Process for preparing dry powder formulation comprising anticholinergic, corticosteroid and beta-adrenergic

Abstract

The present invention relates to a process for preparing a powder formulation for inhalation for use in a dry powder inhaler, the powder formulation comprising: (A) a carrier comprising: (a) a physiologically acceptable coarse particle fraction of the carrier having a particle size of at least 60 microns; and optionally (b) a fine particle fraction comprising a physiologically acceptable excipient wherein at least 90% of all of the fine particles have a volume diameter of less than 15 microns, (B) micronized particles of glycopyrronium bromide, an inhalation corticosteroid (ICS) and optionally a long-acting beta2-agonist (LABA) as active ingredients, wherein the method comprises: (i) preparing, by co-grinding, microparticles consisting of glycopyrronium bromide and a first portion of ICS in a weight ratio of 80: 20 to 70: 30, wherein the volume diameter of the microparticles is not greater than 15 microns; (ii) mixing a carrier, the remainder of the ICS and an optional long-acting beta2-agonist to obtain a first mixture; and (iii) adding the co-milled microparticles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second final mixture.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of May 9, 2018, application number 201880029972.X, and invention name “Method for preparing a dry powder preparation containing anticholinergics, corticosteroids and beta-adrenergic drugs”. Technical Field

[0002] The present invention relates to powder formulations for administration by inhalation via a dry powder inhaler.

[0003] In particular, the present invention relates to a method for preparing a dry powder formulation comprising a combination of an anticholinergic, a β2-adrenergic receptor agonist and a corticosteroid for inhalation. Background of the Invention

[0005] Respiratory diseases are a common and important cause of illness and death throughout the world. In fact, many people are affected by inflammatory and / or obstructive lung disease (a category characterized by inflamed and easily collapsed airways, obstruction to airflow, problems exhaling, and frequent doctor visits and hospitalizations). Types of inflammatory and / or obstructive lung disease include asthma, bronchiectasis, bronchitis, and chronic obstructive pulmonary disease (COPD).

[0006] Specifically, chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by airflow limitation and airway inflammation. Exacerbations of COPD have a significant impact on the patient's quality of life, daily activities, and general health, and are a huge burden on the health system. Thus, the goals of COPD management include not only relieving symptoms and preventing disease progression, but also preventing and treating exacerbations.

[0007] Although available treatments improve clinical symptoms and reduce airway inflammation, they do not clearly slow long-term progression or address all disease components. As the burden of COPD continues to increase, research is ongoing on new and improved treatment strategies to optimize drug therapy, and specifically combination therapy, in order to achieve their complementary modes of action, thereby addressing multiple components of the disease. Evidence from recent clinical trials indicates that triple therapy combining an anticholinergic with an inhaled corticosteroid and a long-acting β2-adrenergic receptor agonist may provide clinical benefits in patients with more severe COPD in addition to those associated with each treatment alone.

[0008] Currently, there are several recommended treatment categories for COPD, with bronchodilators such as beta2-agonists and anticholinergics being the mainstay for symptom management of mild and moderate disease, prescribed as needed for mild COPD and as maintenance therapy for moderate COPD.

[0009] The bronchodilators are effectively administered by inhalation, thereby increasing the therapeutic index and reducing side effects of the active material.

[0010] For the treatment of more serious COPD, guidelines recommend the addition of inhaled corticosteroids (ICS) to long-acting bronchodilator therapy. The combination of therapies has been studied to achieve their complementary modes of action, thereby ensuring that multiple components of the disease are addressed. Data from recent clinical trials indicate that triple therapy combining anticholinergics and long-acting β2-agonists (LABAs) with ICS may provide clinical benefits in addition to those clinical benefits associated with each treatment alone in patients with moderate to severe COPD.

[0011] An interesting triple combination currently under investigation includes:

[0012] i) Formoterol, in particular its fumarate salt (hereinafter FF), a long-acting beta-2 adrenergic receptor agonist currently used clinically for the treatment of asthma, COPD and related disorders;

[0013] ii) glycopyrrolate, an anticholinergic recently approved for maintenance treatment of COPD;

[0014] iii) Beclomethasone dipropionate (BDP), a potent anti-inflammatory corticosteroid available under various trade names for the prevention and / or treatment of asthma and other respiratory disorders.

[0015] However, despite their popularity, pMDI formulations may have some disadvantages, particularly in elderly and pediatric patients, primarily due to their difficulty synchronizing device actuation with inspiration.

[0016] Dry powder inhalers (DPIs) constitute an effective alternative to MDIs for administration to the airways.

[0017] Generally, medications intended for inhalation as dry powders should be used in the form of micronized particles.

[0018] For example, WO 2015 / 004243 discloses a powder formulation for inhalation by a dry powder inhaler (DPI), the powder formulation comprising all three active ingredients in micronized form. The formulation utilizes the technology platform disclosed in WO01 / 78693, thereby requiring the use of a carrier composed of a fraction of coarse excipient particles and a fraction made of fine excipient particles and magnesium stearate.

[0019] In the specification, possible processes for preparing micronized glycopyrrolate are described, but no preferences are given.

[0020] On the other hand, similar to other antimuscarinics, glycopyrronium salts may face significant stability issues, especially following conventional micronization methods by milling.

[0021] Indeed, glycopyrrolate, once micronized, has a strong tendency to aggregate and / or agglomerate, which severely hampers downstream pharmaceutical processing, in particular the preparation of dry powder formulations for administration by inhalation capable of delivering a good respirable fraction.

[0022] It is therefore an object of the present invention to provide a process for the preparation of a powder formulation suitable for the administration of glycopyrrolate in combination with a LABA and an ICS, overcoming the above mentioned problems. Summary of the invention

[0023] The present invention relates to a method for preparing a powder preparation for inhalation in a dry powder inhaler, the powder preparation comprising:

[0024] (A) a vector comprising:

[0025] (a) a coarse particle fraction of a physiologically acceptable carrier having a mass diameter of at least 60 micrometers; and optionally

[0026] (b) a fine particle fraction comprising a physiologically acceptable excipient, wherein at least 90% of said fine particles have a volume diameter of less than 15 micrometers,

[0027] (B) micronized particles of glycopyrrolate, an inhaled corticosteroid (ICS) and optionally a long-acting β2-agonist (LABA) as active ingredients,

[0028] The method comprises:

[0029] (i) preparing microparticles consisting of glycopyrrolate and a first portion of ICS in a weight ratio of 80:20 to 70:30 by co-milling, wherein the volume diameter of the microparticles is no greater than 15 microns;

[0030] (ii) mixing a carrier, the remaining portion of the ICS and optionally a long-acting β2-agonist to obtain a first mixture; and

[0031] (iii) adding the co-milled microparticles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second final mixture.

