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 microparticles of a compound of formula (I) and a carrier. The present invention also relates to a 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 microparticles of a compound of formula (I) and a carrier. The present invention also relates to a 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, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema, and cystic fibrosis.

[0005] Due to the well-known systemic side effects associated with the class of PDE4 inhibitors, tanimilast is under development as an inhaled composition.

[0006] Indeed, one of the advantages of the inhaled route over the systemic route is the possibility of localized delivery of drugs to the site of action, significantly avoiding any systemic absorption and associated side effects.

[0007] Currently, tanimilast is in the form of a powder composition utilizing the platform technology disclosed in WO2012 / 016889, a proprietary multi-dose Nexthaler (登録商標) It is administered via an inhaler. This product is hereafter referred to as the "control product."

[0008] 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."

[0009] Due to the nature of both the inhaler and platform technology, the composition provides an excellent respirable fraction as well as a substantial amount of very fine particles.

[0010] Tanimilast has been tested at two single doses per actuation: 400 μg and 800 μg.

[0011] Systemic effects of inhaled drugs are not a major concern due to low absorption, but there may be an increased risk of adverse events associated with systemic absorption, assuming the 800 μg dose is most effective.

[0012] Furthermore, for drugs administered as powder compositions, a dose of 800 μg, corresponding to a 4% concentration, is not optimal from a manufacturing standpoint. In fact, aggregates are formed that affect the homogeneity of the active ingredient in the mixture. Suboptimal homogeneity, in turn, increases the risk of over- or under-dosing. Summary of the Invention [Problem to be solved by the invention]

[0013] It would therefore be advantageous to provide a platform technology for compounds of formula (I) that offers good inhalation performance, allowing the administration of the drug at low doses while maintaining therapeutic efficacy at higher doses, which also produces the same fraction of ultrafine particles.

[0014] Due to the nature of both the inhaler and the platform technology, the composition provides an excellent respirable fraction and a substantial 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, Respir Care 2020;65(9):1392-1412; Scichilone N, Patient Relat Outcome Meas 2014;5:153-162).

[0015] The present invention provides a technical solution. [Means for solving the problem]

[0016] Summary of the Invention In a first aspect, the present invention provides a formulation 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 external airflow to mix with the pharmaceutical composition in the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a single-dose dry powder inhaler device comprising a pharmaceutical composition filled in the capsule, the pharmaceutical composition comprising fine particles of a compound of formula (I) and carrier particles having a size in the range of 0.1 to 1 micron, wherein the inhalation flow rate of the inhaler device is between 30 l / min and 65 l / min at a pressure drop of 4 kPa, and wherein the unit nominal dose of the compound of formula (I) is comprised between 450 and 600 μg.

[0017] Advantageously, the carrier comprises a three component agent.

[0018] Preferably, the carrier is: a particulate fraction made from a mixture consisting of 90 to 99.5 weight percent particles of a physiologically acceptable excipient and 0.5 to 10 weight percent particles of a ternary agent, the mixture having a volume median diameter of less than 20 microns; and A coarse particle fraction consisting of physiologically acceptable additives with a volume median diameter of 100 microns or greater wherein the particle size is measured by means of laser diffraction or a sieve analyzer, and wherein the ratio of fine to coarse particles is 1:99 to 30:70 weight percent.

[0019] In a second aspect, the present invention relates to a pharmaceutical composition of the invention for use in the treatment of a respiratory disease, wherein the composition is administered using a single dose dry powder inhaler device having an inspiratory flow rate in the range of 30 l / min to 65 l / min at a pressure drop of 4 kPa and comprising a unit nominal dose of 450 to 600 μg of the compound of formula (I).

[0020] In a third aspect, the present invention provides a method of treating a respiratory disorder, comprising administering to a patient by inhalation a compound of formula (I), wherein the formulation is as described in accordance with the present invention and wherein the nominal dose of compound of formula (I) per actuation is comprised between 450 and 600 μg.

