阅读说明：本技术 制备包含抗胆碱能药、皮质类固醇和β-肾上腺素能药的干粉制剂的方法 (Method for preparing dry powder formulations comprising anticholinergics, corticosteroids and beta-adrenergic agents ) 是由 A·卡韦奇 C·梅鲁西 F·皮韦蒂 F·斯基亚雷蒂 于 2018-05-09 设计创作，主要内容包括：本发明涉及一种制备用于干粉吸入器中的吸入用粉末制剂的方法,所述粉末制剂包含:(A)载体,其包含:(a)生理学上可接受的载体的粗颗粒级分,其具有至少60微米的粒度；和任选地(b)包含生理学上可接受的赋形剂的细颗粒级分,其中所有所述细颗粒的至少90％具有小于15微米的体积直径,(B)作为活性成分的格隆溴铵、吸入用皮质类固醇(ICS)和任选的长效β<Sub>2</Sub>-激动剂(LABA)的微粉化颗粒,其中所述方法包括:(i)通过共研磨来制备由重量比为80:20至70:30的格隆溴铵和ICS的第一部分组成的微粒,其中所述微粒的体积直径不大于15微米；(ii)将载体、所述ICS的剩余部分和任选的长效β<Sub>2</Sub>-激动剂混合,得到第一混合物；和(iii)将步骤(i)中获得的共研磨的微粒添加到步骤(ii)中获得的第一混合物中,得到第二最终混合物。(The present invention relates to a process for the preparation of a powder formulation for inhalation for use in a dry powder inhaler, the powder formulation comprising (a) a carrier 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 physiologically acceptable excipients, wherein at least 90% of all the fine particles have a volume diameter of less than 15 microns, (B) glycopyrrolate as active ingredient, an Inhaled Corticosteroid (ICS) and optionally a long-acting beta 2 -micronized particles of an agonist (LABA), wherein the process comprises (i) preparing a mixture of compounds prepared by co-milling in a weight ratio of 80:20To 70:30 of microparticles consisting of glycopyrrolate and a first portion of an ICS, wherein said microparticles have a volume diameter of no more than 15 microns; (ii) (ii) mixing the vector, the remainder of said ICS and optionally a long-acting beta 2 -agonist mixing to obtain a first mixture; and (iii) adding the co-milled particles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second final mixture.)

1. A method of preparing an inhalation powder formulation for use in a dry powder inhaler, the powder formulation 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 physiologically acceptable excipients, wherein at least 90% of all the fine particles have a volume diameter of less than 15 microns,

(B) glycopyrrolate as active ingredient, Inhaled Corticosteroids (ICS) and optionally long-acting beta₂-micronized particles of an agonist (LABA),

wherein the method comprises:

(i) preparing microparticles consisting of glycopyrrolate and a first fraction of ICS in a weight ratio of 80:20 to 70:30 by co-milling, wherein the microparticles have a volume diameter of no more than 15 microns;

(ii) (ii) mixing the vector, the remainder of said ICS and optionally a long-acting beta₂-agonist mixing to obtain a first mixture; and

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

2. The method of preparing a powder formulation for inhalation for use 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 from 5:95 to 30: 70; and

(B) comprising a long-acting beta₂-an active ingredient of an agonist;

and wherein in the method:

-subjecting the mixing of step (ii) to a rotation speed not lower than 16r.p.m in the vessel of a shaking mixer for a time not less than 60 minutes to obtain a first mixture; and is

-blending the second mixture obtained in step (iii) at a rotation speed not higher than 16r.p.m for a time not exceeding 40 minutes to obtain a blend.

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

4. A process 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 process according to any one of claims 1-4, wherein the LABA is selected from formoterol, salmeterol, indacaterol, olodaterol, and vilanterol.

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

7. The process according to claim 2, wherein the fatty acid salt is selected from magnesium stearate, sodium stearyl fumarate, sodium stearyl 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 16-32r.p.m. for a time comprised between 60 and 120 minutes.

10. The process according to any one of claims 2 to 9, wherein said 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 a-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.

Technical Field

The present invention relates to powder formulations for inhalation administration by dry powder inhalers.

