Capsule inhalers for administering phosphodiesterase 4 inhibitors

Abstract

The present invention relates to a pharmaceutical product comprising a single dose dry powder inhalation device and a pharmaceutical composition filled in a capsule, the pharmaceutical composition comprising micronized particles of a compound of formula (I) and a carrier. The invention also relates to a pharmaceutical or pharmaceutical composition for the treatment of respiratory diseases and to a method for the treatment of respiratory diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a medicine comprising a single-dose dry powder inhalation device and a pharmaceutical composition filled in a capsule, wherein the pharmaceutical composition comprises micronized particles of a compound of formula (I) and a carrier. The present invention also relates to a medicine or a pharmaceutical composition for treating respiratory diseases and to a method for treating respiratory diseases. Background Art

[0002] Compound of formula (I)

[0003]

[0004] Also known as tanimilast or CHF6001 or CHF-6001, its INN is (3,5-dichloro-4-[(2S)-2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-{[3-(cyclopropylmethoxy)-4-(methylsulfonylamino)benzoyl]oxy}ethyl]pyridine 1-oxide), is a highly potent and selective PDE4 inhibitor with potent anti-inflammatory activity and is currently in clinical development.

[0005] The compound of formula (I) has been disclosed in the prior art documents of Chiesi: WO 2009 / 018909, which relates to its general formula, preparation method, composition and therapeutic use; WO 2010 / 089107 particularly relates to sulfonylamino derivatives in the form of (-) enantiomers, including compounds of formula (I), preparation methods, compositions and therapeutic uses; WO 2012 / 016889 relates to dry powder compositions containing compounds of formula (I); WO 2015 / 059050 relates to a crystalline form of the compound of formula (I) named Type A characterized by specific XRPD peaks, and a method for obtaining it.

[0006] Like other members of the pharmacological class of PDE4 inhibitors, the drugs are indicated for the treatment of pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema, and cystic fibrosis.

[0007] Due to the well-known systemic side effects associated with the class of PDE4 inhibitors, tanimilast is under development as a composition for inhalation. In fact, one of the advantages of the inhaled route over the systemic route is the delivery of the drug directly at the site of action, avoiding any possibility of systemic side effects.

[0008] Tanimilast is currently in late clinical trials, testing two different unit nominal doses, 400 and 800 μg. The product is in the form of a powder composition, utilizing the platform technology disclosed in WO 2012 / 016889, and is delivered via a proprietary multi-dose Inhaler administration. The product is denoted below as the "reference product".

[0009] As carriers, cracked coarse lactose and a fraction consisting of a mixture of fine lactose and magnesium stearate were used as ternary agents. Said composition as disclosed in WO 2012 / 016889 is hereinafter indicated as "reference composition".

[0010] Due to the properties of both the inhaler and the platform technology, the composition provides an excellent respirable fraction as well as a large number of very fine particles. There is indeed a consensus on the fact that very fine particles are able to reach the distal end of the respiratory tree and thus improve small airway prognosis and related control in patients affected by the small airway asthma phenotype (Santus P et al., Respir Care 2020; 65(9): 1392-1412; Scichilone N et al., Patient Relat Outcome Meas 2014; 5: 153-162).

[0011] On the other hand, ternary agents are inhaled by the patient, thus increasing the regulatory burden when seeking product approval.

[0012] It would therefore be advantageous to provide a platform technology for administering compounds of formula (I) in powder form, with the same inhalation properties as the reference product, but without the use of a ternary agent.

[0013] The inventors have surprisingly found that the medicinal product of the present invention has the same inhalation performance as the reference product without the use of a ternary agent. Summary of the invention

[0014] In a first aspect, the present invention relates to a medicament comprising a single-dose dry powder inhalation device, comprising an inhaler body (2) defining a recess (3) for a capsule (4), a nasal or oral mouthpiece (5) communicating with the recess (3), at least one rupturing element (7), and a pharmaceutical composition filled in the capsule, wherein the capsule (4) contains therein a pharmaceutical composition to be inhaled, the at least one rupturing element (7) being connected to the inhaler body (2) and being configured to rupture the capsule (4) to allow an external airflow to mix with the pharmaceutical composition (4) in the capsule and be inhaled through the nasal or oral mouthpiece (5), the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and a carrier consisting of a mixture of coarse and fine particles of a pharmaceutically inert acceptable excipient.

[0015]

[0016] The inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min, and the carrier consists of a mixture of coarse and fine particles of a physiologically acceptable inert excipient in a ratio of 70:30 to 95:5 by weight, the coarse particles having an equivalent volume diameter of 200 to 500 microns and the fine particles having a dv(0.1) of 1 to 5 μm, a dv(0.5) of 18 to 30 μm, a dv(0.9) of 65 to 95 μm, as measured by means of a laser diffraction or sieve analyzer.

[0017] In a second aspect, the invention relates to a pharmaceutical composition according to the invention for use in the treatment of respiratory diseases, wherein said composition is administered using a single-dose dry powder inhalation device, wherein said inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min.

[0018] In a third aspect, the present invention provides a method for treating a respiratory disease, the method comprising administering to a patient by inhalation a compound of formula (I) using a medicament as described according to the present invention.

[0019] In a fourth aspect, the present invention relates to a pharmaceutical composition according to the present invention for use in the preparation of a medicament for the treatment of a respiratory disease, wherein the composition is administered using a single-dose dry powder inhalation device, wherein the inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min.

[0020] In a fifth aspect, the present invention provides a method for preparing a medicament according to the present invention, the method comprising the steps of: i) sieving a compound of formula (I) through a suitable sieve, ii) adding carrier particles to the compound of formula (I), iii) sieving the final blend and mixing to obtain a pharmaceutical composition, iv) filling the obtained pharmaceutical composition in capsules, and v) loading the capsules into the chambers of a single dry powder inhalation device. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : Deposition of the compound of formula (I) in each stage of the NGI device after delivery of 400 μg of the reference product

[0022] Figure 2 : Deposition of the compound of formula (I) in each stage of the NGI device after delivery of 800 μg of the reference product

[0023] Figure 3 : Deposition of the compound of formula (I) in various stages of the NGI device after delivery of 400 μg of the drug product of the invention in the RS01 high resistance (HR) inhalation device

[0024] Figure 4 : Deposition of the compound of formula (I) in various stages of the NGI equipment after delivery of 800 μg of the drug product of the present invention in the RS01 HR inhalation device

[0025] Figure 5 : Comparison of deposition of the compound of formula (I) after delivery of 400 μg of the reference product and 400 μg of the drug product of the present invention in the RS01 HR inhalation device

[0026] Figure 6 : Comparison of deposition of the compound of formula (I) after delivery of 800 μg of the reference product and 800 μg of the drug product of the present invention in the RS01 HR inhalation device

[0027] Figure 7 : Comparative in vitro dissolution (%) of the reference product and the drug product of the present invention at a nominal dose of 800 μg unit.