[0021] In a fourth aspect, the present invention provides a method for producing a formulation of the present invention, comprising: a) preparing microparticles consisting of a mixture of particles of a physiologically acceptable pharmacologically inactive substance and particles of an additive, the inactive substance and the additive being first mixed together and then co-micronized; b) mixing the fine particles of step a) with coarse particles of a physiologically acceptable pharmacologically inactive substance such that the fine particles adhere to the surfaces of the coarse particles; c) mixing the active particles in micronized form with the particles of step b) to obtain the final pharmaceutical composition; d) filling the resulting final pharmaceutical composition into capsules; and e) Loading the capsule into the medicine chamber of a single dry powder inhaler device A method is provided, comprising the steps of: [Brief explanation of the drawings]

[0022] [Figure 1] Comparative deposition in a Next Generation Impactor of a 20 mg 800 micron formulation with the composition of a control product aerosolized with a Nexthaler, HR RS01, or UHR RS01 device.

[0023] [Figure 2] In vitro dissolution profile of the control product at 400 and 800 μg doses.

[0024] [Figure 3] Comparative in vitro dissolution of the reference product and the formulation of the present invention at an 800 μg dose by aerosolization with Nexthaler, HR RS01 or UHR RS01.

[0025] [Figure 4] FIG. 1 is a three-dimensional view of a single dose dry powder inhaler device according to an embodiment of the present invention.

[0026] [Figure 5] FIG. 5 is a cross-section of the single-dose dry powder inhaler device of FIG. 4 in a first operating configuration.

[0027] [Figure 6] Figure 4. Cross-section of the single-dose dry powder inhaler device in a second operating configuration. DETAILED DESCRIPTION OF THE INVENTION

[0028] 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.

[0029] 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.

[0030] The terms "micron," "micrometer," and μm are used synonymously.

[0031] The terms "microgram" and μg are used synonymously.

[0032] The terms "percent" and % are used synonymously.

[0033] 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.

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

[0044] The term "micronized" refers to materials having a size of a few microns, typically in the range of 0.1 to 15 microns.

[0045] The term "microparticle" refers to particles having a size down to a few tenths of a micron.

[0046] The term "ultrafine particles" refers to particles having a particle size of 2.0 microns or less.

[0047] The term "coarse" refers to materials having a size of one hundred to several hundred microns.

[0048] The term "surface coating" refers to the surface of the additive particle being covered by the formation of a thin film of the ternary agent around the particle.

[0049] The terms "additive" and "ternary agent" are used synonymously and mean substances that can modify the separation of the active ingredient from the surface of the carrier particles and result in a respirable fraction.

[0050] In general terms, particle size of particles is determined by measuring a characteristic equivalent particle size, known as the volume diameter, by laser diffraction or sieve analyzer.

[0051] Particle size can also be determined by measuring the mass diameter by means of suitable known equipment, such as, for example, a sieve analyzer or laser diffraction.

[0052] 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).

[0053] In this application, particle size and fine particle fraction of the active ingredient are expressed in terms of volume diameter.

[0054] 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.

[0055] Another common approach to defining particle size distributions is to quote three values: i) the median diameter d(0.5), which is the diameter above which 50% of the distributions lie and below which 50% lie; ii) d(0.9), which is the value below which 90% of the distributions lie; and iii) d(0.1), which is the value below which 10% of the distributions lie. The diameters are equivalent sphere diameters (the diameter of an imaginary sphere having the same volume as the particle under test), and the three parameters are designated as dv(0.5), dv(0.9), and dv(0.1).

[0056] 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 term "hard pellet" refers to a spherical or semi-spherical unit whose core consists of a coarse additive particle.

[0061] 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.

[0062] The term "peak inspiratory flow" refers to the maximum rate of airflow during a patient's inspiration with or without an inhalation device.

[0063] The term "inspiratory flow rate" refers to the constant rate of airflow capable of producing a pressure drop of 4.0 kPa (40.8 cm H2O) across the inhaler during in vitro testing according to the European Pharmacopoeia (Eur. Ph.), 11th Edition, paragraph 0671 Inhalation Formulations: Inhalanda, 998.

[0064] The delivered dose 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.

[0065] 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.

[0066] 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).