[0032] In a particular variant, the invention relates to a method for preparing a powder formulation for inhalation in a dry powder inhaler, the powder formulation comprising:

[0033] (A) a vector comprising:

[0034] (a) a coarse particle fraction of a physiologically acceptable carrier having a mass median diameter of at least 175 μm; and

[0035] (b) a fine particle fraction consisting of a mixture of 90 to 99.5% by weight of particles of a physiologically acceptable excipient and 0.5 to 10% by weight of a fatty acid salt, wherein at least 90% of said fine particles have a volume diameter equal to or less than 15 micrometers,

[0036] wherein the weight ratio of the fine particles to the coarse particles is 5:95 to 30:70; and

[0037] (B) micronized particles of glycopyrrolate, a long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS) as active ingredients,

[0038] The method comprises:

[0039] (i) preparing microparticles consisting of glycopyrrolate and a first portion of ICS in a weight ratio of 80:20 to 70:30 by co-milling, wherein the volume diameter of the microparticles is no greater than 15 microns;

[0040] (ii) mixing the carrier, LABA and the remaining portion of the ICS in a container of an oscillating mixer at a speed of not less than 16 rpm for not less than 60 minutes to obtain a first mixture; and

[0041] (iii) adding the co-milled particles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second mixture, and blending the second mixture at a rotation speed of not more than 16 rpm for a period of not more than 40 minutes to obtain a blend.

[0042] In a preferred embodiment, the ICS is beclomethasone dipropionate.

[0043] In an even more preferred embodiment, the LABA is formoterol fumarate dihydrate.

[0044] definition

[0045] The terms "muscarinic receptor antagonist," "antimuscarinic drug," and "anticholinergic drug" are synonymous.

[0046] The term "glycopyrrolate" refers to the bromide salt of the compound (3S,2'R),(3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium (also known as glycopyrrolate) in an approximately 1:1 racemic mixture.

[0047] The term "pharmaceutically acceptable salt of formoterol" refers to a salt of the compound 2'-hydroxy-5'-[(RS)-1-hydroxy-2{[(RS)-p-methoxy-α-methylphenethyl]amino}ethyl]carboxanilide.

[0048] The term "beclomethasone dipropionate" refers to the compound (8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate.

[0049] The term "pharmaceutically acceptable salt" includes inorganic salts and organic salts. Examples of organic salts include formates, acetates, trifluoroacetates, propionates, butyrates, lactates, citrates, tartrates, malates, maleates, succinates, methanesulfonates, benzenesulfonates, xinafoates, pamoates and benzoates. Examples of inorganic salts include fluorides, chlorides, bromides, iodides, phosphates, nitrates and sulfates.

[0050] The term "physiologically acceptable excipient" refers to a pharmacologically inert substance used as a carrier. In the context of the present invention, fatty acid salts, which are also physiologically acceptable excipients, are considered additives.

[0051] The expression "oscillating mixer" refers to a universal mixer with a wide and adjustable range of rotation speeds and inversion cycles. In such mixers, the mixing vessel is fixed with a universal bracket. The two rotating shafts are positioned perpendicular to each other and are independently powered. The direction of rotation and the speed of rotation of the two shafts are changed continuously and independently. These kinds of settings of the mixing process parameters ensure high values ​​of mixing efficiency. Typical oscillating mixers are dyna-MIX TM(Willy A. Bachofen AG, Switzerland) or 3D.S mixer (Erhard Muhr GmbH, Germany) are commercially available.

[0052] The expression "tumble mixer" refers to a mixer operating with different mixing times and mixing speeds, but having a typical movement characterized by the interaction of rotation, translation and inversion.

[0053] Typical drum mixer as Turbula TM (Willy A. Bachofen AG, Switzerland) commercially available.

[0054] The expression constant or high shear mixer refers to a mixer in which a rotor or impeller is used with a stationary component called a stator in a tank containing the powders to be mixed to generate shear.

[0055] Typical high shear mixers are P 100 and P 300 (Diosna GmbH, Germany), Roto Mix (IMA, Italy) and Cyclomix TM (Hosokawa Micron Group Ltd, Japan).

[0056] The term "micronized" refers to material having a size of several micrometers.

[0057] The term "coarse" refers to a substance having a size of one hundred micrometers or several hundred micrometers.

[0058] In general, the size of particles is quantified by measuring the characteristic equivalent spherical diameter, called the volume diameter, by means of laser diffraction.

[0059] The particle size can also be quantified by measuring the mass diameter by means of a suitable known instrument (eg a sieve analyser).

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

[0061] In the present application, the particle sizes of the active ingredient and the fine particle fraction are expressed in terms of volume diameter, whereas the particle size of the coarse particles is expressed in terms of mass diameter.

[0062] The particles have a normal (Gaussian) distribution, which is defined in terms of a volume or mass median diameter (VMD or MMD), respectively, 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.

[0063] Another common way to define particle size distribution is by three values: i) the median diameter d(0.5), which is the diameter when 50% of the distribution is above and 50% of the distribution is below; ii) d(0.9), where 90% of the distribution is below this value; iii) d(0.1), where 10% of the distribution is below this value.

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

[0065]

[0066] In general, particles with the same or similar VMD or MMD may have different particle size distributions, and in particular different widths of the Gaussian distribution represented by the d(0.1) and d(0.9) values.

[0067] After aerosolization, the particle size is expressed as mass aerodynamic diameter (MAD), while the particle size distribution is expressed in terms of mass median diameter (MMAD) and geometric standard deviation (GSD). MAD indicates the ability of particles to be suspended in an air stream for transport. MMAD corresponds to the mass aerodynamic diameter of the particles at 50 weight percent.

