Capsule inhalers for the administration of phosphodiesterase-4 inhibitors

Abstract

The present invention relates to a single dose dry powder inhaler device and a formulation comprising a pharmaceutical composition filled into a capsule, the pharmaceutical composition comprising fine particles of a compound of formula (I) and a carrier. The present invention also relates to a formulation or pharmaceutical composition for use in treating respiratory disorders and a method of treating respiratory disorders.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a single dose dry powder inhaler device and a formulation comprising a pharmaceutical composition filled into a capsule, the pharmaceutical composition comprising fine particles of a compound of formula (I) and a carrier. The present invention also relates to a formulation or pharmaceutical composition for use in treating respiratory disorders and a method of treating respiratory disorders. [Background technology]

[0002] Background of the Invention Formula (I) [ka] The compound, also known as Tanimilast or CHF6001 or CHF-6001, has INN (3,5-dichloro-4-[(2S)-2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-{[3-(cyclopropylmethoxy)-4-(methanesulfonamido)benzoyl]oxy}ethyl]pyridine 1-oxide), and is a highly potent and selective PDE4 inhibitor with robust anti-inflammatory activity, currently in clinical development.

[0003] The compound of formula (I) has been disclosed in prior art documents in the name of Chiesi; WO2009 / 018909 relating to a general formula, methods of preparation, compositions and therapeutic uses; WO2010 / 089107 relating to sulfonamide derivatives, particularly comprising the compound of formula (I) as the (-) enantiomer, methods of preparation, compositions and therapeutic uses; WO2012 / 016889 relating to dry powder compositions comprising the compound of formula (I); and WO2015 / 059050 relating to a crystalline form termed Form A of the compound of formula (I) characterized by specific XRPD peaks and methods for obtaining same.

[0004] Like other members of the pharmacological class of PDE4 inhibitors, the drugs may be applied in the treatment of 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.

[0005] Due to the well-known systemic side effects associated with the class of PDE4 inhibitors, tanimilast is being developed as an inhaled composition. Indeed, one of the advantages of the inhaled route over the systemic route is the possibility of delivering the drug directly to the site of action, avoiding any systemic side effects.

[0006] Tanimilast is currently in clinical trials at two different nominal unit doses, namely 400 μg and 800 μg. The product is in the form of a powder composition utilizing the platform technology disclosed in WO2012 / 016889 and is marketed under the proprietary multi-dose Nexthaler brand name. (登録商標) It is administered via an inhaler. This product is hereafter referred to as the "control product."

[0007] The carrier used is a fraction consisting of a mixture of cracked coarse and fine lactose and magnesium stearate as a triple component, as disclosed in WO2012 / 016889 and referred to herein as the "control composition."

[0008] Due to the nature of both the inhaler and the platform technology, the composition provides an excellent respirable fraction and a significant amount of ultrafine particles. Indeed, there is agreement that ultrafine particles can reach the distal tracts of the respiratory tree, thus improving small airway outcomes and related management in patients with small airway asthma phenotypes (Santus P et al, Respir Care 2020;65(9):1392-1412; Scichilone N et al, Patient Relat Outcome Meas 2014;5:153-162).

[0009] On the other hand, triple-component drugs are inhaled by the patient, thus adding regulatory burdens when trying to gain product approval.

[0010] It would therefore be advantageous to provide a platform technology for the administration of a compound of formula (I) in powder form that does not use a three component agent and has the same inhalation performance of the control product. Summary of the Invention [Problem to be solved by the invention]

[0011] The inventors have surprisingly discovered that the formulation of the present invention has the same inhalation performance as the control product without the use of a triple component agent. [Means for solving the problem]

[0012] Summary of the Invention In a first aspect, the present invention provides a formulation comprising a single-dose dry powder inhaler device comprising an inhaler body (2) defining a recess (3) for a capsule (4) (wherein the capsule (4) holds a pharmaceutical composition to be inhaled), a nosepiece or mouthpiece (5) connected to the recess (3), at least one disruption portion (7) connected to the inhaler body (2) and configured to disrupt the capsule (4) to allow an external airflow to mix with the pharmaceutical composition of the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a pharmaceutical composition filled in the capsule, wherein the pharmaceutical composition is a compound of formula (I) having a size of 0.1 to 15 microns. [ka] and lactose carrier particles, wherein the inhalation flow rate of the inhalation device is in the range of 30 l / min to 65 l / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns as measured by means of laser diffraction or a sieve analyzer.

[0013] In a second aspect, the present invention relates to a pharmaceutical composition comprising microparticles of a compound of formula (I) having a size in the range of 0.1 to 15 microns and lactose carrier particles for use in the treatment of respiratory diseases, wherein the composition is administered using a single dose dry powder inhaler device, wherein the inspiratory flow rate of the inhaler device is in the range of 30 l / min to 65 l / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns as measured by means of laser diffraction or a sieve analyzer.

[0014] In a third aspect, the present invention provides a method of treating a respiratory disease, comprising administering to a patient by inhalation a compound of formula (I) using a formulation described in accordance with the present invention.