[0028] Figure 8 : Comparative in vitro dissolution of the reference product and the drug of the present invention at a nominal dose of 400 μg (%)

[0029] Fig. 9 : A three-dimensional view of a single-dose dry powder inhalation device according to an embodiment of the present invention

[0030] Fig.10 : Fig. 9 Section of a single-dose dry powder inhaler device in a first operating configuration

[0031] Fig.11 : Fig. 9 Section of a single-dose dry powder inhaler device in a second operating configuration DETAILED DESCRIPTION

[0032] definition

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0034] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to also include polymorphs, stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0035] The terms "micron" or "micrometer" and μm are used synonymously.

[0036] The terms "microgram" and μg are used synonymously.

[0037] The terms "percent" and % are used synonymously.

[0038] The term "pharmaceutically acceptable salt" as used herein refers to a derivative of a compound of formula (I) wherein the parent compound is modified by converting any free acid or basic group (if present) into a corresponding addition salt with any conventional base or acid intended to be pharmaceutically acceptable. Thus, suitable examples of the salt may include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic basic addition salts of acid residues such as carboxyl groups.

[0039] Cations of inorganic bases which may be suitably used to prepare salts include ions of alkali metals or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0040] Salts obtained by reacting the main compound serving as a base with an inorganic or organic acid to form a salt include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0041] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid, the solvate will be able to separate. The solvate may include stoichiometric or non-stoichiometric amounts of solvent molecules.

[0042] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0043] The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

[0044] The term "tautomer" refers to each of two or more isomers of a compound which coexist in equilibrium and are readily interconvertible by migration of atoms or groups within the molecule.

[0045] The term "composition" as in pharmaceutical composition is intended to include a product comprising the active ingredients and any pharmaceutically acceptable excipients or carriers, as well as any product resulting directly or indirectly from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other type of reaction or interaction of one or more ingredients.

[0046] The term "physiologically acceptable" refers to safe, pharmacologically inert substances used as excipients.

[0047] The term "bioequivalence" generally means that there are no significant differences in bioavailability, ie, extent of absorption and peak concentration, between two drug products (eg, a test product and a reference product) at the same dose and under the same conditions over a period of time.

[0048] The determination of whether a test product is bioequivalent to a reference product is made by conducting studies in a group of subjects, known as bioequivalence or comparative bioavailability studies.

[0049] For locally acting inhaled products, the term “bioequivalence” is based on additional evidence, namely similarity in in vitro testing, similarity in systemic exposure, and similarity in pharmacokinetic and pharmacodynamic studies to demonstrate equivalence in local delivery.

[0050] The term "biowaiver" refers to a waiver granted to biopharmaceutical companies to show in vivo bioequivalence based on in vitro studies.

[0051] The term "in vitro-in vivo correlation" (IVIVC) refers to an in vitro dissolution test that predicts the in vivo performance of a drug product.

[0052] The term "micronized" means a material having a size of a few micrometers, typically 0.1 to 15 micrometers.

[0053] The term "fine particles" means particles having a size of at most several tens of micrometers.

[0054] The term "ultrafine particles" means particles having a particle size equal to or less than 2.0 microns.

[0055] The term "coarse" refers to material having a size of one hundred or several hundred micrometers.

[0056] Generally speaking, the particle size of particles is quantified by measuring a characteristic equivalent spherical diameter, known as the equivalent volume diameter, by means of laser diffraction or a sieve analyzer.

[0057] In other cases, the particle size may be quantified by measuring the mass diameter gravimetrically, for example using a suitable known instrument such as a sieve analyzer.

[0058] The volume diameter (VD) is related to the mass diameter (MD) by the density of the particle (assuming that the density of the particle is independent of size).

[0059] In the present application, the particle size of the active ingredient and the particle size of the fractions of fine and coarse particles are expressed as an equivalent volume diameter.

[0060] The particles have a lognormal distribution defined by a volume median diameter or mass median diameter (VMD or MMD) corresponding to the volume or mass diameter of 50% by weight of the particles, and optionally, by the volume or mass diameters of 10% and 90%, respectively, of the particles.

[0061] Another common way to define a particle size distribution is to quote three values: i) the median diameter d(0.5), which is the diameter above which 50% of the distribution is and below which 50% is; ii) d(0.9), where 90% of the distribution is below this value; iii) d(0.1), where 10% of the distribution is below this value. If the diameters are determined as equivalent volume diameters (assuming that the diameter of a sphere has the same volume as the particle being examined), the three diameter parameters are denoted dv(0.5), dv(0.9), and dv(0.1). VMD corresponds to dv(0.5). MMD corresponds to d(0.5).

[0062] The span is the width of the distribution based on the 10%, 50%, and 90% quantiles and is calculated according to the following formula.

[0063]

[0064] In general, particles with the same or similar VMD or MMD may have different particle size distributions, and in particular different Gaussian distribution widths, as represented by the d(0.1) and d(0.9) values.

[0065] After aerosolization, the particle size is expressed as mass aerodynamic diameter (MAD), while the particle size distribution is expressed as mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). MAD indicates the ability of particles to be suspended and transported in an air stream. MMAD corresponds to the mass aerodynamic diameter of 50% by weight of the particles.

[0066] The terms "additive" and "ternary agent" are used synonymously and by this term we mean substances that can alter the detachment of the active ingredient from the surface of the carrier particles.

[0067] The term "hard granules" refers to spherical or hemispherical units whose core is made of coarse excipient particles.

