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, said pharmaceutical composition comprising micronized particles of a compound of formula (I) and a carrier. The invention also relates to a pharmaceutical product or a 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 pharmaceutical product 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 pharmaceutical product or a pharmaceutical composition for treating respiratory diseases and a method for treating respiratory diseases. Background Art

[0002] Compound of formula (I)

[0003]

[0004] Also known as tanimilast or CHF6001 or CHF-6001, with INN (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 currently in clinical development.

[0005] The compound of formula (I) has been disclosed in the prior art literature under the name of Chiesi: WO2009 / 018909 relates to its general formula, preparation method, composition and therapeutic use; WO2010 / 089107 specifically relates to sulfonylamino derivatives as (-) enantiomers, including compounds of formula (I), preparation methods, compositions and therapeutic uses; WO2012 / 016889 relates to dry powder compositions containing compounds of formula (I); WO2015 / 059050 relates to a crystalline form of the compound of formula (I) characterized by a specific XRPD peak (referred to as Form A) and a method for obtaining it.

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

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

[0008] Tanimilast is currently in late clinical stages testing two different unit nominal doses (i.e., 400 and 800 μg) and is in the form of a powder composition that utilizes the platform technology disclosed in WO2012 / 016889 and is delivered via a proprietary multi-dose Inhaler administration. The product is denoted hereinafter as "reference product".

[0009] As carrier, cracked coarse lactose and as ternary agent a fraction consisting of a mixture of fine lactose and magnesium stearate were used. Said composition as disclosed in WO2012 / 016889 is hereinafter indicated as "reference composition".

[0010] Due to the characteristics of the inhaler and platform technology, the composition provides an excellent respirable fraction as well as a large number of ultrafine particles. There is indeed a consensus on the fact that ultrafine particles are able to reach the distal parts of the respiratory tree and thus improve small airway outcomes 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, the third agent is inhaled by the patient and thus increases the regulatory burden when seeking approval for the product.

[0012] It would therefore be advantageous to provide a platform technology for administering a compound of formula (I) in powder form which has the same inhalation performance as a reference product but without the use of a third agent.

[0013] The inventors surprisingly found that the pharmaceutical product of the invention has the same inhalation performance as the reference product, but without the use of a third agent. SUMMARY OF THE INVENTION

[0015] In a first aspect, the present invention relates to a pharmaceutical product comprising a single-dose dry powder inhalation device, the device comprising an inhaler body (2) defining a recess (3) for a capsule (4), wherein the capsule (4) contains a pharmaceutical composition to be inhaled therein, a nosepiece or a mouthpiece (5) communicating with the recess (3), at least one rupturing element (7), the 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 be inhaled through the nosepiece or the mouthpiece (5), and a pharmaceutical composition filled in the capsule, the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and comprising lactose carrier particles, wherein the inhalation flow rate of the inhalation device is 30 l / min to 65 l / min, and wherein the lactose carrier particles have an equivalent volume diameter of less than 110 microns as measured by a laser diffraction or sieve analyzer,

[0016]

[0017] In a second aspect, the present invention relates to a pharmaceutical composition for the treatment of respiratory diseases, comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and comprising lactose carrier particles, 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, and wherein the equivalent volume diameter of the lactose carrier particles measured by laser diffraction or sieving analyzer is less than 110 microns.

[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 pharmaceutical product 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 process for preparing a pharmaceutical product according to the present invention, said process comprising the steps of: i) sieving a compound of formula (I) through a suitable sieve, ii) adding lactose carrier particles to the compound of formula (I), iii) sieving the final blend and mixing to obtain the final pharmaceutical composition, iv) filling the obtained pharmaceutical composition in capsules, v) loading the drug chamber of the single-dose dry powder inhalation device with said capsules. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : Deposition of the compound of formula (I) in the stages of the NGI device after delivery of 400 μg of the reference product

[0023] Figure 2 : Deposition of the compound of formula (I) in the stages of the NGI device after delivery of 800 μg of the reference product

[0024] Figure 3 : Deposition of the compound of formula (I) in the NGI device stage after delivery of 400 μg of the drug product of the invention in the RS01 HR inhalation device

[0025] Figure 4 : Deposition of the compound of formula (I) in the NGI device stage after delivery of 800 μg of the drug product of the invention in the RS01 HR inhalation device

[0026] Figure 5 : Comparison of deposition of the compound of formula (I) after delivery of 400 μg of the reference product vs 400 μg of the drug product of the invention in the RS01 HR inhalation device

[0027] Figure 6 : Comparison of deposition of the compound of formula (I) after delivery of 800 μg of the reference product vs 800 μg of the drug product of the invention in the RS01 HR inhalation device

[0028] Figure 7 : In vitro dissolution profiles of 400μg and 800μg reference products

[0029] Figure 8 : Comparison of in vitro dissolution of the reference product and the pharmaceutical product of the invention at a nominal dose of 400 μg unit: a) μg; b) %.

