HK1224589A1 - Dry powder formulation comprising a corticosteroid and a beta-adrenergic for administration by inhalation - Google Patents

Description

Dry powder formulations for inhalation administration comprising a corticosteroid and a BETA-adrenergic agent

Technical Field

The present application is a divisional application entitled "dry powder formulation for inhalation administration comprising a corticosteroid and a BETA-adrenergic drug" filed on a date of 2013, 1 and 23, and having an application number of 201380006645.

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

In particular, the invention relates to dry powder formulations comprising a corticosteroid and beta in combination₂-adrenergic agents, processes for their preparation and therapeutic uses.

Background

Active substances that are typically delivered by inhalation include bronchodilators such as beta-2 adrenergic receptor agonists and anticholinergics, corticosteroids, antiallergics and other active ingredients that can be effectively administered by inhalation, thereby increasing the therapeutic index and reducing the side effects of the active substance.

Formoterol, i.e. 2 '-hydroxy-5' - [ (RS) -1-hydroxy-2 { [ (RS) -p-methoxy- α -methylphenylethyl ] amino } ethyl ] carboxanilide, particularly the fumarate salt thereof (hereinafter FF), is a well known β -2 adrenergic receptor agonist and is currently used clinically for the treatment of bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD) and related disorders.

Beclomethasone Dipropionate (BDP) is a potent anti-inflammatory steroid, designated (8S,9R,10S,11S,13S,14S,16S,17R) -9-chloro-11-hydroxy-10, 13, 16-trimethyl-3-oxo-17- [2- (propionyloxy) acetyl ] -6,7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl propionate, used in a number of brands for the prevention and/or treatment of inflammatory respiratory disorders.

Formulations for pressurized metered dose inhalers (pMDIs) are currently on the market, which contain a mixture of the two active ingredients in combination, both dissolved in HFA134a and ethanol as co-solvent. It has been cited in the literature as FF/BDP ultrafine formulations.

The formulation provides high lung deposition and uniform distribution throughout the bronchial tree and is characterized by the fact that it is capable of delivering a high fraction of particles having a diameter equal to or less than 1.1 micron. In particular, it provides about 40% of the respirable fraction and about 12% of the particle fraction with a diameter equal to or less than 1.1 microns for both active ingredients at the time of inhaler actuation.

The main advantage of the formulation relates to an improved penetration into the bronchiolo-alveolar distal part of the respiratory tree, where inflammation is known to play a role in the spontaneous exacerbation of asthma symptoms and where the density of β -2 adrenergic receptors is known to be particularly high.

However, although widely accepted, pMDI formulations may have some disadvantages, especially in elderly and paediatric patients, most of the reason being that they have difficulty in synchronising device actuation with inhalation.

Dry Powder Inhalers (DPIs) constitute an effective alternative to MDIs for administering drugs to the respiratory tract.

On the other hand, it is expected that drugs for inhalation as dry powders should be used in micronized particulate form. Their volumetric effect can represent a barrier to designing formulations that are therapeutically equivalent to formulations in which the drug is delivered in liquid droplets.

WO 01/78693 discloses a dry powder formulation comprising a fraction of a combination of formoterol and BDP as active ingredients and as carrier a fraction of coarse and fine excipient particles and magnesium stearate.

At start-up, the respirable fraction of BDP is about 40% and the respirable fraction of formoterol is about 47%.

Mariotti et al (European Respiratory Society annular Congress, held at Amsterdam, 9, 24-28, 2011) have recently presented data on FF/BDP dry powder formulations having a respirable fraction of about 70% for both active ingredients.

It is therefore an object of the present invention to provide powder formulations for DPIs comprising formoterol fumarate and BDP in combination, which overcome the problems indicated above and in particular provide powder formulations having therapeutic characteristics which match those of corresponding pMDI formulations in solution form.

Said problem is solved by the formulations according to the invention.

Summary of The Invention

The present invention relates to a dry powder formulation for use in a Dry Powder Inhaler (DPI) comprising:

a) a fraction of fine particles prepared from a mixture of 90 to 99.5% by weight of physiologically acceptable excipient particles and 0.5 to 10% by weight of magnesium stearate, said mixture having a mass median diameter of less than 20 microns;

b) a fraction of coarse particles consisting of physiologically acceptable excipients having a mass median diameter equal to or higher than 100 microns, wherein the ratio of fine particles to coarse particles is from 1:99 to 30: 70% by weight; and

c) formoterol fumarate dihydrate in the form of micronized particles and Beclometasone Dipropionate (BDP) in combination therewith, as active ingredient; wherein i) no more than 10% of the BDP particles have a diameter below 0.6 microns, ii) no more than 50% of the particles have a diameter of 1.5 to 2.0 microns; and iii) at least 90% of said particles have a diameter below 4.7 microns.