[0067] The term "prevention" refers to slowing the progression of a disease, delaying its onset and / or reducing the risk of developing the disease.

[0068] 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.

[0069] "Unit therapeutic effective dose" or "unit nominal dose" means the amount of active ingredient administered in a single inhalation upon actuation of the inhaler. The dose may be delivered in one or more actuations of the inhalation device, preferably in one or two actuations (shots) of the device, more preferably in one actuation.

[0070] "Actuation" refers to the release of the active ingredient from the device with a single activation (eg, mechanical or exhalation).

[0071] "Daily dose" means the amount of active ingredient administered by inhalation upon actuation of the inhaler in one day.

[0072] The term "delivered dose" refers to the amount of drug that is effectively delivered to the respiratory tree after each actuation of the inhaler.

[0073] 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%, preferably less than 2.5%, more preferably less than 1.5%.

[0074] The pharmaceutical compositions of the present invention encompass any type of composition made by mixing a compound of the present invention and a pharmaceutically acceptable excipient and / or carrier.

[0075] 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:

[0076] Reported flow rates refer to a pressure drop of 4 kPa (kilopascals) according to the European Pharmacopoeia (Eur. Ph.), 11th Edition, paragraph 0671 Inhalation Formulations: Inhalanda, 998.

[0077] It has been found that a single-dose dry powder inhaler device with an inspiratory flow rate ranging from 30 l / min to 65 l / min at a pressure drop of 4 kPa, combined with a high-performance powder technology platform, can improve inhalation performance, particularly FPF, thereby enabling the administration of drugs at lower doses while maintaining the therapeutic effect at higher doses.

[0078] Indeed, the results reported in Tables 5 and 7 of Example 3 of the experimental part show that for single-dose dry powder inhaler devices with inspiratory flow rates ranging from 30 l / min to 65 l / min at a pressure drop of 4 kPa, combined with the same technology platform of the control composition, an increase in FPF of approximately 25-35% could be achieved compared to the control product.

[0079] Additionally, extraFPF was found to increase by approximately 28-58% compared to the control product.

[0080] The increase is calculated by multiplying by 100 the ratio of the difference between the test product value and the control value.

[0081] The improved performance is confirmed by in vitro dissolution results using a system specifically designed to evaluate the in vitro dissolution profile of drugs by inhalation.

[0082] As can be seen from Figure 3, approximately 7-20% higher amounts of the compound of formula (I) were dissolved compared to the control product. This allows for approximately 25-35% reduction in the nominal dose of 800 μg units. Previous studies have used capsule-based single-dose dry powder inhalers to administer tanimilast. For example, Mariotti F., International Journal of COPD, 2018:13 3399-3410, described a first study in which tanimilast was administered via a capsule-based single-dose dry powder inhaler, Aerolizer, and in a second study, the same compound was administered via a reservoir-based multiple-dose dry powder inhaler (MDDPI), NEXThaler®. The results showed that the AUC systemic bioavailability of the compound of formula (I) of the present invention was approximately 30% higher after administration via the multi-dose dry powder inhaler Nexthaler than via the single-dose dry powder inhaler Aerolizer, suggesting that, in contrast to the findings of the present invention, Nexthaler may provide better pulmonary drug deposition. The Aerolizer is a low-resistance device (0.019 kPa). 1 / 2 / L*min -1) and indicates that an inspiratory flow rate of approximately 105 l / min is required for a pressure loss of 4 kPa (Dal Negro, RW Dry powder inhalers and the right things to remember: a concept review. Multidiscip Resp Med 10, 13 (2015)).

[0083] Thus, 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.

[0084] 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 code 239700002AA and the ultra-high resistance device RS01 with code 239700005AA.

[0085] The intake flow rate is in the range of 30 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, and even more preferably 40 l / min, based on a pressure drop of 4 kPa.

[0086] The unit nominal dose delivered after each actuation of the inhaler is between 450 μg and 600 μg, preferably between 480 μg and 550 μg.