[0068] The expression "respirable fraction" refers to the percentage index of active particles that will reach the patient's lungs. The respirable fraction, also known as the fine particle fraction (FPF), is evaluated according to the procedures reported in common pharmacopeias, especially the European Pharmacopoeia (Eur.Ph.) 11th edition, paragraph 2.9.18, pages 372-378, using suitable in vitro equipment such as Andersen Cascade Impactor (ACI), Multi Stage Liquid Impinger (MLSI) or Next Generation Impactor (NGI). It is calculated by the percentage ratio of fine particle mass (FPM) (formerly fine particle dose, FPD) to the delivered dose.

[0069] The term "peak inspiratory flow rate" refers to the maximum air flow rate during inspiration by a patient with or without the aid of an inhalation device.

[0070] The term "inspiratory flow rate" refers to the constant rate of airflow capable of producing a pressure drop of 4.0 kPa (40.8 cm H2O) across the inhaler during in vitro testing according to the European Pharmacopoeia (Eur Ph) 11th Edition, paragraph 0671, Preparations for Inhalation: Inhalanda, 998.

[0071] Based on the required inspiratory flow rate (l / min), which in turn depends strictly on their design and mechanical characteristics, DPIs are also divided into:

[0072] i) Low resistance device (about 100l / min);

[0073] ii) medium resistance device (about 80 l / min);

[0074] iii) High resistance device (about 65l / min);

[0075] iv) Ultra-high resistance device (about 40l / min).

[0076] The reported flow rates refer to a 4 kPa (kilopascal) pressure drop according to the European Pharmacopoeia (Eur. Ph.), 11th edition, paragraph 0671, Preparations for Inhalation: Inhalanda, 998.

[0077] The delivered dose, ie the amount of drug effectively delivered to the respiratory tree after each actuation of the inhaler, was calculated from the cumulative deposition in the device, whereas the fine particle mass was calculated from the deposition of particles having a diameter equal to or less than 5.0 microns.

[0078] In the context of the present application, a composition is defined as a "superfine" composition when it is capable of delivering a fraction of particles having a particle size equal to or greater than 20%, preferably equal to or greater than 25%, more preferably equal to or greater than 30% and / or it is capable of delivering a fraction of particles having a particle size equal to or less than 1.0 micron, equal to or greater than 10%.

[0079] The expression "physically stable in the device before use" refers to a composition in which the active particles do not substantially separate and / or detach from the surface of the carrier particles in the delivery device during preparation of the dry powder and before use. The tendency to separate can be evaluated according to Staniforth et al., J. Pharm. Pharmacol. 34, 700-706, 1982, and if the distribution of the active ingredient in the powder composition after the test (expressed as relative standard deviation (RSD)) does not change significantly relative to the distribution of the composition before the test, it is considered acceptable.

[0080] The term "prevent" or "preventing" means slowing the progression, delaying the onset, and / or reducing the risk of developing a disease.

[0081] The term "treatment" means a method for obtaining a beneficial or desired result (including a clinical result). A beneficial or desired clinical result may include, but is not limited to, alleviating or ameliorating one or more symptoms or conditions, alleviating the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing disease spread, delaying or slowing disease progression, improving or alleviating the disease state, and alleviating (whether partially or completely), whether detectable or undetectable. The term may also mean prolonging survival compared to the expected survival without treatment.

[0082] "Unit therapeutically effective dose" or "unit nominal dose" means the amount of active ingredient administered by inhalation at one time when the inhalation device is actuated. The dose can be delivered in one or more actuations, preferably one or two actuations (sprays) of the inhalation device, more preferably in one actuation of the device.

[0083] "Daily dose" means the amount of active ingredient that is administered by inhalation in one day when the inhalation device is actuated.

[0084] "Actuation" refers to the release of the active ingredient from the inhalation device by a single activation (eg mechanical or respiratory).

[0085] The term "delivered dose" refers to the amount of drug effectively delivered to the respiratory tree following each actuation of an inhalation device.

[0086] In the present context, the term "ordered mixture" refers to a homogeneous composition obtained by mixing a mixture of a compound of formula (I) according to the present invention and a pharmaceutically acceptable excipient and / or carrier.

[0087] The expression "good homogeneity" refers to a composition wherein upon mixing the uniformity of the distribution of the active ingredient, expressed as the coefficient of variation (CV), also called relative standard deviation (RSD), is less than 5.0%, preferably equal to or less than 2.5%.

[0088] It has been found that a pharmaceutical product having a compound of formula (I) can be provided wherein the composition produces an in vitro dissolution profile substantially similar to that of a reference product without the use of additional additives, and thus appears to be reliably demonstrated to be bioequivalent. This is achieved by utilizing a single-dose dry powder inhalation device having an inspiratory flow rate of 30 l / min to 65 l / min in combination with an ordered mixture of blended carrier particles having a selected and well-defined particle size.

[0089] Furthermore, as reported in Table 10, the drug product according to the present invention showed consistent inhalation parameters independent of the applied flow rate.

[0090] As standard procedure, the inhalation performance has been determined using the NGI apparatus, testing single nominal doses of 400 and 800 μg of the compound of formula (I).

[0091] Both products according to the invention produced good respirable fractions in the HR RS01 device, i.e., FPF of about 56-58%, and also a significant very fine particle fraction (about 29-30%), as reported in Tables 6 and 7 of Example 3 of this experimental part, and were not substantially different from the respirable fraction and very fine particle fraction of the reference product. Both products according to the invention produced good respirable fractions in the UHR RS01 device, i.e., FPF of about 53-58%, and also a significant very fine particle fraction (about 27-30%), as reported in Tables 8 and 9 of Example 3 of this experimental part, and were not substantially different from the respirable fraction and very fine particle fraction of the reference product.

[0092] In order to determine the similarity between the reference product and the medicinal product of the present invention, a comparative analysis of the complete particle size distribution profiles of the individual grades was also performed according to CPMP / EWP / 4151 / 00, which according to the EMA biowaiver guidance should be considered to be met if the difference is within + / -15%. Although not all grades met this condition, it is well known that the inherent variability of the multi-stage impactor / impactor method is quite high, especially for grades in which small amounts of drug are deposited.

[0093] Therefore, an in vitro dissolution system was established to predict the in vivo performance. Figure 7 and Figure 8 The results reported in show almost superimposable curves for both the medicinal product of the invention at single nominal doses of 400 and 800 μg and the reference product at the same doses.

[0094] Based on these in vitro results and the indications / assumptions of the inhalation bioclassification system (Hastedt JE et al., AAPS / FDA / USP Workshop March 16-17th, Baltimore, AAPS Open, 2016, 2(1), 2016), an IVIV-related model can be developed to demonstrate in vitro equivalence and plausibly demonstrate in vivo bioequivalence, so the product is considered biowaived.