[0015] In a fourth aspect, the present invention relates to a pharmaceutical composition of the present invention for use in the manufacture of a medicament for the treatment of a respiratory disease, wherein the composition is administered using a single-dose dry powder inhaler device, wherein the inhalation flow rate of the inhaler device is in the range of 30 l / min to 65 l / min.

[0016] In a fifth aspect, the present invention provides a process for preparing the formulation of the present invention, comprising the steps of: i) sieving a compound of formula (I) through a suitable mesh; ii) adding lactose carrier particles to the compound of formula (I); iii) sieving and blending the final mixture to obtain the final pharmaceutical composition; iv) filling the resulting pharmaceutical composition into a capsule; and v) filling the capsule into the medicament chamber of a single dry powder inhaler device. [Brief explanation of the drawings]

[0017] [Figure 1] Deposition of compound of formula (I) in stages of the NGI device by delivery of 400 μg control product.

[0018] [Figure 2] Deposition of compound of formula (I) in stages of the NGI device by delivery of 800 μg control product.

[0019] [Figure 3] Deposition of the compound of formula (I) in the NGI device stage upon delivery of 400 μg of a formulation of the invention in an RS01 HR inhalation device.

[0020] [Figure 4] Deposition of the compound of formula (I) in the NGI device stage upon delivery of 800 μg of a formulation of the invention in an RS01 HR inhalation device.

[0021] [Figure 5] Comparison of deposition of compound of formula (I) upon delivery of 400 μg of a formulation of the invention in an RS01 HR inhalation device versus a 400 μg control product.

[0022] [Figure 6] Comparison of deposition of compound of formula (I) upon delivery of 800 μg of a formulation of the invention in an RS01 HR inhalation device versus an 800 μg control product.

[0023] [Figure 7] In vitro dissolution profiles of 400 μg and 800 μg control products.

[0024] [Figure 8] In vitro dissolution comparison of a control product and a formulation of the invention at a nominal dose of 400 μg: a) μg; b) %.

[0025] [Figure 9] In vitro dissolution comparison of a control product and a formulation of the invention at a nominal dose of 800 μg: a) μg; b) %.

[0026] [Figure 10] FIG. 1 is a three-dimensional view of a single dose dry powder inhaler device according to an embodiment of the present invention.

[0027] [Figure 11] FIG. 11 is a cross-sectional view of the single-dose dry powder inhaler device of FIG. 10 in a first operating configuration.

[0028] [Figure 12] FIG. 11 is a cross-sectional view of the single-dose dry powder inhaler device of FIG. 10 in a second operating configuration. DETAILED DESCRIPTION OF THE INVENTION

[0029] Detailed Description of the Invention definition Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0030] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include any polymorphs, stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof.

[0031] The terms "micron," "micrometer," and μm are used synonymously.

[0032] The terms "microgram" and μg are used synonymously.

[0033] The terms "percent" and % are used synonymously.

[0034] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) in which the parent compound, if any, is suitably modified by converting any free acid or basic group, if any, into the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable. Thus, suitable examples of such salts include inorganic or organic acid addition salts of basic residues such as amino groups and inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0035] Inorganic base cations suitable for use in preparing salts include ions of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0036] Those obtained by reacting the main compound, which functions as a base, with an inorganic or organic acid to form a salt include, for example, 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.

[0037] The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvates contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0038] 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.

[0039] The terms "racemate" or "racemic mixture" refer to a composition consisting of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.

[0040] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interconverted by shifting an atom or group within the molecule.

[0041] The term "composition," as in pharmaceutical composition, refers to a product comprising an active ingredient(s) and any pharmaceutically acceptable excipient(s) or carrier(s), and any product resulting directly or indirectly from the combination, complex formation, or aggregation, or dissociation of one or more of the components, or any other type of reaction or interaction of one or more of the components, of two or more components.

[0042] The term "physiologically acceptable" refers to a safe, pharmacologically active substance that is utilized as an excipient.

[0043] The term "bioequivalence" generally means that there is no significant difference in bioavailability, i.e., the extent of absorption and peak concentration, between two pharmaceutical formulations (e.g., test and reference products) at the same dose and under the same conditions over a period of time.

[0044] Determining whether a test product is bioequivalent to a reference product is determined by conducting what is called a bioequivalence or comparative bioavailability study in a control group.

[0045] For locally acting inhaled products, the term "bioequivalence" is based on more evidence to demonstrate equivalence of local delivery: similarity in in vitro testing, similarity of systemic exposure, and similarity in pharmacokinetic and pharmacodynamic testing.

[0046] The term "biowaiver" refers to an exemption granted to biopharmaceutical companies to demonstrate in vivo bioequivalence based on in vitro testing.

[0047] The term "vitro-in vivo correlation" (IVIVC) refers to an in vitro dissolution test that is predictive of a formulation's in vivo performance.

[0048] The term "micronized" refers to materials having a size of a few microns, typically in the range of 0.1 to 15 microns.

[0049] The term "microparticle" refers to particles having a size down to a few tenths of a micron.

[0050] The term "ultrafine particles" refers to particles having a particle size of 2.0 microns or less.

[0051] The term "coarse" refers to materials having a size of one hundred to several hundred microns.

