092] Therefore, said formulations show good aerosol performances, and hence permit to reach withvaluable efficiency the distal and peripheral part of lungs. Without being limited by the theory, it is hypothesized that said outstanding aerosol performances are due to the fact that the active ingredient particles, the excipient particles and the ternary agent particles are co-milled together. The co-micronization creates a homogeneous particle population in terms of size distribution in which all the components are micronized to very fine dimensions (Dv(50) <3 micron).

[0093] The formulations according to the invention are also endowed with excellent flow properties as deduced by their dynamic repose angle, as well as good physico-chemical stability. Good powder flowability helps the manufacturing and filling process of the device as well as enhance the delivered dose in respect to the micronized powder formulation.

[0094] Advantageously the diameter of the soft pellets according to the invention is comprised between 100 and 800 micrometers, preferably between 150 and 710 micrometers.

[0095] Advantageously the micronized particles of all the excipient, the active ingredient and the ternary agent have a mass median diameter equal to or less than 15 micrometers, preferably equal to or less than 10 micrometers, more preferably between 1 and 5 micrometers. Even more advantageously the micronized particles of all the excipient, the active ingredient and the ternary agent have a Dv(10) comprised between 0.5 and 2 pm, a Dv(50) comprised between 2 and 4 pm and a Dv(90) comprised between 6 and 10 pm.

[0096] Advantageously the excipient particles are made of a crystalline sugar. Preferably, said particles are made of lactose, more preferably of alpha-lactose monohydrate or mannitol. In a preferred embodiment, the excipient particles are made of mannitol as it gives rise to higher aerosol performances.

[0097] Advantageously, the ternary agent is an anti-adherent agent or a lubricant.

[0098] The anti-adherent agent is selected from the group consisting of leucine and isoleucine, preferably L-leucine and L-isoleucine.

[0099] The lubricant may include or consist of one or more agents selected from the group consisting of stearic acid and salts thereof, such as magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, stearyl alcohol and sucrose monopalmitate.

[0100] In a preferred embodiment of the invention, the ternary agent is magnesium stearate as it provides higher aerosol performances.

[0101] Therefore, according to a preferred embodiment of the invention, the soft pellets comprise mannitol as excipient and magnesium stearate as ternary agent.

[0102] Advantageously, the ternary agent is present in an amount comprised between 1 and 30%, preferably between 2 and 20%, more preferably between 5 and 10% based on the total weight of the soft pellets.

[0103] Advantageously the bulk density of the formulation is comprised between 0.15 g / mL and 0.8 g / mL, more preferably between 0.2 g / mL and 0.7 g / mL, even more preferably between 0.4 and 0.6 g / mL.

[0104] Advantageously, the flowability is comprised between 15 and 50 degrees, more preferably between 20 and 45 degrees, even more preferably between 30 and 42 degrees, as determined by dynamic repose angle.

[0105] In another aspect, the invention is also directed to a process for preparing the formulation of the invention, said process comprising the steps of:i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;

[0106] iii) co-milling the obtained mixture;

[0107] iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers. In a preferred embodiment of the invention, the step i) and ii) of mixing is carried out in a suitable apparatus such as Turbula shaker mixer (WAB Group) or other mixers for at least 30 minutes, preferably for no longer than 4 hours, more preferably for 3 hours.

[0108] In a general way, the person skilled in the art shall adjust the time of mixing and the speed of rotation of the mixer to obtain a homogenous mixture.

[0109] In another preferred embodiment, the step iii) of co-milling the mixture is carried out in a suitable apparatus such as FPS LaboMill or other jet mills. The co-milling process is carried out at a powder feed rate comprised between 0.1 g / min and 10 g / min, preferably comprised between 0.5 g / min and 5 g / min. The feed pressure is preferably set in a range comprised between 2 and 12 bar, more preferably between 3 and 10 bar and even more preferably between 4 and 9 bar. The milling pressure is preferably set in a range comprised between 1 and 10 bar, more preferably between 2 and 8 bar, and even more preferably between 3 and 7 bar. Additional cycles of co-milling may be performed, preferably comprised between 1 and 8 cycles, more preferably 8.

[0110] Spheronisation of step iv) may be carried out according to methods reported in the art, for example in WO 98 / 31351 or WO 95 / 24889 or alternative methods based on tumbling or vibration.

[0111] Typically, vibrating screening apparatus commercially available could be used, such as the vibrating screening AS 200 available from Retsch GmbH, Germany. The skilled person in the art shall select the method, adjust the time of processing and other parameters to obtain the desired spheronized particles. In fact, vibration time and amplitude have an impact on the overall quality of said particles, and they can be fine-tuned to adjust particle size, sphericity and to limit the irregularities in the shape.