[0095] Advantageously, as through Figure 3 and Figure 4 As can be appreciated from the graph, for the product of the present invention, the aerosolized drug fraction deposited in the inhalation port (IP) and pre-separator (PS) (which simulates the upper (respiratory) tract of the respiratory tree (Sou T et al., J Pharm Sci 2021 110, 66-86)) is reduced, thus indicating lower systemic absorption.

[0096] More advantageously, as reported in Table 10, the products of the present invention exhibited consistent values ​​of aerodynamic parameters at different air flow rates and pressure drops employed in the experiments.

[0097] In a preferred embodiment of the present invention, with reference to the accompanying drawings, a single dose dry powder inhalation, generally indicated by reference numeral 1, comprises an inhaler body 2 and a nasal or oral mouthpiece 5, wherein the inhaler body 2 defines a groove 3 for a capsule 4, and the nasal or oral mouthpiece 5 is communicated with the groove 3 and has an opening 6. Two rupture elements 7 are connected to the inhaler body 2 and are configured to rupture the capsule 4 and allow an external airflow to mix with the pharmaceutical composition contained in the capsule 4 and to be inhaled through the nasal or oral mouthpiece 5. The two rupture elements 7 of the single dose dry powder inhalation device 1 of this embodiment are shaped like nails or needles and are configured to pierce the capsule 4 when a button 8 with rupture elements 7 is pressed and the capsule 4 is located in the groove 3. An air inlet 9 is provided in the inhaler body 2. The air inlet 9 is communicated with the groove 3 to allow the airflow to enter the groove 3 when the user inhales through the nasal or oral mouthpiece 5. The shape and size of the mentioned air inlet 9 can determine the inherent resistance of the single dose dry powder inhalation device to the airflow.

[0098] In a preferred embodiment, the present invention provides a drug comprising a single-dose dry powder inhalation device selected from a high resistance and an ultra-high resistance device. More preferably, the high resistance device is RS01 with code 239700002AA, and the ultra-high resistance device is RS01 with code 239700005AA (Plastiape Spa, Osnago, Italy).

[0099] The inspiratory flow rate is 30 l / min to 65 l / min, more preferably 40 l / min to 65 l / min, as mentioned a pressure drop of 4 kPa, preferably 35 l / min to 65 l / min, more preferably 40 l / min to 65 l / min, even more preferably 35 l / min to 55 l / min, even more preferably 65 l / min, even more preferably 40 l / min.

[0100] The unit nominal dose is between 200 μg and 1000 μg, preferably between 400 μg and 800 μg, more preferably it is 400 μg, even more preferably 800 μg.

[0101] The unit nominal dose may be delivered in one or more actuations of the inhalation device.

[0102] The pharmaceutical composition comprising the compound of general formula (I) should be administered at a daily dose of 800 μg to 4800 μg, preferably 1200 μg to 3800 μg, more preferably 1600 μg to 3200 μg.

[0103] In one embodiment, the daily dose may be achieved by single or double administration.

[0104] In another preferred embodiment, the daily dose may be achieved by a single administration and delivered in one actuation of the inhaler.

[0105] In another preferred embodiment, the daily dose may be achieved by a single administration and delivered in more, preferably two, actuations of the inhaler.

[0106] In another preferred embodiment, the daily dose may be achieved by two administrations and delivered in one actuation of the inhaler.

[0107] In another preferred embodiment, the daily dose may be achieved by two administrations and delivered in more, preferably two, actuations of the inhaler.

[0108] Advantageously, the carrier particles of the present invention may be composed of any physiologically acceptable substance or combination thereof, suitable for use by inhalation, so that the preparation of the present composition results in a convenient and versatile process.

[0109] For example, the carrier particles can be composed of one or more substances selected from the following: polyols, such as sorbitol, mannitol and xylitol; crystalline sugars, including monosaccharides and disaccharides; inorganic salts, such as sodium chloride and calcium carbonate; organic salts, such as sodium lactate; other organic compounds, such as urea; polysaccharides, such as starch and its derivatives; and oligosaccharides, such as cyclodextrin and dextrin.

[0110] Preferably, the particles are made of crystalline sugar, even more preferably selected from: monosaccharides, such as glucose or arabinose, or disaccharides, such as maltose, sucrose, dextrose or lactose.

[0111] Preferably, the particles are made of lactose, more preferably of alpha-lactose monohydrate.

[0112] The carrier consists of a mixture of two different fractions, a coarse particle fraction and a fine particle fraction, both made of physiologically acceptable inert excipients, in a ratio of 70:30 to 95:5, preferably 80:20 to 90:10 by weight. In a preferred embodiment, the ratio is 85:15 by weight. Advantageously, the coarse particle fraction has an equivalent volume diameter of 200 to 500 microns. More advantageously, their equivalent volume diameter is 300 to 480 microns, preferably 350 to 450 microns.

[0113] Advantageously, the fraction of fine particles has an equivalent volume diameter of less than 100 microns, preferably 0.5 microns to 99 microns. More advantageously, the particles have the following distribution measured in equivalent volume diameter: dv(0.1) of 1 to 5 microns, dv(0.5) of 18 to 30 microns, and dv(0.9) of 65 to 95 microns.

[0114] As explained above, the diameter of a particle measured by volume diameter by suitable tools such as laser diffraction or a sieve analyser can be converted to an equivalent mass diameter knowing the density of the particle.

[0115] In a specific embodiment, at least 90% of the active ingredient particles have an equivalent volume diameter of less than 6 microns, even more preferably less than 5 microns. More preferably, the particles may have a mean median diameter of 1.8-4 microns.

[0116] In another embodiment, the compound of formula (I) has an equivalent volume diameter represented by dv(0.1) of 0.5 to 1 micron, dv(0.5) of 1.9 to 2.5 microns, dv(0.9) of 4 to 6 microns, and a span of 1.7 to 2.3 microns.

[0117] In fact, span values ​​within this range ensure that the overall distribution of microparticles is distributed around the median diameter. Therefore, for small values ​​of dv(0.5) (<2.5 μm), there will be a high proportion of very fine particles, which will favor peripheral deposition of the drug in the lungs.