In particular, the invention relates to a method for preparing a dry powder formulation comprising an anticholinergic, beta₂-a combination of an adrenoceptor agonist and an inhaled corticosteroid.

Background

Respiratory diseases are a common and important cause of illness and death worldwide. Indeed, many people are affected by inflammatory and/or obstructive pulmonary diseases (a category characterized by inflamed and easily collapsible airways, obstruction to airflow, exhalation problems (publications exhaling), and frequent medical office visits and hospitalizations). Types of inflammatory and/or obstructive pulmonary disease include asthma, bronchiectasis, bronchitis, and Chronic Obstructive Pulmonary Disease (COPD).

In particular, Chronic Obstructive Pulmonary Disease (COPD) is a multi-component disease characterized by airflow limitation and airway inflammation. Exacerbations of COPD have a significant impact on the quality of life, daily activities and general health of the patient and are a huge burden on the health system. Thus, the goals of COPD management include not only alleviating symptoms and preventing disease progression, but also preventing and treating exacerbations.

Although available treatments improve clinical symptoms and reduce airway inflammation, they do not specifically slow long-term progression or address all disease components. As the burden of COPD continues to increase, research into new and improved therapeutic strategies to optimize drug therapy, and in particular combination therapy, is ongoingTo achieve their complementary modes of action, thereby addressing multiple components of the disease. Evidence from recent clinical trials indicates that anticholinergics are combined with inhaled corticosteroids and long-acting beta₂Triple therapy (triple therapy) of an adrenoreceptor agonist combination may provide clinical benefits in patients with more severe COPD in addition to those associated with each treatment alone.

Currently, there are several recommended treatment categories for COPD, among which bronchodilators such as β₂Agonists and anticholinergics are the main drugs for the symptomatic management of mild and moderate diseases (mainstay), prescribed as needed for mild COPD and as maintenance therapy for moderate COPD.

The bronchodilators are effectively administered by inhalation, thereby increasing the therapeutic index and alleviating side effects of the active material (material).

For the treatment of more severe COPD, the guidelines recommend the addition of Inhaled Corticosteroids (ICS) to long-acting bronchodilator therapy. Combinations of therapies have been investigated in order to achieve their complementary modes of action, thereby ensuring resolution of multiple components of the disease. Data from recent clinical trials indicate that anticholinergics and long-acting β are to be administered₂Triple combination therapy of agonists (LABA) with ICS may provide clinical benefits in patients with moderate to severe COPD in addition to those associated with each treatment alone.

One interesting triple combination currently under investigation includes:

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

ii) glycopyrrolate, an anticholinergic recently approved for maintenance therapy of COPD;

iii) Beclomethasone Dipropionate (BDP), a potent anti-inflammatory corticosteroid available under various trademarks for the prevention and/or treatment of asthma and other respiratory disorders.

However, despite the popularity of pMDI formulations, there may be some drawbacks in particular in elderly and pediatric patients, mainly due to their difficulty in synchronizing the actuation of the device with the inhalation.

Dry Powder Inhalers (DPIs) constitute an effective alternative to MDIs, and may be used for administration to the airways.

Generally, it is contemplated that the drug to be inhaled as a dry powder should be used in the form of micronized particles.

For example, WO 2015/004243 discloses a powder formulation for inhalation by a Dry Powder Inhaler (DPI) comprising all three micronized forms of the active ingredient. The formulation utilizes the technical platform disclosed in WO01/78693, thus requiring the use of a carrier consisting of a fraction of coarse excipient particles (fraction) and a fraction made of fine excipient particles and magnesium stearate.

In the specification, possible methods for preparing micronized glycopyrronium bromide are described, but no preference is given.

On the other hand, similar to other antimuscarinic agents, glycopyrronium salts may face significant stability problems, especially immediately after the conventional micronization process by milling.

In fact, 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, which are capable of delivering a good respirable fraction.

It is therefore an object of the present invention to provide a process for the preparation of a powder formulation suitable for the application of glycopyrronium bromide in combination with LABA and ICS, which overcomes the above-mentioned problems.