[0068] In the final formulation, the particle size of the active ingredient can be determined by scanning electron microscopy according to known methods.

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

[0070] The term "spheronization" refers to the process of rounding the particles that occurs during processing.

[0071] The term "good flowability" refers to a formulation that is easy to handle during the manufacturing process and ensures accurate and reproducible delivery of a therapeutically effective dose.

[0072] Flow characteristics can be evaluated by different tests such as the angle of repose, the Karlsruhe index, the Hausner ratio or the flow rate through an orifice.

[0073] In the context of the present application, the flow properties are tested by measuring the flow rate through the orifice according to the method described in the European Pharmacopoeia (Eur. Ph.) 8.6, 8th edition. The expression "good homogeneity" means a powder in which, after mixing, the uniformity of distribution of the components, expressed as coefficient of variation (CV), also known as relative standard deviation (RSD), is less than 5.0%. It is often determined according to known methods, for example by taking samples from different parts of the powder and testing the components by HPLC or other equivalent analytical methods.

[0074] The expression "respirable fraction" indicates an index of the percentage of active particles reaching the lungs of a patient.

[0075] The respirable fraction is evaluated using a suitable in vitro device such as Andersen Cascade Impactor (ACI), Multi Stage Liquid Impinger (MLSI) or Next Generation Impactor (NGI) according to the procedures reported in the general pharmacopoeia, in particular in the European Pharmacopoeia (Eur. Ph.) 8.4, 8th edition. It is calculated as a percentage of the fine particle mass (formerly fine particle dose) to the delivered dose.

[0076] The delivered dose was calculated from the cumulative deposition in the device, while the fine particle mass was calculated from the deposition of particles with a diameter < 5.0 microns.

[0077] Typically, a respirable fraction above 30% is considered an indicator of good aerosol performance.

[0078] An ultrafine formulation is defined as one that, when inhaled, is capable of delivering equal to or greater than 20% of the active ingredient having a fraction that is equal to or less than 2.0 microns in size.

[0079] The term 'medium FPF' refers to the delivered dose fraction having a particle size between 2.0 and 5.0.

[0080] The expression "physically stable in the device prior to use" refers to a formulation in which the active particles do not substantially separate and / or detach from the surface of the carrier particles during the preparation of the dry powder and in the delivery device prior to use. According to Staniforth et al. J. Pharm. Pharmacol. 34, 700-706, 1982, the tendency to separate can be evaluated and is considered acceptable if the distribution of the active ingredient in the powder formulation after the test (expressed as relative standard deviation (RSD)) does not change significantly relative to the distribution of the formulation before the test.

[0081] The expression "chemically stable" means a preparation which, after storage, meets the requirements of the EMEA guideline CPMP / QWP / 122 / 02 on "Stability Testing of Existing Active Substances and Related Finished Products".

[0082] The term "surface coating" means covering the surface of the carrier particles by forming a thin film of magnesium stearate around the particles. The thickness of the film has been estimated by X-ray photoelectron spectroscopy (XPS) to be approximately less than 10 nm. The percentage of surface coating indicates the extent to which magnesium stearate coats the surface of all carrier particles.

[0083] The term "prevention" refers to a regimen used to reduce the risk of developing a disease.

[0084] The term "treatment" refers to a regimen for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, a stable (i.e., non-worsening) state of the disease, prevention of the spread of the disease, delay or slowing of the progression of the disease, improvement or alleviation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. The term may also refer to prolonging survival compared to the survival expected if not receiving treatment.

[0085] According to the Global Initiative for Asthma (GINA), "uncontrolled persistent asthma" is defined as a pattern with the following characteristics: daily symptoms, frequent exacerbations, frequent nocturnal asthma symptoms, physical activity limitations, and a forced expiratory volume in one second (FEV1) equal to or less than 80% of the expected value with a variability higher than 30%. According to the Global Initiative for Asthma (GINA) 2014 guidelines, "partially uncontrolled asthma" is defined as a pattern with the following characteristics: daily symptoms less than 2 times per week, nocturnal asthma symptoms, and a forced expiratory volume in one second (FEV1) higher than 80% with a variability between 20-30%.

[0086] According to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines, "severe COPD" is a form characterized by a FEV1 to forced vital capacity (FVC) ratio of less than 0.7, and a FEV1 between 30% and 50% of the expected value. Very severe forms are further characterized by chronic respiratory failure.

[0087] "Therapeutically effective dose" refers to the amount of active ingredient administered in one shot by inhalation after actuation of the inhaler. The dose can be delivered in one or more actuations, preferably one actuation (shot) of the inhaler. The term "actuation" means that the active ingredient is released from the device by a single activation (e.g., mechanical or respiratory).

[0088] The term "milling" refers to any mechanical process that applies sufficient energy to the particles to reduce the coarse particles to micronized particles (fine particles) having a volume diameter not exceeding 15 microns.

[0089] The terms 'co-milling' and 'co-micronization' are used synonymously.

[0090] Wherein, numerical ranges are as described herein, including endpoints. DETAILED DESCRIPTION OF THE INVENTION

[0092] The present invention relates to a process for preparing a dry powder formulation for use in a dry powder inhaler (DPI), comprising a carrier and particles of glycopyrrolate, an inhaled corticosteroid (ICS), optionally a long-acting β2-agonist (LABA) as active ingredients, wherein as a first step, microparticles of glycopyrrolate and ICS in a certain ratio are prepared by co-grinding.

[0093] Examples of LABAs that may be present in the form of their pharmaceutically acceptable salts and / or solvates include formoterol, salmeterol, indacaterol, olodaterol, vilanterol and the ultra long-acting β2-adrenergic receptor agonist (uLABA) compound, code AZD3199.

[0094] Examples of ICS that may be anhydrous or in hydrate form include beclomethasone dipropionate and its monohydrate form, budesonide, fluticasone propionate, fluticasone furoate and mometasone furoate.

[0095] Preferably, the ICS is beclomethasone dipropionate.More preferably, the LABA is formoterol fumarate dihydrate.