[0112] Typically, the time for achieving spheronisation is less than 5 minutes, or even lesser.

[0113] The presence and complete formation of the spheronised particles could be detected by microscopic analysis for example by optical microscope with a magnitude of 32x (Citoval2, Alessandrini, Italy) or by a scanning electronic microscopy (SEM) according to methods known to the skilled person. Any microscope available on the market could be suitably used, for instance the apparatus JSM-F100 (Jeol Ltd, Tokyo, Japan).

[0114] If necessary, the obtained spheronised particles are sieved according to methods known to the skilled person to better targeting the desired particle size.

[0115] The extent of molecular surface coating, which indicates the percentage of the total surface of the excipient particles coated by the ternary agent, may be determined by water contact angle measurement followed by application of the Cassie and Baxter equation described in Colombo I. et al II Farmaco 1984, 39(10), 328-341 and reported below, using the example of MgSt as ternary agent and lactose as excipient:

[0116] cos J-mixture = f-MgSt * cos J-MgSt + f-lactose * cos J-lactosewhere

[0117] f-MgSt and f-lactose are the surface area fractions of magnesium stearate and of lactose;

[0118] J-MgSt is the water contact angle of magnesium stearate;

[0119] J-lactose is the water contact angle of lactose

[0120] J-mixture are the experimental contact angle values.

[0121] The water contact angles of MgSt and lactose, as well as other excipients and ternary agents for use in the present invention, are known or may be determined experimentally. For example, the water contact angles of the following excipients and ternary agents are shown below:

[0122] Water contact angle

[0123] MgSt 106.0°

[0124] Lactose 2.12°

[0125] Mannitol 2.5°

[0126] Isoleucine 73.3°

[0127]

[0128] Leucine 64.9°

[0129] The water contact angles of a mixture of components (J-mixture), or of further excipients and ternary agents according to the present invention, may be determined by the method described below.”

[0130] A particularly useful approach is the sessile or static drop method as referenced on page 332 of Colombo et al (ibidem), that is carried out by depositing a liquid drop onto the surface of the powder in form of disc obtained by compaction (compressed powder disc method).

[0131] The compressed disc (120-150 mg) having a 6.5 or 8 mm diameter was prepared by adding the sample into the die of a tableting machine (Stylone Evolution, MedelPharma, France) and a compression force of 10 kN was applied for a dwelling time of 33 millisec. After the production the porosity of tablet was calculated as the equation below:

[0132] Porosity=(apparent volume-real volume) / (apparent volume) x 100

[0133] where, the apparent volume is the volume of a cylinder with the same radius and thickness of the tablet and the real volume is the ratio between the tablets weight and the true density. The true density of the disk was considered equal to the one of the weighted average of the components (1.44-1.47 g / cm3).

[0134] Then the compressed disc was placed on a plate of a surface wettability tester and a water drop of about 10 pl at 20 C° was placed on the surface of the disc.

[0135] The picture of the contact between the liquid drop and the solid surface was taken using a Sony alpha 5100 and the angle was measured using the software Image J (Wayne Rasband, NHI, USA). Three discs and 6 drops were analysed for each sample.

[0136] Advantageously, the extent of coating by the ternary agent of the surface of the excipient particles of this invention is comprised between 30 and 65% as determined by Cassie and Baxter equation and contact angle analysis.

[0137] Advantageously the fine particle fraction of the formulations of the invention is higher than 60%, preferably higherthan 70%, more preferably higher than 85%, while the extrafine particle fraction is higher than 25%, preferably higher than 30%, even more preferably higher than 40%.

[0138] Any suitable active ingredient useful for the treatment of respiratory disease which benefit of a highextrafine particle fraction could be used.

[0139] The respirable dose depends on the concentration of the active ingredient within the formulation, on the shot weight of the formulation delivered upon actuation of the inhaler, and on the dispersibility of the particles.

[0140] The concentration of the active substance in the powder formulation will depend on several aspects, such as the therapeutic dose of drug to be administered and the weight of the formulation dose delivered when the inhaler is actuated.

[0141] For example, considering an expected single dose of 0.8 mg, if the shot weight of the formulation delivered upon actuation of the inhaler is 20 mg, this would correspond to a concentration of the active ingredient of 4 % w / w. Analogously, for a shot weight of 10 mg, the concentration of the active ingredient would be of 8% w / w, while for a shot weight of 30 mg, the concentration of the active ingredient would be of 2.6% w / w.

[0142] Therefore, the formulation of the invention might be particularly useful for the administration of active ingredients present in a high concentration, for instance comprised between 0.5 % and 20%, more preferably between 1 and 10%, even more preferably between 3 and 7% based on the weight of the formulation.

