Novel carrier particles for dry powder formulations for inhalation

Abstract

The present invention relates to carrier particles for dry powder formulations for inhalation and methods for their preparation.

Description

Technical Field

[0001] The present invention relates to carrier particles for dry powder formulations for inhalation and methods for their manufacture.

Background Art

[0002] Dry powder inhalation (DPI) drug therapy has been used for many years to treat respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis.

[0003] Compared to oral drug intake, first-pass metabolism is significantly reduced, so relatively low doses are required for effective treatment. Such low doses reduce the body's exposure to the drug and minimize side effects. Local delivery to the lungs reaches the drug directly to the site of action, so systemic adverse effects are also reduced. Low-dose regimens can also provide significant cost savings, especially when expensive therapeutic agents are a concern.

[0004] The dry powder form is typically formulated by mixing the micronized form of the drug with carrier coarse particles, resulting in a regular mixture in which the micronized active particles adhere to the surface of the carrier particles while in the inhaler device.

[0005] The carrier reduces the adhesiveness of the micronized powder, improves its flowability, and facilitates the handling of the powder during the manufacturing process (injecting, filling, etc.).

[0006] During inhalation, the drug particles separate from the surface of the carrier particles and enter the lower lungs, while the larger carrier particles mostly remain in the oropharyngeal cavity.

[0007] Redispersion of drug particles from the carrier surface is considered to be the most important factor affecting the availability of the drug to the lungs. This depends on the mechanical stability of the powder mixture and the way it is affected by external forces necessary to break the adhesion properties between the drug and the carrier and the non-covalent bonds formed between the adhering particles. Excessively strong bonds between the adhering particles can actually prevent the separation of the micronized drug particles from the carrier particle surface.

[0008] Various approaches aimed at modulating adhesion have been presented in the art to facilitate the detachment of drug particles from the carrier particles, thereby increasing the inhalable fraction.

[0009] For example, it has been suggested to add lubricants or excipients with anti-adhesion properties and / or fine particles of a third drug.

[0010] Examples of such approaches are reported in European Patent No. 663815, International Publication Nos. 96 / 02231, 96 / 23485, 00 / 33789, 01 / 78693 and US Patent No. 2015 / 017248.

[0011] Another method for formulating dry powders for inhalation with improved flowability is to aggregate the fine particles in a controlled manner to form relatively high-density and small spheres. This method is called spheronization, and when the active ingredient is mixed with a plurality of fine particles of one or more excipients before spheronization, the resulting product is also called a soft pellet.

[0012] Examples thereof are reported in International Publication Nos. 95 / 24889, 98 / 31350, 98 / 31351, 01 / 89491 and 01 / 89492.

[0013] In International Publication Nos. 01 / 89491 and 01 / 89492, it is generally envisaged that a coarse carrier with an average particle size exceeding 25 micrometers may be added.

[0014] However, soft pellets can reach a high internal coherence that risks their breakdown into small particles during inhalation; such a drawback can be considered an important process when using a medium-high resistance or high resistance dry powder inhaler.

[0015] With the inhaler, the energy available to break down the pellets into small primary particles of the active ingredient is actually small.

[0016] On the other hand, since the third agent is inhaled by the patient, a regulatory burden is imposed at the time of approval application.

[0017] Therefore, it is advantageous to provide a platform technology for the administration of the active ingredient in a dry form by inhalation with improved aerosol performance without using the third agent. SUMMARY OF THE INVENTION

[0018] The present invention is a dry powder formulation for administration by a dry powder inhaler (DPI), a) a fraction of spheronized particles having a mass diameter of 100 to 800 micrometers containing fine particles of one or more active ingredients and fine particles of a physiologically acceptable excipient in an appropriate weight ratio; b) a fraction of coarse particles containing a physiologically acceptable excipient having a mass diameter including 150 to 400 micrometers and wherein the ratio of fraction a) to fraction b) is 5:95 to 50:50 weight percent, relating to a dry powder formulation.

[0019] In a second aspect, the present invention is a method for manufacturing the claimed formulation, i) preparing a fraction of fine particles of the active ingredient and a physiologically acceptable excipient; ii) optionally conditioning the resulting mixture; iii) aggregating and spheronizing the mixture to obtain spheronized particles; iv) optionally, sieving to isolate a fraction having a desired diameter; v) adding a fraction b) of coarse particles; vi) mixing the resulting mixture relates to a method comprising.

[0020] In one embodiment, the fraction of step i) is prepared by mixing fine particles of the active ingredient and fine particles of a physiologically acceptable excipient.

[0021] In another embodiment, the fraction of step i) is prepared by co - micronizing fine particles of the active ingredient and particles of a physiologically acceptable excipient and then mixing them.

[0022] A fourth aspect is a dry powder formulation for administration by a dry powder inhaler (DPI), a) a fraction of spheronized particles having a mass diameter of 100 - 800 micrometers, comprising fine particles of one or more active ingredients and fine particles of a physiologically acceptable excipient in a suitable weight ratio; b) a fraction of coarse particles comprising a physiologically acceptable excipient having a mass diameter including 150 - 400 micrometers comprising, wherein the ratio of fraction a) to fraction b) is 5:95 to 50:50% by weight, and the formulation is i) a step of preparing a fraction of fine particles of the active ingredient and a physiologically acceptable excipient; ii) optionally, conditioning the resulting mixture; iii) aggregating and spheronizing the mixture to obtain spheronized particles; iv) optionally, sieving to isolate a fraction having a desired diameter; v) adding a fraction b) of coarse particles; and vi) mixing the resulting mixture relates to a dry powder formulation obtainable by a method comprising.