[0096] The first part of the microparticles made of glycopyrrolate and ICS were obtained by co-milling.

[0097] Advantageously, the two active ingredients are premixed before co-grinding using equipment and according to conditions known to the skilled person in order to obtain a homogeneous mixture.

[0098] Advantageously, the ratio of glycopyrrolate to ICS is from 80:20 to 70:30, preferably 75:25 by weight.

[0099] For example, if a single therapeutically effective dose of 25 micrograms of glycopyrrolate is required, appropriate amounts of active ingredient will be used so that the ratio between glycopyrrolate and the first part of the ICS in the microparticles will vary between 25 micrograms to 5 micrograms and 25 micrograms to 15 micrograms.

[0100] If the ICS to be delivered is a single therapeutically effective dose of 100 micrograms of BDP, then the remainder will be added in an appropriate amount to equate to a single dose of 95 to 85 micrograms.

[0101] A variety of grinding arrangements and conditions are suitable.

[0102] The selection of appropriate grinding conditions, such as grinding intensity and duration, to provide the desired force is within the ability of a technician who understands how to arrange those grinding conditions so that grinding can break down coarse particles. Ball milling is a preferred method. Alternatively, a high pressure homogenizer can be used, in which a fluid containing particles is forced through a valve under high pressure to produce high shear and turbulent conditions. Shear forces on the particles, collisions between particles and machine surfaces or other particles, and cavitation due to fluid acceleration may all contribute to particle breakage. Such a homogenizer may be more suitable than a ball mill for large-scale preparation of the above-mentioned microparticles.

[0103] Suitable homogenizers include EmulsiFlex high pressure homogenizers with pressures up to 4000Bar, Niro Soavi high pressure homogenizers (pressures up to 2000Bar) and Microfluidics Microfluidizers (maximum pressure 2750Bar). Alternatively, the grinding step may include a stirred bead mill, for example, a DYNO-grinder (Willy A.Bachofen AG, Switzerland) or a Netzsch high energy media grinder. Mechano-Fusion systems (Hosokawa Micron Ltd) and Hybridizer (Nara) are also suitable for use in the present invention. Other possible grinding equipment include air jet mills, spiral jet mills, pin mills, hammer mills, knife mills and ultracentrifugal grinders. In a preferred embodiment of the present invention, a spiral jet mill may be used.

[0104] After the grinding step, the volume diameter of the microparticles is no greater than 15 microns, advantageously no greater than 12 microns, more preferably no greater than 10 microns. In a preferred embodiment, 90% by weight of the microparticles may have a diameter less than 8 microns, preferably less than 7 microns, the volume median diameter may be comprised between 1.0 and 3.0 microns, and no more than 10% of the microparticles may have a volume diameter less than 0.6 microns.

[0105] The carrier A) comprises a coarse excipient particle fraction a) and a fine particle fraction b).

[0106] The mass diameter of the coarse excipient particles of fraction a) must be equal to or greater than 60 microns, preferably equal to or greater than 90 microns, more preferably equal to or greater than 175 microns.

[0107] Advantageously, the mass diameter of all coarse particles is in the range between 40 and 600 micrometers.

[0108] In certain embodiments of the invention, the mass diameter of the coarse particles may be between 60 and 90. In other embodiments, the mass diameter may be between 90 and 150 microns or between 150 and 500 microns. Preferably, the mass diameter is comprised between 200 and 400 microns.

[0109] In a preferred embodiment of the invention, the mass diameter of the coarse particles is comprised between 210 and 360 micrometers.

[0110] In general, the skilled person will select the most appropriate coarse excipient particle size (if commercially available) or sieve using an appropriate classifier.

[0111] Advantageously, the coarse excipient particles may have a relatively high cracked surface, i.e., there are cracks and depressions and other recessed areas thereon, collectively referred to herein as fissures. "Relatively high cracking" coarse particles may be defined according to a fissure index and / or a roughness coefficient, as described in WO 01 / 78695, particularly from line 28 on page 15 to line 26 on page 17, and in WO 01 / 78693, particularly from line 16 on page 12 to line 11 on page 14, which teachings are incorporated herein by reference, and may be characterized according to the description reported therein. Advantageously, the fissure index of the coarse particles is at least 1.25, preferably at least 1.5, more preferably at least 2.0. The coarse particles may also be characterized in a manner of a tap density or total intrusion volume as measured as reported in WO 01 / 78695.

[0112] The tap density of the coarse particles may advantageously be less than 0.8 g / cm 3, preferably between 0.8 and 0.5 g / cm 3 The total intrusion volume may be at least 0.8 cm 3 , preferably at least 0.9 cm 3 .

[0113] The fine particle fraction b) comprises particles of the physiologically acceptable excipient, wherein at least 90% of said particles have a volume diameter of less than 15 microns, preferably equal to or less than 12 microns.

[0114] In a preferred variant, the fine particle fraction b) consists of a mixture of 90 to 99.5% by weight of particles of a physiologically acceptable excipient and 0.5 to 10% by weight of a fatty acid salt, wherein at least 90% of the particles have a volume diameter of less than 15 microns, preferably less than 12 microns, more preferably equal to or less than 10 microns.

[0115] In one embodiment of the present invention, the above mixture can be obtained by co-micronizing the excipient particles and the fatty acid salt particles by grinding, for example, in a ball mill.

[0116] In some cases, a co-micronisation of at least two hours has been found to be advantageous, although it will be appreciated that this treatment time will generally result in the desired size being reduced. In a more preferred embodiment of the invention, the particles are co-micronised by using a jet mill.

[0117] In a preferred embodiment of the present invention, at least 90% of the particles of fraction b) have a volume diameter of less than 15 microns, preferably less than 12 microns, the volume median diameter of the particles is comprised between 3 and 7 microns, preferably between 4 and 6 microns, and no more than 10% of the particles have a volume diameter of less than 2.5 microns, preferably less than 2.0 microns.