[0143] Advantageously, the active ingredients could be selected from the groups including but not limited to phosphodiesterase (PDE) inhibitors such as PDE3 and PDE4 inhibitors, tyrosine kinases inhibitors, TGF-P inhibitors, steroids for inhalation.

[0144] For example, active ingredients such as tanimilast, ensifentrine, nintenadib, pirfenidone and beclomethasone dipropionate (BDP) could be used. Preferred active ingredients are tanimilast, and BDP.

[0145] Said active ingredients are typically administered at single therapeutically effective doses comprised between 50 micrograms and 10 mg, more preferably between 100 micrograms and 4 mg, even more preferably between 800 micrograms and 1 mg.

[0146] In a preferred embodiment of the invention, the dry powder formulation of the invention is in form of soft pellets, said pellets comprising tanimilast, mannitol, L-leucine, or beclomethasone dipropionate, mannitol, L-leucine.

[0147] In another preferred embodiment of the invention, the dry powder formulation of the invention is in form of soft pellets, said pellets comprising tanimilast, mannitol, L-isoleucine, or tanimilast, mannitol, magnesium stearate.

[0148] In a further preferred embodiment, the dry powder formulation of the invention is in form of soft pellets, said pellets comprising tanimilast, lactose, L-leucine, or beclomethasone dipropionate, lactose, L-leucine.

[0149] In another embodiment of the invention, the dry powder formulation of the invention is useful for the administration of active ingredients to be delivered at single doses per actuation of the inhaler comprised between 0.1 mg and 5 mg, more preferably between 0.5 mg and 4 mg, even more preferably between 0.8 mg and 1 mg.

[0150] Preferred high doses are comprised between 0.5 mg and 10 mg, more preferably between 0.8 and 4mg, and even more preferably between 1 mg and 2 mg.

[0151] In another embodiment of the invention, the present invention refers to the formulation as herein described in detail for use as a medicament, even more preferably for the treatment of respiratory diseases. In preferred embodiments, said respiratory diseases are selected from chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), bronchiolitis and bronchiectasis.

[0152] Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatin, or blisters of for example laminated aluminum foil, for use in an inhaler or an insufflator.

[0153] 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 dosages can be withdrawn on demand through actuation of the device.

[0154] A preferred multi -dose device is the inhaler described in WO 2004 / 012801 and in WO 2016 / 000983. Other multi-dose devices that may be used are for instance the Diskus™, the Turbohaler™, Twisthaler™, Easyhaler™, Spiromax™, Airmax™, Clickhaler™ and Genuair™. Single-dose devices that may be used are Rotohaler™, Handihaler™ and RS01.

[0155] All preferred groups or embodiments described above may be combined among each other and apply as well mutatis mutandis.

[0156] The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.

[0157] EXAMPLES EXAMPLE 1

[0158] Two powder formulations were prepared having the unitary composition, i.e. the composition per shot of the inhaler, reported in Tables 1 and 2.

[0159] Table 1: tanimilast, mannitol, L-leucine formulation composition

[0160] Amount per shot of the inhaler Composition

[0161] mg %

[0162] tanimilast 0.8 4

[0163] mannitol 17.2 86

[0164] L-leucine 2 10

[0165]

[0166] Total weight 20 100

[0167] Table 2: beclomethasone dipropionate (BDP), mannitol, L-leucine formulation composition Amount per shot of the inhaler Composition

[0168] mg %

[0169] BDP 0.1 1

[0170] mannitol 8.9 89

[0171] L-leucine 1 10

[0172]

[0173] Total weight 10 100

[0174] Mannitol and L-leucine blend were mixed in a Turbula mixer operating at a rotation speed of 38 rpm for 60 minutes, according to the proportion described in Table 1 and 2 respectively for the compositioncomprising tanimilast and the composition comprising BDP. The active ingredient, i.e. tanimilast (0.8 mg) or beclomethasone dipropionate (0.1 mg), was sieved through 500 pm mesh with one-third of the prepared blend and mixed in Turbula at 38 rpm for 40 min, a second-third of the prepared blend was added and mixed at 38 rpm for 40 min and, finally, the last third of the prepared blend was added and mixed at 38 rpm for 40 min. The resulting mixture was sieved through 500 pm mesh to remove any aggregates and mixed for 10 min at 38 rpm. The resulting mixture was micronized by jet milling. The parameters employed for the co-micronization process are reported in Table 3.