Disclosure of Invention

The present invention relates to a method for preparing a powder formulation for inhalation for use in a dry powder inhaler, the powder formulation comprising:

(A) a vector, comprising:

(a) a coarse particle fraction of a physiologically acceptable carrier having a mass diameter of at least 60 microns; and optionally

(b) A fine particle fraction comprising physiologically acceptable excipients, wherein at least 90% of the fine particles have a volume diameter of less than 15 microns,

(B) glycopyrrolate as active ingredient, Inhaled Corticosteroids (ICS) and optionally long-acting beta₂-micronized particles of an agonist (LABA),

wherein 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 (co-milling), wherein the microparticles have a volume diameter of no more than 15 microns;

(ii) (ii) mixing the vector, the remainder of said ICS and optionally a long-acting beta₂-agonist mixing to obtain a first mixture; and

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

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

(A) a vector, comprising:

(a) a coarse particle fraction of a physiologically acceptable carrier having a mass median diameter (mass median diameter) of at least 175 μm; 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 at least 90% of the fine particles have a volume diameter equal to or less than 15 microns,

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

(B) glycopyrrolate, long-acting beta as active ingredient₂-micronized particles of an agonist (LABA) and an Inhaled Corticosteroid (ICS),

wherein the method comprises:

(i) preparing microparticles consisting of glycopyrrolate and a first fraction of ICS in a weight ratio of 80:20 to 70:30 by co-milling, wherein the microparticles have a volume diameter of no more than 15 microns;

(ii) mixing the support, the LABA and the remainder of said ICS in a container of a shaking mixer at a speed not lower than 16r.p.m. for a time not less than 60 minutes, obtaining a first mixture; and

(iii) (iii) adding the co-milled particles obtained in step (i) to the first mixture obtained in step (ii) to obtain a second mixture, and admixing said second mixture at a rotational speed of not more than 16r.p.m. for a period of not more than 40 minutes to obtain an admixture.

In a preferred embodiment, the ICS is beclomethasone dipropionate.

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

Definition of

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

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

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

The term "beclomethasone dipropionate" refers to the compound propionic acid (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 ester.

The term "pharmaceutically acceptable salts" includes inorganic 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.

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.

The expression "oscillating mixer" means a universal mixer with a wide and adjustable range of rotation speeds and inversion cycles. In the mixer, the mixing vessel is secured by a gimbal. The two rotating shafts are positioned in a perpendicular manner to each other and are independently powered. The direction of rotation and the speed of rotation of the two shafts are continuously and independently changed. The setting of these kinds of mixing method parameters can ensure high-value mixing efficiency. Typical oscillatory mixers are referred to as dyna-MIX^TM(Willy a. bachofen AG, switzerland) or 3d.s mixers (Erhard MuhrGmbH, germany).

The expression "drum mixer" refers to mixers operating at different mixing times and mixing speeds, but having typical motions characterized by rotation, tumbling and inversion interactions.

A typical tumble mixer is used as Turbula^TMCommercially available (Willy a. bachofen AG, switzerland).

The expression constant or high shear mixer refers to a mixer in which a rotor or impeller and a stationary part called a stator are used in a tank containing the powders to be mixed to generate the shear.

Typical high shear mixers are P100 and P300 (Diosna GmbH, Germany), Rotomix (IMA, Italy) and Cyclomix^TM(Hosokawa Micron Group Ltd, Japan).

The term "micronized" refers to a substance having a size of a few microns.

The term "coarse" refers to a substance having a size of one hundred microns or several hundred microns.

In general, the particle size of the particles is quantified by measuring the characteristic equivalent sphere diameter (referred to as volume diameter) by means of laser diffraction.

The particle size can also be quantified by measuring the mass diameter by means of a suitable known instrument, for example a sieve analyser.

The Volume Diameter (VD) is related to the Mass Diameter (MD) by the particle density (assuming the size of the particles is independent of the density).

In the present application, the particle size of the active ingredient and the fine particle fraction is expressed in terms of volume diameter, while the particle size of the coarse particles is expressed in terms of mass diameter.