[0023] The fifth aspect is a dry powder formulation for administration by a dry powder inhaler (DPI), comprising a) a fraction of spheronized particles having a mass diameter of 100 to 800 micrometers, containing fine particles of one or more active ingredients and fine particles of a physiologically acceptable excipient in an appropriate weight ratio; b) a fraction of coarse particles containing a physiologically acceptable excipient having a mass diameter including 150 to 400 micrometers wherein the ratio of fraction a) to fraction b) is 5:95 to 50:50% by weight, and the formulation comprises i) a step of conditioning the fraction of the fine particles of the active ingredient and the physiologically acceptable excipient; ii) optionally, a step of preparing the resulting mixture; iii) a step of aggregating and spheronizing the mixture to obtain spheronized particles; iv) optionally, a step of sieving to isolate a fraction having a desired diameter; v) a step of adding the fraction b) of the coarse particles; and vi) a step of mixing the resulting mixture and is obtained by a method comprising, relating to a dry powder formulation.

[0024] In a sixth aspect, the invention relates to a dry powder inhaler filled with the claimed dry powder pharmaceutical formulation.

[0025] In a seventh aspect, the invention relates to a package comprising the dry powder pharmaceutical formulation and the dry powder inhaler according to the invention.

[0026] In a further aspect, the invention refers to the above formulation for use as a medicament, preferably for the prevention and / or treatment of a respiratory disease selected from respiratory diseases, more preferably asthma and COPD.

[0027] Detailed Description of the Invention Definitions The terms "micron" and "micrometer" are used synonymously.

[0028] The term "physiologically acceptable" means a safe and pharmacologically inert substance.

[0029] "Daily therapeutic effective amount" means the amount of the active ingredient administered by inhalation by actuation of the inhaler.

[0030] Said daily dose can be delivered in one or more actuations (puffs or blows) of the inhaler.

[0031] The term "fine particles" means particles having a size of one tenth of the maximum number of microns.

[0032] The term "micronized" refers to a substance having a size including several microns, typically 1 to 15 microns.

[0033] "Coarse" means particles having a size greater than 30 microns, typically 100 or several hundred microns.

[0034] In general terms, the particle size of particles is quantified by measuring the characteristic spherical equivalent diameter known as the volume diameter by laser diffraction.

[0035] The particle size can also be quantified by measuring the mass diameter with a suitable known instrument, for example, a sieve analyzer.

[0036] The volume diameter (VD) is related to the mass diameter (MD) by the density of the particles (assuming a density independent of the particle size).

[0037] In this specification, the particle size of the active ingredient is expressed from the viewpoint of the volume diameter, while the particle size of the excipient is expressed from the viewpoint of the mass diameter.

[0038] Particles have a normal (Gaussian) distribution defined in terms of the volume or mass median diameter (VMD or MMD) corresponding to 50% by weight of the volume or mass diameter of the particles, and optionally, in terms of the volume or mass diameters of 10% and 90% of the particles respectively.

[0039] Another common approach for defining the particle size distribution utilizes three values: i) the volume median diameter d(v, 0.5), which is the volume diameter such that 50% of the distribution is above this value and 50% is below it; ii) d(v, 0.9), below which 90% of the volume distribution lies; iii) d(v, 0.1), below which 10% of the volume distribution lies. The span is the width of the distribution based on the 10%, 50%, and 90% percentiles and is calculated by the following formula.

Number

[0040] After aerosolization, the particle size is expressed as the mass aerodynamic diameter (MAD), and the particle size distribution is expressed as the mass median aerodynamic diameter (MMAD). The MAD indicates the ability of the particles to be transported while floating in the air stream. The MMAD corresponds to the mass aerodynamic diameter of 50 wt% of the particles.

[0041] As used herein, the term "spheronized" refers to the term used in the art to denote soft pellets as in the examples disclosed in WO 98 / 31351.

[0042] The term "spheronization" refers to the process for manufacturing spheronized particles and includes various processes such as mixing and vibration.

[0043] It is carried out before adding the excipient coarse particles. In contrast, in WO 01 / 78693 and WO 2013 / 110632, the term was used to denote the process of finishing the excipient coarse particles at the end of the manufacture of the final formulation. When the amount of the fine particles is less than 20 wt% of the final formulation, spheronized particles are not formed during this process.

[0044] The term "loading capacity" refers to the ability of the excipient coarse particles to accommodate fine particles of a specific amount of excipient and / or active ingredient on the surface. In the context of the present invention, it refers to the ability of the excipient coarse particles to accommodate an amount of spheroidized particles that exceeds 20% but is less than 60%, preferably about 30 - 40%, without segregation from the powder.

[0045] The term "good flowability" refers to a formulation that is easy to handle during the manufacturing process, can deliver a therapeutically effective dose accurately and reproducibly.

[0046] Flow characterization can be evaluated by various tests such as the angle of repose, Carr index, Hausner ratio, or the flow rate through an orifice.

[0047] In the context of the present application, the flow characteristics were tested by measuring the flow rate through an orifice according to the method described in the European Pharmacopeia (Eur. Ph.) 7.3, 7th Edition, or by the angle of repose according to the United States Pharmacopeia, page 1174.

[0048] The expression "good uniformity" refers to a formulation in which, after mixing, the uniformity of the distribution of the active ingredient, expressed as the coefficient of variation (CV), also known as the relative standard deviation (RSD), is less than 2.5%, preferably 1.5% or less.

[0049] The expression "physically stable in the device before use" refers to a formulation in which the active particles do not substantially separate and / or detach from the carrier particles both during the manufacture of the dry powder and in the delivery device before use. The tendency for separation can be measured according to Staniforth et al. J. Pharm. Pharmacol. 34, 700 - 706, 1982, and it is considered acceptable if the distribution of the active ingredient in the powder formulation after testing, expressed as the relative standard deviation (RSD), does not change significantly compared to the distribution in the formulation before testing.