[0030] Fig. 9 : Comparison of in vitro dissolution of the reference product and the pharmaceutical product of the invention at a nominal dose of 800 μg unit: a) μg; b) %.

[0031] Fig.10 : A three-dimensional view of a single-dose dry powder inhalation device according to an embodiment of the present invention

[0032] Fig.11 : In the first operating configuration Fig.10 Cross section of a single-dose dry powder inhaler device

[0033] Fig.12 : In the second operating configuration Fig.10 Cross section of a single-dose dry powder inhaler device DETAILED DESCRIPTION OF THE INVENTION

[0035] definition

[0036] 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.

[0037] Unless otherwise stated, the compounds of formula (I) of the present invention are intended to also include polymorphs, stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0038] The terms "micron", "micrometers" and μm are used synonymously.

[0039] The terms "microgram" and μg are used synonymously.

[0040] The terms "percent" and % are used synonymously.

[0041] The term "pharmaceutically acceptable salts" as used herein refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any free acid or basic group (if present) into the corresponding addition salt with any base or acid conventionally expected to be pharmaceutically acceptable. Thus, suitable examples of such salts may include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acid residues such as carboxyl groups.

[0042] Suitable cations of inorganic bases for preparing salts include ions of alkali metals or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0043] Those obtained by reacting the main compound acting as a base with an inorganic or organic acid to form a salt include, for example, 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 salts.

[0044] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. Such physical associations include hydrogen bonding. In certain instances, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0045] The term "stereoisomers" refers to isomers of identical composition that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0046] The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric species, wherein the composition is devoid of optical activity.

[0047] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0048] The term "composition" as in pharmaceutical composition is intended to encompass 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, complex or aggregation of any two or more of such ingredients, or from the dissociation of one or more such ingredients, or from other types of reactions or interactions of one or more such ingredients.

[0049] The term "physiologically acceptable" refers to safe, pharmacologically inert substances used as excipients.

[0050] The term "bioequivalence" generally refers to the absence of significant differences in bioavailability, i.e., the extent of absorption and peak concentrations over a period of time, at the same dose and under the same conditions, between two drug products (e.g., a test product and a reference product).

[0051] Whether a test product is bioequivalent to a reference product is determined by conducting a study in a group of subjects (called a bioequivalence or comparative bioavailability study).

[0052] 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.

[0053] The term “biowaiver” refers to a waiver granted to biopharmaceutical companies to show in vivo bioequivalence based on in vitro studies.

[0054] The term "in vitro-in vivo correlation" (IVIVC) refers to an in vitro dissolution test that is predictive of the in vivo performance of a drug product.

[0055] The term "micronized" refers to material that is a few microns in size, typically 0.1 to 15 microns.

[0056] The term "fine particles" refers to particles having a size of at most several tens of micrometers.

[0057] The term "ultrafine particles" refers to particles having a particle size equal to or less than 2.0 microns.

[0058] The term "coarse" refers to material that is one hundred or several hundred microns in size.

[0059] Generally, the particle size is quantified by laser diffraction, measuring a characteristic equivalent spherical diameter, called the equivalent volume diameter. Otherwise, the particle size can be quantified by measuring the mass diameter by gravimetric methods, for example using a suitable known instrument such as a sieve analyzer.

[0060] The volume diameter (VD) is related to the mass diameter (MD) through the density of the particle (assuming that the density of the particle is independent of size).

[0061] In the present application, the particle size of the active ingredient is expressed in terms of an equivalent volume diameter, and the particle size of the carrier particles is also expressed in terms of an equivalent volume diameter.

[0062] The particles have a lognormal distribution defined by a volume 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% of the particles, respectively.

[0063] Another common way to define particle size distribution is to quote three values: i) the median diameter d(0.5), which is the diameter where 50% of the distribution is above this value and 50% is below this value, 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 volumes, the three 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).

[0064] The span is the width of the distribution based on the 10%, 50%, and 90% quantiles and is calculated according to the formula.

[0065]

[0066] 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 indicated by the d(0.1) and d(0.9) values.

[0067] In atomization, particle size is expressed as mass aerodynamic diameter (MAD), while particle size distribution is expressed as mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). MAD indicates the ability of particles to be transported in suspension in an air stream. MMAD corresponds to the mass aerodynamic diameter of 50% by weight of the particles.