In a second aspect, the present invention relates to a method of preparing the dry powder formulation of the present invention comprising the step of mixing carrier particles with the active ingredient.

In a third aspect, the present invention relates to a dry powder inhaler filled with the above dry powder formulation.

In a fourth aspect, the invention refers to a formulation as claimed for use in the prevention and/or treatment of inflammatory or obstructive airways diseases such as asthma or Chronic Obstructive Pulmonary Disease (COPD).

In a fifth aspect, the present invention is directed to a method of prevention and/or treatment of an inflammatory or obstructive airways disease such as asthma or Chronic Obstructive Pulmonary Disease (COPD) which comprises administering by inhalation an effective amount of a formulation of the present invention.

In a sixth aspect, the invention refers to the use of a claimed formulation in the manufacture of a medicament for the prevention and/or treatment of an inflammatory or obstructive airways disease such as asthma or Chronic Obstructive Pulmonary Disease (COPD).

Definition of

The term "physiologically acceptable" means a safe pharmacologically-inert substance.

By "daily therapeutically effective dose" is meant the amount of active ingredient administered by inhalation upon actuation of the inhaler.

The daily dose may be delivered in one or more actuations (shots or puffs) of the inhaler.

The term "fine particles" means particles having a size of at most a few tenths of a micrometer.

The term "micronized" means that the substance has a size of a few microns.

The term "coarse" means that the particles have a size of one or several hundred microns.

Typically, the particle size of a particle is quantified by measuring the characteristic equivalent spherical diameter, referred to as the volume diameter, by laser diffraction.

The particle size can also be quantified by measuring the mass diameter by suitable known equipment such as a sieve analyser.

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

In the present application, the particle size of the active ingredient is expressed as the volume diameter, while the particle size of the excipient is expressed as the mass diameter.

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

Yet another common method of defining particle size distribution is to enumerate three values: i) a volume median diameter d (v,0.5), which is the volume diameter above which 50% is distributed and below which 50% is distributed; ii) d (v,0.9), wherein 90% of the volume is distributed below this value; iii) d (v,0.1), where 10% of the volume is distributed below this value. The range (span) is the width of the distribution based on the 10%, 50% and 90% quantiles and is calculated according to the following formula.

Upon aerosolization, particle size is expressed as Mass Aerodynamic Diameter (MAD) and particle size distribution is expressed as Mass Median Aerodynamic Diameter (MMAD). MAD indicates the ability of particles to be transported suspended in an air stream. MMAD corresponds to mass aerodynamic diameter of 50% particle weight.

The term "hard pellet" refers to a spherical or hemispherical unit with a core composed of coarse excipient particles.

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

The term "good flowability" means that the formulation is easy to handle during the manufacturing process and is capable of ensuring the delivery of an accurate and reproducible therapeutically effective dose.

The flow characteristics can be evaluated by different tests such as angle of repose, Carr index, Hausner ratio or flow rate through the orifice.

In the context of the present application, the flow characteristics are measured by measuring the flow rate through the orifice according to the european pharmacopoeia (eur. ph.)7.3, 7^thThe method of the plate was tested.

The expression "good homogeneity" refers to a formulation wherein the homogeneity of the distribution of the active ingredient upon mixing, expressed as the Coefficient of Variation (CV), also known as the Relative Standard Deviation (RSD), is less than 2.5%, preferably equal to or less than 1.5%.

The expression "respirable fraction" refers to an index of the percentage of active particles that will reach the deep lung of a patient.

Respirable fraction, also called Fine Particle Fraction (FPF), according to the general pharmacopoeia, in particular the european pharmacopoeia (eur.ph.)7.3, 7^thThe procedure reported in the edition was evaluated with suitable in vitro equipment, such as an Andersen Cascade Impactor (ACI), a multi-stage liquid impact dust filter (MLSI) or a Next Generation Impactor (NGI), preferably ACI.

It is calculated as the percentage ratio between the fine particle mass (formerly fine particle dose) and the delivered dose.