[0050] The expression "inhalable fraction" refers to an index of the proportion of active particles that can reach deep into the patient's lungs.

[0051] The inhalable fraction, also referred to as the fine particle fraction (FPF), is evaluated using a suitable in vitro device such as an Andersen Cascade Impactor (ACI), a Multi-Stage Liquid Impinger (MLSI) or a Next Generation Impactor (NGI), preferably by the ACI, according to the method reported in the common pharmacopoeias, in particular the European Pharmacopoeia (Eur. Ph.) 7.3, 7th Edition.

[0052] It is calculated by the ratio of the fine particle mass (previous fine particle dose) to the delivered dose.

[0053] The delivered dose is calculated from the cumulative deposition in the device and the fine particle mass is calculated from the deposition of particles having a diameter < 5.0 microns.

[0054] The term "prevention" means an approach for reducing the risk of onset of a disease.

[0055] The term "treatment" means an approach for obtaining a beneficial or desired result, including clinical results. Beneficial or desired clinical results include, but are not limited to, reduction or improvement of one or more symptoms or conditions, whether or not detectable, diminution of the degree of a disease, stabilization of the state of a disease (i.e., not getting worse), prevention of spread of a disease, delay or blunting of disease progression, improvement or alleviation and remission (partial or complete) of the state of a disease. The term can also mean prolonging the survival period as compared to the expected survival period assuming that no treatment is received.

[0056] The term "therapeutically effective amount" means the amount of an active ingredient that provides a desired biological effect when delivered to the lung by the dry powder formulation described herein.

[0057] The term "surface coating" refers to covering the surface of the excipient particles by forming a thin film of a third agent around the particles.

[0058] The term "dry powder inhaler (DPI)" refers to a device that delivers a medicament to the lungs in the form of a dry powder. DPIs can be divided into two basic forms: i) A single-dose inhaler for administering a pre-divided single dose of an active compound; ii) A multi-dose dry powder inhaler (MDPI) having pre-divided single doses or pre-filled with a sufficient amount of the active ingredient for multiple doses; each dose is provided by measuring the units in the inhaler.

[0059] Depending on the inhalation flow rate (l / min) required, which strictly depends on their design and mechanical characteristics, DPIs can also be divided as follows: i) Low resistance devices (>90 l / min); ii) Medium resistance devices (about 60 - 90 l / min); iii) Medium - high resistance devices (about 50 - 60 l / min); iv) High resistance devices (<30 l / min).

[0060] The reported classification occurs for the flow rate required to produce a pressure drop of 4 kPa (kilopascals) according to the European Pharmacopoeia (Eur Ph).

[0061] "High single dose" means a dose of 1 mg or more.

[0062] The present invention relates to: a) A fraction of spheronized particles having a diameter of 100 - 800 micrometers, containing microparticles of one or more active ingredients and microparticles of a physiologically acceptable excipient in an appropriate weight ratio; b) A fraction of coarse particles consisting of a physiologically acceptable excipient having a mass diameter including 150 - 400 micrometers A dry powder formulation for use in a dry powder inhaler (DPI), comprising, wherein the ratio of fraction a) to fraction b) is 5:95 to 50:50 weight percent, relates to a dry powder formulation.

[0063] In fact, if the excipient microparticles are pre-spheronized with the active ingredient particles and then combined with the excipient coarse particles, it is possible to achieve a high inhalable fraction after administration by inhalation and avoid the use of a third agent.

[0064] Spheronized particles having a selected diameter enable good uniformity of the distribution of the active ingredient and a small amount of drug dose variation, or in other words, appropriate accuracy of the delivered dose. The round shape of the spheronized particles also improves the flowability of the powder formulation as defined in detail herein.

[0065] In fact, the formulations according to the invention containing pre-spheronized microparticles exhibit better flow properties than the corresponding formulations containing non-spheronized microparticles.

[0066] Dilution of the spheronized particles with a coarse carrier consisting of particles is resistant to shear stress and compression and can be distributed into capsules or DPI devices, for example, using filling techniques that are usually suitable for carrier-based powder formulations and not convenient for pure soft pellets.

[0067] The particles have also been found to be particularly suitable for the cup size of reservoir-based multiple-dose inhalers. The particles have been found to be advantageously able to substantially avoid the loss of powder during filling of the metering chamber.

[0068] The desired particle size can be obtained by sieving according to known methods.

[0069] Furthermore, another advantage of the present invention is that the presence of excipient coarse particles having a selected, clearly defined particle size is advantageous for the disintegration of the spheronized particles into small particles during inhalation, making the technology of the present invention particularly useful for the administration of active ingredients by medium-high resistance or high resistance dry powder inhalers.

[0070] By developing the platform technology of the present invention, that is, by combining the spheroidized particles and the coarse particles in the claimed ratio, it is also possible to achieve good fluidity and sufficient stability in the device before use.

[0071] Advantageously, the micronized excipient coarse particles can be composed of any physiologically acceptable substance or combination thereof suitable for inhalation use, and thus the manufacture of the formulations of the present invention provides a convenient and versatile method.

[0072] For example, the particles can be composed of one or more substances selected from polyols such as sorbitol, mannitol and xylitol and crystalline sugars including monosaccharides and disaccharides; inorganic salts such as sodium chloride and calcium carbonate; organic salts such as sodium lactate; organic compounds such as urea, polysaccharides such as starch and its derivatives; oligosaccharides such as cyclodextrin and dextrin.