[0175] Table 3: parameters employed for the powder co-micronization process Tanimilast-mannitol-L-leucine BDP-Mannitol-L-leucine (0.8mg / 20 mg) (0.1 mg / lOmg) Feed pressure 5 7

[0176] Milling pressure 3.6 6

[0177] Feed rate 1 gr / min 1 gr / min Number of cycles 8 5

[0178] Uniformity of drug content

[0179] post micronization 0.62±0.02 (3.20%) 0.089±0.008(9.82%)

[0180]

[0181] Mean ± St. dev (CV%)

[0182] The co-micronized formulation was subjected to a spheronization process using two different techniques. The parameters employed for the soft pellets preparation by vibratory separator with a calibrated set of sieves mesh (collector - 106 pm - 710 pm - cover) were:

[0183] shaking time 3 minutes, sieving speed low of 3, collection soft pellets size range: 106-710 pm. The parameters employed for the soft pellets preparation by tumbling were: 35 rpm; 40 minutes; collection SP size range: 106-710 pm.

[0184] The bulk density of the soft pellets formulations was measured as reported in European Pharmacopoeia 11.0thEdition (2.9.34. Bulk Density and Tapped Density of powders).

[0185] Table 4: bulk density (g / mL) of the soft pellets formulations on a 10 ml cylinder

[0186] T animilast-Mannitol-L-leucine BDP-Mannitol-L-leucine (0.8m g / 20 mg) (0.1 mg / lOmg) Bulk density (g / ml)_Vibration 0.34 0.33

[0187] Bulk density (g / ml)_Tumbling 0.42 0.32

[0188]

[0189] The flowability of the formulations was measured determining the dynamic repose angle. A cylindrical glass vial used has a height of 5 cm and a width of 2.5 cm. Approximately 1.5 g of powder was inserted. The vial was inclined by 15° and it was rotated at speed of 32 rpm / min. The powder sample during the rotation is dragged on the cylindrical wall of the vial to a certain height from which it falls due to collapse under gravity. The angle formed by the slope of the inclined plane of falling powder and the horizontal plan was measured by a photographic shot taken from the base of the rotating vial. The image obtained was analyzed using the Image J software in order to calculate the angle of the slope. The scale offlowability evaluation was adopted as described in European Pharmacopoeia 11 ,0thEdition of 2024 (2.9.34. Bulk Density and Tapped Density of powders).

[0190] Table 5: Dynamic angle of repose (degrees) and classification of the flow property of the formulations Formulation Dynamic angle of repose (degrees) Flow property Tanimilast-Mannitol-L-leucine

[0191] 39.9 ± 2.2 good 0.8mg / 20 mg

[0192] BDP-Mannitol-L-leucine

[0193] 29.0 ±2.1 excellent

[0194]

[0195] 0.1mg / 20 mg

[0196] The in vitro respirability of the soft pellets formulations, obtained by vibrating for tanimilast and by tumbling for BDP, were analysed.

[0197] Plastiape RS01 device was used to conduct the analysis. The soft pellets formulations were filled in Quali-V®-I capsules, size 3 TAA (Qualicaps Europe, S.A.U.) and loaded with 20 mg of the formulation of tanimilast, mannitol, L-leucine (for the dose of 800 pg) and 10 mg for the formulation of BDP, mannitol, L-leucine (for the dose of 100 pg). The RS01 inhaler was activated at a pressure drop of 4 kPa corresponding to a flow rate of 65 L / min, for a duration of time sufficient to sample an air volume of 4.0 liters (i.e. 3.7 s).

[0198] The evaluation of the aerosol performances was carried out using the Next Generation Impactor (NGI), according to procedures reported in the European Pharmacopeia (Eur. Ph.) 11, 11thEdition.

[0199] The drug remaining in capsule and device, and the drug deposited in the different portions of the impactor was recovered using an adequate solvent. The samples were filtered and quantified using HPLC to determine the amount of drug.

[0200] The following parameters were calculated: i) the Delivered Dose; ii) the Fine Particle Dose (FPD); (iii) the Fine Particle Fraction (FPF); iv) the Extra-Fine Particle Dose (EFPD); v) the Extra Fine Particle Fraction (EFPF).

[0201] Table 6: shot weight (mg), Delivered Dose (pg), FPD (pg), FPF (%), EFPD (pg), EFPF (%), mean values of RS01 device loaded with composition of tanimilast, mannitol, L-leucine (vibration) (0.8 mg / 20 mg) or BDP, mannitol, L-leucine (tumbling) (0.1 mg / lOmg) ± St.dev and CV% in (n=3).

[0202] T animilast-Mannitol-L-leucine BDP-Mannitol-L-leucine (vibration) (tumbling) (0.8mg / 20 mg) (0.1 mg / lOmg) Mean ± St. Dev CV(%) Mean ± St. Dev CV(%) Shot weight (mg) 22.0± 1.2 5.70 10.5 ± 0.2 1.6 Delivered dose (pg) 657.1 ± 14.3 2.20 81.4 ± 0.8 1.0 Fine Particle Dose (pg) 498.3 ± 34.1 6.80 67.6 ± 1.3 1.9 Fine Particle Fraction (%) 75.8 ± 3.6 4.70 83.0 ±1.0 1.2 Extra Fine Particle Dose (pg) 221.1 ± 17.1 7.70 35.8 ± 1.6 4.4 Extra Fine Particle Fraction

[0203] 33.6 ± 1.9 5.60 44.0 ± 1.5 3.5

[0204]

[0205] (%) _Example 2

[0206] Two powder formulations were prepared having the unitary composition, i.e. the composition per shot of the inhaler, reported in Tables 7 and 8.