[0068] The terms "additive" and "third agent" are used synonymously and by these terms we mean a substance that can alter the detachment of the active ingredient from the surface of the carrier particles.

[0069] The term "hard pellets" refers to spherical or hemispherical units whose core is made of coarse excipient particles.

[0070] The expression "respirable fraction" refers to an index of the percentage of active particles that will reach the patient's lungs. The respirable fraction, also expressed as fine particle fraction (FPF), is evaluated according to the procedures reported in the general pharmacopoeia, in particular the European Pharmacopoeia (Eur.Ph.), 11th edition, paragraph 2.9.18, 372-378, using a suitable in vitro device such as Andersen cascade impactor (ACI), multi-stage liquid impactor (MLSI) or next generation impactor (NGI). It is calculated as a percentage of fine particle mass (FPM) (formerly fine particle dose, FPD) to delivered dose.

[0071] The term "peak inspiratory flow rate" refers to the maximum rate of air flow during inspiration by a patient with or without the aid of an inhalation device.

[0072] The term "inspiratory flow rate" refers to the ability to produce 4.0 kPa (40.8 cmH 2 O) on an inhalation device during in vitro testing according to the European Pharmacopoeia (Eur. Ph.), 11th edition, paragraph 0671, Preparations for Inhalation: Inhalanda, 998. 2 O) is a constant rate of air flow with a pressure drop of 1.

[0073] Based on the required inspiratory flow rate (l / min), which in turn strictly depends on its design and mechanical characteristics, DPI is also divided into:

[0074] i) Low resistance device (about 100l / min);

[0075] ii) medium resistance device (about 80 l / min);

[0076] iii) High resistance device (about 65l / min);

[0077] iv) Ultra-high resistance device (about 40l / min).

[0078] According to the European Pharmacopoeia (Eur. Ph.), 11th edition, paragraph 0671, Preparations for Inhalation: Inhalanda, 998, the reported flow rates refer to a pressure drop of 4 kPa (kilopascals).

[0079] 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 with a diameter equal to or less than 5.0 microns.

[0080] In the context of the present application, a composition is defined as an "ultrafine" composition when it is capable of delivering a fraction of particles having a size equal to or less than 2.0 microns equal to or higher than 20%, preferably equal to or higher than 25%, more preferably equal to or higher than 30% and / or it is capable of delivering a fraction of particles having a size equal to or lower than 1.0 microns equal to or higher than 10%.

[0081] The expression "physically stable in the device prior to use" refers to a composition in which the active particles do not substantially separate from and / or break away from the surface of the carrier particles during preparation of the dry powder and in the delivery device prior to use. The tendency to separate can be evaluated according to Staniforth et al. J. Pharm. Pharmacol. 34, 700-706, 1982 and is considered acceptable if the distribution of the active ingredient in the powder composition after the test (expressed as relative standard deviation (RSD)) does not change significantly relative to the distribution of the composition before the test.

[0082] The term "prevent" means to slow the progression, delay the onset and / or reduce the risk of contracting a disease.

[0083] 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 if not receiving treatment.

[0084] "Unit therapeutically effective dose" or "unit nominal dose" refers to 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 of the device, preferably in one or two actuations (ejections), more preferably in one actuation of the device.

[0085] "Daily dose" means the amount of active ingredient which is administered by inhalation in one day when the inhalation device is actuated.

[0086] "Actuation" refers to the release of the active ingredient from the device by a single activation (eg, mechanical or respiratory).

[0087] The term "delivered dose" refers to the amount of drug effectively delivered to the respiratory tree following each actuation of the inhalation device.

[0088] Herein, the term "ordered mixture" refers to a homogeneous composition obtained by mixing the compound of formula (I) of the present invention with a pharmaceutically acceptable excipient and / or carrier.

[0089] The expression "good homogeneity" refers to a composition wherein after mixing the active ingredient has a uniformity of distribution (expressed as coefficient of variation (CV), also called relative standard deviation (RSD)) of less than 5.0%, preferably equal to or less than 2.5%.

[0090] It has surprisingly been found that a pharmaceutical product having a compound of formula (I) can be provided wherein the composition produces a substantially similar in vitro dissolution profile to a reference product without the use of further additives, and is therefore reasonably 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 comprising carrier particles of a selected and well-defined particle size.

[0091] As standard procedure, the inhalation performance was determined using the NGI apparatus, and the compounds of formula (I) were tested at nominal doses of 400 and 800 μg.