[0073] Preferably, the particles are composed of crystalline sugar, and more preferably, the crystalline sugar is selected from monosaccharides such as glucose or arabinose, or disaccharides such as maltose, sucrose, dextrose or lactose.

[0074] Since the excipient is chemically and physically stable during storage and easy to handle, preferably, the particles are composed of lactose, and more preferably, α-lactose monohydrate.

[0075] Advantageously, the spheroidized particles have a mass diameter including 100 to 800 micrometers. More advantageously, these diameters include 200 to 800 micrometers, preferably 300 to 700 micrometers. In fact, it has been found that particles having a starting diameter of 200 microns give particularly convenient fluidity characteristics. In a particular preferred embodiment of the present invention, the spheroidized particles have a mass diameter including 200 to 350 microns.

[0076] In one embodiment, the fine particles of both the excipient and the active ingredient have a mass median diameter of 15 micrometers or less, preferably 10 micrometers or less, more preferably 1 to 6 micrometers.

[0077] The latter particle size is particularly suitable for active ingredients useful for the prevention and / or treatment of respiratory diseases.

[0078] In certain embodiments, at least 90% of the particles of both the excipient and the active ingredient have a diameter of less than 6 microns, even more preferably less than 5 microns. More preferably, they may have an average median diameter of 2 to 4 microns.

[0079] According to the present invention, one or more active ingredients are present in the spheronized particles in an overall proportion of 0.5 to 100% by weight, and the remaining portion is fine particles of the excipient and optionally additive particles. In some embodiments, the proportion of one or more active ingredients includes 1.0 to 99.5%, preferably 2.0 to 95%, and in other embodiments, the proportion includes 10 to 90% by weight or 20 to 30% by weight.

[0080] In one embodiment, the spheronized particles are composed only of fine particles of one or more active ingredients and a physiologically acceptable excipient.

[0081] In certain embodiments of the present invention, the carrier coarse particles of fraction b) preferably have a mass diameter (MD) including 150 to 400 micrometers, preferably MD200 to 380 micrometers, together with a mass median diameter (MMD) of more than 175 micrometers, and more preferably, MD may include 210 to 355 micrometers.

[0082] The desired particle size can be obtained by sieving by known methods.

[0083] When those MDs include from 210 to 355 microns, the carrier coarse particles can have a relatively large and cracked surface. That is, on their surfaces, there are cracks, depressions and other concave regions, which are collectively referred to as cracks herein.

[0084] As further explained, when a proportion of the active ingredient exceeding 20% is used, the presence of said cracks enables the spontaneous formation of spheroidized particles during mixing.

[0085] Furthermore, when a proportion of the active ingredient exceeding 20% is used, the spheroidized particles have better flow properties than the fine particles, but the presence of said cracks on the surface of the excipient coarse particles enables the improvement of the fluidity of the final formulation.

[0086] The "relatively large and cracked" coarse particles can be defined by a crack index or a roughness coefficient as described in the examples of WO 01 / 78695 and WO 01 / 78693, which are incorporated herein by reference and can be characterized according to the descriptions reported therein.

[0087] The carrier coarse particles can also be defined by the tap density or the total intrusion volume measured as described in the examples of WO 01 / 78695.

[0088] The tap density of the carrier coarse particles is preferably less than 0.8 g / cm 3 and preferably from 0.8 to 0.5 g / cm 3 3.

[0089] According to a preferred embodiment, in order to avoid separation from the powder, the spheroidized particles and the carrier coarse particles shall have substantially similar mass diameters. For example, if carrier coarse particles having a mass diameter of from 210 to 355 microns are used, the spheroidized particles shall preferably have a mass diameter including from 200 to 350 microns.

[0090] According to a preferred embodiment, fraction a) consists only of microparticles of one or more active ingredients and microparticles of a physiologically acceptable excipient.

[0091] In a further embodiment, the formulation of the present invention further comprises a third agent.

[0092] When present, the third agent is preferably contained in the spheronized particles.

[0093] Said third agent may preferably be an amino acid selected from the group consisting of leucine, isoleucine, lysine, valine, methionine and phenylalanine.

[0094] Alternatively, the third agent may comprise or consist of one or more water-soluble surfactants, for example lecithin.

[0095] In a particular embodiment, the third agent may comprise or consist of one or more lubricants selected from the group consisting of stearic acid and its salts, such as magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate.

[0096] Advantageously, the particles of the third agent have a mass median diameter of 15 micrometers or less, 10 micrometers or less, more preferably 1 to 6 micrometers.

[0097] The optimal amount of the additive substance shall depend on the chemical composition and other properties of the additive substance.

[0098] Generally, the amount of the additive substance shall not exceed 10% by weight based on the total weight of the formulation.

[0099] However, for many third agents, their amount should preferably not exceed 5%, more preferably not exceed 2% based on the total weight of the formulation.

[0100] When magnesium stearate is used as the third agent, its amount generally ranges from 0.01% to 2%, preferably from 0.02% to 1%, more preferably from 0.1% to 0.5% by weight based on the total weight of the formulation.

[0101] For example, depending on its amount and mixing time, magnesium stearate can coat the surface of the excipient microparticles such that the degree of molecular surface coating is at least 5%, preferably less than 10%, more preferably less than 15%, and even more preferably 25% or less.

[0102] When active ingredients with relatively low dosage strengths such as β2 agonists, antimuscarinic drugs, and corticosteroids are used, the amount of magnesium stearate included is preferably 0.1% to 0.5% by weight, and the degree of molecular surface coating exceeds 15%.

[0103] The degree of molecular surface coating indicating the total surface ratio of the excipient particles coated with magnesium stearate can be determined by water contact angle measurement reported in the literature, for example, International Publication No. WO 2011 / 120779.