The particles have a normal (gaussian) distribution, defined by the volume or mass median diameter (VMD or MMD), respectively, corresponding to 50 weight percent of the volume or mass diameter of the particles, and optionally by 10% and 90% of the volume or mass diameter of the particles.

Another common method of defining the particle size distribution is by three values: i) a median diameter d (0.5), which is the diameter when 50% of the distribution exceeds and 50% of the distribution falls below; ii) d (0.9), wherein 90% of the distribution is below this value; iii) d (0.1), wherein 10% of the distribution is below this value.

The span is the width of the distribution based on 10%, 50%, and 90% quantile (quantile) and is calculated according to the following equation:

in general, particles having the same or similar VMD or MMD may have different particle size distributions, and in particular different widths of the gaussian distributions represented by d (0.1) and d (0.9) values.

After aerosolization, particle size is expressed as Mass Aerodynamic Diameter (MAD), while particle size distribution is expressed in terms of Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD). MAD indicates the ability of particles to be transported suspended in a gas stream. MMAD corresponds to a mass aerodynamic diameter of 50 weight percent of the particles.

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

The term "hard pellets" denotes spherical or hemispherical units, the core of which is made of coarse excipient particles.

The term "rounding" refers to the process of rounding of particles that occurs during processing.

The term "good flow" denotes a formulation which is easy to handle during manufacture and which ensures accurate and reproducible delivery of a therapeutically effective dose.

The flow characteristics may be evaluated by different tests, such as angle of repose, karman's index, hausner's ratio (ratio) or flow rate through an orifice.

In the context of the present application, the flow properties were tested by measuring the flow rate through the orifice according to the method described in the european pharmacopoeia (eur.ph.)8.6, 8 th edition. The expression "good homogeneity" denotes a powder: wherein the uniformity of distribution of the components, expressed as Coefficient of Variation (CV), also referred to as Relative Standard Deviation (RSD), after mixing, is less than 5.0%. It is often determined according to known methods, for example by sampling different parts of the powder and testing the components by HPLC or other equivalent analytical methods.

The expression "respirable fraction" denotes an index of the percentage of active particles that reach the lungs of a patient.

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

The delivered dose is calculated from the cumulative deposition in the apparatus, while the fine particle mass is calculated from the deposition of particles with a diameter <5.0 microns.

Generally, respirable fractions above 30% are considered indicators of good aerosol performance.

The following formulations were defined as ultra-fine formulations: when inhaled, equal to or greater than 20% of the active ingredient having a fraction with a size equal to or less than 2.0 microns can be delivered.

The term 'medium FPF' refers to a delivered dose fraction having a particle size of 2.0 to 5.0.

The expression "physically stable in the device before use" denotes a formulation: wherein the active particles are substantially not detached and/or detached 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 segregation can be evaluated, which 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 with respect to the distribution of the formulation before the test.

The expression "chemically stable" denotes formulations in which: which after storage meet the EMEA guidelines CPMP/QWP/122/02 for the Stability test of Existing actives and Related Finished Products.

The term "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 to be less than about 10nm by X-ray photoelectron spectroscopy (XPS). The percentage of surface coating indicates the extent to which magnesium stearate coats the surface of all carrier particles.

The term "prevention" refers to a regimen for reducing the risk of onset of disease.

The term "treatment" refers to a regimen for achieving a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include, but are not limited to: alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stable (i.e., not worsening) state of disease, prevention of spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. The term may also refer to an extended survival compared to that expected if not receiving treatment.

According to the Global asthma prevention and treatment Initiative (Global Initiative for asset)a, GINA), "uncontrolled persistent asthma" is defined as a form with the following characteristics: daily symptoms, frequent exacerbations, frequent nocturnal asthma symptoms, physical activity limitation, forced expiratory volume in one second (FEV) equal to or less than 80% of expected value and with variability higher than 30%₁). According to the global guidelines for asthma control initiative (GINA)2014, "partially uncontrolled asthma" is defined as a form having the following characteristics: daily symptoms less than 2 times a week, nocturnal asthma symptoms, and forced expiratory volume in one second (FEV) higher than 80% with a variability between 20-30%₁)。

According to the Global guidelines for chronic Obstructive Pulmonary Disease prevention initiative (GOLD) the "severe COPD" is a form with the following characteristics: FEV below 0.7₁Ratio to Forced Vital Capacity (FVC), and FEV between 30% and 50% of expected value₁. A very severe form is further characterized by chronic respiratory failure.