[0207] Table 7: tanimilast, mannitol, L-isoleucine composition

[0208] Amount per shot of the inhaler Composition

[0209] mg %

[0210] tanimilast 0.8 4

[0211] mannitol 17.2 86

[0212] L-isoleucine 2 10

[0213]

[0214] Total weight 20 100

[0215] Table 8: tanimilast, mannitol, magnesium stearate composition

[0216] Amount per shot of the inhaler Composition

[0217] mg %

[0218] tanimilast 0.8 4

[0219] mannitol 17.2 86

[0220] Magnesium stearate 2 10

[0221]

[0222] Total weight 20 100

[0223] Mannitol with the ternary agent, L-isoleucine or magnesium stearate (MgSt), were mixed together in a Turbula mixer operating at a rotation speed of 38 rpm for 60 minutes. Then tanimilast was sieved through 500 pm mesh with one-third of the prepared blend and mix in Turbula at 38 rpm for 40 min, a second-third of the prepared carrier blend was added and mixed at 38 rpm for 40 min and finally, the last third of the prepared blend was added and mixed at 38 rpm for 40 min. The resulting mixture was sieved through 500 pm mesh and ultimately mixed for 30 min at 38 rpm.

[0224] The resulting mixture was micronized. The parameters employed for the co-micronization process are showed in Table 9. The uniformity of drug content after micronization was determined via HPLC. The co-micronized formulation was subjected to a spheronization process using the tumbling technique. The parameters employed for the soft pellets preparation by tumbling were: 35 rpm; 40 minutes; collection soft pellets size range: 106-800 pm.

[0225] Table 9: parameters employed for the powder co-micronization process.

[0226] T animilast-MannitoI-L- T animilast-MannitoI- isoleucine MgSt

[0227] (0.8 mg / 20mg) (0.8 mg / 20mg) Feed pressure 7 bar 7 bar

[0228] Milling pressure 6 bar 6 bar

[0229] Feed rate 1 gr / min 1 gr / min Number of cycles 5 4

[0230] Uniformity of drug content

[0231] 0.7 ± 0.01 (1.21%) 0.71 ± 0.02 (2.30%)

[0232]

[0233] Mean ± St. dev (CV%)

[0234] Both the soft pellets powders showed a dynamic angle of repose in the range 38.5- 39.8 degree, indicating a good flow property.The soft pellets formulations were aerosolized using a RS01 inhaler in the NGI, as described in the Example 1. The in vitro respirability data are reported in Table 10.

[0235] Table 10: shot weight (mg), Delivered Dose (pg), FPD (pg), FPF (%), EFPD (pg), EFPF (%) mean values of RS01 device loaded with composition of tanimilast, mannitol, L-isoleucine, or tanimilast, mannitol, MgSt ± St.dev and CV% in (n=3)

[0236] T animilast-Mannitol-L- T animilast-Mannitol-MgSt isoleucine (tumbling) (tumbling)

[0237] (0.8m g / 20 mg) (0.8mg / 20 mg) Mean ± St. Dev CV(%) Mean ± St. Dev CV(%) Shot weight (mg) 11.7± 0.6 4.9 19.9 ± 0.1 0.2 Delivered dose (pg) 508.7± 15.1 3.0 655.2 ± 14.0 2.1 Fine Particle Dose (pg) 428.8 ± 10.3 2.4 605.2 ± 10.8 1.8 Fine Particle Fraction (%) 84.3 ± 2.3 2.7 92.4 ± 0.9 0.9 Extra Fine Particle Dose (pg) 199.4 ± 11.2 5.6 361.9 ± 12.0 3.3 Extra Fine Particle Fraction (%) 39.2±2.8 7.1 55.2 ± 0.7 1.3

[0238]

[0239] Example 3

[0240] Two powder formulations were prepared having the unitary composition, i.e. the composition per shot of the inhaler, reported in Tables 11 and 12.