[0104] In certain embodiments, the ratio of fraction a) to fraction b) ranges from 5:99 to 50:50% by weight, more preferably from 10:90 to 30:70% by weight. In even more preferred embodiments, the ratio includes 10:90 to 15:85% by weight. In specific embodiments, the ratio is 10:90% by weight.

[0105] When active ingredients with relatively low dosage strengths such as β2 agonists, antimuscarinic drugs, and corticosteroids are used, the ratio of fraction a) to fraction b) is preferably 10:90.

[0106] In another aspect, the present invention also provides: i) a step of preparing fractions of microparticles of an active ingredient and a physiologically acceptable excipient; ii) optionally, conditioning the resulting mixture; iii) aggregating and spheronizing the mixture to obtain spheronized particles; iv) optionally, sieving to isolate a fraction having a diameter comprising from 100 to 800 micrometers; v) adding a fraction of coarse particles comprising a physiologically acceptable excipient having a mass diameter comprising from 150 to 400 micrometers; vi) mixing the resulting mixture relates to a method comprising.

[0107] In certain embodiments, the fraction of step i) is prepared by mixing fine particles of the active ingredient and fine particles of a physiologically acceptable excipient.

[0108] Said mixing can be suitably carried out in any suitable mixer, such as a Turbula TM mixer, until a uniform distribution is achieved. Typically, when a Turbula TM mixer is used, the mixing time can vary, for example, from 30 minutes to 2 hours depending on the amounts of the active ingredient and excipient and the experimental conditions.

[0109] In another embodiment, the fraction of step i) is prepared by co - micronizing the particles of the active ingredient and the particles of the physiologically acceptable excipient, preferably milling and then mixing.

[0110] This may make it possible to avoid the usual problems encountered during mixing of fine powders, namely that the mixer cannot break down powder aggregates and requires, for example, a further step of re - micronization as disclosed in WO 98 / 31350.

[0111] Milling can be carried out by methods known in the art, for example, using a ball mill or a jet mill for a time sufficient to achieve the desired particle size.

[0112] In step ii), the fraction of particles a) may optionally be subjected to a process of preparation under conditions known in the art, for example, as disclosed in WO 2011 / 131663.

[0113] The spheroidization of step iii) can be carried out in the art, for example, by the methods reported in WO 98 / 31351 or WO 95 / 24889 or by another method based on mixing and vibration.

[0114] Typically, a commercially available vibrating screening device can be used, for example, the vibrating screening AS200 available from Retsch GmbH, Germany. Those skilled in the art will select a method for adjusting the processing time and other parameters to obtain the desired spheroidized particles. In fact, the vibration time and amplitude affect the overall quality of the particles and can be finely adjusted to adjust the particle size and sphericity and limit the shape irregularities.

[0115] Typically, the time to achieve spheroidization is less than 5 minutes or even shorter.

[0116] In a preferred embodiment of the present invention, the spheroidization of step iii) is carried out with a vibrating screening device operating at a vibration frequency of 50 Hz, a vibration amplitude of 0.2 - 1.2 mm and a vibration time of 60 - 200 seconds.

[0117] By adopting the above parameters, it is possible to obtain spheroidized particles with diameters including 200 - 350 microns.

[0118] The presence and complete formation of the spheroidized particles can be detected by microscopic analysis, for example, by scanning electron microscopy (SEM), according to methods known to those skilled in the art. Any microscope available on the market can be appropriately used, for example, the device JSM - F100 (JEOL Ltd., Tokyo, Japan).

[0119] If necessary, the obtained spheroidized particles are sieved according to methods known to those skilled in the art, aiming at a better target of the desired particle size.

[0120] Step vi) of mixing the excipient coarse particles b) and the fine particles a) is typically carried out in a suitable mixer, for example, a Tumbler mixer such as Turbula TM (Willy A. Bachofen AG, Switzerland) or other mixer for at least 30 minutes, preferably 4 hours or less, more preferably 3 hours.

[0121] In a general method, those skilled in the art will adjust the mixing time and the rotational speed of the mixer in order to obtain a uniform mixture while avoiding the disintegration of the spheronized particles.

[0122] In a preferred embodiment of the present invention, the mixing in step vi) is operated at a rotational speed of 72 rpm. In fact, if spheronized particles with a sufficiently defined particle size are desired, it has been found that by operating at a low speed, their size increases with the mixing time.

[0123] In another method, the spheronized particles are formed in situ while mixing all the components for at least 3 hours, preferably 4 hours.

[0124] When the proportion of the active ingredient is more than 20% of the formulation, preferably 25% or more, more preferably 30% by weight or more, and cracked coarse particles are used, the spheronized particles are spontaneously formed during mixing. Therefore, in such a case, the powder of the present invention can advantageously be produced by mixing together all of the excipient coarse particles, excipient fine particles and the active ingredient. This results in time savings and / or an increase in the industrial feasibility of manufacturing the formulation of the present invention.

[0125] In particular, in practice, the approach is less time-consuming than an approach where the pre-preparation of the spheronized particles is considered. Furthermore, the formation of the spheronized particles by direct mixing with the coarse carrier described herein supports the control and consistency of their size and improves the reproducibility and reliability of the processes for their manufacture in this way.

[0126] As described above, the obtained mixture may optionally be sieved. Sieving can be useful when a selected, predefined particle size is used.

[0127] The active ingredient can be any pharmaceutically active compound that can be administered by inhalation as a dry powder.