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

The term "prevention" means a means for reducing the risk of disease onset.

The term "treatment" means the route by which a beneficial or desired result, including a clinical result, is obtained. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, prevention of disease progression, 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 can also mean extended survival compared to the expected survival if not receiving treatment.

The term "coating" means covering the surface of the excipient particles by forming a thin film of magnesium stearate around the particles.

Detailed Description

The present invention relates to a dry powder formulation for a Dry Powder Inhaler (DPI) comprising a fine particle fraction a), a fraction of coarse particles b) and as active ingredient Formoterol Fumarate (FF) dihydrate in combination with beclometasone propionate (BDP), having the features disclosed herein.

Fractions a) and b) constitute "carrier" particles.

It has been surprisingly found that in order to obtain a FF/BDP dry powder formulation which is therapeutically equivalent to the corresponding pMDI formulation currently on the market, it is necessary for both active ingredients to produce a higher respirable fraction (FPF) and a higher fraction of particles having a diameter equal to or less than 1.1 micron.

It has also been found that this can be achieved by tightly controlling the particle size, and preferably the specific surface area, of the micronised BDP.

Surprisingly, it was also found that by setting the particle size distribution of BDP to the values claimed herein, not only the respirable fraction thereof is increased, but also the fraction of formoterol fumarate (greater than 60% vs about 47%).

In addition, the use of micronized BDP characterized by the above-mentioned selected, narrow and well-defined particle size distribution allows a better reproducibility of its Fine Particle Fraction (FPF) during repeated dosing.

The formulations according to the invention also show good homogeneity of the active ingredient, good flowability and suitable physical and chemical stability in the inhaler before use for pharmaceutical purposes.

Advantageously, the fine and coarse excipient particles may be composed of any physiologically acceptable substance or combination thereof; preferred excipients are those composed of crystalline sugars, especially lactose; most preferred are those composed of alpha-lactose monohydrate.

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

The fine particle fraction a) must have a Mass Median Diameter (MMD) lower than 20 microns, advantageously equal to or lower than 15 microns, preferably equal to or lower than 10 microns, even more preferably equal to or lower than 6 microns.

Advantageously, 90% of the fine particles a) have a mass diameter lower than 35 microns, more advantageously lower than 25 microns, preferably lower than 15 microns, even more preferably lower than 10 microns.

The ratio between the excipient particles and the magnesium stearate in fraction a) can vary according to the active ingredient dose.

Advantageously, said fraction consists of 90 to 99.5% by weight of excipients and 0.5 to 10% by weight of magnesium stearate, preferably 95 to 99% of excipients and 1 to 5% of magnesium stearate. The preferred ratio is 98% excipient and 2% magnesium stearate.

Advantageously, at least 90% by weight of the magnesium stearate particles have an initial mass diameter of no more than 35 microns and an MMD of no more than 15 microns, preferably no more than 10 microns.

Advantageously, magnesium stearate may coat the surface of the excipient particles such that the degree of surface coating is at least 5%, preferably greater than 10%, more preferably greater than 15%, even more preferably equal to or greater than 35%.

In the case where the excipient particles are composed of lactose, the degree of surface coating, which represents the percentage of the total surface of the excipient particles that is coated with magnesium stearate, can be determined by water contact angle measurement and then using the formula known in the literature, e.g., Cassie and Baxter, Colombo I et al, Il Farmaco 1984, 39(10), 328-341, page 338 and reported below.

cosθ_{Mixture of}＝f_{Magnesium stearate}cosθ_{Magnesium stearate}+f_Lactosecosθ_Lactose

Wherein f is_{Magnesium stearate}And f_LactoseIs the surface area fraction of magnesium stearate and lactose;

θ_{magnesium stearate is}Water contact angle of magnesium stearate;

θ_lactoseIs the water contact angle of lactose

θ_{Mixture of}Is the experimental contact angle value.

For the purposes of the present invention, the contact angle can be determined using methods which are essentially based on goniometric measurements. This means that the angle formed between the tested solid substrate and the liquid is directly observed. It is therefore very easy to perform, with only the limitation concerning possible deviations from operator-to-operator variability. It should be emphasized, however, that this disadvantage can be overcome with fully automated programs such as computer-aided image analysis. Particularly useful methods are the sessile or static drip method, which generally proceeds by depositing droplets on the surface of the powder in the form of a compact disc obtained by compaction (the compressed powder disc method).