[0092] Both products according to the invention produced good respirable fractions, i.e. FPFs of about 56-58%, and also had a significant fraction of ultrafine particles (about 25-26%), as reported in Tables 6 and 7 of Example 3 in this experimental part, and were substantially similar to those of the reference product.

[0093] A comparative analysis of the complete particle size distribution curves of the various stages was also performed in accordance with CPMP / EWP / 4151 / 00 in order to establish the similarity between the reference product and the medicinal product of the invention, which should be considered to be met according to the EMA biowaiver guidance if the difference is within + / -15%. Although not all stages met this condition, it is well known that the inherent variability of the multi-stage impactor / impactor method is quite high, especially with regard to the stages where small amounts of drug are deposited.

[0094] Therefore, an in vitro dissolution system was established to predict the in vivo performance.

[0095] Figure 8 and Fig. 9 The results reported in show almost superimposable curves for the drug product of the invention at nominal unit doses of 400 and 800 μg and the reference product at the same nominal unit doses.

[0096] Based on these in vitro results and the indications / assumptions of the inhalation bioclassification system (Hastedt JE et al AAPS / FDA / USP Workshop March 16-17 th, Baltimore, AAPS Open, 2016, 2(1), 2016), an IVIV correlation model can be established to demonstrate in vitro equivalence and reasonable in vivo bioequivalence, thus candidate the product for biowaiver.

[0097] More advantageously, by Figure 3 and Figure 4 As can be understood from the figure, for the product of the present invention, the fraction of aerosolized drug deposited in the air inlet (IP) and the pre-separator (PS), simulating the upper respiratory tract of the respiratory tree (Sou T et al JPharm Sci 2021 110, 66-86), is relatively Figure 1 and Figure 2 The reference product is shown to be reduced, thus indicating lower systemic absorption.

[0098] 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 defining a recess 3 for a capsule 4 and a nasal or oral inhalation portion 5 communicating with the recess 3 and having an opening 6. Two rupture elements 7 are connected to the inhaler body 2 and are configured to rupture the capsule 4 to allow external airflow to mix with the pharmaceutical composition contained in the capsule 4 and be inhaled through the nasal or oral inhalation portion 5. The two rupture elements 7 of the single-dose dry powder inhalation device 1 of this embodiment are shaped like a nail or a needle and are configured to pierce the capsule 4 when a button 8 carrying the rupture elements 7 is pushed and the capsule 4 is located in the recess 3. An air inlet 9 is provided in the inhaler body 2. The air inlet 9 is communicated with the recess 3 so as to allow airflow to enter the recess 3 when the user inhales through the nasal or oral inhalation portion 5. The shape and size of the cited air inlet 9 can determine the inherent airflow resistance of the single-dose dry powder inhalation device.

[0099] In a preferred embodiment, the present invention provides a pharmaceutical product 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 Plastiape code 239700002AA, and the ultra-high resistance device is RS01 with Plastiape code 239700005AA (Plastiape Spa, Osnago, Italy).

[0100] For a pressure drop of 4 kPa, the inspiratory flow rate should be 30 l / min to 65 l / min, more preferably 40 l / min to 65 l / min, 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.

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

[0102] The daily dosage of the pharmaceutical composition comprising the compound of formula (I) is 800 μg to 4800 μg, preferably 1200 μg to 3800 μg, and 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 can be achieved by a single administration and delivered in one actuation of the inhaler.

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

[0106] In another preferred embodiment, the daily dose can be achieved by double administration and delivered in one actuation of the inhaler.

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

[0108] Advantageously, the carrier particles of the present invention may be composed of any physiologically acceptable material or combination of materials suitable for use by inhalation, resulting in a convenient and versatile method of preparing the compositions of the present invention.

[0109] For example, the carrier particles can be composed of one or more materials 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] Advantageously, the carrier particles have an equivalent volume diameter (the diameter of an imaginary sphere having the same volume as the particle under examination) of between 0.2 and 110 micrometers. More advantageously, their equivalent volume diameter is between 0.5 and 95 micrometers, preferably between 1 and 90 micrometers.

[0113] The equivalent volume diameter can be measured by laser diffraction or sieving analyzer.

[0114] As explained above, particle diameters measured by volume diameter by suitable means (eg laser diffraction or sieve analyzer) can be converted to equivalent mass diameters given a known particle density.

[0115] In a specific embodiment, the physiologically acceptable excipient used as a carrier has an equivalent volume diameter of 1 to 95 microns.