[0128] By way of example, they are short-acting and long-acting β2 agonists, such as terbutaline, reproterol, salbutamol, salmeterol, formoterol, carmoterol, milbeterol, abediterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambuterol, broxaterol, isoprenaline or hexoprenaline or stereoisomers thereof, salts and / or solvate forms; short-acting and long-acting muscarinic antagonists, such as tiotropium, ipratropium, oxitropium, oxybutynin, acridinium, trospium, glycopyrronium, salts and / or solvate forms thereof; short-acting and long-acting corticosteroids, such as butixocort, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and esters thereof, namely furoate, fluticasone and esters thereof, namely propionate and furoate, beclomethasone and esters thereof, namely propionate, loteprednol or triamcinolone acetonide and solvates thereof; leukotriene antagonists, such as andrast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; phosphodiesterase inhibitors, such as filaminast, piclamilast or roflumilast; neutrophil elastase (HNE) inhibitors, such as the inhibitors disclosed in WO 2013 / 037809 and WO 2014 / 095700; and phosphoinositide 3-kinase inhibitors, such as the inhibitors disclosed in WO 2015 / 091685, and may be selected from these.

[0129] As long as any of these compounds has a chiral center, the compound can be used in optically pure form or can exist as a mixture of diastereomers or a racemic mixture.

[0130] Formulations containing a long-acting β2 agonist, an antimuscarinic antagonist and / or a corticosteroid for inhalation, either alone or in any combination thereof, constitute particular embodiments of the present invention.

[0131] Advantageously, the muscarinic antagonist is an acridinium salt, preferably the bromide salt, darifenacin, preferably the hydrobromide salt, daclidinium salt, preferably the bromide salt, fesoterodine salt, preferably the fumarate salt, glycopyrronium salt, preferably the bromide salt, oxitropium salt, preferably the bromide salt, oxybutynin, preferably the hydrochloride or hydrobromide salt, solifenacin salt, preferably the succinate salt, tiotropium salt, preferably the bromide salt, tolterodine salt, preferably the tartrate salt, trospium salt, preferably the chloride salt, and umeclidinium salt, preferably the bromide salt. Glycopyrronium bromide and tiotropium bromide in the form of the (3R,2R’) enantiomer or the racemic mixture of (3S,2R’) and (3R,2S’) are more preferred, and the racemic mixture of (3S,2R’) and (3R,2S’) of glycopyrronium bromide (hereinafter, rac-glycopyrronium bromide) is even more preferred.

[0132] The long-acting β2 agonists which may be present in specific salt and / or solvate forms are preferably formoterol fumarate dihydrate, salmeterol xinafoate, milbeterol hydrochloride, olodaterol hydrochloride, tulobuterol hydrochloride and vilanterol trifenatate. Formoterol fumarate dihydrate is more preferred.

[0133] Corticosteroids for inhalation that may exist in a specific ester form and / or solvate form include, for example, beclomethasone dipropionate or its monohydrate form, fluticasone propionate, fluticasone furoate, ciclesonide, flunisolide or its hemihydrate form, mometasone furoate and triamcinolone acetonide. Budesonide is more preferred, and beclomethasone dipropionate is even more preferred.

[0134] In certain embodiments, formulations comprising the dihydrate form of formoterol fumarate and a corticosteroid for inhalation and / or a muscarinic antagonist, particularly its combination with beclomethasone dipropionate and / or rac-glycopyrronium bromide, are preferred.

[0135] In another embodiment of the present invention, the dry powder formulation of the present invention is useful for the administration of an active ingredient that is delivered in a single dose per actuation of an inhaler at 1 mg or more, i.e., 2 mg or more, 5 mg or more (hereinafter referred to as a high-dose active ingredient).

[0136] Powder formulations containing high-dose active ingredients such as antibiotics, e.g., Tobi PodiHaler TM are known to be currently on the market.

[0137] Thus, examples of high-dose active ingredients are antibiotics such as ciprofloxacin, levofloxacin and colistin, tobramycin, amikacin and gentamicin; proteins such as insulin and α1-antitrypsin; antiviral drugs such as zanamivir and ribavirin; antifungal agents such as itraconazole, and phosphodiesterase (PDE)-5 inhibitors such as sildenafil and tadalafil.

[0138] The concentration of the active ingredient in the powder formulation depends on several aspects, such as the ejection weight of the formulation delivered upon actuation of the inhaler.

[0139] For example, considering an expected single dose of 1 mg, if the ejection weight of the formulation delivered upon actuation of the inhaler is 10 mg, this corresponds to a concentration of the active ingredient of 10% w / w. Similarly, for an ejection weight of 5 mg, the concentration of the active ingredient is 20% w / w, and for an ejection weight of 20 mg, the concentration of the active ingredient is 5% w / w.

[0140] Thus, the formulations of the present invention may be particularly useful for the administration of active ingredients present at high concentrations, for example, 4 - 30%, preferably 10 - 25% w / w.

[0141] According to one aspect, the present invention refers to the formulations described herein for use as a medicament, more preferably for the treatment of respiratory diseases. In a preferred embodiment, said respiratory disease is selected from asthma and COPD.

[0142] The formulations of the present invention are also useful for the manufacture of a medicament for use in the treatment of respiratory diseases, preferably asthma and COPD.

[0143] The dry powder formulations for inhalation of the present invention can be utilized with any dry powder inhaler currently known to those skilled in the art.

[0144] In this regard, dry powder inhalers can generally be classified into: i) single - dose (unit - dose) inhalers for the administration of a dose of the active compound divided into single - use portions; ii) pre - metered multi - dose inhalers or reservoir inhalers pre - filled with an amount of the active ingredient sufficient for a longer treatment cycle.

[0145] The dry powder formulation can be in unit dosage form.

[0146] The dry powder composition for local delivery to the lungs by inhalation can be present in gelatin capsules and cartridges, or blisters, for use in an inhaler or nebulizer, for example, in a thin - sheet aluminum foil.