The extent to which the magnesium stearate coats the surface of the excipient particles can also be determined by Scanning Electron Microscopy (SEM) which is a well-known multi-purpose analytical technique.

The microscopy technique can be coupled with an EDX analyzer (electron dispersive X-ray analyzer) which is capable of producing images selective for certain types of atoms, such as magnesium atoms. In this way it is possible to obtain a clear data set on the distribution of magnesium stearate over the surface of the excipient particles.

SEM may alternatively be combined with IR or raman spectroscopy for determining the degree of coating according to known procedures.

Yet another analytical technique that can be advantageously used is X-ray photoelectron spectroscopy (XPS), from which the degree of coating and the depth of the magnesium stearate film around the excipient particles can be calculated.

The fine particle fraction a) can be prepared according to one of the processes disclosed in WO 01/78693. Preferably, it can be prepared by co-micronization, more preferably with a ball mill. In some cases, it has been found that co-milling for at least 2 hours may be advantageous, although it will be appreciated that the processing time will generally depend on the initial particle size of the excipient particles and the desired size reduction to be obtained.

In a preferred embodiment of the invention, the particles are co-micronised, starting from excipient particles having a mass diameter of less than 250 microns and magnesium stearate particles having a mass diameter of less than 35 microns, with a jet mill, preferably in an inert atmosphere, for example under nitrogen.

For example, commercially available alpha-lactose monohydrate such as Meggle D30 or sphenolac 100(Meggle, Wasserburg, germany) can be used as the initial excipient.

Optionally, the fine particle fraction a) may be subjected to a conditioning step according to the conditions disclosed in pending application No. WO 2011/131663.

The coarse excipient particles of fraction b) must have an MMD of at least 100 microns, preferably greater than 125 microns, more preferably equal to or greater than 150 microns, even more preferably equal to or greater than 175 microns.

Advantageously, the total coarse particles have a mass diameter of 50-1000 microns, preferably 60 to 500 microns.

In certain embodiments of the invention, the coarse particles may have a mass diameter of 80 to 200 microns, preferably 90 to 150 microns, while in yet another embodiment, the mass diameter may be 200 to 400 microns, preferably 210 to 355 microns.

In a preferred embodiment of the invention, the coarse particles have a mass diameter of 210 to 355 microns.

Generally, one skilled in the art will select the most appropriate coarse excipient particle size by sieving with a suitable classifier.

In the case where the coarse particles have a mass diameter of 200 to 400 microns, the coarse excipient particles preferably have a relatively highly fractured surface, i.e., there are cracks and valleys and other depressed regions thereon, collectively referred to herein as fractures (fractures). "relatively highly fractured" coarse particles can be defined as the fracture index or rugate state coefficient described in WO 01/78695 and WO 01/78693, incorporated herein by reference, and they can be characterized according to the description therein. The coarse particles may also be characterized by a measured tap density or total intrusion volume, as reported in WO 01/78695, the teachings of which are incorporated herein by reference.

The tapped density of the coarse particles is advantageously less than 0.8g/cm³Preferably 0.8 to 0.5g/cm³. The total intrusion volume is at least 0.8cm³Preferably at least 0.9cm³。

The ratio between the fine fraction a) and the coarse fraction b) is from 1:99 to 30: 70% by weight, preferably from 2:98 to 20: 80% by weight. In a preferred embodiment, the ratio is 10:90 to 15: 85% by weight, even more preferably 10:90 by weight.

The step of mixing the coarse excipient particles b) and the fine particles a) is generally carried out in a suitable mixer, for example a roller mixer such as a Turbula^TMRotary or instant stirrers such as Diosna^TMFor at least 5 minutes, preferably at least 30 minutes, more preferably at least 2 hours. In a general manner, one skilled in the art will adjust the mixing time and the rotational speed of the stirrer to obtain a homogeneous mixture.

In the case where it is desired to spheronize the coarse excipient particles in order to obtain hard pellets according to the above definition, the mixing step is generally carried out for at least 4 hours.

The overall micronized particles of Beclomethasone Dipropionate (BDP) are characterized by a selected, narrow and well-defined particle size distribution such that: i) no more than 10% of the particles have a diameter of less than 0.6 micron, preferably equal to or less than 0.7 micron; ii) no more than 50% of the particles have a diameter of 1.5 to 2.0 microns, preferably 1.6 to 1.9 microns; and iii) at least 90% of said particles have a diameter equal to or lower than 4.7 microns, preferably equal to or lower than 4.0 microns, more preferably equal to or lower than 3.8 microns.