[0087] The daily dose at which the pharmaceutical composition containing the compound of general formula (I) is administered ranges from 800 μg to 4800 μg, preferably from 1200 μg to 3800 μg, and more preferably from 1600 μg to 3200 μg.

[0088] In certain embodiments, the daily dose can be achieved in a single or two administrations.

[0089] In other preferred embodiments, the daily dose is reached in a single administration and can be delivered by one actuation of the inhaler.

[0090] 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.

[0091] In another preferred embodiment, the daily dose is reached in two administrations, which can be delivered by a single actuation of the inhaler.

[0092] 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.

[0093] Advantageously, the carrier comprises a mixture of fine and coarse excipient particles of any physiologically acceptable substance or combination thereof suitable for inhalation use.

[0094] For example, the particles may be composed of one or more substances selected from polyols, such as sorbitol, mannitol, and xylitol, and crystalline sugars, including mono- and disaccharides; inorganic salts, such as sodium chloride and calcium carbonate; organic salts, such as sodium lactate; and other organic compounds, such as urea, polysaccharides, such as starch and its derivatives; oligosaccharides, such as cyclodextrins and dextrins.

[0095] 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.

[0096] Preferably, the particles are made from lactose, more preferably alpha-lactose monohydrate, as this additive is known to be chemically and physically stable on storage and easy to process.

[0097] Preferably, the coarse and fine additive particles both consist of alpha-lactose monohydrate.

[0098] The fine particle fraction should a) have a mass median diameter (MMD) of less than 20 microns, advantageously 1 micron or less, preferably 10 microns or less, and even more preferably 6 microns or less.

[0099] Advantageously, the mass diameter of 90% of the microparticles is a) less than 3 microns, more advantageously less than 2 microns, preferably less than 1 micron, even more preferably less than 10 microns.

[0100] The ratio of additive particles to triple agent within a fraction may vary depending on a) the dose of the active ingredient.

[0101] Advantageously, said fractions consist of 90-99.5% by weight of additive and 0.5-10% by weight of triple agent, preferably 95-99% of additive and 1-5% of triple agent, the preferred ratio being 98% of additive and 2% of triple agent.

[0102] The tripartite agent may preferably be an amino acid selected from the group consisting of leucine, isoleucine, lysine, valine, methionine and phenylalanine.

[0103] Alternatively, the triple component may comprise or consist of one or more water-soluble surfactants, such as lecithin.

[0104] In certain embodiments, the triple component may comprise or consist of one or more lubricants selected from the group consisting of stearic acid and salts thereof such as magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate.

[0105] The tripartite agent may preferably be an amino acid selected from the group consisting of leucine, isoleucine, lysine, valine, methionine and phenylalanine.

[0106] Alternatively, the triple component may comprise or consist of one or more water-soluble surfactants, such as lecithin.

[0107] In some embodiments, the triple component may comprise or consist of one or more lubricants selected from the group consisting of stearic acid and salts thereof, such as magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, and sucrose monopalmitate. A preferred active agent is magnesium stearate.

[0108] When magnesium stearate is used as a ternary agent, depending for example on its amount and the time of mixing, the magnesium stearate may coat the surface of the fine additive particles such that the degree of molecular surface coating is at least 5%, preferably more than 10%, more preferably more than 15%, and even more preferably 25% or more.

[0109] The degree of molecular surface coating, which indicates the percentage of the total surface of the additive particle that is coated with magnesium stearate, can be determined by water contact angle measurements, as reported in the literature, for example in WO2011 / 120779.

[0110] The fine particle fraction can be produced by one of the methods disclosed in WO 01 / 78693, preferably by co-milling, more preferably by using a ball mill. In some instances, co-milling for at least 2 hours may prove advantageous, although it will be appreciated that the processing time will generally depend on the starting particle size of the additive particles and the desired reduction in size to be achieved.

[0111] In a preferred embodiment of the invention, the particles are co-micronized, preferably using a jet mill in an inert atmosphere, e.g., under nitrogen, starting with additive particles having a mass diameter of less than 250 microns and magnesium stearate particles having a mass diameter of less than 3 microns.