[0052] In general terms, particle size of particles is determined by measuring their characteristic equivalent particle size, known as the volumetric equivalent spherical diameter, by laser diffraction. Alternatively, particle size can be determined by measuring the mass diameter by means of gravimetric methods, for example, using suitable known equipment such as a sieve analyzer.

[0053] The volume diameter (VD) is related to the mass diameter (MD) by the density of the particle (assuming a size-independent density of the particle).

[0054] In this application, particle sizes of active ingredients are expressed in terms of equivalent sphere volume diameter, and particle sizes of carrier particles are also expressed in terms of equivalent sphere volume diameter.

[0055] The particles have a log-normal distribution defined in terms of the volume or mass median diameter (VMD or MMD) corresponding to the volume or mass diameter of 50 weight percent of the particles and optionally in terms of the volume or mass diameter of 10% and 90% of the particles, respectively.

[0056] Another common approach to defining 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 greater and below which 50% of the distribution is smaller; ii) d(0.9), which is the value below which 90% of the distribution is smaller; and iii) d(0.1), which is the value below which 10% of the distribution is smaller. If the diameters are defined as equal volumes, these three parameters are designated as dv(0.5), dv(0.9), and dv(0.1). VMD corresponds to dv(0.5). MMD corresponds to d(0.5).

[0057] The span is the width of the distribution based on the 10%, 50%, and 90% quantiles and is calculated according to the following formula:

number

[0058] In general terms, particles with the same or similar VMD or MMD may have different particle size distributions, particularly different Gaussian distribution widths, expressed as d(0.1) and d(0.9) values.

[0059] Upon aerosolization, particle size is expressed as the mass aerodynamic diameter (MAD), while particle size distribution is expressed in terms of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). MAD indicates the ability of particles to be transported and suspended in an airstream. MMAD corresponds to the mass aerodynamic diameter of 50 percent of the particles by weight.

[0060] The terms "additive" and "ternary agent" are used synonymously and by these terms we mean substances that are capable of modifying the separation of the active ingredient from the surface of the carrier particles.

[0061] The term "hard pellet" refers to a spherical or semi-spherical unit whose core consists of a coarse additive particle.

[0062] The expression "respirable fraction" refers to the index of the percentage of active particles that reach the patient's lungs. The respirable fraction, also called fine particle fraction (FPF), is evaluated according to the procedures reported in common pharmacopoeias, in particular the European Pharmacopoeia (Eur. Ph.), 11th Edition, paragraph 2.9.18, pages 372-378, using suitable in vitro equipment such as an Andersen cascade impactor (ACI), a multistage liquid impinger (MLSI) or a next generation impactor (NGI). It is calculated as the percentage ratio of the fine particle mass (FPM) (formerly the fine particle dose, FPD) to the delivered dose.

[0063] The term "peak inspiratory flow" refers to the maximum rate of airflow during a patient's inspiration with or without an inhalation device.

[0064] 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 an inhalation device during in vitro testing according to the European Pharmacopoeia (Eur. Ph.), 11th Edition, paragraph 0671 Inhalation Formulations: Inhalanda, 998.

[0065] Based on the required inspiratory flow rate (l / min), which in turn depends strictly on the design and mechanical characteristics, the DPI is: i) low resistance devices (approximately 100 l / min); ii) medium resistance devices (approximately 80 l / min); iii) High resistance devices (approximately 65 l / min); iv) Ultra-high resistance device (approximately 40 l / min) It can also be divided into:

[0066] Reported flow rates refer to a pressure drop of 4 kPa (kilopascals) according to the European Pharmacopoeia (Eur. Ph.), 11th Edition, paragraph 0671 Inhalation Preparations: Inhalanda, 998.

[0067] The delivered dose, i.e., the amount of drug effectively delivered to the respiratory tree after each actuation of the inhaler, is calculated from the cumulative deposition in the device, while the fine particle mass is calculated from the deposition of particles having a diameter of 5.0 microns or less.

[0068] In the context of this application, a composition is defined as an "ultra-fine" composition when it is capable of delivering a fraction of particles having a particle size of 2.0 microns or less that is 20% or more, preferably 25% or more, more preferably 30% or more, and / or a fraction of particles having a particle size of 1.0 microns or less that is 10% or more.

[0069] 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 both during dry powder production and in the delivery device before use. The tendency for separation can be evaluated by Staniforth et al. J. Pharm. Pharmacol. 34,700-706, 1982, and is considered acceptable when the active ingredient distribution in the powder composition after testing does not change significantly compared to the pre-test composition, expressed as relative standard deviation (RSD).

[0070] The term "prevention" refers to slowing the progression of a disease, delaying its onset and / or reducing the risk of developing the disease.

[0071] The term "treatment" refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, the alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, the reduction in the extent of the disease, the stabilization (i.e., not worsening) of the disease, the prevention of the spread of the disease, the delay or slowing of the progression of the disease, the improvement or palliation and remission (whether partial or complete) of the disease state. The term can also mean prolonging survival compared to expected survival in the absence of treatment.

[0072] "Unit therapeutically effective dose" or "unit nominal dose" means the amount of active ingredient administered by inhalation in one actuation of an inhalation device. The dose can be delivered in one or more actuations of the device, preferably in one or two actuations (shots) of the device, more preferably in one actuation.