A particular BDP scale distribution is characterized by: d (v0.1) is 0.8 to 1.0 microns, preferably 0.85 to 0.95 microns; d (v0.5) is from 1.5 to 2.0 microns, preferably from 1.6 to 1.9 microns, and d (v0.9) is from 2.5 to 4.7 microns, preferably from 3.0 to 4.0 microns.

However, the width of the particle size distribution of the BDP particles, expressed as a range, should be 1.2 to 2.2, preferably 1.3 to 2.1, more preferably 1.6 to 2.0, according to Chew et al J PharmPharmaceut Sci 2002, 5, 162-168, which range corresponds to [ d (v,0.9) -d (v,0.1) ]/d (v, 0.5).

Advantageously, at least 99% of said particles [ d (v,0.99) ] have a diameter equal to or lower than 6.0 microns, and substantially all the particles have a volume diameter of from 6.0 to 0.4 microns, preferably from 5.5 to 0.45 microns.

The size of the particulate active is determined by measuring the characteristic equivalent spherical diameter (referred to as the volume diameter) by laser diffraction. In the reported example, the volume diameter has been determined with a Malvern apparatus, however other equivalent apparatus may be used by those skilled in the art.

Advantageously, the micronized particles of BDP also have a particle size of 5.5 to 7.0m²Per g, preferably from 5.9 to 6.8m²Specific surface area in g. Specific surface area is determined by the Brunauer-Emmett-Teller (BET) nitrogen adsorption method according to procedures known in the art.

The total micronized particles of formoterol fumarate dihydrate may have a diameter of less than 10 microns, preferably less than 6 microns. Advantageously, at least 90% of the particles have a volume diameter below 5.0 microns. In a particular embodiment, the particle size distribution is: i) no more than 10% of the particles have a volume diameter below 0.8 micron, ii) no more than 50% of the particles have a volume diameter below 1.7 micron; and iii) at least 90% of the particles have a volume diameter below 5.0 microns. The micronized formoterol fumarate dihydrate used in the formulations of the invention also advantageously passes through 5 to 7.5m²In g, preferably from 5.2 to 6.5m²G, more preferably from 5.5 to 5.8m²The specific surface area in g is characterized.

Both micronized active ingredients used in the formulations of the present invention can be prepared by grinding in a suitable mill. Preferably, they are prepared by grinding with conventional fluid energy mills, such as commercially available jet mill micronizers having grinding cavities of different diameters. Depending on the type of equipment and batch size, one skilled in the art will suitably adjust milling parameters such as operating pressure, feed rate, and other operating conditions to achieve the desired particle size.

In particular, in order to achieve the claimed particle size distribution of the BDP, it is highly advantageous to use an abrasive jet micronizer having a grinding chamber with a diameter of 300 mm.

In a preferred embodiment, the present invention relates to a dry powder formulation for a Dry Powder Inhaler (DPI) comprising:

a) a fraction of fine particles prepared from a mixture consisting of 98% by weight of alpha-lactose monohydrate particles and 2% by weight of magnesium stearate, said mixture having a mass median diameter equal to or lower than 6 microns;

b) a fraction of coarse particles consisting of alpha-lactose monohydrate having a mass diameter of 212 to 355 microns, and a ratio of fine to coarse particles of 10:90 wt%; and

c) formoterol fumarate dihydrate in the form of micronized particles and Beclometasone Dipropionate (BDP) in combination therewith, as active ingredient; wherein i) no more than 10% of the BDP particles have a diameter [ d (v,0.1) ] of less than 0.7 micron, ii) no more than 50% of the particles have a diameter [ d (v,0.5) ] of from 1.6 micron to 1.9 micron; and iii) at least 90% of said particles have a diameter below 4.0 microns.

The present invention also relates to a process for preparing the dry powder formulations disclosed herein comprising the step of mixing the fine particle fraction a), the coarse particle fraction b) with two micronised active ingredients.

The carrier particles comprising the fine particle fraction and the coarse particle fraction can be prepared by suitable equipment known to the skilled worker, for example Turbula^TMMixing in a stirrer. The two fractions are preferably in Turbula^TMMixing in a stirrer operated at a speed of 16r.p.m. for a period of 30 to 300 minutes, preferably 150 to 240 minutes.