[0112] By way of example, commercially available alpha-lactose monohydrate such as Meggle D 30 or Spherolac 100 (Meggle, Wasserburg, Germany) is used as starting additive.

[0113] If desired, the fine particle fraction may be subjected to a conditioning step according to the conditions disclosed in a) pending application no. WO2011 / 131663.

[0114] The fraction of coarse additive particles b) has an MMD of at least 100 microns, preferably greater than 12 microns, more preferably 150 microns or greater, even more preferably 17 microns or greater.

[0115] Advantageously, all the coarse particles have a mass diameter ranging from 50 to 1000 microns, preferably from 60 to 500 microns.

[0116] In certain embodiments of the invention, the mass diameter of the coarse particles ranges from 80 to 200 microns, preferably from 90 to 150 microns, while in other embodiments the mass diameter ranges from 200 to 400 microns, preferably from 210 to 35 microns.

[0117] In a preferred embodiment of the present invention, the mass diameter of the coarse particles ranges from 210 to 35 microns.

[0118] Generally, one skilled in the art will select the most appropriate size of the coarse additive particles by sieving using an appropriate sizer.

[0119] When the mass diameter of the coarse particles is in the range of 200 to 400 microns, the coarse additive particles preferably have a relatively highly cracked surface, i.e., have crevices, valleys, and other recessed areas on the surface, collectively referred to herein as cracks. "Relatively highly cracked" coarse particles can be defined in terms of the crack index or wrinkling factor as described in WO 01 / 78695 and WO 01 / 78693, the teachings of which are incorporated herein by reference, and can be characterized according to the descriptions therein. The coarse particles can also be characterized in terms of tap density or total pore volume, measured as described in WO 01 / 78695, the teachings of which are incorporated herein by reference.

[0120] The tap density of the coarse particles is advantageously 0.8 g / cm 3 less than 0.8 to 0.5 g / cm 3 The total pore volume is at least 0.8 cm 3 , preferably at least 0.9 cm 3 is.

[0121] The ratio of the fine particle fraction a) to the coarse particle fraction b) is in the range of 1:99 to 30:70% by weight, preferably 2:98 to 20:80% by weight. In a preferred embodiment, the ratio is in the range of 10:90 to 15:85% by weight, even more preferably 10:90% by weight.

[0122] The step of mixing the coarse additive particles b) with the fine particles a) is typically carried out using a suitable mixer, such as a tumbler type mixer, e.g., a Turbula TM , rotary mixer or instant mixer, e.g. Diosna TM The mixing is carried out at 500° C. for at least 5 minutes, preferably at least 30 minutes, more preferably at least 2 hours. In a typical manner, a person skilled in the art will adjust the mixing time and the rotation speed of the mixer to obtain a homogeneous mixture.

[0123] When spheronized coarse additive particles are desired to obtain hard pellets according to the above definition, the mixing step is typically carried out for at least 4 hours.

[0124] In a preferred embodiment, the carrier of the composition of the present invention is: a) a fine particle fraction made from a mixture of 98 weight percent alpha-lactose monohydrate particles and 2 weight percent magnesium stearate, the mixture having a mass median diameter of 6 microns or less; b) a coarse particle fraction made from alpha-lactose monohydrate having a mass diameter in the range of 210 to 35 microns, the ratio of fine particles to coarse particles being 10:90 weight percent. It consists of:

[0125] More preferably, the physiologically acceptable excipient used as a coarse carrier has a d(0.1) in the range of 170-190 microns, a d(0.5) in the range of 270-300 microns, and a d(0.9) in the range of 300-400 microns, all values ​​expressed as mass diameter.

[0126] 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.

[0127] Advantageously, the compounds of formula (I) have the following distribution, measured as equivalent spherical diameter by volume: 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, with a span in the range of 1.7 to 2.3 microns.

[0128] 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 μm) are accompanied by a high proportion of very fine particles that favor peripheral deposition of the drug in the lungs.

[0129] 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.

[0130] 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.