By "therapeutically effective dose" is meant the amount of active ingredient administered in one dose by inhalation after actuation of the inhaler. The dose may be delivered in one or more actuations of the inhaler, preferably in one actuation (shot). The term "activation" means the release of the active ingredient from the device by a single activation (e.g. mechanical or respiratory).

The term "milling" refers to any mechanical process that imparts sufficient energy to particles that is capable of breaking down coarse particles into micronized particles (microparticles) having a volume diameter of no more than 15 microns.

The terms 'co-milling' and 'co-micronization' are used as synonyms.

Wherein numerical ranges are as described herein, including the endpoints.

Detailed Description

The present invention relates to a process for the preparation of a dry powder formulation for use in a Dry Powder Inhaler (DPI) comprising a carrier and glycopyrronium bromide as active ingredient, an Inhalation Corticosteroid (ICS), optionally a long-acting beta₂Particles of agonist (LABA) wherein as a first stepStep, prepare microparticles of a certain ratio of glycopyrronium bromide and ICS by co-milling.

Examples of LABAs which may be present in the form of pharmaceutically acceptable salts and/or solvates thereof include formoterol, salmeterol, indacaterol, olopaterol, vilanterol and ultra-long acting β 2-adrenoceptor agonist (uLABA) compounds, coded AZD 3199.

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

Preferably, the ICS is beclometasone dipropionate. More preferably, the LABA is formoterol fumarate dihydrate.

Microparticles made of glycopyrronium bromide and the first fraction of ICS were obtained by co-milling.

Advantageously, the two active ingredients are premixed before being co-milled, using equipment and according to conditions known to the skilled person, so as to obtain a homogeneous mixture.

Advantageously, the ratio of glycopyrronium bromide to ICS is from 80:20 to 70:30, preferably 75:25, by weight.

For example, if a single therapeutically effective dose of glycopyrronium bromide at 25 micrograms is required, a suitable amount of active ingredient will be used such that the ratio between glycopyrronium bromide and the first part of the ICS in the microparticles will vary between 25 micrograms to 5 micrograms and 25 micrograms to 15 micrograms.

If the ICS to be delivered is a single therapeutically effective dose of 100 micrograms of BDP, the appropriate amount of the remainder, equivalent to a single dose of 95 to 85 micrograms, will be added.

A variety of grinding devices and conditions are suitable.

The selection of appropriate grinding conditions, such as grinding intensity and duration, to provide the desired force is within the ability of the skilled person to understand how to arrange those grinding conditions to enable the grinding to break down coarse particles. Ball milling is the preferred method. Alternatively, a high pressure homogenizer may be used, wherein the fluid containing the particles is forced through a valve under high pressure that creates high shear and turbulent flow conditions. Shear forces on the particles, collisions between the particles and machine surfaces or other particles, and cavitation (cavitation) due to fluid acceleration may contribute to particle breakage. Such homogenizers may be more suitable than ball mills for large scale preparation of the above-mentioned microparticles.

Suitable homogenizers include EmulsiFlex high pressure homogenizers capable of pressures up to 4000Bar, Niro Soavi high pressure homogenizers (pressures up to 2000Bar) and Microfluidics Microfluidizer (maximum pressure 2750 Bar). Alternatively, the milling step may comprise a stirred bead mill, for example, a DYNO-mill (Willy A. Bachofen AG, Switzerland) or a Netzsch high energy media mill. The Mecano-Fusion System (Hosokawa Micron Ltd) and the hybridizer (Nara) are also suitable for use in the present invention. Other possible grinding devices include air jet mills, screw jet mills, pin mills, hammer mills, knife mills, and ultracentrifugal mills. In a preferred embodiment of the present invention, a spiral jet mill may be used.