[0118] The particle size of the compound of formula (I) can be measured in dispersed form by laser diffraction, for example, using a Mastersizer instrument (Malvern instrument). In particular, the technique is a wet dispersion. The equipment is provided with the following optical parameters: refractive index of the compound of formula (I) = 1.52, refractive index of the dispersant water = 1.330, absorptivity = 1.0 and obscuration = 7-13%. The sample suspension is prepared by mixing approximately 5 mg of sample with 10 ml of water in a 25 ml beaker and adding 2 drops of Tween 80. The dispersion unit (Malvern instrument) is filled with water, and the pump / agitator in the dispersion unit tank is turned to 3500 rpm and then dropped to zero to remove any bubbles. The sample suspension is sonicated for 1 minute. The pump / agitator is turned to 1000 rpm and the background is then measured. The prepared suspension sample is slowly dripped into the dispersion unit until a stable obscuration of 7-13% is reached and the analysis is started. The analysis is repeated three times.

[0119] According to the present invention, the material of the capsule filled with the pharmaceutical composition of the present invention is selected from the list including but not limited to: hard gelatin, HPMC, plant-based materials, fish gelatin, starch, pullulan, polyvinyl acetate (PVA) and soft gelatin. Preferably, the capsule is made of HPMC capsule or hard gelatin or plant-based materials.

[0120] According to the present invention, the capsules filled with the pharmaceutical composition of the present invention have a range of sizes, 000 to 5, preferably 00el to 4, even more preferably 00 to 3. Even more preferably, the capsules have a size of 2 or 3.

[0121] Depending on the chosen inhaler and the desired dose, the skilled person will select the most appropriate size. According to a preferred embodiment of the invention, when using the RS01 Plastiape inhaler, the size of the capsule will be 2 or 3.

[0122] According to the invention, the composition shows a homogeneity of distribution of the compound of formula (I), expressed as a coefficient of variation (CV), also called relative standard deviation (RSD), of less than 5.0%, preferably equal to or less than 2.5%, as shown in Table 3 of Example 2 in the experimental part.

[0123] Furthermore, the composition is physically and chemically stable after storage in an inhaler at room temperature at 60% relative humidity for at least 24 months.

[0124] In a preferred embodiment, the present invention provides a medicament comprising a single-dose dry powder inhalation device, comprising an inhaler body (2) defining a recess (3) for a capsule (4), a nasal or oral mouthpiece (5) communicating with the recess (3), at least one rupturing element (7), and a pharmaceutical composition filled in the capsule, wherein the capsule (4) contains therein a pharmaceutical composition to be inhaled, the at least one rupturing element (7) being connected to the inhaler body (2) and being configured to rupture the capsule (4) to allow an external airflow to mix with the pharmaceutical composition (4) in the capsule and be inhaled through the nasal or oral mouthpiece (5), the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and a carrier consisting of a mixture of coarse and fine particles of a pharmaceutically inert acceptable excipient,

[0125]

[0126] The inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min, and the carrier consists of a mixture of coarse and fine particles of a physiologically acceptable inert excipient in a ratio of 70:30 to 95:5 by weight, the coarse particles having an equivalent volume diameter of 200 to 500 microns, and the fine particles having a dv(0.1) of 1 to 5 μm, a dv(0.5) of 18 to 30 μm, a dv(0.9) of 65 to 95 μm, as measured by means of a laser diffraction or sieve analyzer.

[0127] In another preferred embodiment, the present invention provides a pharmaceutical composition according to the present invention for use in the treatment of respiratory diseases, wherein the composition is administered using a single-dose dry powder inhalation device, wherein the inhalation flow rate of the inhalation device is 30 l / min to 65 l / min.

[0128] In another preferred embodiment, the present invention provides the use of the medicament of the present invention for treating inflammatory or obstructive respiratory diseases. Alternatively, the present invention provides a pharmaceutical preparation according to the present invention for treating inflammatory or obstructive respiratory diseases after administration by a single-dose inhaler according to the present invention.

[0129] In another preferred embodiment, the present invention provides a medicament as defined above for use in the treatment of an inflammatory or obstructive respiratory disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema and cystic fibrosis.

[0130] Although the carrier should consist of the particles according to the invention, the composition may contain additional active ingredients and optionally other excipients, such as sweeteners and flavorings.

[0131] The additional active ingredients may be selected from active ingredients currently used for the prevention and treatment of respiratory diseases by inhalation, such as beta 2 agonists, corticosteroids and anticholinergics.

[0132] In an even further preferred embodiment, the present invention provides a medicament according to the invention as defined above as an add-on treatment to mono, dual or triple therapy.

[0133] In an even further preferred embodiment, the present invention provides a medicament according to the invention as defined above as an add-on treatment to mono, dual or triple therapy.

[0134] In another preferred embodiment, the present invention provides a medicament according to the present invention as defined above, wherein the single, dual or triple therapy active agent is selected from the group consisting of a beta 2 agonist, a corticosteroid and an anticholinergic.

[0135] In another embodiment, the present invention provides a process for preparing a pharmaceutical composition according to the present invention, comprising the steps of sieving the compound of formula (I) through a suitable sieve, adding the carrier to the compound of formula (I), sieving the final blend and mixing.

[0136] In another preferred embodiment, the present invention provides a method for preparing a pharmaceutical composition according to the present invention, comprising the steps of sieving a compound of formula (I) with one-third of a carrier through a sieve and mixing in a mixer, adding a second one-third of the carrier to the blend and mixing, adding the last one-third of the carrier and mixing, sieving the blend and mixing.

[0137] The capsules are then filled with the pharmaceutical composition according to the invention and loaded into the chambers of individual dry powder inhalation devices.

[0138] The filling of the capsules and the loading of the inhaler are carried out according to the knowledge of a person skilled in the art.

[0139] In another preferred embodiment, the present invention provides a method for preparing a medicament, comprising the step of filling a chamber of a single dry powder inhalation device with a capsule filled with a pharmaceutical composition according to the present invention.

[0140] In an even further preferred embodiment, the present invention provides a method for treating a respiratory disease, which method comprises administering to a patient by inhalation a compound of formula (I) using a medicament as described according to the present invention.

[0141] In another preferred embodiment, the present invention provides a method as defined above for treating a respiratory disease selected from the inflammatory or obstructive respiratory diseases mentioned above.