[0131] According to the present invention, the capsules filled with the pharmaceutical composition of the present invention have a size ranging from 000 to 5, preferably from 001 to 4, and even more preferably from 00 to 3. Even more preferably, the capsules have a size 2 or 3. Depending on the inhaler selected and the required dosage, the skilled artisan will select the most appropriate size. According to a preferred embodiment of the present invention, when using the RS01 Plastiape device, the capsules are size 2 or 3.

[0132] 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 1 of Example 2 in the experimental part.

[0133] 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.

[0134] The present invention also relates to a method for preparing the compositions disclosed herein, which comprises the step of mixing the fine particle fraction a) and the coarse particle fraction b) with both micronized active ingredients.

[0135] The carrier particles, including the fine particle fraction and the coarse particle fraction, can be mixed in any suitable apparatus known to those skilled in the art, e.g., a Turbula TM It can be prepared by mixing the two fractions in a Turbula mixer, preferably operating at a rotation speed of 16 rpm for a time comprised between 30 and 300 minutes, preferably between 150 and 240 minutes. TM Mix in a mixer.

[0136] The mixture of carrier particles and active ingredient particles is placed in a Turbula TM This can be done by mixing the ingredients in a suitable device known to those skilled in the art, such as a mixer, for a time sufficient to achieve homogeneity of the active ingredient in the final mixture, preferably in the range of 30 to 120 minutes, more preferably 45 to 100 minutes.

[0137] Optionally, in another embodiment, one active ingredient is first mixed with a portion of the carrier particles, the resulting mixture is sieved, then the additional active ingredient and the remaining portion of the carrier particles are mixed with the sieved mixture; and finally the resulting mixture is sieved and mixed again.

[0138] Those skilled in the art will select the mesh size of the sieve depending on the particle size of the coarse particles.

[0139] 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.

[0140] 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, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema and cystic fibrosis.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In a preferred embodiment, the present invention provides 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 in the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a pharmaceutical composition filled in the capsule, wherein the pharmaceutical composition comprises fine particles of a compound of formula (I) and carrier particles having a size in the range of 0.1 to 1 micron, wherein the inhalation flow rate of the inhaler device is 65 l / min or less, wherein the nominal dose of the compound of formula (I) per actuation is in the range of 450 to 600 μg, and wherein the carrier is: a) a fine particle fraction made from a mixture of 98 weight percent alpha-lactose monohydrate particles and 2 weight percent magnesium stearate, the mixture having a mass median diameter of 6 microns or less; b) a coarse particle fraction made from alpha-lactose monohydrate having a mass diameter in the range of 210 to 35 microns, the ratio of fine particles to coarse particles being 10:90 weight percent. The present invention relates to a formulation comprising:

[0146] In an even more preferred embodiment, the particle size of the compound of formula (I) has a dv(0.1) in the range of 0.5 to 1 micron, a dv(0.5) in the range of 1.9 to 2.5 microns, and a dv(0.9) in the range of 4 to 6 microns.

[0147] In another preferred embodiment, the present invention relates to a pharmaceutical composition of the present invention for use in the treatment of a respiratory disease, wherein the composition is administered using a single dose dry powder inhaler device having an inspiratory flow rate in the range of 30 l / min to 65 l / min.

[0148] In an even more preferred embodiment, the present invention provides a method for treating a respiratory disease, comprising administering to a patient by inhalation a compound of formula (I), wherein the formulation is as described in accordance with the present invention, and wherein the nominal dose of compound of formula (I) per actuation is comprised between 450 and 600 μg.

[0149] In another embodiment, the present invention provides a method for producing a pharmaceutical composition of the present invention, comprising: a) preparing microparticles consisting of a mixture of particles of a physiologically acceptable pharmacologically inactive substance and particles of an additive, the inactive substance and the additive being first mixed together and then co-micronized; b) mixing the fine particles of step a) with coarse particles of a physiologically acceptable pharmacologically inactive substance such that the fine particles adhere to the surfaces of the coarse particles; c) adding the active particles in micronized form to the particles of step b) by mixing. A method is provided, comprising the steps of:

[0150] In an even more preferred embodiment, the present invention provides a method of producing a formulation comprising the step of loading a capsule filled with a pharmaceutical composition of the present invention into the medicament chamber of a single dry powder inhalation device.