After the milling step, the volume diameter of the particles is not greater than 15 microns, advantageously not greater than 12 microns, more preferably not greater than 10 microns. In a preferred embodiment, 90% by weight of the microparticles may have a diameter of 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 of less than 0.6 microns.

Carrier a) comprises a coarse excipient particle fraction a) and a fine particle fraction b).

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.

Advantageously, the mass diameter of all coarse particles is in the range between 40 and 600 microns.

In certain embodiments of the invention, the coarse particles may have a mass diameter 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.

In a preferred embodiment of the invention, the coarse particles have a mass diameter comprised between 210 and 360 microns.

In general, the skilled person will select the most suitable coarse excipient particle size (if available commercially) or will use a suitable classifier (classifier) for sieving.

Advantageously, the coarse excipient particles may have a relatively high cracking surface, i.e., there are cracks and pits and other recessed areas thereon, collectively referred to herein as cracks (fractures). "relatively highly cracked" coarse particles may be defined in terms of fracture index and/or roughness coefficient, as described in WO 01/78695, in particular from page 15, line 28 to page 17, line 26, and in WO01/78693, in particular from page 12, line 16 to page 14, line 11, the teachings of which are incorporated herein by reference and which may be characterized according to the description reported therein. Advantageously, the coarse particles have a fracture index of at least 1.25, preferably at least 1.5, more preferably at least 2.0. The coarse particles may also be characterized in terms of measured tap density or total intrusion volume as reported in WO 01/78695.

The tap density of the coarse particles may advantageously be less than 0.8g/cm³Preferably between 0.8 and 0.5g/cm³In the meantime. The total intrusion volume may be at least 0.8cm³Preferably at least 0.9cm³。

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

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.

In one embodiment of the invention, the above mixture may be obtained by co-micronization of the excipient particles and the fatty acid salt particles, for example by milling in a ball mill.

In some cases, at least two hours of co-micronization was found to be advantageous, although it will be appreciated that this processing time will generally be such that a reduced desired size is obtained. In a more preferred embodiment of the invention, the particles are co-micronised by using a jet mill.

In a preferred embodiment of the 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 said particles being comprised between 3 and 7 microns, preferably between 4 and 6 microns, and not more than 10% of said particles have a volume diameter of less than 2.5 microns, preferably less than 2.0 microns.

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 may be co-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 for at least 1 hour, more preferably for at least 2 hours; otherwise, the components are blended in a high energy apparatus for less than about 30 minutes, preferably less than 20 minutes, as disclosed in WO 2015/004243, the entire detailed description of which is incorporated herein by reference.

Since the co-mixing step does not alter the particle size of the particulate fraction, the skilled person will select fine particles of physiologically acceptable excipient and of fatty acid salt of appropriate size, which can be sieved, using a classifier to achieve the desired particle size distribution.

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

Advantageously, the fine and coarse excipient particles may be composed of any pharmacologically inert, physiologically acceptable material or combination thereof; preferred excipients are those made from crystalline sugars, in particular lactose; most preferred are those made from alpha-lactose monohydrate.

Preferably, the coarse excipient particles and the fine excipient particles both consist of alpha-lactose monohydrate.

Advantageously, the fatty acid salts used as additives to improve the respirable fraction consist of fatty acid salts such as lauric acid, palmitic acid, stearic acid, behenic acid or derivatives (e.g. esters and salts) thereof. Specific examples of such substances are: magnesium stearate; sodium stearyl fumarate; sodium stearoyl lactylate (sodium stearoyl lactylate); sodium lauryl sulfate, magnesium lauryl sulfate.

The preferred fatty acid salt is magnesium stearate.

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

In some embodiments, depending on the amount of magnesium stearate and processing conditions, a degree of surface coating of greater than 50%, preferably greater than 60%, may be achieved.

The extent to which magnesium stearate coats the surface of 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.

The step of mixing the coarse excipient particles a) with the fine fraction b) is typically carried out in any suitable mixer, for example a tumble mixer (such as 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.

In general, the skilled person will adjust the mixing time and the rotational speed of the mixer to obtain a homogeneous mixture.