[0118] In order to achieve the above-mentioned control of particle size to improve the flowability of the powder, the mixture of micronized excipient particles and optionally micronized fatty acid salt particles can be mixed in any suitable mixer, preferably for at least 1 hour, more preferably for at least 2 hours, or in a high energy mixer for more than 30 minutes, preferably at least 1 hour, more preferably at least 2 hours; otherwise, as disclosed in WO 2015 / 004243, the components are mixed in a high energy device for less than about 30 minutes, preferably less than 20 minutes, the entire detailed description of which is incorporated herein by reference.

[0119] Since the co-blending step does not change the particle size of the particle fraction, a person skilled in the art should select fine particles of physiologically acceptable excipients and fine particles of fatty acid salt of appropriate sizes, and the desired particle size distribution can be achieved by sieving and using a classifier.

[0120] Materials having the desired particle size distribution are also commercially available.

[0121] Advantageously, the fine and coarse excipient particles may consist of any pharmacologically inert, physiologically acceptable material or combinations thereof; preferred excipients are those made of crystalline sugars, in particular lactose; most preferred are those made of α-lactose monohydrate.

[0122] Preferably, both the coarse excipient particles and the fine excipient particles consist of α-lactose monohydrate.

[0123] Advantageously, the fatty acid salt used as an additive to improve the respirable fraction consists of fatty acid salts such as lauric acid, palmitic acid, stearic acid, behenic acid or their derivatives (e.g. esters and salts). Specific examples of said substances are: magnesium stearate; sodium stearyl fumarate; sodium stearyl lactylate; sodium lauryl sulfate, magnesium lauryl sulfate.

[0124] A preferred fatty acid salt is magnesium stearate.

[0125] Advantageously, when it is used as an additive, magnesium stearate may coat the surface of the excipient particles of the fine fraction b) in such a way that the degree of surface coating is at least 10%, more advantageously higher than 20%.

[0126] In some embodiments, depending on the amount of magnesium stearate and processing conditions, a degree of surface coating above 50%, preferably above 60%, can be achieved.

[0127] The extent to which magnesium stearate coats the surface of the excipient particles can be determined according to the method disclosed in WO 2015 / 004243, the teachings of which are incorporated herein by reference, particularly from page 12, line 16 to page 14, line 11.

[0128] The step of mixing the coarse excipient particles a) with the fine particle fraction b) is usually carried out in any suitable mixer, for example a tumble mixer (such as a Turbula TM ) or a high shear mixer (such as those available from Diosna) for at least 5 minutes, preferably at least 30 minutes, more preferably at least 2 hours.

[0129] Generally, the skilled person will adjust the mixing time and the rotation speed of the mixer to obtain a homogeneous mixture.

[0130] When spheronized carrier particles are required to obtain hard pellets as defined above, the mixing step should typically be carried out for at least 4 hours.

[0131] In a specific embodiment, the carrier consisting of the coarse particle fraction a) and the fine particle fraction b) can be prepared by mixing any suitable mixer. For example, if a Turbula TM The two fractions should be mixed at a mixer speed of 11 to 45 rpm, preferably 16 to 32 rpm, for at least 30 minutes, preferably 30 to 300 minutes, more preferably 150 to 240 minutes.

[0132] In an even more specific embodiment, the carrier can be obtained by blending together the coarse excipient particles, the micronized excipient particles and the fatty acid salt micronized particles in any suitable mixer. TM The three components should be mixed for a period of more than 30 minutes, advantageously from 60 to 300 minutes, if a mixer is used.

[0133] The ratio of fine particle fraction b) to coarse particle fraction a) can be comprised between 1:99 and 30:70% by weight, preferably between 2:98 and 20:80% by weight.

[0134] Preferably, the ratio may be comprised between 5:95 and 15:85% by weight.

[0135] In certain embodiments, the ratio may be 10:90 by weight, while in other embodiments, the ratio may be 5:95 by weight.

[0136] If the process is carried out according to a particular variant, in step ii), the carrier, the LABA active ingredient and the ICS active ingredient are loaded into the container of a suitable oscillating mixer, the rotation and reversal speeds of which can be adjusted over a wide range.

[0137] In fact, it has been found that said mixer type is particularly suitable due to its versatility. In fact, with said mixer, frequent changes of the revolution cycle can be set in order to continuously change the powder flow inside the mixing tank and generate different powder flow patterns to increase the mixing efficiency.

[0138] The carrier may be mixed with the remainder of the ICS and the LABA active ingredient in an oscillating mixer at a rotation speed of not less than 16 rpm, preferably 16 to 32 rpm, for a period of not less than 60 minutes, preferably 60 to 120 minutes.

[0139] In step iii), the co-milled microparticles of glycopyrrolate and ICS are added to the above mixture and blended at a rotation speed not higher than 16 rpm, preferably 15 rpm or lower for a period of not more than 40 minutes, preferably 20 to 40 minutes to obtain a blend.

[0140] In a preferred embodiment of the present invention, dyna-MIX TM mixer.

[0141] Optionally, the obtained mixture is screened through a sieve. Those skilled in the art should select the mesh size of the sieve according to the different coarse particle sizes.

[0142] The blend of step iii) is finally mixed in any suitable mixer to obtain a homogeneous distribution of the active ingredient iv).

[0143] Those skilled in the art should select a suitable mixer and adjust the mixing time and speed of the mixer to obtain a uniform mixture.

[0144] Advantageously, each active ingredient present in the formulation of the invention is in crystalline form, more preferably with a degree of crystallinity higher than 95%, even more preferably higher than 98%, as determined according to known methods.

[0145] Since the powder preparation obtained using the method of the present invention should be administered to the lungs by inhalation, at least 99% [d(v,0.99)] of the active ingredient particles should have a volume diameter equal to or less than 10 microns, and substantially all particles should have a volume diameter between 8 and 0.4 microns.

[0146] Advantageously, in order to better reach the distal channels of the respiratory tree, 90% of the micronized particles of ICS and LABA active ingredients should have a volume diameter of less than 6.0 microns, preferably equal to or less than 5.0 microns, the volume median diameter should be from 1.2 to 2.5 microns, preferably from 1.3 to 2.2 microns, and no more than 10% of the particles should have a diameter of less than 0.6 microns, preferably equal to or less than 0.7 microns, more preferably equal to or less than 0.8 microns.