[0241] Table 11: tanimilast, lactose, L-leucine formulation composition

[0242] Amount per shot of the inhaler Composition

[0243] mg %

[0244] tanimilast 0.8 4.0

[0245] lactose 17.2 86.0

[0246] L-leucine 2.0 10.0

[0247]

[0248] Total weight 20.0 100.0

[0249] Table 12: BDP, lactose, L-leucine formulation composition

[0250] Amount per shot of the inhaler Composition

[0251] mg %

[0252] BDP 0.1 1.0

[0253] lactose 8.9 89.0

[0254] L-leucine 1.0 10.0

[0255]

[0256] Total weight 10.0 100.0

[0257] Lactose with L-leucine were mixed in a Turbula mixer operating at a rotation speed of 38 rpm for 60 minutes. Then active ingredient was sieved through 500 pm mesh with one-third of the prepared blend and mix in Turbula at 38 rpm for 40 min, a second-third of the prepared blend was added and mixed at 38 rpm for 40 min and finally, the last third of the prepared blend was added and mixed at 38 rpm for 40 min. At the end, the blend was sieved through 500 pm mesh and ultimately mixed for 30 min at 38 rpm.The prepared blend was micronized. The parameters employed for the co-micronization process are showed in Table 13.

[0258] Table 13: parameters employed for the co-micronization process and active ingredient content in the powder blend before and after micronization (n=6)

[0259] T animilast-Lactose-L-leucine BDP-Lactose-L-leucine (0.8m g / 20 mg) (0.1 mg / lOmg) Feed pressure 7 7

[0260] Milling pressure 6 6

[0261] Feed rate 1 gr / min 1 gr / min Number of cycles 5 6 Uniformity of drug content post

[0262] micronization 0.57 ± 0.01 (1.76) 0.073 ± 0.004 (5.40)

[0263]

[0264] Mean ± St. dev (CV%)

[0265] The uniformity of drug content in the blends was determined with HPLC.

[0266] The parameters employed for the soft pellets preparation by vibration on sieve mesh were:

[0267] Sieving interval: 100-800 pm; Sieving time: 3 minutes; Sieving speed: low.

[0268] The parameters employed for the soft pellets preparation by tumbling were: 35 rpm, 40 minutes, Sieving interval: 100-800 pm.

[0269] The particle size distribution of the powders was determined using a Spraytec (Malvern Instruments Ltd, Worcestershire, UK) laser diffraction. The measurement was done in a wet dispersion, using cyclohexane with a 0.01 % w / v of SPAN as antisolvent and the Dv(10), Dv(50) and Dv(90) were obtained for each powder.

[0270] Table 14: Dv(10), Dv(50), Dv(90) of tanimilast, lactose, L-leucine and BDP, lactose, L-leucine formulation after micronization (n=3)

[0271] Dv(10) Dv(50) Dv(90) tanimilast lactose L-leucine 1.58±0.05 3.25±0.27 6.27±0.95 BDP lactose L-leucine 1.58±0.05 3.25±0.27 6.27±0.95

[0272]

[0273] The In vitro aerodynamic profiles were investigating by using a Next Generation Impactor (NGI), following the procedure detailed in the European Pharmacopoeia 11.0thEdition of 2024 (2.9.18. p.369). The formulations were: tanimilast, lactose, L-leucine (0.8mg / 20mg) and BDP, lactose, L-leucine (O.lmg / lOmg).

[0274] Soft pellets obtained by vibration on sieve mesh have been used for tanimilast, lactose, L-leucine (0.8 mg / 20mg) formulation and BDP, lactose, L-leucine (0.1 mg / lOmg) formulation.

[0275] RS01 device was used to perform the analysis on in vitro respirability, according to the procedure described in Example 1.

[0276] Table 15: Shot weight (mg), Delivered Dose (pg), FPD (pg), FPF (%), EFPD (pg), EFPF (%) mean values of RS01 device loaded tanimilast, lactose, L-leucine (0.8mg / 20mg) and BDP, lactose, L-leucine (O.lmg / lOmg) ± St.dev and CV% in (n=3)T animilast-lactose-L-leucine

[0277] BDP-lactose-L-leucine (vibration)

[0278] (vibration) (0.1 mg / lOmg) (0.8mg / 20 mg)

[0279] Mean ± St. Dev CV(%) Mean ± St. Dev CV(%) Shot weight (mg) 22.9 ± 0.4 1.6 11.5 ± 0.1 0.5 Delivered dose (pg) 665.8 ± 7.4 1.1 80.7 ± 1.0 1.2 Fine Particle Dose (pg) 442.3 ± 6.4 1.4 64.9 ± 0.2 0.4 Fine Particle Fraction (%) 66.4 ± 0.4 0.7 80.4 ± 1.0 1.2 Extra Fine Particle Dose (pg) 175.0 ± 3.5 2.0 33.3 ± 0.6 1.8 Extra Fine Particle Fraction

[0280] 26.3 ± 0.3 1.0 41.3 ± 1.1 2.6

[0281]

[0282] (%)

[0283] The bulk density of the formulations was measured according to the procedure described in European Pharmacopoeia 11.0thEdition of 2024 (2.9.34. Bulk Density and Tapped Density of powders). The bulk density of a powder is the ratio of the mass of an untapped powder sample to its volume and it could be determined by measuring the volume of a known mass of powder sample, which may have been passed through a sieve, in a graduated cylinder. To calculate the bulk density, 1-2 grams of the powder were passed through a sieve with apertures equal to 1.0 mm. The powder was gently introduced into a 5 ml or 10 ml cylinder without compacting and the unsettled apparent volume (Vo) to the nearest graduated unit was read.