[0073] "Daily dose" means the amount of active ingredient administered by inhalation in one day upon actuation of the inhalation device.

[0074] "Actuation" refers to the release of the active ingredient from the device with a single activation (eg, mechanical or exhalation).

[0075] The term "delivered dose" refers to the amount of drug that is effectively delivered to the respiratory tree after each actuation of the inhalation device.

[0076] In this context, the term "ordered mixture" refers to a homogeneous composition obtained by mixing a compound of formula (I) of the present invention with pharmaceutically acceptable excipients and / or carriers.

[0077] The expression "good homogeneity" refers to a composition in which, upon mixing, the uniformity of distribution of the active ingredient, expressed as the coefficient of variation (CV), also known as the relative standard deviation (RSD), is less than 5.0%, preferably less than or equal to 2.5%.

[0078] It has surprisingly been found that it is possible to provide a formulation of the compound of formula (I) that produces an in vitro dissolution profile substantially similar to that of the reference product without the use of further additives, and is likely to be bioequivalent. This is achieved by utilizing a single-dose dry powder inhaler device with an inspiratory flow rate comprised between 30 l / min and 65 l / min, in combination with an ordered mixture comprising carrier particles having a selected and well-defined particle size.

[0079] As a standard procedure, inhalation performance was determined using an NGI apparatus testing compounds of formula (I) at unit nominal doses of 400 μg and 800 μg.

[0080] Both products of the present invention yield good respirable fractions, i.e., FPFs of about 56-58%, as well as a significant fraction of very fine particles (about 25-26%), and are substantially similar to the control product, as reported in Tables 6 and 7 of Example 3 in this experimental section.

[0081] A comparative analysis of the complete particle size distribution profiles of the individual stages was also performed according to CPMP / EWP / 4151 / 00 to establish the similarity between the reference product and the formulation of the present invention, which according to the EMA guidelines for biowaivers is considered to be fulfilled if the difference is within ±15%. Even if not all stages fulfill the criteria in this condition, it is well known that the inherent variability of multi-stage impactor / impinger methods is rather high, especially for stages where small amounts of drug are deposited.

[0082] Therefore, an in vitro dissolution system was established to predict in vivo performance.

[0083] The results reported in Figures 8 and 9 show nearly overlapping profiles for both the 400 μg and 800 μg unit nominal doses of the formulation of the invention and the control product at the same unit nominal doses.

[0084] These in vitro results and the indications / assumptions of the inhalation classification system (Hastedt JE et al AAPS / FDA / USP Workshop March 16-17 th , Baltimore, AAPS Open, 2016, 2(1), 2016), the IVIV correlation model indicates in vitro equivalence and possibly in vivo bioequivalence, thus potentially setting the product up to be a candidate for biowaiver.

[0085] More advantageously, as can be seen from the plots in Figures 3 and 4 for the product of the present invention, the fraction of aerosolized drug that deposits in the induction port (IP) and pre-separator (PS), which mimic the upper airways of the respiratory tree (Sou T et al J Pharm Sci 2021 110, 66-86), is reduced relative to the control product as shown in Figures 1 and 2, thus indicating lower systemic absorption.

[0086] In a preferred embodiment of the present invention, with reference to the accompanying drawings, a single-dose dry powder inhaler, generally designated by reference numeral 1, comprises an inhaler body 2 defining a recess 3 for a capsule 4, and a nosepiece or mouthpiece 5 connected to the recess 3 and having an opening 6. Two breaking members 7 are connected to the inhaler body 2 and break the capsule 4, allowing an external airflow to mix with the pharmaceutical composition contained in the capsule 4 and be inhaled through the nosepiece or mouthpiece 5. The two breaking members 7 of the single-dose dry powder inhaler device 1 of this embodiment are shaped like stakes or needles and are positioned to pierce the capsule 4 when a button 8 equipped with the breaking members 7 is pressed and the capsule 4 is positioned in the recess 3. An air inlet 9 is located on the inhaler body 2. The air inlet 9 is connected to the recess 3 and allows the airflow to enter the recess 3 when a user inhales through the nosepiece or mouthpiece 5. The shape and size of the air inlet 9 can determine the intrinsic resistance to airflow of the single-dose dry powder inhaler device.

[0087] In a preferred embodiment, the present invention provides a formulation comprising a single-dose dry powder inhaler device selected from high resistance and ultra-high resistance devices. More preferably, the high resistance device is RS01 with Plastiape code 239700002AA and the ultra-high resistance device RS01 with Plastiape code 239700005AA (Plastiape Spa, Osnago, Italy).

[0088] The intake flow rate is in the range of 30 l / min to 65 l / min, more preferably 40 l / min to 65 l / min based on a pressure loss 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, and even more preferably 40 l / min.

[0089] The unit nominal dose is comprised between 200 μg and 1000 μg, preferably between 400 μg and 800 μg, more preferably 400 μg, and even more preferably 800 μg. The unit nominal dose can be delivered in one or more actuations of the inhalation device.

[0090] The daily dose at which the pharmaceutical composition containing the compound of general formula (I) can be administered is comprised between 800 μg and 4800 μg, preferably between 1200 μg and 3800 μg and more preferably between 1600 μg and 3200 μg.