[0151] Experimental part Abbreviation Moc = micro-orifice collector; IP = induction port; PS = pre-separator [Example]

[0152] Example 1 : Preparation of the composition of the present invention The composition of the present invention was prepared according to the method disclosed in WO2012 / 016889.

[0153] 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. [Table 1] The mixtures in Table 1 show excellent precision and uniformity of distribution of the active ingredient (exact as CV).

[0154] 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 chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles" on pages 347-360 of the European Pharmacopoeia 10.0.

[0155] Nexthaler (Chiesi, Parma, Italy) in combination with 400 μg and 800 μg of the composition prepared according to WO2012 / 016889 was considered as the control product.

[0156] The analysis of 400 μg and 800 μg formulations of the composition of the invention was carried out using RS01 high resistance and RS01 ultra-high resistance devices with code 239700002AA and 239700005AA (Plastiape, Osnago, LC, Italy). (登録商標)The DPI inhalers were size 3 TAA (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 HR RS01, and 40 L / min for the UHR RS01, 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. Three different devices were used for each type of DPI. Residual drug in the capsule and device (RS01 analysis only) and drug deposits at three different sites on 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.

[0157] 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). Quantitation of the MD was not possible for the multi-dose Nexthaler DPI because it is a reservoir-type multi-dose inhaler and could not be wetted and rinsed at the end of the experiment.

[0158] Emitted Dose (ED) The emitted dose (ED) is the amount of drug that exits the device and enters the impactor, and was calculated by adding the drug recovered from the impactor (IP, PS, stages 1-7, and MOC).

[0159] Drug deposition in the impactor allowed for the calculation of aerodynamic parameters.

[0160] 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 the MMAD and GSD.

[0161] 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.

[0162] The extremely fine particle mass (EFPM) 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.

[0163] [Table 2]

[0164] [Table 3]

[0165] [Table 4]

[0166] [Table 5]

[0167] [Table 6]

[0168] [Table 7]

[0169] As shown in Figure 1, aerosolization of the composition of the present invention from a capsule inhaler (800 μg) significantly reduces drug deposition in the pre-separator (PS) and IP, both of which mimic the oropharyngeal tract. In parallel, deposition in the stages that collect the fine particle fraction of drug (S4, S5, S6, and MOC) is high using a capsule inhaler for both the HR or UHR RS01 device. As a result, the dose loaded into the inhaler can be reduced to match the fine particle fraction emitted by Nexthaler.

[0170] Example 4: Dissolution Test In vitro dissolution tests were performed on 170 cm 2 filled with dissolution media. 3 RespiCell, a vertical diffusion cell device containing a reservoir and a 10 cm long side arm TM The performance of the reference product and the formulation of the present invention at 800 μg was compared using a RespiCell (EU registration No. 006649570-0001). The apparatus consists of an upper donor chamber and a lower acceptor chamber, connected by a clamp and separated by a glass fiber filter used as a diffusion membrane, both of which are horizontally positioned in contact with the dissolution medium. 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 in the analysis was phosphate-buffered saline (PBS) with 0.5% sodium dodecyl sulfate (SDS). 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. 1 ml of dissolution medium was applied to the filter, which was allowed to wet thoroughly before analysis. Analysis was performed using the fine fraction deposited on the diffusion membrane filter after aerosolization with a Fast Screening Impactor (FSI). In vitro aerodynamic evaluation was performed according to the method detailed in chapter 2.9.18 "Preparation for inhalation: Aerodynamic assessment of fine particles" of the European Pharmacopoeia 10.0, pages 347-360. Analysis was performed using the HR RS01 and UHR RS01 devices. The capsules used were Quali-V (登録商標) The inhalers were size 3 TAA (Qualicaps Europe, SAU) and filled with approximately 20 mg. The HR RS01 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 UHR RS01 inhaler was activated at a pressure drop of 4 kPa, corresponding to a flow rate of 40 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 FSI was connected to the FSI via a rubber adapter; two capsules were aerosolized and two doses were collected in the device. Analysis was performed in triplicate for each selected composition. After aerosolization, the filter was removed from the FSI and the RespiCell TMA filter was placed between the donor and acceptor chambers. 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, the remaining undissolved powder was recovered by washing the filter with 10 mL of acetonitrile:water 60:40 at the end of the experiment. The amount of drug in the sample was assessed by HPLC. Data were expressed as the percentage of compound of formula (I) dissolved, 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 and total amount dissolved over time using the difference coefficient (f1) and similarity coefficient (f2). The difference coefficient (f1) calculates the percent difference between the two dissolution profiles at each time point and is an indicator of the relative error between the two profiles. The difference coefficient (f1) is calculated as follows:

