HK1224589B - Dry powder formulation comprising a corticosteroid and a beta-adrenergic for administration by inhalation - Google Patents

Description

Dry powder formulation for inhalation administration containing a corticosteroid and a beta-adrenergic drug

Technical Field

The present application is a divisional application of an application filed on January 23, 2013, with application number 201380006645.X, and the invention title is “Dry powder formulation containing corticosteroids and beta-adrenergic drugs for inhaled administration”.

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

In particular, the present invention relates to dry powder formulations comprising a combined corticosteroid and a beta ₂ -adrenergic agent, methods for their preparation and therapeutic uses.

Background of the Invention

Active substances 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-methylphenethyl]amino}ethyl]carboxanilide, particularly its fumarate salt (hereinafter referred to as FF), is a well-known β-2 adrenergic receptor agonist currently used clinically to treat bronchial asthma, chronic obstructive pulmonary disease (COPD) and related disorders.

Beclomethasone dipropionate (BDP) is a potent anti-inflammatory steroid designated as (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 under a number of brand names for the prevention and/or treatment of inflammatory respiratory disorders.

There are currently formulations on the market for pressurized metered dose inhalers (pMDIs) containing the two active ingredients in combination, both dissolved in a mixture of HFA 134a and ethanol as a cosolvent. These have 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 able to deliver a high fraction of particles with a diameter equal to or less than 1.1 microns. In particular, upon actuation of the inhaler, it provides a respirable fraction of about 40% and a fraction of particles with a diameter equal to or less than 1.1 microns of about 12% for both active ingredients.

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

Despite their widespread acceptance, however, pMDI formulations can have some disadvantages, particularly in elderly and pediatric patients, largely due to their difficulty synchronizing device actuation with inspiration.

Dry powder inhalers (DPIs) constitute an effective alternative to MDIs for administering medication to the respiratory tract.

On the other hand, it is desired that drugs intended for inhalation as dry powders should be used in the form of micronized particles. Their volume effect can represent an obstacle to designing formulations that are therapeutically equivalent to formulations in which the drug is delivered in the form of liquid droplets.

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

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

Recently Mariotti et al. (European Respiratory Society Annual Congress, Amsterdam, September 24-28, 2011) presented data on FF/BDP dry powder formulations with a respirable fraction of approximately 70% for both active ingredients.

It was therefore an object of the present invention to provide a powder formulation for DPIs comprising formoterol fumarate and BDP in combination which overcomes the problems identified above and in particular provides a powder formulation having therapeutic characteristics matching those of the corresponding pMDI formulations in solution form.

This 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 consisting 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 and beclomethasone dipropionate (BDP) as active ingredients, both in the form of micronized particles; wherein i) no more than 10% of the BDP particles have a diameter of less than 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 the particles have a diameter of less than 4.7 microns.

In a second aspect, the present invention relates to a method for preparing a dry powder formulation according to the 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 dry powder formulation described above.

In a fourth aspect, the invention is directed to the claimed formulation 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 for preventing and/or treating inflammatory or obstructive airways diseases such as asthma or chronic obstructive pulmonary disease (COPD), comprising administering by inhalation an effective amount of a formulation of the invention.

In a sixth aspect, the invention relates to the use of the claimed formulation for the preparation of a medicament for the prevention and/or treatment of inflammatory or obstructive airways diseases such as asthma or chronic obstructive pulmonary disease (COPD).

definition

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

"Therapeutically effective daily dose" means the amount of active ingredient administered by inhalation when the inhaler is actuated.

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 micron.

The term "micronized" means that the material has a size of several microns.

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

Typically, the particle size of particles is quantified by measuring the characteristic equivalent spherical diameter, called the volume diameter, by laser diffraction.

Particle size can also be quantified by measuring mass diameter using suitable known equipment such as a sieve analyzer.

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

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

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

Another common way to define a particle size distribution is to list three values: i) the volume median diameter d(v,0.5), which is the volume diameter above which 50% of the distribution is distributed and below which 50% is distributed; ii) d(v,0.9), below which 90% of the volume distribution is distributed; and iii) d(v,0.1), below which 10% of the volume distribution is distributed. The span is the width of the distribution based on the 10%, 50%, and 90% quantiles and is calculated according to the following formula.

In 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 a particle to be transported in a suspended air stream. MMAD corresponds to the mass aerodynamic diameter at which 50% of the particle weight is present.

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

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

The term "good flowability" refers to the ease with which the formulation can be handled during the manufacturing process and ensures the delivery of an accurate and reproducible therapeutically effective dose.

Flow characteristics can be evaluated by different tests such as angle of repose, Carr index, Hausner ratio or flow velocity through an orifice.

In the context of this application, flow properties are tested by measuring the flow rate through an orifice according to the method described in European Pharmacopoeia (Eur. Ph.) 7.3, ^7th edition.

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 called relative standard deviation (RSD), is less than 2.5%, preferably equal to or less than 1.5%.