[0142] The present invention also relates to an inhalation device in the form of a single-dose dry powder inhaler loaded with a pharmaceutical composition comprising micronized particles of a compound of formula (I) and a carrier, wherein the inhaler has an inspiratory flow rate of 30 l / min to 65 l / min and wherein the carrier consists of a blend of physiologically acceptable inert excipients, having a coarse fraction of particles with an equivalent volume diameter between 200 and 500 microns and a fine fraction of particles with an equivalent volume diameter of less than 100 microns, as described above according to the present invention.

[0143] The following non-limiting examples are illustrative of the present disclosure and should not be construed as limiting the scope of the invention in any way.

[0144] Experimental Section

[0145] abbreviation

[0146] MOC = Micro-Orifice Collector; HR = High Resistance; IP = Intake Port; PS = Pre-Separator; UHR = Ultra High Resistance

[0147] Example

[0148] Example 1 : Prepare a blended composition using a mixture of formula (I) compound and crude lactose:fine lactose 85:15

[0149] The crude lactose and fine lactose used to prepare the composition were Pharmatose 50M (490 μm dv 0.9) and 150 (dv0.9 < 95 μm). The coarse lactose is mechanically vibrated and sieved for 30 min, and only particles within the range of 355-490 μm are used for the next step. Coarse: fine ratio is 85:15. Thin and coarse carriers are first mixed in a Turbula mixer at 38 rpm for 50 minutes. Tanimilast and one-third of the carrier are sieved through a 500 μm sieve, and mixed for 40 minutes in a Turbula mixer running at 38 r.pm. Then, the second one-third of the carrier is added to the blend and mixed for 40 minutes at 38 r.pm. Finally, the last part of the carrier is added and mixed for 40 minutes at 38 r.pm. The resulting mixture is forced to pass through a 500 μm sieve to remove any agglomerates, and mixed for 30 minutes at 38 r.pm. A batch size of 10 grams has been produced.

[0150] Table 1: Composition of the present invention, 400 μg

[0151]

[0152] Table 2: Composition of the present invention, 800 μg

[0153]

[0154] Example 2 : Content of the compound of formula (I) (μg) / 20 mg of the composition of the present invention, ± standard deviation and CV% (n=6)

[0155] The uniformity of drug content in the blend was determined by HPLC. Six samples were analyzed, which were randomly collected in the mixture and dissolved in 100 ml of acetonitrile / water (60 / 40) v / v used as solvent. 20 mg of each sample was weighed.

[0156] Table 3: Content of the compound of formula (I) in 400 or 800 μg strength / 20 mg composition of the present invention, ± standard deviation and CV% (n=6)

[0157] sample 400 μg of compound of formula (I) / 20 mg 800 μg of compound of formula (I) / 20 mg #1 402.1 802.9 #2 393.1 792.4 #3 388.9 806.0 #4 407.6 804.9 #5 405.7 810.3 #6 380.2 798.4 Mean (± standard deviation) 396.2±10.7 802.5±6.3 CV(%) 2.7 0.8

[0158] The blends in Table 3 show excellent accuracy and uniformity of distribution of the active ingredient (precision is CV).

[0159] Example 3 :Determination of aerodynamic particle size distribution (APSD)

[0160] In vitro aerodynamic assessments were performed using a new generation impactor (NGI), following the procedure detailed in European Pharmacopoeia 10.0 in chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles", pages 347-360. Nexthaler (Chiesi, Parma, Italy) was combined with 400 μg and 800 μg of a composition prepared according to WO2012 / 016889, considered as a reference product.

[0161] RS01 high resistance with code 239700002AA and RS01 ultra high resistance with code 239700005AA (Plastiape, Osnago, LC, Italy) were used to analyze 400 μg and 800 μg of the drug product according to the composition invention. The capsules used were Size 3 (Qualicaps Europe, SAU) and loaded with approximately 20 mg. The DPI inhaler was activated at a pressure drop of 4 kPa, corresponding to flow rates of: Nexthaler 57.5 L / min, RS01 high resistance 65 L / min, RS01 ultra-high resistance 40 L / min, for a duration sufficient to sample an air volume of 4.0 liters. The NGI was connected to a vacuum pump and the air flow was fixed using a flow meter. The analysis was performed under critical flow control conditions. The device was connected to the NGI via a rubber adapter, a single dose was released and collected in the device. Acetonitrile / water (60 / 40) v / v was used as solvent to recover the drug remaining in the capsule and device (only for RS01 analysis) and the drug deposited in different parts of the impactor. The samples were filtered with an RC filter (0.45 μm) and quantified using HPLC to determine the amount of drug. In all experiments performed, the percentage of active ingredient recovered in the entire instrument was higher than 85% of the nominal dose.

[0162] The measured dose (MD) was calculated by summing the drug recovered from the impactor (IP, PS, Levels 1 to 7, and MOC) with the drug remaining in the inhaler (capsule and device). The MD of the multidose Nexthaler DPI could not be quantified because it is a reservoir-type multidose inhaler and could not be wetted and rinsed at the end of the experiment.

[0163] The emitted dose (ED) is the amount of drug that leaves the device and enters the impactor and is calculated by summing the drug recovered from the impactors (IP, PS, levels 1 to 7, and MOC).

[0164] Drug deposition in the impactor allows calculation of aerodynamic parameters.

[0165] The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) are determined by plotting the cumulative mass percentage of each NGI class less than a specified aerodynamic diameter on a probability scale versus the aerodynamic diameter of that class on a logarithmic scale. A linear regression is performed on the six data points closest to 50% of the cumulative particle mass entering the impactor to calculate the MMAD and GSD.

[0166] Fine particle mass (FPM) was calculated as the mass of drug <5 μm (calculated by the log-probability plot equation) and fine particle fraction (FPF) was determined as the percentage ratio between FPD and ED.

[0167] The very fine particle mass (EFPM) was calculated as the mass of drug below 2 μm (calculated by the log-probability plotting equation) and the very fine particle fraction (EFPF) was determined as the percentage ratio between EFPD and ED.