number

[0171] The similarity coefficient (f2) is calculated as follows:

number

[0172] 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 2, show excellent proportionality between dose and amount of drug dissolved.

[0173] Comparative in vitro dissolution testing between the control product and the formulation of the present invention was then performed, which, as can be seen from Figure 3, showed a lower dissolution profile for the control product released from Nexthaler compared to the formulation of the present invention released from the HR RS01 and UHR RS01 devices.

[0174] 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), an IVIV correlation model can be established to prove the possibility of bioequivalence and make the formulation of the present invention a candidate product for biowaiver.

Claims

1. 1. A formulation comprising an inhaler body (2) defining a recess (3) for a capsule (4) (in which 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 in the capsule (4) and be inhaled through the nosepiece or mouthpiece (5), and a single-dose dry powder inhaler device containing a pharmaceutical composition filled in a capsule, the pharmaceutical composition being a pharmaceutical composition of formula (I) having a size in the range of 0.1 to 1 micron. 【Chemical 1】 A formulation comprising fine particles of a compound and carrier particles, wherein the inspiratory flow rate of the inhaler is between 30 l / min and 65 l / min at a pressure drop of 4 kPa, and wherein the unit nominal dose of the compound of formula (I) is in the range of 450 to 600 μg.

2. 10. The formulation of claim 1, wherein the unit nominal dose ranges from 480 to 550 μg.

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

4. 4. The formulation of any of claims 1 to 3, wherein the carrier particles comprise a mixture of particles having a size of hundreds or hundreds of microns and particles having a size down to a few tenths of a micron, and the three component agent.

5. 1. The carrier has a molecular weight of: a) a particulate fraction made from a mixture consisting of 90 to 99.5 weight percent particles of a physiologically acceptable excipient and 0.5 to 10 weight percent of a ternary agent, the mixture having a volume median diameter of less than 20 microns; and b) A coarse particle fraction consisting of physiologically acceptable excipients having a volume median diameter of 100 microns or more.

5. The formulation of any of claims 1 to 4, wherein the ratio of fine particles to coarse particles is in the range of 1:99 to 30:70 weight percent.

6. 6. The formulation of claim 1 or 5, wherein the inspiratory flow rate is in the range of 40 l / min to 65 l / min at a pressure drop of 4 kPa.

7. 1. A compound of formula (I) having a size in the range of 0.1 to 1 micron for use in the treatment of respiratory diseases 【Chemistry 2】 and carrier particles, wherein the composition is administered using a single dose dry powder inhaler device having an inspiratory flow rate in the range of 30 l / min to 65 l / min and a unit dose of the compound of formula (I) in the range of 450 to 600 μg.

8. 8. The pharmaceutical composition for use according to claim 7, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

9. A method for producing the formulation of any of claims 1 to 6, comprising: a) providing microparticles comprising a mixture of particles of a physiologically acceptable pharmacologically inactive substance and particles of an additive, the inactive substance and the additive being first mixed together and then co-micronized; b) mixing the fine particles of step a) with coarse particles of a physiologically acceptable pharmacologically inactive substance so that the fine particles adhere to the surfaces of the coarse particles; c) adding the active particles in micronized form to the particles of step b) by mixing to obtain the final pharmaceutical composition; d) filling the resulting final pharmaceutical composition into capsules; and e) Loading the capsule into the medicine chamber of a single dry powder inhaler device A method comprising the steps of:

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