[0091] In certain embodiments, the daily dose can be achieved in a single or two administrations.

[0092] In other preferred embodiments, the daily dose is reached in a single administration and can be delivered by one actuation of the inhaler.

[0093] In other preferred embodiments, the daily dose is reached by a single administration and can be delivered by more actuations of the inhaler, preferably two actuations.

[0094] In another preferred embodiment, the daily dose is reached in two administrations, which can be delivered by a single actuation of the inhaler.

[0095] In another preferred embodiment, the daily dose is reached by two administrations and can be delivered by more actuations of the inhaler, preferably two actuations.

[0096] Advantageously, the carrier particles of the present invention are comprised of any physiologically acceptable substance or combination thereof suitable for inhalation use, making preparation of the composition a simple and versatile process.

[0097] For example, the carrier particles may be composed of one or more materials selected from 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 cyclodextrins and dextrins.

[0098] Preferably, the particles are made from a crystalline sugar, even more preferably selected from monosaccharides such as glucose or arabinose or disaccharides such as maltose, sucrose, dextrose or lactose.

[0099] Preferably, the particles are made from lactose, more preferably alpha-lactose monohydrate.

[0100] Advantageously, the carrier particles have a volume equivalent spherical diameter (diameter of a hypothetical sphere having the same volume as the particle under test) in the range of 0.2 to 110 micrometers, more advantageously in the range of 0.5 to 95 micrometers, preferably 1 to 90 micrometers.

[0101] The volume equivalent sphere diameter can be measured by laser diffraction or a sieve analyzer.

[0102] As explained above, particle diameters, measured by volume diameter with a suitable tool such as laser diffraction or a sieve analyzer, can be converted to equivalent mass diameters by knowing the density of the particles.

[0103] In certain embodiments, the physiologically acceptable excipient used as a carrier has a volume equivalent sphere diameter ranging from 1 to 95 micrometers.

[0104] More preferably, the physiologically acceptable excipient used as a carrier has the following distribution, measured as volume diameter: dv(0.1) in the range of 1 to 5 microns, dv(0.5) in the range of 18 to 30 microns, and dv(0.9) in the range of 65 to 95 microns. The excipient with the desired particle size can be conveniently prepared by sieving or is commercially available, for example as InhaLac® 150 (Meggle GmbH, Wasserburg am Inn, Germany).

[0105] Advantageously, at least 90% of the particles of the active ingredient 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 in the range of 1.8 to 4 microns.

[0106] In a preferred embodiment, the compounds of formula (I) have equivalent sphere volume diameters expressed as dv(0.1) in the range of 0.5 to 1 micron, dv(0.5) in the range of 1.9 to 2.5 microns, dv(0.9) in the range of 4 to 6 microns, and a span in the range of 1.7 to 2.3 microns.

[0107] Indeed, span values ​​in this range ensure that the population distribution of fine particles is distributed around the median diameter. Therefore, small values ​​of dv(0.5) (<2.5 microns) are accompanied by a high proportion of very fine particles that favor peripheral deposition of the drug in the lungs.

[0108] The particle size of the compound of formula (I) can be measured by laser diffraction as a dispersion, for example, using a Mastersizer (Malvern Instruments). This technique is particularly useful for wet dispersions. The instrument is set to 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%. A sample suspension is prepared by mixing approximately 5 mg of sample with 10 ml of water containing two drops of Tween 80 in a 25 ml beaker. The dispersion unit (Malvern Instruments) is filled with water, and the pump / stirrer of the dispersion unit tank is turned on at 3500 rpm and then turned down to 0 to eliminate any bubbles. The sample suspension is sonicated for 1 minute. The pump / stirrer is turned on at 1000 rpm, and the background is then measured. The prepared suspension sample is slowly added dropwise to the dispersion unit until a stabilized obscuration of 7-13% is reached, and the analysis is initiated. Analysis was performed in triplicate.

[0109] According to the present invention, the material of the capsule filled with the pharmaceutical composition of the present invention is selected from, but not limited to, hard gelatin, HPMC, plant-based substances, fish gelatin, starch, pullulan, polyvinyl acetate (PVA) and soft gelatin. Preferably, the capsule is made of HPMC capsule or hard gelatin or plant-based substances.

[0110] According to the present invention, the capsules filled with the pharmaceutical composition of the present invention have a size in the range included in 000 to 5, preferably included in 001 to 4, and even more preferably included in 00 to 3. Even more preferably, the capsules have size 2 or 3.

[0111] Depending on the inhaler selected and the required dosage, one skilled in the art will select the most appropriate size. According to a preferred embodiment of the present invention, when using the RS01 Plastiape inhaler, the capsule size is 2 or 3.

[0112] According to the present invention, the composition exhibits a uniformity of distribution of the compound of formula (I), expressed as the coefficient of variation (CV), also known as the relative standard deviation (RSD), of less than 5.0%, preferably less than or equal to 2.5%, as shown in Table 3 of Example 2 in the experimental part.

[0113] Furthermore, the composition is physically and chemically stable after storage in the inhaler at room temperature and 60% relative humidity for at least 24 months.