When spheroidized carrier particles are required to obtain hard pellets as defined in the above report, the mixing step should typically be carried out for at least 4 hours.

In a particular embodiment, the carrier consisting of the coarse fraction a) and the fine fraction b) can be prepared by mixing any suitable mixer. For example, if Turbula is used^TMThe mixer should then mix the two fractions at a speed of from 11 to 45rpm, preferably from 16 to 32rpm, for at least 30 minutes, preferably from 30 to 300 minutesMore preferably from 150 to 240 minutes.

In an even more specific embodiment, the carrier may be obtained by blending together the coarse excipient particles, the micronized excipient particles and the micronized particles of the fatty acid salt in any suitable mixer. For example, if Turbula is used^TMThe mixer, the three components should then be mixed for a period of time exceeding 30 minutes, advantageously 60 to 300 minutes.

The ratio of the fine fraction b) to the coarse fraction a) can be comprised between 1:99 and 30:70 wt.%, preferably between 2:98 and 20:80 wt.%.

Preferably, said ratio may be comprised between 5:95 and 15: 85% by weight.

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

If the process is carried out according to a particular variant, then in step ii) the carrier, the LABA active ingredient and the ICS active ingredient are loaded into the container of a suitable shaking mixer whose rotation and inversion speeds are wide and adjustable.

In practice it has been found that the mixer type is particularly suitable because of its versatility. In fact, with said mixer, it is possible to set frequent changes of the revolution cycles in order to continuously vary the powder flow inside the mixing tank and to generate different powder flow patterns to increase the mixing efficiency.

The carrier may be mixed with the remainder of the ICS and LABA active ingredient in a shaking mixer at a rotation speed not lower than 16r.p.m., preferably 16 to 32r.p.m., for a time not less than 60 minutes, preferably 60 to 120 minutes.

In step iii), the co-milled microparticles of glycopyrronium bromide and ICS are added to the above mixture and blended at a rotational speed of not more than 16r.p.m., preferably 15r.p.m. or less for a period of not more than 40 minutes, preferably 20 to 40 minutes, to obtain a blend.

In a preferred embodiment of the invention, dyna-MIX is used^TMA mixer.

Optionally, the resulting mixture is sieved through a screen. The person skilled in the art should select the mesh of the screen depending on the size of the coarse particles.

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

One skilled in the art should select a suitable mixer and adjust the mixing time and speed of the mixer to obtain a homogeneous mixture.

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

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

Advantageously, in order to better reach the distal passages of the respiratory tree, 90% of the micronized particles of the 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 between 1.2 and 2.5 microns, preferably between 1.3 and 2.2 microns, and no more than 10% of said 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.

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 the ISC and LABA active ingredients, expressed as span, should advantageously be between 1.0 and 4.0, more advantageously between 1.2 and 3.5, the span corresponding to [ d (v,0.9) -d (v,0.1) ]/d (v, 0.5).

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

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) lens, 1 bar pressure.

Regarding particle size determination, consider within experimental error: 30% of CV, d (v0,1) and 20% of CV, d (v0,5), d (v0,9) and d (v0, 99).

All micronized LABA and ICS active ingredients used in the process of the invention can be prepared by processing in a suitable mill according to known methods.

In one embodiment of the invention, they may be prepared by grinding using conventional fluid energy mills, such as commercially available jet-micronizers having grinding chambers of different diameters.

Depending on the type of equipment and the size of the batch, one skilled in the art will adjust the grinding parameters such as operating pressure, feed rate, and other operating conditions appropriately to achieve the desired particle size. Preferably all micronized active ingredient is obtained without any additives during the micronization process.

The powder formulation obtainable according to the process of the present invention comprising micronized particles of glycopyrronium bromide, LABA and ICS as active ingredient is physically and chemically stable, free flowing and exhibits good homogeneity of the active ingredient.

Furthermore, the above powder formulations are capable of delivering a high respirable fraction for all three active ingredients, as measured by the Fine Particle Fraction (FPF).

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

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

Advantageously, the formulation will be suitable for delivering a therapeutically effective dose of all three active ingredients comprised between 50 and 600 μ g, preferably between 100 and 500 μ g.