[0147] As a result, according to Chew et al. J Pharm Pharmaceut Sci 2002, 5, 162-168, the width of the particle size distribution of the particles of ISC and LABA active ingredients, expressed as a span, should advantageously be 1.0-4.0, more advantageously 1.2-3.5, the span corresponding to [d(v,0.9)-d(v,0.1)] / d(v,0.5).

[0148] The size of the active particles is determined by laser diffraction measurement of a characteristic equivalent spherical diameter called volume diameter. In the examples reported, the volume diameter has been determined using a Malvern apparatus. However, other equivalent apparatus may be used.

[0149] In a preferred embodiment, a Helos Aspiros instrument (Sympatec GmbH, Clausthal-Zellerfeld, Germany) is used. Typical conditions are: Fraunhofer FREE or Fraunhofer HRLD algorithm, R1 (0.1 / 0.18-35 microns) or R2 (0.25 / 0.45-87.5 microns) lenses, 1 bar pressure.

[0150] Regarding the particle size determination, the experimental errors were considered: ±30% of the CV, d(v0,1) and ±20% of the CV, d(v0,5), d(v0,9) and d(v0,99).

[0151] The fully micronized LABA and ICS active ingredients used in the process of the present invention can be prepared by processing in suitable grinders according to known methods.

[0152] In one embodiment of the present invention, they can be prepared by grinding using a conventional fluid energy mill, such as a commercially available air jet micronizer having grinding chambers of varying diameters.

[0153] Depending on the type of equipment and the size of the batch, a person skilled in the art will appropriately adjust the grinding parameters such as operating pressure, feed rate and other operating conditions to achieve the desired particle size. It is preferred that all micronized active ingredients are obtained without using any additives during the micronization process.

[0154] The powder formulation comprising micronized particles of glycopyrrolate, LABA and ICS as active ingredients obtainable by the process of the present invention is physically and chemically stable, free-flowing and exhibits good homogeneity of the active ingredients.

[0155] Furthermore, the powder formulations described above are capable of delivering high respirable fractions, as measured by fine particle fraction (FPF), for all three active ingredients.

[0156] The ratio between carrier particles and active ingredient will depend on the type of inhaler used and the dose desired.

[0157] The powder formulation obtained by the process of the present invention may be suitable for delivering a therapeutic amount of all active ingredients in one or more actuations (puffs or puffs) of an inhaler.

[0158] Advantageously, the formulation will be suitable for delivering a therapeutically effective dose of all three active ingredients contained between 50 and 600 μg, preferably between 100 and 500 μg.

[0159] For example, the formulation should be suitable for delivering 3-15 μg formoterol (as fumarate dihydrate) / prime, advantageously 4-13.5 μg / prime, 25-240 μg beclomethasone dipropionate (BDP) / prime, advantageously 40-220 μg / prime and 5-65 μg glycopyrronium (as bromide) / prime, advantageously 11-30 μg / prime. In a particularly preferred embodiment of the invention, the formulation is suitable for delivering 3 or 6 μg or 12 μg formoterol (as fumarate dihydrate) / prime, 50 or 100 or 200 μg beclomethasone dipropionate / prime and 6.5 or 12.5 μg or 25 μg glycopyrronium (as bromide) / prime.

[0160] In a specific embodiment, the formulation is adapted to deliver 6 μg formoterol (as the fumarate dihydrate) per actuation, 100 μg beclomethasone dipropionate per actuation, and 12.5 μg glycopyrronium (as the bromide) per actuation.

[0161] In another embodiment, the formulation is adapted to deliver 12 μg formoterol (as the fumarate dihydrate) per actuation, 200 μg beclomethasone dipropionate per actuation, and 25 μg glycopyrronium (as the bromide) per actuation.

[0162] The dry powder formulation may be used with any dry powder inhaler.

[0163] Dry powder inhalers (DPIs) can be divided into two basic types:

[0164] i) single-dose inhalers, for administering a single subdivided dose of an active compound; each single dose is usually filled in a capsule;

[0165] ii) Multi-dose inhalers which are pre-loaded with sufficient amounts of active ingredient for longer treatment cycles.

[0166] Depending on the required inspiratory flow rate (liters / minute) (the inspiratory flow rate is strictly determined by its design and mechanical characteristics), DPI is also divided into the following types:

[0167] i) Low resistance device (>90 L / min);

[0168] ii) medium resistance device (about 60-90 liters / minute);

[0169] iii) medium-high resistance device (about 50-60 L / min);

[0170] iv) High resistance devices (less than 30 L / min).

[0171] The reported classification is generated according to the European Pharmacopoeia (EurPh) for the flow rate required to produce a pressure drop of 4KPa (KiloPascal).

[0172] The dry powder formulation is particularly suitable for use in a multi-dose DPI comprising a reservoir from which individual therapeutic doses can be removed as required by actuation of a device such as that described in WO 2004 / 012801.

[0173] Other multi-dose devices that may be used are, for example, the Diskus from GlaxoSmithKline. TM , AstraZeneca's Turbohaler TM , Schering's Twisthaler TM 、Innovata's Clickhaler TM 、Teva's Spiromax TM 、Meda's Novolizer TM and Almirall's Genuair TM .

[0174] Examples of commercially available single-dose devices include GlaxoSmithKline's Rotohaler TM , Handihaler of Boehringer Ingelheim TM and Breezehaler of Novartis TM .

[0175] Preferably, the formulation obtained by the method of the present invention is used with a DPI device disclosed in WO 2004 / 012801, in particular from the first line of page 1 to the last line of page 39, or a variant thereof disclosed in WO 2016 / 000983, in particular from line 5 of page 1 to line 34 of page 15, the teachings of which are incorporated herein by reference, said device being particularly suitable for delivering ultrafine formulations.

[0176] To protect the DPI from moisture ingress into the formulation, it may be desirable to overwrap the device in a flexible package that is resistant to moisture ingress, such as that disclosed in EP 1760008, in particular from page 2, paragraph

[0009] to page 9, paragraph

[102] .

[0177] The formulations prepared according to the methods of the present invention are indicated for use in the prevention and / or treatment of chronic obstructive pulmonary disease (COPD) and asthma of all types and severities.