[0168] Table 4: APSD of Nexthaler device loaded with 400 μg of reference composition

[0169] Nexthaler device loaded with reference composition (400 μg of CHF001 / 20 mg) ejection weight (mg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3)

[0170]

[0171] Table 5: APSD of Nexthaler device loaded with 800 μg of reference composition

[0172] Nexthaler device loaded with reference composition (800 μg of CHF001 / 20 mg) ejection weight (mg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3)

[0173]

[0174] Table 6: APSD of HR RS01 device loaded with 400 μg of the composition of the invention

[0175] Ejection weight (mg), measured dose (μg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3) of RS01 device loaded with the composition of the present invention (400 μg of the compound of formula (I) / 20 mg)

[0176]

[0177] Table 7: APSD of HR RS01 device loaded with 800 μg of the composition of the invention

[0178] Ejection weight (mg), measured dose (μg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3) of RS01 device loaded with the composition of the present invention (800 μg of the compound of formula (I) / 20 mg)

[0179]

[0180] As shown in Tables 6 and 7, both products according to the present invention produced good respirable fractions in the HR RS01 device, i.e. FPF of about 56-58%, as well as significant very fine particle fractions (about 29-30%), and according to the results compared with Tables 4 and 5, the respirable fractions and very fine particle fractions were similar to those of the reference product.

[0181] like Figure 5 and Figure 6 As shown in, after in vitro evaluation of inhalation performance, the amount of emitted dose remaining in the first two stages of the impactor simulating the upper part of the respiratory tree (larynx, large bronchi) is less for the composition of the present invention than for the reference composition. This will lead to lower systemic absorption of the API.

[0182] Table 8: APSD of UHR device loaded with 400 μg of the composition of the invention

[0183] Ejection weight (mg), measured dose (μg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3) of the UHR RS01 device loaded with the composition of the present invention (400 μg of the compound of formula (I) / 20 mg)

[0184]

[0185] Table 9: APSD of UHR device loaded with 800 μg of the composition of the invention

[0186] Ejection weight (mg), measured dose (μg), emitted dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3) of the UHR RS01 device loaded with the composition of the present invention (800 μg of the compound of formula (I) / 20 mg)

[0187]

[0188] As shown in Tables 8 and 9, both products according to the present invention produced good respirable fractions, i.e. FPF of about 53-58%, and significant very fine particle fractions (about 27-30%) in the UHR RS01 device, and according to the results compared with Tables 4 and 5, the respirable fractions and very fine particle fractions were similar to those of the reference product.

[0189] Example 4: Dissolution Test

[0190] Using RespiCell TM(EU Registration No. 006649570-0001) In vitro dissolution testing was performed to compare the performance of 400 μg and 800 μg of the reference product and the drug product of the present invention. The apparatus has been constructed to overcome some of the shortcomings of the type of dissolution testing currently used for pulmonary products (Sonvico F. et al., Pharmaceutics 2021, 13(10), 1541).

[0191] It is a vertical diffusion cell apparatus consisting of a 170 cm 3 reservoir and 10 cm long side arms. The device consists of an upper part (donor chamber) and a lower part (receiver chamber), connected by a bayonet and separated by a glass fiber filter, which serves as a diffusion membrane and is placed horizontally in contact with the dissolution medium. The receptor chamber contains a magnetic stirrer in its interior. A 76 mm diameter A / E type glass fiber filter (PALL Corporation, Port Washington; NY, USA) is used as a diffusion membrane. The dissolution medium used for the analysis is phosphate buffered saline (PBS) with 0.5% sodium dodecyl sulfate (SDS). RespiCell TM Connected to a heating thermostat (Lauda eco silver E4, DE) set at 37 ± 0.5 ° C. The receptor chamber is filled with dissolution medium and samples are taken through the side arm of the cell at preset time intervals. After aerosolization by a fast screening impactor (Fast Screening Impactor, FSI), the fine fractions deposited on the diffusion membrane filter are analyzed. The in vitro aerodynamic evaluation is performed according to the procedures detailed in the European Pharmacopoeia 10.0 chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles" on pages 347-360. RS01 equipment is used for analysis. The capsules used are Size 3 (Qualicaps Europe, SAU) and loaded with approximately 20 mg of the composition powder. The inhaler was activated at a pressure drop of 4 kPa, corresponding to a flow rate of 65 L / min, for a duration sufficient to sample an air volume of 4.0 liters. The FSI was connected to a vacuum pump and the air flow was fixed using a flow meter. The analysis was performed under critical flow control conditions. The device was connected to the FSI via a rubber adapter; the contents of two or four capsules were aerosolized and two or four fine particle doses were collected in the device for 800 or 400 μg strength, respectively. For each selected composition, the analysis was performed in triplicate. After aerosolization, the filter was removed by the FSI and placed in the RespiCell TMThe dissolution medium of 1mL is applied to the filter before analysis so that it is fully wetted. 1mL receiving solution is removed by the receptor chamber at fixed intervals, and after each taking out, replaced with the fresh dissolution medium of 1mL, to keep constant volume. In order to assess the amount of the medicine that is not dissolved or trapped in the filter, at the end of the experiment, the remaining undissolved powder is reclaimed by washing the filter with 10mL of acetonitrile: water 60:40. The amount of the medicine in the sample is assessed by HPLC. Data are represented by the percentage of dissolved formula (I) compound, and 100% dissolution corresponds to the amount of medicine dissolved at the end of the experiment. The difference factor (f1) and similarity factor (f2) that have been proposed are used to compare the dissolution profiles of oral dosage forms, examining the dissolution profile from the perspective of the fraction and total amount dissolved over time (Shah, VP et al., FDA Guidance for Industry 1 Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Dissolut. Technol. 1997, 4, 15-22; EMA, CHMP, Guideline on the Investigation of Bioequivalence, https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-investigationbioequivalence-rev1_en.pdf).

[0192] The difference factor (f1) calculates the percent difference between the two dissolution profiles at each time point and is a measure of the relative error between the two profiles.

[0193] The difference factor (f1) is calculated as follows:

[0194]

[0195] The similarity factor (f2) is calculated as follows:

[0196]

[0197] n is the number of time points, Rt is the average dissolution value of the reference product at time t, and Tt is the average dissolution value of the test product at the same time point. The evaluation of f1 and f2 is based on the following conditions: at least three time points should be considered (excluding zero), and the time points of the two compositions should be the same, and for any composition, no more than one average value should exceed 85% of the dissolved drug. In addition, for the first time point, the relative standard deviation (coefficient of variation) should be less than 20%, and for the other considered time points should be less than 10%. Difference factor (f1) values ​​below 15 (0-15) indicate that there are no significant differences between the dissolution curves. Similarity factor (f2) values ​​above 50 (50-100) indicate the similarity between the two dissolution curves.