For example, the formulation should be suitable for delivering 3-15 μ g formoterol (as fumarate dihydrate)/start-up, advantageously 4-13.5 μ g/start-up, 25-240 μ g Beclometasone Dipropionate (BDP)/start-up, advantageously 40-220 μ g/start-up and 5-65 μ g glycopyrronium salt (as bromide)/start-up, advantageously 11-30 μ g/start-up. In a particularly preferred embodiment of the invention, the formulation is suitable for delivering 3 or 6 μ g or 12 μ g formoterol (as fumarate dihydrate)/start-up, 50 or 100 or 200 μ g beclometasone dipropionate/start-up and 6.5 or 12.5 μ g or 25 μ g glycopyrronium salt (as bromide)/start-up.

In a specific embodiment, the formulation is suitable for delivering 6 μ g formoterol (as fumarate dihydrate)/start-up, 100 μ g beclometasone dipropionate/start-up and 12.5 μ g glycopyrronium salt (as bromide)/start-up.

In another embodiment, the formulation is suitable for delivering 12 μ g formoterol (as fumarate dihydrate)/start-up, 200 μ g beclometasone dipropionate/start-up and 25 μ g glycopyrronium salt (as bromide)/start-up.

The dry powder formulation can be utilized with any dry powder inhaler.

Dry Powder Inhalers (DPIs) can be divided into two basic types:

i) a single dose inhaler for administering a single sub-divided dose of an active compound; each single dose is typically filled in a capsule;

ii) a multi-dose inhaler pre-loaded with an amount of active ingredient sufficient for a longer treatment period.

Depending on the desired inspiratory flow rate (liters per minute) (which is strictly dependent on its design and mechanical properties), DPIs are also classified as follows:

i) low resistance devices (>90 l/min);

ii) resistance means (about 60-90 liters/min);

iii) medium-high resistance devices (about 50-60 liters/min);

iv) high resistance devices (less than 30 liters/min).

The classification reported was generated according to the european pharmacopoeia (Eur Ph) for the flow rates required to produce a pressure drop of 4kpa (kilopascal).

The dry powder formulation is particularly suitable for use in a multi-dose DPI containing a reservoir from which a single therapeutic dose can be withdrawn on demand by actuation of a device, such as the device described in WO 2004/012801.

Other multi-dose devices that may be used are, for example, Diskus from GlaxoSmithKline^TMAstraZeneca Turbohaler^TMSching twist Twisthaler^TMClickhaler of Innovata^TMSpiromax of Teva^TMNovolizer from Meda^TMAnd Almirall Genuair^TM。

Examples of commercially available single dose devices include Rotohaler by GlaxoSmithKline^TMHandihaler of Boehringer Ingelheim^TMAnd Breezhaler by Novartis^TM。

Preferably, the formulation obtained by the process of the present invention is used with a DPI device as disclosed in WO2004/012801, in particular from page 1, line one to page 39, line last, or a variant thereof as disclosed in WO2016/000983, in particular from page 1, line 5 to page 15, line 34, the teachings of which are incorporated herein by reference, said device being particularly suitable for delivering ultra-fine formulations.

In order to protect the DPI from moisture ingress into the formulation, it may be desirable to overwrap the device with a flexible package capable of resisting moisture ingress, such as that disclosed in EP 1760008, particularly from page 2, paragraph [0009] to page 9, paragraph [102 ].

The administration of the formulations prepared according to the method of the invention is indicated for the prevention and/or treatment of Chronic Obstructive Pulmonary Disease (COPD) and asthma of all types and severity.

The administration of the preparation prepared according to the method of the invention is also indicated for the prevention and/or treatment of additional respiratory diseases characterized by obstruction of the peripheral airways and the presence of mucus as a result of inflammation, such as chronic obstructive bronchiolitis.

In certain embodiments, the formulations are particularly suitable for the prevention and/or treatment of 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.

Furthermore, it may be suitable for the prevention and/or treatment of persistent asthma and asthma in patients not controlled by a combination of medium or high dose ICS and LABA.

The following examples illustrate the invention in detail.

Examples