[0178] Administration of the formulations prepared according to the methods of the present invention is also indicated for the prevention and / or treatment of additional respiratory diseases characterized by peripheral airway obstruction and the presence of mucus as a result of inflammation, such as chronic obstructive bronchiolitis.

[0179] In certain embodiments, the formulations are particularly suitable for preventing and / or treating severe and / or very severe forms of COPD, and in particular for the maintenance treatment of COPD patients with symptoms, airflow limitation and a history of exacerbations.

[0180] Furthermore, it may be suitable for the prevention and / or treatment of persistent asthma and asthma in patients not controlled by moderate or high doses of ICS in combination with LABA.

[0181] The following examples illustrate the invention in detail. Example

[0182] Example 1 - Preparation of carrier

[0183] Micronized α-lactose monohydrate (DFE Pharma, Germany) with the following particle sizes was used: d(v0.1) = 1.7 μm; d(v0.5) = 4.3 μm; and d(v0.9) = 9.8 μm

[0184] About 3388 g of the micronized α-lactose monohydrate mixed with about 69.17 g of magnesium stearate (Peter Greven, Germany) was fed into the dyna-MIX TM The mixture was placed in a container of a mixer (Willy A. Bachofen AG, Germany) and mixed with fractured coarse particles of α-lactose monohydrate having a mass diameter of 212-355 μm in a ratio of 10:90 wt %. The mixing was alternatively carried out with two rotating shafts at a rotation speed of 16 and 24 rpm for 240 minutes.

[0185] The ratio between micronized α-lactose monohydrate and magnesium stearate was 98:2 wt %.

[0186] The resulting particle mixture is hereinafter referred to as the "carrier".

[0187] The extent of coating of the surface of fine and coarse lactose particles with magnesium stearate (MgSt) was determined by water contact angle measurements and then applying the equation known from the literature as Cassie and Baxter according to the conditions reported in the specification.

[0188] The results showed that the surface coating was 26%.

[0189] Example 2 - Preparation and Characterization of Co-milled Microparticles

[0190] Commercially available Rac-glycopyrrolate (rac-GB) and beclomethasone dipropionate (BDP) were used.

[0191] The crystalline active ingredients were TM Premix in a mixer at a weight ratio of 75:25 to obtain a homogeneous mixture.

[0192] The crystallized mixture was then micronized using a spiral jet mill MC50 (Micro-Macinazione, Lugano, Switzerland) using the following parameters:

[0193] -Powder feeding speed: 0.875Kg / h

[0194] -Grinding volume flow rate: 16nm 3 / h

[0195] -Feed volume flow rate: 8nm 3 / h

[0196] For comparison, only crystalline rac-GB was micronized using the following process parameters:

[0197] -Powder feeding speed: 0.875Kg / h

[0198] -Grinding volume flow rate: 16nm 3 / h

[0199] -Feed volume flow rate: 8nm 3 / h

[0200] The co-micronized microparticles and reference micronized glycopyrrolate were exposed to the following conditions:

[0201] - Thin layers (~0.5 cm) in open trays at 30°C / 65% relative humidity (RH) for 3 days;

[0202] - Thin layer (~0.5 cm) in open tray for 4 hours at 25°C / 90% RH

[0203] The following analyses were performed:

[0204] i) Particle size distribution (PSD) expressed as d(v0.1), d(v0.5) and d(v0.9) by Malvern analysis,

[0205] ii) analyzing the specific surface area (SSA) by the Brunauer-Emmett-Teller (BET) nitrogen adsorption method according to known procedures, and

[0206] iii) Water was recrystallized using a Dynamic Vapor Sorption (DVS) instrument (Mettler Toledo GmbH, Switzerland).

[0207] The analysis results are summarized in Table 1.

[0208]

[0209] It can be appreciated that the co-micronized microparticles showed no significant changes in particle size distribution and other relevant parameters when exposed to both conditions, while the singly micronized GB underwent a significant increase in particle size, especially at 25 °C and 90% RH, indicating severe agglomeration.

[0210] Example 3 - Preparation of dry powder formulation

[0211] The microparticles obtained in Example 2 were used.

[0212] Micronized formoterol fumarate dihydrate having the following particle sizes was used: d(v0.1) = 0.9 microns; d(v0.5) = 2.3 microns; and d(v0.9) = 4.2 microns.

[0213] Beclomethasone dipropionate (BDP) having the following particle sizes was used: d(v0.1) = 0.7 microns; d(v0.5) = 1.5 microns; and d(v0.9) = 2.8 microns.

[0214] The carrier obtained in Example 1 was placed in dyna-MIX TM Mix with formoterol fumarate dihydrate and BDP in a mixer so that the final therapeutically effective dose is 100 micrograms per actuation of the inhaler.

[0215] The mixer was operated with both shafts at 22 to 28 rpm for 88 minutes.

[0216] The microparticles (the microparticles from Example 2 comprising micronized GB and co-micronized GB / BDP) were then added and mixed for 36 minutes with two rotating shafts rotating at a speed of 15 to 13 rpm.

[0217] The resulting mixture was poured into a sifter from Frewitt (Fribourg, Switzerland) equipped with a 600 micron mesh screen.

[0218] After sieving, the blend is finally placed in dyna-MIX TM Mixing was performed in a mixer alternatively with two rotating shafts at 15 and 13 rpm for 60 minutes to achieve a uniform distribution of the active ingredient.

[0219] The ratio of active ingredient to 10 mg carrier was 6 micrograms (μg) of FF dihydrate (theoretical delivered dose 4.5 μg), 100 micrograms (μg) of BDP, and 12.5 micrograms (μg) of glycopyrrolate (theoretical delivered dose 10.0 μg).

[0220] After loading into the multidose dry powder inhaler disclosed in WO2004 / 012801, the powder formulations were characterized with respect to active ingredient distribution uniformity and aerosol performance.

[0221] The uniformity of distribution of the active ingredient was evaluated by withdrawing 12 samples from different parts of the blend and assessed by HPLC.

[0222] The results (mean ± RSD) are reported in Table 2.