[0114] The present invention relates to a formulation comprising a single-dose dry powder inhaler device, the device comprising an inhaler body (2) defining a recess (3) for a capsule (4) (wherein the capsule (4) holds a pharmaceutical composition to be inhaled), a nosepiece or mouthpiece (5) connected to the recess (3), at least one disruption portion (7) connected to the inhaler body (2) and configured to disrupt the capsule (4), allowing an external airflow to mix with the pharmaceutical composition in the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a pharmaceutical composition filled in the capsule, the pharmaceutical composition being a compound of formula (I) having a size of 0.1 to 15 microns. [ka] and lactose carrier particles, wherein the inhalation flow rate of the inhalation device is in the range of 30 l / min to 65 l / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns as measured by means of laser diffraction or a sieve analyzer.

[0115] In another preferred embodiment, the present invention provides a pharmaceutical composition of the present invention for use in treating a respiratory disease, wherein the composition is administered using a single dose dry powder inhaler device, wherein the inspiratory flow rate of the inhaler is in the range of 30 L / min to 65 L / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns.

[0116] In other preferred embodiments, the present invention provides a formulation of the present invention for use in treating an inflammatory or obstructive respiratory disease. Alternatively, the present invention provides a pharmaceutical composition of the present invention for use in treating an inflammatory or obstructive respiratory disease by administration with a single dose inhaler of the present invention.

[0117] In a further preferred embodiment, the present invention provides a formulation as defined above for use in the treatment of an inflammatory or obstructive respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema and smoking-induced emphysema.

[0118] The carriers comprise the particles of the present invention, but the compositions may also contain additional active ingredients and, if desired, other additives, such as sweeteners and flavoring agents.

[0119] The further active ingredients are selected from those currently used for the prevention and treatment of respiratory diseases by inhalation, such as beta2-agonists, corticosteroids and anticholinergics.

[0120] In an even more preferred embodiment, the present invention provides a formulation of the invention as defined above as an add-on to a mono-, bi- or tri-therapy.

[0121] In another preferred embodiment, the present invention provides a formulation of the invention as defined above, wherein the mono-, bi- or tritherapy active agent is selected from beta2-agonists, corticosteroids and anticholinergics.

[0122] In another embodiment, the present invention provides a method of providing a formulation of the present invention, comprising the steps of: i) sieving a compound of formula (I) through a suitable mesh; ii) adding lactose carrier particles to the compound of formula (I); iii) sieving and blending the final mixture to obtain the final pharmaceutical composition; iv) filling the resulting pharmaceutical composition into a capsule; and v) filling the capsule into the medicament chamber of a single dry powder inhaler device.

[0123] In another preferred embodiment, the present invention provides a method for producing the pharmaceutical composition of the present invention, comprising the steps of sieving a compound of formula (I) together with one-third of a carrier through a mesh, mixing in a mixer, adding a second one-third of the carrier to the mixture and mixing, adding the final one-third of the carrier and mixing, sieving the mixture and mixing.The pharmaceutical composition of the present invention is then filled into a capsule, and the capsule is loaded into the medication chamber of a single dry powder inhaler device.

[0124] Filling of the capsules and loading of the inhaler are carried out according to the knowledge of those skilled in the art.

[0125] In an even further preferred embodiment, the present invention provides a method for treating respiratory diseases, which method comprises administering to a patient by inhalation a compound of formula (I) using a formulation described in accordance with the present invention.

[0126] In another preferred embodiment, the present invention provides a method as defined above for the treatment of a respiratory disease selected from the inflammatory or obstructive respiratory diseases mentioned above.

[0127] The present invention also relates to an inhalation device in the form of a single-dose dry powder inhaler filled with a pharmaceutical composition comprising fine particles of a compound of formula (I) and a carrier according to the present invention as described above, wherein the inhalation device has an inspiratory flow rate in the range of 30 l / min to 65 l / min, and wherein the carrier consists of a physiologically acceptable inert excipient having a mass diameter of less than 110 microns.

[0128] The following non-limiting examples are illustrative of the present invention and should not be construed as limiting the scope of the invention in any way.

[0129] Experimental part Abbreviation MOC = Micro Orifice Collector; HR = High Resistance; IP = Induction Port; PS = Pre-Separator; UHR = Ultra High Resistance [Example]

[0130] Example 1 Preparation of the composition of the present invention using the compound of formula (I) and finely divided lactose The fine lactose carrier used was InhaLac® 150 (Meggle, DE). The compound of formula (I) was sieved with 1 / 3 of the carrier through a 355 μm mesh and stirred in a Turbula at 38 rpm for 40 minutes; the second 1 / 3 of the carrier was added to the mixture and stirred at 38 rpm for 40 minutes; finally, the last 1 / 3 of the carrier was added and stirred at 38 rpm for 40 minutes. Finally, the mixture was sieved through a 355 μm mesh to remove any agglomerates formed in the second step, and mixed for 30 minutes at 38 rpm. A 10 gram batch size was produced.

[0131] [Table 1]

[0132] [Table 2]

[0133] 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) The drug content uniformity in the mixture was determined by HPLC. Analysis was performed on six randomly collected samples from the mixture dissolved in 100 ml of acetonitrile / water (60 / 40) v / v, which was used as the solvent. 20 mg was weighed out for each sample.