The mixing of the carrier particles with the active ingredient particles can be carried out by: suitable devices known to the skilled person, such as Turbula^TMMixing each in a stirrerComponent (b) for a period of time sufficient to achieve homogeneity of the active ingredient in the final mixture, preferably from 30 to 120 minutes, more preferably from 45 to 100 minutes.

Optionally, in an alternative embodiment, the active ingredient is first mixed with a portion of the carrier particles, the resulting blend is forced through a sieve, and then additional active ingredient and the remaining portion of the carrier particles are blended with the sieved mixture; and finally the resulting mixture is sieved through a filter and mixed again.

The skilled person will select the mesh size of the filter according to the particle size of the coarse particles.

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

Advantageously, the formulations of the present invention may be adapted to deliver therapeutic amounts of both active ingredients in one or more actuations (shots or puffs) of the inhaler.

For example, the formulation is suitable to deliver 6-12 μ g formoterol (as fumarate dihydrate) per actuation, in particular 6 μ g or 12 μ g per actuation, and 50-200 μ g beclometasone dipropionate per actuation, in particular 50, 100 or 200 μ g per actuation.

A therapeutically effective daily dose may be 6 to 24 μ g of formoterol and 50 to 800 μ g of BDP.

The dry powder formulations of the present invention may be used 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 administration is typically filled into a capsule;

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

The dry powder formulations are particularly suitable for multi-dose DPIs comprising a reservoir from which individual therapeutic doses can be drawn upon demand by actuation of the device,for example as described in WO 2004/012801. Other multi-dosing devices that may be used are DISKUS, such as GlaxoSmithKline^TMTURBOHALER from AstraZeneca^TMSchering TWISTHALER^TMAnd CLICKHALER to Innovata^TM. Examples of marketed single-dose devices may be mentioned the ROTOLHALER by GlaxoSmithKline^TMAnd HANDIHALER to Boehringer Ingelheim^TM。

In a preferred embodiment of the invention, the dry powder formulation is filled into a DPI as disclosed in WO 2004/012801.

In case moisture is to be avoided entering the formulation, it may be desirable to wrap the DPI in a flexible package that is resistant to moisture ingress, such as those disclosed in EP 1760008.

Administration of the formulations of the invention may be indicative of the prevention and/or treatment of a wide range of conditions including respiratory disorders such as Chronic Obstructive Pulmonary Disease (COPD) and asthma of all types and severity.

Other respiratory disorders characterized by inflammation and mucus-induced peripheral respiratory obstruction such as chronic obstructive bronchiolitis and chronic bronchitis may also benefit from such formulations.

The invention is illustrated in detail by the following examples.

Examples

Example 1 preparation of different batches of micronized particles of beclomethasone dipropionate

Micronizer MC of beclomethasone dipropionate in different batches in jet mill having a grinding chamber with a diameter of 300mm(Jetpharma Sa, Switzerland).

The particle size distribution and specific surface area of the micronized batches were characterized.

The particle size was determined by laser diffraction using a Malvern apparatus. The parameters considered are the micron VD of 10%, 50% and 90% of the particles, expressed as d (v,0.1), d (v,0.5) and d (v,0.9) respectively, which correspond to the mass diameter, assuming that the size of the particles is independent of the density. The range [ d (v,0.9) -d (v,0.1) ]/d (v,0.5) is also reported. The Specific Surface Area (SSA) was determined by BET nitrogen adsorption using a CoulterSA3100 apparatus as an average of 3 measurements.

The relevant data are reported in table 1.

TABLE 1 particle size distribution and Specific Surface Area (SSA) of different batches of micronized beclomethasone dipropionate

Example 2 preparation of Fine particle fraction a)

Approximately 40kg of co-micronized particles were prepared.

A 98: 2% by weight ratio of alpha-lactose monohydrate particles having a particle size of less than 250 microns (Meggle D30, Meggle), and magnesium stearate particles having a particle size of less than 35 microns were co-micronized by milling in a jet mill operated under nitrogen to obtain a fine particle fraction a).

At the end of the treatment, the co-micronized particles had a Mass Median Diameter (MMD) of about 6 microns.

Example 3 preparation of "Carrier" [ fraction a) + fraction b) ]

A sample of the fine particles of example 1 was mixed with a sample obtained by sieving having a mass diameter of 212 and 355 microns in a ratio of 90: 10% by weightThe coarse particles of lactose monohydrate that are fractured are mixed.