[0284] Table 16: bulk density of soft pellets based on lactose (g / mL)

[0285] T animilast-lactose-L-leucine BDP-lactose-L-leucine (0.8mg / 20 mg) (0.1 mg / lOmg)

[0286] Bulk density (g / ml)_Vibration 0.34 0.36

[0287] Bulk density (g / ml)_Tumbling 0.33 0.37

[0288]

[0289] Example 5

[0290] Three powder formulations were prepared having the unitary composition, i.e. the composition per shot of the inhaler, reported in Table 17. In particular, these three formulations differed based on their ternary agent concentration and type.

[0291] Table 17: tanimilast, mannitol L-leucine (5 %w / w); tanimilast, mannitol L-isoleucine (5% w / w) and tanmilast, mannitol, MgSt (2% w / w) formulation composition

[0292] Composition Concentration (% w / w) 0.8 mg tanimilast 4.0 tanimilast mannitol L-leucine 18.2 mg mannitol 91.0

[0293] 1 mg L-leucine 5.0

[0294] 0.8 mg tanimilast 4.0 tanimilast mannitol L-isoleucine 18.2 mg mannitol 91.0

[0295] 1 mg L-isoleucine 5.0

[0296] 0.8 mg tanimilast 4.0

[0297] tanmilast mannitol MgSt 18.8 mg mannitol 94.0

[0298] 0.4 mg MgSt 2.0

[0299]

[0300] The above prepared blend was micronized by jet milling.

[0301] The parameters employed for the co-micronization process are showed in Table 18.

[0302] Table 18: parameters employed for the co-micronization process

[0303] Tanimilast, mannitol, Tanimilast, mannitol, L- Tanimilast, mannitol, L-leucine (5 %w / w) isoleucine (5 %w / w) Mg St (2 %w / w) Feed pressure 6 7 5 Milling pressure 5 6 4

[0304] Feed rate 1 gr / min 1 gr / min 1 gr / min Number of cycles 6 6 6 Uniformity of drug

[0305] content post 0.82 ± 0.01 0.77 ± 0.01 0.71 ± 0.016 micronization (1.31) (1.21) (2.30)

[0306]

[0307] Mean ± St. dev (CV%)

[0308] Table 19: Dv(10), Dv(50), Dv(90) of tanimilast, mannitol, L-leucine (5 %w / w); tanimilast, mannitol, L- isoleucine (5 %w / w), and tanimilast, mannitol, MgSt (2 %w / w) formulation after micronization (n=3)

[0309] Dv(10) Dv(50) Dv(90) tanimilast mannitol L-leucine (5 %w / w) 1.17±0.25 2.49±0.65 5.64±2.03 tanimilast mannitol L-isoleucine (5

[0310] 1.08±0.02 2.52±0.02 7.69±1.51 %w / w)

[0311] tanimilast mannitol Mg St (2 %w / w) 1.24±0.23 2.92±0.43 7.51±0.73

[0312]

[0313] Table 20: bulk density (g / mL) of the soft pellets formulations

[0314] Bulk density (by Bulk density (by Formulation

[0315] vibration) (g / mL) tumbling) (g / mL) tanimilast mannitol L-leucine (5 %w / w) 0.269 0.286 tanimilast mannitol L-isoleucine (5 %w / w) 0.250 0.286 tanimilast mannitol Mg St (2 %w / w) 0.356 0.315

[0316]

[0317] The data of Table 20 show that, even at concentrations of the ternary agent of, respectively, 5 %w / w for L-leucine and L-isoleucine, and 2 %w / w for magnesium stearate, a suitable bulk density was achieved.Table 21: Shot weight (mg), Delivered Dose (pg), FPD (pg), FPF (%), EFPD (pg), EFPF (%) mean values of RS01 device loaded with tanimilast, mannitol, L-leucine (5 %w / w); tanimilast, mannitol, L-isoleucine (5 %w / w); tanimilast, mannitol, Magnesium Stearate (2 %w / w)± St.dev and CV% in (n=3) tanimilast mannitol

[0318] tanimilast mannitol tanimilast mannitol L-isoleucine (5

[0319] L-leucine (5 %w / w) Mg St (2 %w / w) %w / w)

[0320] Mean ± St. Mean ± St. Mean ± St.