[0147] The dry powder formulation for inhalation according to the present invention is particularly suitable for a multi-dose dry powder inhaler comprising a reservoir from which individual therapeutic doses can be withdrawn through the operation of the device.

[0148] Preferred multi-dose devices are the inhalers described in WO 2004 / 012801 and WO 2016 / 000983.

[0149] Other multi-dose devices that can be used are, for example, the DISKUS from GlaxoSmithKline TM , the TURBOHALER from AstraZeneca TM , the TWISTHALER from Schering TM , the EASYHALER from Orion TM , the SPIROMAX from Teva TM and the AIRMAX TM as well as the CLICKHALER from Innovata TM .

[0150] Examples of commercially available single-dose devices include the ROTOHALER from GlaxoSmithKline TM and the HANDIHALER from Boehringer Ingelheim TM as well as the RS01 from Plastiape.

[0151] The present invention will be described in detail by the following examples.

Examples

[0152] Example 1 A powder formulation having a single composition, i.e., the composition per injection of the inhaler shown in Table 1, was produced. Approximately 300 g of micronized beclomethasone dipropionate (BDP) and 100 g of micronized lactose monohydrate were mixed in a vibrating screening device for 2 minutes at a vibration frequency of 50 Hz and an amplitude of 0.2 mm. After passing through a 100 μm cascade, the powder mixture was collected in the bottom dish. The recovered spheronized pellets were gently sieved through an 800 μm sieve. The obtained spheronized particles were mixed with approximately 600 g of cracked coarse particles of α-lactose monohydrate having a mass diameter of 212 - 355 microns and obtained in a 40:60 wt% ratio. The mixing was carried out at 23 rpm for 2 hours in a Turbula TM mixer. [Table 1] The formulation was filled into a multiple-dose dry powder inhaler (DPI) described in International Publication No. WO 2016 / 000983. Aerosol performance was evaluated using a Next Generation Impactor (NGI) according to the conditions reported in the European Pharmacopoeia, 8th Edition, 2015, 2.9.18, pages 309 - 320. After 3-dose aerosol administration from the inhaler device, the NGI apparatus was disassembled and the amount of drug present at this stage was recovered by washing with a 50:50 v / v water:acetonitrile mixture and then quantified by high performance liquid chromatography (HPLC). The following parameters were calculated: i) the delivered dose, which is the amount of drug delivered from the device recovered in all parts of the impactor; ii) the fine particle mass (FPM), which is the amount of the delivered dose having a particle size of 5.0 microns or less; iii) the fine particle fraction (FPF), which is the ratio between the fine particle mass and the delivered dose; iv) the MMAD. The results (mean ± S.D) are shown in Table 2. [Table 2] As can be seen, an FPF of approximately 40% was achieved. Based on further data collected by the applicant, it was found that similar results can be obtained if the total amount of a single injection of the inhaler is 20 mg. In the prior art, for example, in International Publication No. 01 / 78693, a powder formulation comprising a carrier consisting only of excipient coarse particles and excipient fine particles is disclosed in Example 5, which results in lower aerosol performance and has little FPF exceeding 20%. In clear contrast, the formulation produced according to the teachings of the present invention surprisingly results in good aerosol performance and in particular achieves an FPF of approximately 40%.

[0153] Example 2 A powder formulation having a single composition, i.e., the composition per injection of the inhaler shown in Table 3, can be produced. An appropriate amount of micronized formoterol fumarate dihydrate (about 0.3 g), micronized beclomethasone dipropionate (about 5 g) and micronized lactose monohydrate (about 144.7 g) are mixed in a Turbula TM mixer to obtain the proportions in the spheronized particles shown in Table 3. The mixture is conditioned at a temperature of 22 ± 1 °C and a relative humidity of 75% for 1 hour, and then spheronized and aggregated at room temperature at a controlled relative humidity of less than 50%. The obtained spheronized particles are sieved to isolate the fraction having a mass diameter comprising 200 - 800 microns, and then mixed with about 350 g of cracked coarse particles of α-lactose monohydrate having a mass diameter comprising 212 - 355 microns in a ratio of 30:70% by weight. [Table 3] The formulation is filled into the multi-dose dry powder inhaler described in International Publication No. 2016 / 000983.

[0154] Example 3 Similar to Example 2, another powder formulation having a single composition, i.e., the composition per injection of the inhaler shown in Table 4, can be produced. An appropriate amount of micronized formoterol fumarate dihydrate (about 0.1 g), micronized beclomethasone dipropionate (about 1.67 g), micronized glycopyrronium bromide (0.21 g) and micronized lactose monohydrate (about 48.02 g) were mixed in a Turbula TM mixer to obtain the ratios in the spheronized particles shown in Table 4. The mixture was conditioned at a temperature of 22 ± 1 °C and a relative humidity of 75% for 1 hour, and then spheronized and agglomerated at room temperature with a controlled relative humidity of less than 50%. The obtained spheronized particles were sieved to isolate the fraction having a diameter including 200 - 800 microns, and then mixed with about 450 cracked coarse particles of α-lactose monohydrate having a mass diameter including 212 - 355 microns, and obtained at a ratio of 10:90% by weight. [Table 4] The formulation was filled into a multi-dose dry powder inhaler described in WO 2016 / 000983.