Mixing was carried out in a Turbula mixer operating at 16r.p.m. speed for a period of 240 minutes.

Hereinafter, the resulting particle mixture is referred to as "carrier".

Example 4 preparation of Dry powder formulations

A portion of the "carrier" obtained in example 3 was mixed with micronized formoterol fumarate dihydrate (FF) at 32r.p.m. for 30 minutes in a Turbula mixer, the resulting blend was forced through a sieve of 0.3mm (300 microns) mesh size.

The micronized Beclomethasone Dipropionate (BDP) batch 1 or 4 obtained as in example 1 and the remainder of the "carrier" were blended in 16r.p.m. for 60 minutes in a Turbula mixer and the mixture was sieved to obtain the final formulation.

The ratio of active ingredient to 10mg of "carrier" was 6 micrograms FF dihydrate (4.5 micrograms theoretical delivered dose) and 100 micrograms BDP.

The aerosol potency of the powder formulation was characterized after loading it in the multi-dose dry powder inhaler described in WO 2004/012801.

Evaluation of Aerosol efficacy Using an Andersen Cascade Impactor (ACI) according to European pharmacopoeia 6^thEd 2008, par 2.9.18, page 293-295.

After aerosolization of 3 doses, the ACI equipment was disassembled and the amount of drug deposited at this stage was recovered by washing with a solvent mixture and then quantified by High Performance Liquid Chromatography (HPLC). The following parameters were calculated: i) a delivered dose, which is the amount of drug recovered in the impactor delivered from the device; ii) Fine Particle Mass (FPM), which is the amount of medicament delivered with a particle size equal to or below 5.0 micron; iii) a Fine Particle Fraction (FPF), which is a percentage of the fine particle dose; iv) MMAD.

The results (mean ± s.d) are reported in table 2.

TABLE 2 Aerosol potency

^a)GSD, which is the geometric standard deviation

From the data of table 2, it can be appreciated that the formulations prepared with the micronized batch of example 1BDP showed a higher respirable fraction (FPF) than the corresponding pMDI formulation currently on the market (about 40%) (slightly greater than 60%) for both active ingredients.

They also produce a higher fraction of particles with a diameter equal to or less than 1.1 micron (greater than 25% for both active ingredients).

Example 5-FF/BDP therapeutic equivalence of the Dry powder formulation of the invention to the corresponding pMDI formulation currently on the market

A study was designed to show that the FF/BDP dry powder formulation delivered via DPI disclosed in WO2004/012801 is therapeutically equivalent to the corresponding pMDI formulation on the market.

Research and design:

5-Cross, double-Blind, double-simulation clinical study.

69 asthmatics with 160% to 90% of prior diagnosis of FEV were randomized. The 5 single doses tested were: 24/400 μ g FF/BDP via DPI or pMDI, 6/100 μ gFF/BDP via DPI or pMDI and placebo.

The main aims are as follows:

FEV₁AUC_0-12hwhich is the area under the curve of the forced expiratory volume at time intervals of 0 to 12 hours.

FEV1 is the maximum amount of air that can be exhaled vigorously in 1 second.

Results

For FEV₁AUC_0-12hWith low and high doses, non-deterioration (non-inferiority) was demonstrated between the formulations.

Both doses were significantly better than placebo. Both formulations are in FEV₁AUC_0-12hShows superiority of high dose versus low dose, reaching statistical significance for DPI. Safety and tolerability are good and comparable.

Example 6-further evidence of therapeutic equivalence of the FF/BDP dry powder formulations of the invention to the corresponding pMDI formulations currently on the market

The aim of the study was to test the 6/100 μ gFF/BDP dry powder formulation (hereinafter FF/BDP DPI) delivered via WO2004/012801 DPI versus the corresponding pMDI formulation (hereinafter FF/BDP pMDI) on the market and 100 μ g BDP DPI formulation on the market at the same dose(s) ((r) ())Thereafter BDP DPI).

Research and design:

phase III, 8 weeks, multinational, multicenter, randomized, double-blind, triple-mock, activity-controlled 3-arm parallel group clinical trials were performed in adult asthmatic patients.

Each formulation was administered twice daily for 1 month of treatment by inhalation.

The main objectives are:

it was shown that from baseline to the entire treatment period, FF/BDP DPI was not inferior to FF/BDP pMDI in mean predose morning Peak Expiratory Flow (PEF).