[0116] More preferably, the physiologically acceptable excipient used as a carrier has the following distribution measured by volume diameter: dv(0.1) is 1 to 5 microns, dv(0.5) is 18 to 30 microns, and dv(0.9) is 65 to 95 microns. The excipient having the desired particle size can be suitably prepared by sieving, or it is commercially available, for example as 150 (Meggle GmbH, Wasserburg am Inn, Germany).

[0117] Advantageously, at least 90% of the active ingredient particles have a volume diameter of less than 6 microns, even more preferably less than 5 microns. More preferably, the particles may have an average median diameter of between 1.8 and 4 microns.

[0118] In a preferred embodiment, the compound of formula (I) has an equivalent volume diameter expressed as 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.

[0119] In fact, span values ​​within this range ensure that the population distribution of microparticles is distributed around the median diameter. Therefore, for small dv(0.5) values ​​(<2.5 microns), there will be a high proportion of ultrafine particles, which will favor peripheral deposition of the drug in the lung.

[0120] The particle size of the compound of formula (I) can be measured as a dispersion by laser diffraction, for example using a Mastersizer instrument (Malvern instruments). In particular, the technique is wet dispersion. The device 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, absorption = 1.0 and obscuration = 7-13%. The sample suspension is prepared by mixing about 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 instruments) is filled with water, and the pump / agitator in the dispersion unit tank is turned to 3500 rpm and then reduced to zero to remove any bubbles. The sample suspension is ultrasonically treated for 1 minute. The pump / agitator is turned to 1000 rpm and the background is then measured. Slowly, the prepared suspension sample is dripped into the dispersion unit until a stable obscuration reaches 7-13% and the analysis is started. The analysis is performed in triplicate.

[0121] According to the present invention, the material of the capsule that is wherein filled with the pharmaceutical composition of the present invention is selected from and includes but is 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.

[0122] According to the present invention, the size of the capsule filled with the pharmaceutical composition of the present invention ranges from 000 to 5, preferably from 0011 to 4, even more preferably from 00 to 3. Even more preferably, the size of the capsule is 2 or 3.

[0123] Depending on the chosen inhaler and the desired dose, the person skilled in the art will select the most suitable size. According to a preferred embodiment of the invention, when using the RS01 Plastiape inhaler, the capsules are of size 2 or 3.

[0124] According to the invention, the composition shows a homogeneous distribution of the compound of formula (I), expressed as a coefficient of variation (CV), also called relative standard deviation (RSD), less than 5.0%, preferably equal to or less than 2.5%, as shown in Table 3 of Example 2 in the experimental part.

[0125] Furthermore, the composition is physically and chemically stable when stored in an inhaler at room temperature and 60% relative humidity for at least 24 months.

[0126] The present invention relates to a pharmaceutical product comprising a single-dose dry powder inhalation device, the device comprising an inhaler body (2) defining a recess (3) for a capsule (4), wherein the capsule (4) contains a pharmaceutical composition to be inhaled therein, a nasal or oral inhalation portion (5) communicating with the recess (3), at least one rupture element (7), the rupture element (7) being connected to the inhaler body (2) and configured to rupture the capsule (4) to allow an external airflow to mix with the pharmaceutical composition in the capsule (4) and be inhaled through the nasal or oral inhalation portion (5), and a pharmaceutical composition filled in the capsule, the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and comprising lactose carrier particles, wherein the inhalation flow rate of the inhalation device is 30 l / min to 65 l / min, and wherein the equivalent volume diameter of the lactose carrier particles measured by a laser diffraction or sieve analyzer is less than 110 microns,

[0127]

[0128] 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 inspiratory flow rate of the inhaler is 30 l / min to 65 l / min, and wherein the equivalent volume diameter of the lactose carrier particles is less than 110 microns.

[0129] In another preferred embodiment, the present invention provides a pharmaceutical product of the present invention for use in treating inflammatory or obstructive respiratory diseases. As an alternative, the present invention provides a pharmaceutical composition according to the present invention for use in treating inflammatory or obstructive respiratory diseases when administered by a single-dose inhaler according to the present invention.

[0130] In another preferred embodiment, the present invention provides a pharmaceutical product 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, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema and smoking-induced emphysema.

[0131] Although the carrier will consist of the particles according to the invention, the composition may contain additional active ingredients and optionally other excipients, such as sweeteners and flavorings.

[0132] The additional active ingredients may be selected from those currently used for the prevention and treatment of respiratory diseases by inhalation, such as β2-agonists, corticosteroids and anticholinergics.

[0133] In an even further preferred embodiment, the present invention provides a pharmaceutical product according to the invention as defined above as an adjunct to mono, dual or triple therapy.