[0198] Comparative in vitro dissolution testing between the reference product and the drug product of the present invention at 400 μg and 800 μg doses was performed and the results were Figure 7 and 8 It can be appreciated that within the experimental limits of this method, the curves prove to be nearly superimposable.

[0199] Based on these in vitro results and the indications / assumptions of the inhalation bioclassification system (Hasted JE et al., AAPS / FDA / USP Workshop March 16-17 th , Baltimore, AAPS Open, 2016, 2(1), 2016), an IVIV-related model can be established to demonstrate plausible bioequivalence and the product can be considered biowaived.

[0200] Example 4: Aerodynamic characteristics at different air flow rates

[0201] The current European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP) pharmacopeia procedures for evaluating the drug delivery performance of DPIs require that 4.0 L of air be drawn through the inhaler at a pressure drop of 4 kPa to quantify delivered dose uniformity and aerodynamic particle size distribution.

[0202] However, according to the Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products, it is recommended that DPIs demonstrate consistent delivery performance over a specific flow rate / inspiratory force range that should represent the range achievable in the intended patient population.

[0203] Therefore, the deposition characteristics and dose delivery of 800 μg of a drug product according to the present composition invention were determined at different flow rates. In vitro aerodynamic evaluations were performed using a new generation impactor (NGI).

[0204] The analysis was performed using a RS01 high resistance device (Plastiape, Osnago, LC, Italy) with code 239700002AA. The capsule used was Size 3 (Qualicaps Europe, SAU) and loaded with about 20 mg. The DPI inhaler was activated at a pressure drop of 1.5 kPa, corresponding to a flow rate of 40 L / min; at a pressure drop of 4.0 kPa, corresponding to a flow rate of 65 L / min and at a pressure drop of 9.5 kPa, corresponding to a flow rate of 100 L / min. For each test, a duration sufficient to sample 4.0 liters of air volume was set.

[0205] The experimental procedure, sample collection and calculation of aerodynamic parameters were performed as detailed in Example 1.

[0206] Table 10: APSD of RS01 devices loaded with 800 μg of the composition of the invention at different applied air flow rates

[0207] Emission dose (μg), MMAD (μm), FPM (μg), FPF (%) mean ± standard deviation and CV% (n=3) of RS01 device loaded with the composition of the present invention (800 μg of the compound of formula (I) / 20 mg)

[0208] For effective DPI performance, respiratory patient characteristics are issues that must be addressed. Developing a DPI that is independent of flow rate is a strategy to overcome this problem. As can be appreciated from Table 10, the compositions of the present invention show consistent ED, MMAD, FPM and FPF independent of the applied flow rate within the range of 40-100 L / min.

Claims

1. A medicament comprising a single-dose dry powder inhalation device, comprising an inhaler body (2) defining a recess (3) for a capsule (4), a nasal or oral mouthpiece (5) communicating with the recess (3), at least one rupturing element (7), and a pharmaceutical composition filled in the capsule, wherein the capsule (4) contains therein a pharmaceutical composition to be inhaled, the at least one rupturing element (7) being connected to the inhaler body (2) and being configured to rupture the capsule (4) to allow an external airflow to mix with the pharmaceutical composition in the capsule (4) and to be inhaled through the nasal or oral mouthpiece (5), the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and a carrier consisting of a mixture of coarse and fine particles of a pharmaceutically inert acceptable excipient wherein the inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min, and wherein the carrier consists of a mixture of coarse and fine particles of a physiologically acceptable inert excipient in a ratio of 70:30 to 95:5 by weight, the coarse particles having an equivalent volume diameter of 200 to 500 microns, and the fine particles having a dv(0.1) of 1 to 5 μm, a dv(0.5) of 18 to 30 μm, and a dv(0.9) of 65 to 95 μm, as measured by means of a laser diffraction or sieve analyzer.

2. The drug according to claim 1, wherein the carrier is selected from the group consisting of polyols, crystalline sugars, inorganic salts, organic salts, organic compounds, polysaccharides and oligosaccharides.

3. The drug according to claim 1 or 2, wherein the coarse particles have an equivalent volume diameter of 300 to 480 microns. The drug according to claim 3 , wherein the coarse particles have an equivalent volume diameter of 350 to 450 μm.

5. The medicine according to any one of claims 1 to 4, wherein the inspiratory flow rate is 40 l / min to 65 l / min.

6. A medicinal product according to any one of the preceding claims, wherein the unit nominal dose of the compound of formula (I) is 400 to 800 μg.

7. The pharmaceutical product according to claim 6, wherein the unit nominal dose of the compound of formula (I) is 400 μg.

8. The pharmaceutical product according to claim 6, wherein the unit nominal dose of the compound of formula (I) is 800 μg.

9. A pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and a carrier for treating respiratory diseases, The composition is administered using a single-dose dry powder inhalation device, wherein the inhalation device has an inspiratory flow rate of 30 l / min to 65 l / min, and wherein the carrier consists of a mixture of coarse and fine particles of a physiologically acceptable inert excipient in a ratio of 70:30 to 95:5 by weight, the coarse particles having an equivalent volume diameter of 200 to 500 microns as measured by laser diffraction or a sieve analyzer, and the fine particles having a dv(0.1) of 1 to 5 μm, a dv(0.5) of 18 to 30 μm, and a dv(0.9) of 65 to 95 μm, as measured by laser diffraction or a sieve analyzer.

10. The pharmaceutical composition for use according to claim 9, wherein the respiratory disease is selected from asthma and chronic obstructive pulmonary disease (COPD).

11. A pharmaceutical composition for use according to claim 9 or 10, wherein the total daily dose of the compound of formula (I) is 800 to 4800 μg.

12. The pharmaceutical composition for use according to claim 11, wherein the total daily dose of the compound of formula (I) is 1600 to 3200 μg.

13. A method for preparing a medicament according to any one of claims 1 to 8, comprising the following steps: i) sieving the compound of formula (I) through a suitable sieve, ii) adding carrier particles to the compound of formula (I), iii) sieving the final blend and mixing to obtain a pharmaceutical composition, iv) filling the obtained pharmaceutical composition in capsules, and v) loading the chamber of a single dry powder inhalation device with the capsules.

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