PEF is the maximum exhalation rate of a person, measured with a peak anemometer (a small handheld device used to monitor the ability of a person to exhale air). Which measures airflow through the bronchi and thus measures the degree of obstruction in the respiratory tract.

The secondary goal is:

evaluating the superiority of FF/BDP DPI over BDP DPI in terms of mean predose morning PEF from baseline to the entire treatment period;

the effect of FF/BDP DPI on other lung function parameters and on clinical outcome measures, and safety and tolerability were evaluated.

As a result:

a non-deteriorating version of FF/BDP DPI versus FF/BDP pMDI in terms of the primary efficacy parameter has been demonstrated.

The same results have been obtained for pre-dosed morning and evening PEF.

No significant differences were observed between treatments in daily PEF variability.

The superiority of FF/BDP DPI and FF/BDP pMDI over BDP DPI has also been demonstrated.

The FF/BDP DPI formulation is comparable to FF/BDP pMDI in terms of safety and tolerability.

Claims (20)

1. A dry powder formulation for use in a Dry Powder Inhaler (DPI) comprising:

a) a fraction of fine particles consisting of physiologically acceptable excipients having a mass median diameter of less than 20 microns;

b) a fraction of coarse particles consisting of physiologically acceptable excipients having a mass median diameter of 50-1000 microns; and

c1) formoterol fumarate dihydrate in the form of micronized particles having a therapeutic dose of 6 or 12 μ g per actuation of the inhaler;

c2) beclomethasone Dipropionate (BDP) in micronized particulate form having a therapeutic dose of 50, 100 or 200 μ g each time the inhaler is actuated;

wherein i) no more than 10% of the BDP particles have a volume diameter below 0.6 microns, ii) no more than 50% of the particles have a volume diameter of 1.5 to 2.0 microns; and iii) at least 90% of said particles have a volume diameter of less than 4.7 microns; and

wherein the formulation is therapeutically equivalent to a corresponding formulation for a pressurized metered dose inhaler (pMDI) comprising the above active ingredient dissolved in ethanol and HFA134a propellant.

2. The formulation according to claim 1, wherein the BDP particles have a size ranging from 1.2 to 2.2.

3. The formulation according to claim 2, wherein the BDP particles have a particle size range of 1.3 to 2.1.

4. The formulation according to claim 3, wherein the BDP particles have a particle size range of 1.6 to 2.0.

5. The formulation according to any one of claims 1-4, wherein the BDP particles further range from 5.5 to 7.0m²Specific surface area in g.

6. The formulation according to claim 5, wherein the specific surface area is from 5.9 to 6.8m²/g。

7. The formulation according to any one of the preceding claims, wherein i) no more than 10% of the formoterol fumarate dihydrate particles have a volume diameter below 0.8 microns, ii) no more than 50% of the particles have a volume diameter below 1.7 microns; and iii) at least 90% of said particles have a volume diameter below 5.0 microns.

8. A formulation according to claim 7, wherein the formoterol fumarate dihydrate particles are further comprised between 5 and 7.5m²Specific surface area in g.

9. The formulation according to claim 8, wherein the specific surface area is from 5.2 to 6.5m²/g。

10. The formulation according to any of the preceding claims, wherein the ratio of the fine particles a) and the coarse particles b) is from 2:98 to 20: 80% by weight.

11. The formulation according to claim 10, wherein the ratio is 10: 90% by weight.

12. The formulation according to any of the preceding claims, wherein the fraction of fine particles a) has a mass median diameter equal to or lower than 10 microns.

13. The formulation according to any one of the preceding claims, wherein the fine particles a) and the coarse particles b) consist of alpha-lactose monohydrate.

14. The formulation according to any of the preceding claims, wherein the coarse particles b) have a mass median diameter of from 60 to 500 μm.

15. The formulation according to claim 14, wherein the coarse particles b) have a mass median diameter of from 80 to 200 μm.

16. The formulation according to claim 14, wherein the coarse particles b) have a mass median diameter of 200-400 μm.

17. A dry powder inhaler filled with the dry powder formulation of any one of claims 1-16.

18. A multi-dose dry powder inhaler filled with the dry powder formulation of any one of claims 1-16.

19. A dry powder formulation according to any one of claims 1 to 16 for use in the prevention and/or treatment of inflammatory or obstructive airways diseases.

20. The formulation according to claim 19, wherein the disease is asthma or Chronic Obstructive Pulmonary Disease (COPD).