[0134] In another preferred embodiment, the present invention provides a pharmaceutical product according to the invention as defined above, wherein the single, dual or triple therapy active agent is selected from the group consisting of a β2-agonist, a corticosteroid and an anticholinergic agent.

[0135] In another embodiment, the present invention provides a process for preparing a pharmaceutical product according to the present invention, said process comprising the steps of: i) sieving a compound of formula (I) through a suitable sieve, ii) adding lactose carrier particles to the compound of formula (I), iii) sieving the final blend and mixing to obtain the final pharmaceutical composition, iv) filling the obtained pharmaceutical composition in capsules, and v) loading the drug chamber of the single-dose dry powder inhalation device with said capsules.

[0136] In another preferred embodiment, the present invention provides a method for preparing a pharmaceutical composition according to the present invention, the method comprising the steps of sieving the compound of formula (I) and one-third of the 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. Then, filling a capsule with the pharmaceutical composition according to the present invention and loading the capsule into the drug chamber of the single-dose dry powder inhalation device.

[0137] 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.

[0138] In an even further preferred embodiment, the present invention provides a method for treating a respiratory disease, said method comprising administering to a patient a compound of formula (I) by inhalation using a pharmaceutical product according to the present invention.

[0139] In another preferred embodiment, the present invention provides a method as defined above for treating a respiratory disease selected from the above-mentioned inflammatory or obstructive respiratory diseases.

[0140] The present invention also relates to an inhalation device in the form of a single-dose dry powder inhaler, which is loaded with a pharmaceutical composition comprising micronized particles of a compound of formula (I) and a carrier, wherein the inhalation flow rate of the inhalation device is 30 l / min to 65 l / min, and wherein the carrier consists of a physiologically acceptable inert excipient with a mass diameter of less than 110 microns, as described above according to the present invention.

[0141] 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.

[0142] Experimental Section

[0143] abbreviation

[0144] MOC = Microporous Collector; HR = High Resistance; IP = Inlet Port; PS = Pre-Separator; UHR = Ultra High Resistance Example

[0145] Example 1: Preparation of the composition of the present invention using the compound of formula (I) and lactose

[0146] The lactose carrier used was 150 (Meggle, DE). The compound of formula (I) was sieved with one-third of the carrier through a 355 μm screen and mixed in a Turbula at 38 rpm for 40 min; the second one-third of the carrier was added to the blend and mixed at 38 rpm for 40 min; finally, the last one-third of the carrier was added and mixed at 38 rpm for 40 min. Finally, the blend was sieved through a 355 μm screen to remove any aggregates produced in the second step and mixed at 38 rpm for 30 minutes. A 10 gram batch size was produced.

[0147] Table 1: Composition of the present invention, 400 μg

[0148]

[0149] Table 2: Composition of the present invention, 800 μg

[0150]

[0151]

[0152] Example 2: Content (μg) of the compound of formula (I) / 20 mg of the composition of the present invention, ± standard deviation and CV% (n=6)

[0153] The uniformity of drug content in the blend was determined by HPLC. Six samples randomly collected from the mixture and dissolved in 100 ml of acetonitrile / water (60 / 40) v / v used as solvent were analyzed. Each sample weighed 20 mg.

[0154] Table 3: Content of the compound of formula (I) (μg) / 20 mg of the composition of the present invention, ± standard deviation and CV% (n=6)

[0155]

[0156] The blends in Table 3 show excellent uniformity of active ingredient distribution.

[0157] Example 3: Determination of aerodynamic particle size distribution (APSD)

[0158] In vitro aerodynamic evaluation was performed using a Next Generation Impactor (NGI) according to 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) in combination with 400 μg and 800 μg of a composition prepared according to WO2012 / 016889 was considered the reference product.