[0134] [Table 3] The mixtures in Table 3 show excellent uniformity of distribution of the active ingredient.

[0135] Example 3: Determination of aerodynamic particle size distribution (APSD) In vitro aerodynamic evaluation was performed using a Next Generation Impactor (NGI) according to the method detailed in the European Pharmacopoeia 10.0, chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles" on pages 347-360. Nexthaler (Chiesi, Parma, Italy) in combination with 400 μg and 800 μg compositions prepared according to WO 2012 / 016889 was considered as the control product.

[0136] The analysis of 400 μg and 800 μg formulations of the composition of the invention was carried out using the RS01 high resistance device code 239700002AA and the RS01 ultra-high resistance device code 239700005AA (Plastiape, Osnago, LC, Italy). (登録商標)The DPI inhalers were 100 mg, size 3 (Qualicaps Europe, SAU), and filled with approximately 20 mg. The DPI inhalers were activated at a pressure drop of 4 kPa, corresponding to a flow rate of 57.5 l / min for the Nexthaler, 65 l / min for the RS01 high resistance, and 40 l / min for the RS01 extra high resistance, for a time sufficient to sample a 4.0 liter air volume. The NGI was connected to a vacuum pump, and the airflow was constant using a flow meter. 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 instrument. Residual drug in the capsule and device (RS01 analysis only) and drug deposits on various parts of the impactor were recovered using acetonitrile / water (60 / 40) v / v as the solvent. Samples were filtered through an RC filter (0.45 μm) and quantified by HPLC to determine the amount of drug. In all experiments performed, the percentage of active ingredient recovered throughout the device was greater than 85% of the nominal dose. The measured dose (MD) was calculated by adding the drug recovered from the impactor (IP, PS, stages 1-7, and MOC) and the drug remaining in the inhaler (capsule and device). For the multi-dose Nexthaler DPI, quantification of the MD was not possible because it is a reservoir-type multi-dose inhaler and could not be wetted and rinsed at the end of the experiment. The emitted dose (ED), the amount of drug exiting the device and entering the impactor, was calculated by adding the drug recovered from the impactor (IP, PS, stages 1-7, and MOC). Drug deposition in the impactor allowed for the calculation of aerodynamic parameters. Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined by plotting the cumulative percentage of mass smaller than the aerodynamic diameter described by each NGI stage on a probability scale against the aerodynamic diameter of the stage on a logarithmic scale. Linear regression of the six data points closest to 50% of the cumulative particle mass entering the impactor was performed to calculate MMAD and GSD. Fine particle mass (FPM) was calculated as the mass of drug <5 μm (calculated from the log-probability plot equation), and the fine particle fraction (FPF) was determined as the ratio of FPD to ED in percent.The ultrafine particle mass (EFPM) was calculated as the mass of drug below 2 μm (calculated from the log-probability plot equation) and the ultrafine particle fraction (EFPF) was determined as the ratio of EFPD to ED in percent.

[0137] [Table 4]

[0138] [Table 5]

[0139] [Table 6]

[0140] [Table 7]

[0141] As shown in Tables 6 and 7, both products of the invention produced good respirable fractions, i.e., FPF of about 56-58%, with a similarly significant fraction of very fine particles (about 25-26%), similar to the control product, as can be seen from a comparison with Tables 4 and 5.

[0142] As shown in Figure 4, an 800 μg dose of the composition of the present invention in the RS01 HR inhalation device had deposition similar to that of the control product in stages S1-S5, but significantly lower deposition in IP and PS, which has the advantage of less systemic absorption and fewer side effects. For deposition of the very fine fraction (<2 μm), the control product had significantly higher deposition in stages S6, S7, and MOC.

[0143] As shown in Figure 3, although there is slightly less deposition in stages S1-S5 similar to the control product, the 400 μg dose of the composition of the present invention in the RS01 HR inhalation device has significantly lower deposition in the IP and PS.

[0144] [Table 8]

[0145] [Table 9]

[0146] Example 4: Dissolution Test In vitro dissolution testing was performed to confirm the efficacy of RespiCell TM (EU registration No. 006649570-0001) was used to compare the performance of a control product and the formulation of the present invention at 400 μg and 800 μg. The device was constructed to address some of the shortcomings of the types of dissolution tests currently used for pulmonary products (Sonvico F. et al Pharmaceutics 2021, 13(10), 1541).

[0147] 170cm filled with dissolution medium 3 The vertical diffusion cell apparatus includes a reservoir and a 10 cm long side arm. The apparatus consists of an upper donor chamber and a lower acceptor chamber, both of which are horizontally positioned in contact with the dissolution medium and connected by a clamp and separated by a glass fiber filter used as a diffusion membrane. The acceptor chamber contains a magnetic stirrer. A 76 mm diameter Type A / E glass fiber filter (PALL Corporation, Port Washington, NY, USA) was used as the diffusion membrane. The dissolution medium used for the analysis was phosphate-buffered saline (PBS) with 0.5% sodium dodecyl sulfate (SDS). RespiCell TMThe cell was connected to a heating thermostat (Lauda eco silver E4, DE) set at 37 ± 0.5 °C. The receptor chamber was filled with dissolution medium and sampled at scheduled time intervals through the side arm of the cell. Analysis was performed using the fine fraction deposited on a diffusion membrane filter after aerosolization by a Fast Screening Impactor (FSI).