[0155] Example 4 Another powder formulation was produced using, as an active ingredient, a human neutrophil elastase (HNE) inhibitor, hereinafter referred to as CHF6333 in the present specification, disclosed in WO 2014 / 095700. About 800 g of micronized CHF6333 was added to about 3.2 kg of a carrier produced according to WO 01 / 78693. The blend was mixed in a Turbula TM mixer for 3 hours and sieved through a 600 μm sieve. The obtained mixture contains a formulation according to the invention having a single composition shown in Table 5. The presence and complete formation of spheronized particles were detected by scanning electron microscopy. [Table 5] The formulations are filled into a multiple-dose dry powder inhaler as described in International Publication No. WO 2016 / 000983 or into the single-dose dry powder inhaler RS01 of Plastiape SpA (Italy). The evaluation of aerosol performance was carried out as described in Example 1. The results (mean ± S.D) are shown in Table 6. [[Table 6]] As can be understood, good performance with respect to FPF was achieved, in particular, with the single-dose DPI. Based on further data collected by the applicant, it was found that similar results can be obtained if the total amount of a single injection of the inhaler is 20 mg.

[0156] Example 5 Two similar formulations containing CHF6333 as the active ingredient were prepared as shown in Example 4, but these are for the delivery of single doses of 1 mg and 4 mg. The formulations are filled into the single-dose dry powder inhaler RS01 of Plastiape SpA (Italy). The evaluation of aerosol performance was carried out as shown in Example 1. The results (mean ± S.D) are shown in Table 7. [[Table 7]]

[0157] Example 6 Further powder formulations having a single composition as shown in Table 1 were prepared, which contain spheronized particles having a mass diameter including 200 - 350 microns. Approximately 300 g of micronized beclomethasone dipropionate (BDP) and 100 g of micronized lactose monohydrate were stirred in advance for 2 minutes. Thereafter, the mixture was poured into a vibration screening apparatus AS200 from Retsch GmbH, Germany. A system of two sieves and a collection tray on a vibration pad was prepared. The upper sieve (size > 350 μm) is thought to break down any large-sized aggregates or large-scale inhomogeneities that were initially present in the powder sample. The lower sieve (350 μm > size > 250 μm) sets the properties of the desired spheronized particles. The bottom collection dish contains the spheronized material. The micronized powder was poured into the upper dish, and the vibration system was operated, which operated at a vibration frequency of 50 Hz, a vibration amplitude of 0.2 - 1.2 mm, and a vibration time of 60 - 200 seconds. The obtained spheronized particles were mixed with approximately 600 g of cracked coarse particles of α-lactose monohydrate having a mass diameter containing 212 - 355 microns to obtain a ratio of 40:60% by weight. Turbula TM Mix in a mixer for 3 hours at 75 rpm. The formulation is filled into a multi-dose dry powder inhaler (DPI) described in International Publication No. WO 2016 / 000983.

Claims

1. A dry powder formulation for administration by a dry powder inhaler (DPI), a) a fraction of spheronized particles having a mass diameter comprising 100 to 800 micrometers, containing only fine particles of one or more active ingredients and fine particles of a physiologically acceptable excipient in an appropriate weight ratio; b) a fraction of coarse particles containing a physiologically acceptable excipient having a mass diameter comprising 150 to 400 micrometers; comprising, wherein the ratio of fraction a) to fraction b) comprises 5:95 to 30:70 weight percent, the dry powder formulation, wherein the one or more active ingredients are present in the spheronized particles a) at 0.5 to 100% by weight in the overall proportion.

2. The dry powder formulation according to claim 1, wherein the spheronized particles of fraction a) have a mass diameter comprising 200 to 800 micrometers.

3. The dry powder formulation according to claim 1 or 2, wherein the ratio of fraction a) to fraction b) is 10:90 to 15:85% by weight.

4. The dry powder formulation according to any one of claims 1 to 3, wherein the proportion of the one or more active ingredients comprises 1.0 to 99.5% by weight.

5. The dry powder formulation according to any one of claims 1 to 4, wherein the physiologically acceptable excipient is α-lactose monohydrate.

6. The dry powder formulation according to any one of claims 1 to 5, wherein the mass diameter of the coarse particles of fraction b) comprises 210 to 355 micrometers.

7. The dry powder formulation according to any one of claims 1 to 6, wherein the mass diameter of the spheronized particles of fraction a) comprises 200 to 350 micrometers and the mass diameter of the coarse particles of fraction b) comprises 210 to 355 micrometers.

8. The dry powder formulation according to any one of claims 1 to 7, wherein the active ingredient is selected from the group consisting of a β2 agonist, and / or an antimuscarinic and / or an inhaled corticosteroid.

9. The dry powder formulation according to claim 8, wherein the β2 agonist is formoterol fumarate dihydrate.

10. The dry powder formulation according to claim 8, wherein the inhaled corticosteroid is beclomethasone dipropionate (BDP).

11. The dry powder formulation according to claim 8, wherein the muscarinic antagonist is glycopyrronium bromide.

12. The dry powder formulation according to claim 8, wherein the active ingredient is a combination of formoterol fumarate dihydrate, beclomethasone dipropionate and glycopyrronium bromide.

13. A method for producing the powder formulation according to claim 1, comprising: i) preparing a fraction of fine particles of an active ingredient and a physiologically acceptable excipient; ii) conditioning the resulting mixture; iii) aggregating and spheronizing the mixture to obtain spheronized particles; iv) sieving to isolate a fraction having a desired diameter; v) adding a fraction of coarse particles b); vi) mixing the resulting mixture A method comprising the steps of:

14. The method according to claim 13, wherein the fraction in step i) is prepared by mixing fine particles of an active ingredient and fine particles of a physiologically acceptable excipient.

15. The method according to claim 13, wherein the fraction in step i) is prepared by co-micronizing particles of an active ingredient and particles of a physiologically acceptable excipient and then mixing them.

16. A dry powder inhaler filled with the dry powder pharmaceutical formulation according to any one of claims 1 to 12.

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