[0223] The evaluation of aerosol performance was performed using a next generation impactor (NGI) according to the conditions reported in paragraph 2.9.18, pages 309-320, of the European Pharmacopoeia 2015, 8.5 edition. After nebulizing 3 doses from the inhaler device, the NGI device was disassembled, and the amount of drug deposited at each stage was recovered by washing with a solvent mixture and then quantified by high performance liquid chromatography (HPLC). The following parameters were calculated: i) delivered dose, which is the amount of drug delivered from the device recovered from all impactor parts; ii) fine particle mass (FPM), which is the amount of delivered dose with a particle size equal to or less than 5.0 microns; iii) ultrafine FPM, which is the amount of delivered dose with a particle size equal to or less than 2.0 microns and / or equal to or less than 1.0 microns; iv) medium FPM, which is the amount of delivered dose with a particle size between 2.0-5.0 microns; v) fine particle fraction (FPF), which is the ratio of fine particle mass to delivered dose; vi) MMAD.

[0224] The results (mean ± SD) are reported in Table 2.

[0225] Table 2

[0226]

[0227]

[0228] As can be seen from the data in Table 2, the powder formulations showed excellent homogeneity and high respirable fraction (FPF) for all three active ingredients.

[0229] Example 4 - Preparation of another dry powder formulation

[0230] The powder formulation was prepared as described in Example 3, but the ratio of active ingredient to 10 mg carrier was 6 μg FF dihydrate (theoretical delivered dose 4.5 μg), 100 μg BDP and 25 μg glycopyrrolate (theoretical delivered dose 20.0 μg).

[0231] The distribution uniformity of the active ingredient and the aerosol performance were evaluated as reported in Example 2.

[0232] The results are reported in Table 3.

[0233] Table 3

[0234]

[0235]

[0236] As can be seen from the data in Table 3, the powder formulations showed excellent homogeneity and high respirable fraction (FPF) for all three active ingredients.

[0237] Example 5 - Determination of caking tendency

[0238] Moisture is known to increase the cohesive strength between glycopyrrolate (GB) particles to the extent that they may agglomerate. In addition, phase transformation (i.e., crystallization of the amorphous fraction present in micronized GB particles) triggered by ambient relative humidity (RH) above 45% can lead to melting / sintering of GB particles, causing agglomeration and severe agglomeration.

[0239] Tests have been conducted to determine the agglomeration / caking tendency of the co-milled microparticles of the present invention relative to reference micronized GB.

[0240] The material was prepared as reported in Example 2.

[0241] The samples were tested under the following environmental conditions:

[0242] -30% RH, 22℃;

[0243] -60% RH, 32℃;

[0244] - Vary from 30% RH, 32°C to 60% RH, 32°C.

[0245] The experiments were performed using a dynamic vapour sorption (DVS) analyser from Surface Measurement Systems (London, UK).

[0246] The co-milled microparticles of the present invention are significantly less likely to agglomerate than the reference material.

Claims

1. A method for preparing a powder preparation for inhalation in a dry powder inhaler, the powder preparation comprising: (A) a vector comprising: (a) a coarse particle fraction of a physiologically acceptable carrier having a particle size of at least 60 microns; and optionally (b) a fine particle fraction comprising a physiologically acceptable excipient, wherein at least 90% of all said fine particles have a volume diameter of less than 15 microns, (B) micronized particles of glycopyrrolate, inhaled corticosteroid (ICS) and optionally a long-acting β2-agonist (LABA) as active ingredients, The method comprises: (i) preparing microparticles consisting of glycopyrrolate and a first portion of ICS in a weight ratio of 80:20 to 70:30 by co-milling, wherein the volume diameter of the microparticles is no greater than 15 microns; (ii) mixing a carrier, the remainder of the ICS and optionally a long-acting β2-agonist to obtain a first mixture; and (iii) adding the co-milled microparticles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second final mixture.

2. The method for preparing a powder formulation for inhalation in a dry powder inhaler according to claim 1, wherein the powder formulation comprises: (A) a vector comprising: (a) a coarse particle fraction of a physiologically acceptable carrier having a mass median particle size of at least 175 microns; and (b) a fine particle fraction consisting of a mixture of 90 to 99.5% by weight of particles of a physiologically acceptable excipient and 0.5 to 10% by weight of a fatty acid salt; wherein the weight ratio of the fine particles to the coarse particles is 5:95 to 30:70; and (B) an active ingredient comprising a long-acting β2-agonist; And wherein in the method: - the mixing of step (ii) is carried out in a container of an oscillating mixer at a rotation speed of not less than 16 rpm for a period of not less than 60 minutes to obtain a first mixture; and - blending the second mixture obtained in step (iii) at a rotation speed of not more than 16 rpm for a period of not more than 40 minutes to obtain a blend.

3. The method according to claim 2, further comprising: (iv) further mixing the blend obtained in step (iii) to achieve a uniform distribution of the active ingredient.

4. The method according to any one of claims 1 to 3, wherein the ICS is selected from beclomethasone dipropionate and its monohydrate form, budesonide, fluticasone propionate, fluticasone furoate and mometasone furoate.

5. The method according to any one of claims 1 to 4, wherein the LABA is selected from formoterol, salmeterol, indacaterol, olodaterol and vilanterol.

6. The method according to claim 1 or 2, wherein the ICS is beclomethasone dipropionate and the LABA is formoterol fumarate dihydrate.

7. The method according to claim 2, wherein the fatty acid salt is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, sodium stearoyl lactylate, sodium lauryl sulfate and magnesium lauryl sulfate.

8. The method according to claim 7, wherein the fatty acid salt is magnesium stearate.

9. The process according to any one of claims 2 to 8, wherein in said step ii) said mixing is carried out at 16-32 rpm for a time comprised between 60 and 120 minutes.

10. The process according to any one of claims 2 to 9, wherein step iii) is carried out for a time comprised between 20 and 40 minutes.

11. The method according to any one of the preceding claims, wherein the physiologically acceptable excipient is alpha-lactose monohydrate.

12. The method according to any one of the preceding claims, wherein the coarse particles have a mass diameter comprised between 210 and 360 μm.

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