[0321] CV CV CV

[0322] Dev Dev Dev

[0323] Shot weight (mg) 15.5 ± 0.5 3.22 15.7± 1.7 10.82 19.2 ± 0.6 3.12 Delivered Dose (mg) 560.5 ± 2.8 0.49 556.9± 1.4 0.25 617.3 ± 16.0 2.59 Fine Particle Dose (mg) 528.5 ± 7.1 1.34 475.9± 4.6 0.96 437.5 ± 50.1 11.45 Fine Particle Fraction (%) 94.3± 1.2 1.27 85.5± 0.9 1.05 75.0 ± 2.9 3.86 Extra Fine Particle Dose <

[0324] 263.2 ±3.1 1.17 217.6± 5.8 2.66 251.7 ±20.7 8.22 2 pm (mg)

[0325] Extra Fine Particle

[0326] 47.0±0.4 0.85 39.1±1.1 2.81 40.8 ± 3.8 9.31

[0327]

[0328] Fraction < 2 pm (%)

[0329] Example 6

[0330] Soft pellets were prepared according to the method described in Example 1, with spheronization process performed by vibration, but without the active ingredient.

[0331] The extent of molecular surface coating, which indicates the percentage of the total surface of the excipient particles coated by the ternary agent, was determined by water contact angle measurement followed by application of the Cassie and Baxter equation described in Colombo I. et al II Farmaco 1984, 39(10), 328-341. Powder of mannitol and ternary agents at 10% w / w were analysed and data reported in Table 22.

[0332] The compressed disc (120-150 mg) having a 6.5 or 8 mm diameter was prepared by adding the sample into the die of a tableting machine (Stylone Evolution, MedelPharma, France).

[0333] Then the compressed disc was placed on a plate of a surface wettability tester and a water drop of about 10 pl was placed on the surface of the disc.

[0334] Table 22

[0335] Water Contact Extent of surface

[0336] Porosity % Angle (degree0) coating (%)

[0337] MannitoI-MgSt (10% w / w) 64.9±3.6 45.1± 4.5 14.8±0.4 Mannitol-L-leucine (10% w / w) 36.0±1.4 33.1±2.6 14.7± 0.1

[0338]

[0339] Mannitol-L-isoleucine (10% w / w) 41.8±2.2 35.6±3.7 23.9 ±0.8

Claims

CLAIMS1. A dry powder pharmaceutical formulation for inhalation in form of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles.

2. The dry powder formulation according to claim 1, wherein the micronized particles have a mass median diameter equal to or less than 15 micrometers.

3. The dry powder formulation according to claims 1 and 2, wherein the excipient particles are made of a crystalline sugar.

4. The dry powder formulation according to claim 2, wherein particles are made of lactose, more preferably of alpha-lactose monohydrate or mannitol.

5. The dry powder formulation according to any of the preceding claims, wherein the ternary agent is an anti-adherent agent or a lubricant.

6. The dry powder formulation according to claims 1 to 5, wherein the ternary agent is present in an amount comprised between 1 and 30%, preferably between 2 and 20%, more preferably between 8 and 10% based on the total weight of the soft pellets.

7. The dry powder formulation according to claim 5 or claim 6, wherein the anti -adherent agent is selected from the group consisting of leucine and isoleucine, preferably L-leucine and L-isoleucine.

8. The dry powder formulation according to claim 5 or claim 6, wherein the lubricant may include or consist of one or more agents selected from the group consisting of stearic acid and salts thereof such as magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, stearyl alcohol and sucrose monopalmitate.

9. The dry powder formulation according to claim 8, wherein the lubricant is magnesium stearate.

10. The dry powder formulation according to claims 1-7 and 8, wherein the soft pellets comprise mannitol as excipient and magnesium stearate as ternary agent.

11. A dry powder pharmaceutical formulation in form of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles, and wherein said pellets are obtainable by a process comprising the steps of:i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;iii) co -milling the obtained mixture;iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers.

12. A dry powder pharmaceutical formulation consisting of soft pellets, said pellets comprising an active ingredient, an excipient and a ternary agent, all of which being in form of micronized particles, and wherein said pellets are obtained by a process comprising the steps of:i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;iii) co-milling the obtained mixture;iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers.

13. A dry powder inhaler filled with the dry powder pharmaceutical composition according to claims 1 to 10.

14. A process for preparing the dry powder pharmaceutical composition according to claims 1-10, comprising the steps of:i) preparing a mixture of the physiologically acceptable excipient and the ternary agent; ii) adding the active ingredient and mixing;iii) co-milling the obtained mixture;iv) subjecting the mixture to agglomeration and spheronisation to obtain the spheronised particles; v) sieving to isolate the fraction having a diameter comprised between 100 to 800 micrometers.

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