[0159] The analysis was performed using RS01 High Resistance Device with code 239700002AA and RS01 Ultra High Resistance Device with code 239700005AA (Plastiape, Osnago, LC Italy) with 400 μg and 800 μg of the drug product of the composition according to the invention. The capsules used were Size 3 (Qualicaps Europe, SAU) and loaded with about 20 mg. The DPI inhaler was activated at a pressure drop of 4 kPa, corresponding to a flow rate of 57.5 L / min for Nexthaler, 65 L / min for RS01 high resistance, and 40 L / min for RS01 ultra-high resistance, for a duration sufficient to sample 4.0 liters of air volume. The NGI was connected to a vacuum pump and the airflow 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, and a single dose was expelled and collected in the device. Acetonitrile / water (60 / 40) v / v was used as a 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 sample was 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. The metered dose (MD) is calculated by adding the drug recovered from the impactor (IP, PS, stages 1 to 7, and MOC) and the drug remaining in the inhaler (capsule and device). It is impossible to quantify the MD of the multi-dose Nexthaler DPI because it is a reservoir multi-dose inhaler and cannot be wetted and rinsed at the end of the experiment. The released dose (ED) is the amount of drug that leaves the device and enters the impactor and is calculated by adding the drug recovered from the impactor (IP, PS, stages 1 to 7, and MOC). Drug deposition in the impactor allows the calculation of aerodynamic parameters. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) are determined by plotting the cumulative percentage of the mass less than the aerodynamic diameter of each NGI segment on a probability scale relative to the aerodynamic diameter of the segment on a logarithmic scale. Linear regression is performed on the six data points closest to 50% of the cumulative particle mass entering the impactor to calculate MMAD and GSD. The fine particle mass (FPM) was calculated as the mass of drug <5 μm (calculated by the log probability plot equation), and the fine particle fraction (FPF) was determined as the ratio between FPD and ED in percent. The ultrafine particle mass (EFPM) was calculated as the mass of drug below 2 μm (calculated by the log probability plot equation), and the ultrafine particle fraction (EFPF) was determined as the ratio between EFPD and ED in percent.

[0160] Table 4: APSD of Nexthaler device loaded with 400 μg of reference composition

[0161] Nexthaler device loaded with reference composition (400 μg of compound of formula (I) / 20 mg) ejection weight (mg), released dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3)

[0162]

[0163] Table 5: APSD of Nexthaler device loaded with 800 μg of reference composition

[0164] Nexthaler device loaded with reference composition (800 μg of compound of formula (I) / 20 mg) ejection weight (mg), released dose (μg), MMAD (μm), GSD, FPM (μg), FPF (%), EFPM (μg), EFPF (%) mean ± standard deviation and CV% (n=3)

[0165]

[0166] Table 6: APSD of HR RS01 device loaded with 400 μg of the composition of the invention

[0167] Ejection weight (mg), metered dose (μg), released 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)

[0168]

[0169] Table 7: APSD of HR RS01 device loaded with 800 μg of the composition of the invention

[0170] Ejection weight (mg), metered dose (μg), released 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)

[0171]

[0172]

[0173] As shown in Tables 6 and 7, both products according to the invention produced good respirable fractions, i.e. FPFs of about 56-58%, also with significant ultrafine particle fractions (about 25-26%) and similar to those of the reference products, as obtained by comparison with Tables 4 and 5.

[0174] like Figure 4 As shown, the composition of the invention at a dose of 800 μg in the RS01 HR inhalation device has a deposition similar to that of the reference product in stages S1 to S5, while it has a significantly lower deposition in IP and PS. This has the advantages of less systemic absorption and lower side effects. For the deposition of the ultrafine fraction (<2 μm), the reference product is significantly higher in stages S6, S7 and MOC.

[0175] like Figure 3 As shown, although it has a slightly different deposition than the reference product in stages S1 to S5, the composition of the invention at a dose of 400 μg in the RS01HR inhalation device also has significantly lower deposition in IP and PS.

[0176] Table 8: APSD of UHR RS01 device loaded with 400 μg of the composition of the invention

[0177] Ejection weight (mg), metered dose (μg), released dose (μg), MMAD (μm), GSD, FPD (μg), FPF (%), EFPD (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)

[0178]

[0179]

[0180] Table 9: APSD of UHR RS01 device loaded with 800 μg of the composition of the invention

[0181] Ejection weight (mg), metered dose (μg), released 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)

[0182]

[0183] Example 4: Dissolution Test

[0184] Using RespiCellTM (EU registration number 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).

[0185] It is a vertical diffusion cell apparatus consisting of a 170 cm 3 The device consists of an upper part (donor chamber) and a lower part (receiving chamber), which are connected by a clamp and separated by a glass fiber filter used as a diffusion membrane and are in horizontal contact with the dissolution medium. The receiving 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) containing 0.5% sodium dodecyl sulfate (SDS). The RespiCell TM Connected to a heating thermostat (Lauda eco silver E4, DE) set at 37 ± 0.5 ° C. The receiving chamber was filled with the dissolution medium and samples were taken at preset time intervals through the side arm of the cell. After atomization, the analysis was performed by using the fine fraction deposited on the diffusion membrane filter through a fast screening impactor (FSI).