[0148] In vitro aerodynamic evaluation was performed according to the method detailed in the European Pharmacopoeia 10.0, chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles" on pages 347-360. The analysis was carried out using an RS01 device. The capsules used were Quali-V (登録商標) The inhalers were 1000-1, size 3 (Qualicaps Europe, SAU) and filled with approximately 20 mg of composition powder. The inhaler was activated at a pressure drop of 4 kPa, corresponding to a flow rate of 65 l / min, for a time sufficient to sample 4.0 liters of air volume. The FSI was connected to a vacuum pump, and the airflow was kept constant using a flow meter. 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 aerosolized at 800 μg or 400 μg doses, respectively, and two or four fine particle doses were collected in the instrument. Analysis was performed in triplicate for each selected composition. After aerosolization, the filter was removed from the FSI and the RespiCell TM The filter was placed between the donor and acceptor chambers. 1 ml of dissolution medium was applied to the filter and allowed to completely wet before analysis. 1 ml of acceptor solution was removed from the acceptor chamber at fixed intervals and replaced with 1 ml of fresh dissolution medium after each removal to maintain a constant volume. To assess the amount of drug undissolved or trapped in the filter, residual undissolved powder was recovered at the end of the experiment by washing the filter with 10 ml of acetonitrile:water 60:40.

[0149] The amount of drug in the sample was evaluated by HPLC. Data was expressed as the percentage of dissolved compound of formula (I), with 100% dissolution corresponding to the amount of drug dissolved at the end of the experiment. Dissolution profiles were examined in terms of the fraction dissolved over time and the total amount using the difference coefficient (f1) and similarity coefficient (f2) previously proposed for the comparison of dissolution profiles of oral dosage forms (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).

[0150] The difference coefficient (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.

[0151] The difference factor (f1) is calculated as follows:

number

[0152] The similarity coefficient (f2) is calculated as follows:

number

[0153] To test the reliability of the method, in vitro dissolution profiles of two control products, 400 μg and 800 μg doses, were prepared. The results, reported in Figure 7, show excellent proportionality between dose and amount of drug dissolved.

[0154] Therefore, comparative in vitro dissolution studies between the control product and the formulation of the present invention at 400 μg and 800 μg doses were performed, and the profiles were found to be largely overlapping within the experimental limits of the method, as can be seen from Figures 8 and 9. These in vitro results and the dictates / 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 correlation model can be established to demonstrate the possibility of bioequivalence and to qualify a product as a candidate for biowaiver.

Claims

1. 1. A formulation comprising a single-dose dry powder inhaler device comprising an inhaler body (2) defining a recess (3) for a capsule (4) (wherein the capsule (4) holds a pharmaceutical composition to be inhaled), a nosepiece or mouthpiece (5) connected to the recess (3), at least one disruption portion (7) connected to the inhaler body (2) and configured to disrupt the capsule (4), allowing an external airflow to mix with the pharmaceutical composition of the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a pharmaceutical composition filled in the capsule, the pharmaceutical composition being a compound of formula (I) having a size of 0.1 to 15 microns. 【Chemical 1】 and lactose carrier particles, wherein the inspiratory flow rate of the inhalation device is in the range of 30 l / min to 65 l / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns as measured by means of laser diffraction or a sieve analyzer.

2. 10. The formulation of claim 1, wherein the carrier particles are made from alpha-lactose monohydrate.

3. 3. The formulation of claims 1 and 2, wherein the lactose carrier particles have an equivalent volume diameter ranging from 1 to 95 microns.

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

5. 5. The formulation of any one of claims 1 to 4, wherein the inhalation device has an inspiratory flow rate in the range of 40 l / min to 65 l / min.

6. 6. The formulation of any of claims 1 to 5, wherein the unit nominal dose of the compound of formula (I) is comprised between 400 μg and 800 μg.

7. 7. The formulation of claim 6, wherein the unit nominal dose of the compound of formula (I) is 800 μg.

8. 7. The formulation of claim 6, wherein the unit nominal dose of the compound of formula (I) is 400 μg.

9. 1. A method for treating respiratory diseases comprising administering to a subject a composition comprising: 【Chemistry 2】 and lactose carrier particles, wherein the composition is administered using a single dose dry powder inhaler device, wherein the inspiratory flow rate of the inhaler device is in the range of 30 l / min to 65 l / min, and wherein the lactose carrier particles have a volume equivalent sphere diameter of less than 110 microns as measured by means of laser diffraction or a sieve analyzer.

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

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

13. 10. A method for producing the formulation of any of claims 1 to 8, comprising the steps of: i) sieving a compound of formula (I) through a suitable mesh; ii) adding lactose carrier particles to the compound of formula (I); iii) sieving and blending the final mixture to obtain the final pharmaceutical composition; iv) filling the resulting pharmaceutical composition into capsules; and v) filling the capsules into the medicament chamber of a single dry powder inhaler device.

Images