[0186] The in vitro aerodynamic assessment was performed according to the procedure detailed in the European Pharmacopoeia 10.0, chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles", pages 347-360. The analysis was performed using the RS01 apparatus. The capsules used were 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; and the contents of two or four capsules were atomized and two or four fine particle doses were collected into the device at 800 or 400 μg strength, respectively. For each selected composition, the analysis was performed in triplicate. After atomization, the filter was removed by the FSI and positioned in the RespiCell between the donor chamber and the receiving chamber. TM1 ml of dissolution medium was applied to the filter to completely wet it before analysis. 1 ml of receiving solution was taken out through the receiving chamber at fixed intervals and replaced with 1 ml of fresh dissolution medium after each withdrawal to maintain a constant volume. In order to assess the amount of drug that was not dissolved or trapped in the filter, at the end of the experiment, the filter was washed with 10 ml of acetonitrile: water 60:40 to recover the residual undissolved powder.

[0187] The amount of drug in the sample was assessed by HPLC. Data are expressed as the percentage of dissolved formula (I) compound, and 100% dissolution corresponds to the amount of dissolved drug at the end of the experiment. Using the difference factor (f1) and similarity factor (f2) proposed for comparing the dissolution curve of oral dosage forms, according to the fraction and total amount dissolved over time, the dissolution curve is checked (Shah, VPet al., FDA Guidance for Industry 1Dissolution 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).

[0188] The difference factor (f1) calculates the percentage difference between the two dissolution profiles at each time point and is a measure of the relative error between the two profiles.

[0189] The difference factor (f1) is calculated as follows:

[0190]

[0191] The similarity factor (f2) is calculated as follows:

[0192]

[0193] 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 for both compositions, the time points 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 time points considered, the relative standard deviation (coefficient of variation) 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 similarity between the two dissolution curves.

[0194] To test the reliability of the method, in vitro dissolution profiles of two reference products at doses of 400 μg and 800 μg were provided. Figure 7 The results reported in show an excellent proportionality relationship between dose and amount of drug dissolved.

[0195] Then, comparative in vitro dissolution testing between the reference product and the drug product of the present invention was performed at 400 μg and 800 μg doses, and as shown from Figure 8 and Fig. 9 As can be appreciated, within the experimental limits of the method, the curves appear to be nearly superimposable. Based on these in vitro results and the indications / assumptions of the inhalation organism classification system (Hasted JE et al AAPS / FDA / USP Workshop March 16-17 th , Baltimore, AAPS Open, 2016, 2(1), 2016), an IVIV correlation model can be established to demonstrate reasonable bioequivalence and candidate the product for biowaiver.

Claims

1. A pharmaceutical product comprising a single-dose dry powder inhalation device, the device comprising an inhaler body (2) defining a recess (3) for a capsule (4), wherein the capsule (4) contains a pharmaceutical composition to be inhaled therein, a nasal inhalation portion or an oral inhalation portion (5) communicating with the recess (3), at least one rupturing element (7), the 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 be inhaled through the nasal inhalation portion or the oral inhalation portion (5), and a pharmaceutical composition filled in the capsule, the pharmaceutical composition comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and comprising lactose carrier particles, wherein the inhalation flow rate of the inhalation device is 30 l / min to 65 l / min, and wherein the equivalent volume diameter of the lactose carrier particles measured by a laser diffraction or sieve analyzer is less than 110 microns, 2. The pharmaceutical product according to claim 1, wherein the carrier particles are made of α-lactose monohydrate.

3. The pharmaceutical product according to claims 1 and 2, wherein the lactose carrier particles have an equivalent volume diameter of 1 to 95 microns.

4. The drug product of claim 3, wherein the lactose carrier particles have a dv(10) of 1 to 5 microns, a dv(50) of 18 to 30 microns, and a dv(90) of 65 to 95 microns.

5. A pharmaceutical product according to any one of the preceding claims, wherein the inhalation device has an inspiratory flow rate of 40 l / min to 65 l / min.

6. A pharmaceutical 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 800 μg.

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

9. A pharmaceutical composition for treating a respiratory disease, comprising micronized particles of a compound of formula (I) having a size of 0.1 to 15 microns and comprising lactose carrier particles, 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, and wherein the equivalent volume diameter of the lactose carrier particles measured by laser diffraction or sieve analyzer is less than 110 microns, 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. The 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 pharmaceutical product according to any one of claims 1 to 8, comprising the steps of: i) sieving the compound of formula (I) through a suitable sieve, ii) adding lactose carrier particles to the compound of formula (I), iii) sieving the final blend and mixing to obtain the final pharmaceutical composition, iv) filling the obtained pharmaceutical composition in capsules, and v) loading the drug chamber of the single-dose dry powder inhalation device with the capsules.

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