The term "respirable fraction" refers to the percentage of active particles that will reach the deep lungs of a patient.

The respirable fraction, also called fine particle fraction (FPF), is evaluated according to the procedures reported in the common pharmacopoeias, in particular the European Pharmacopoeia (Eur. Ph.) 7.3, ^7th edition, using a suitable in vitro apparatus, such as the Andersen Cascade Impactor (ACI), the Multistage Liquid Impactor (MLSI) or the Next Generation Impactor (NGI), preferably the ACI.

It is calculated as the percentage ratio between fine particle mass (formerly fine particle dose) and 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" refers to approaches used to reduce the risk of developing a disease.

The term "treat" means an approach to obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in disease severity, stabilization of the disease state (i.e., no worsening), prevention of disease development, delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete), whether detectable or undetectable) of the disease state. The term can also mean prolonging survival compared to the expected survival if not receiving treatment.

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

Detailed Description of the Invention

The present invention relates to a dry powder formulation for a dry powder inhaler (DPI) comprising a fine particle fraction a), a coarse particle fraction b) and formoterol fumarate (FF) dihydrate as active ingredients in combination with beclomethasone dipropionate (BDP), having the characteristics disclosed herein.

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

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

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

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

Furthermore, the use of micronized BDP characterized by the above-selected, narrow and well-defined particle size distribution allows for 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 adequate 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 excipient particles and the fine excipient particles consist of α-lactose monohydrate.

The fine particle fraction a) must have a mass median diameter (MMD) lower than 20 μm, advantageously equal to or lower than 15 μm, preferably equal to or lower than 10 μm and even more preferably equal to or lower than 6 μm.

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

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

Advantageously, the fraction is composed 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. A preferred ratio is 98% of excipients and 2% of 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 surface coating degree 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 consist of lactose, the degree of surface coating, which represents the percentage of the total surface of the excipient particles coated with magnesium stearate, can be determined by measuring the water contact angle and then using the formula known from the literature, for example, Cassie and Baxter, Colombo I et al., Il Farmaco 1984, 39(10), 328-341, page 338 and reported below.

cosθ _mixture = f _{magnesium stearate} cosθ _{magnesium stearate} + f _lactose cosθ _lactose

Where f _{magnesium stearate} and f _lactose are the surface area fractions of magnesium stearate and lactose;

_{θMgstearate is} the water contact angle of magnesium stearate;

_θlactose is the water contact angle of lactose

_θmixture is the experimental contact angle value.

For the present invention's purpose, the contact angle can be determined by a method based on goniometric measurement. This refers to the angle formed between the solid substrate and the liquid being tested by direct observation. Therefore, it is very easy to carry out, and the only limitation is the possible deviation from the inter-operator variability. However, it should be emphasized that this shortcoming can be overcome by using a fully automated program such as computer-assisted image analysis. A particularly useful method is the sessile or static dripping method, which is generally carried out by depositing the droplet on the powder surface of the disc form (compressed powder disc method) obtained by compaction.

The extent of magnesium stearate coating on the surface of the excipient particles can also be determined by the well-known versatile analytical technique of scanning electron microscopy (SEM).

The microscopy technique can be coupled with an EDX analyzer (electron scattering X-ray analyzer) which is capable of producing images that are 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 on the surface of the excipient particles.

SEM can alternatively be combined with IR or Raman spectroscopy to determine the extent of coating according to known procedures.

Yet another analytical technique that may be advantageously used is X-ray photoelectron spectroscopy (XPS), whereby 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 methods disclosed in WO 01/78693. Preferably, it can be prepared by co-micronization, more preferably using a ball mill. In some cases, it has been found to be advantageous to co-mill for at least 2 hours, 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 achieved.

In a preferred embodiment of the invention, 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, the particles are co-micronized using a jet mill, preferably in an inert atmosphere, for example under nitrogen.

For example, commercially available α-lactose monohydrate such as Meggle D 30 or Spherolac 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 co-pending application number WO 2011/131663.

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

Advantageously, all coarse particles have a mass diameter of 50-1000 μm, preferably 60 to 500 μm.

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

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

Typically, those skilled in the art will select the most appropriate coarse excipient particle size by sieving using a suitable classifier.

In the case where the mass diameter of the coarse particles is 200 to 400 microns, the coarse excipient particles preferably have a relatively highly fissured surface, that is, there are clefts and valleys and other recessed areas thereon, generally referred to herein as fissures. "Relatively highly fissured" coarse particles can be defined as the fissure index or wrinkle state coefficient described in WO 01/78695 and WO 01/78693, which are incorporated herein by reference, and they can be characterized according to the descriptions therein. The coarse particles can also be characterized as measured by tapping density or total intrusion volume, as reported in WO 01/78695, which is incorporated herein by reference in its teachings.

The tapped density of the coarse particles is advantageously less than 0.8 g/cm ³ , preferably between 0.8 and 0.5 g/cm ³ . The total intrusion volume is at least 0.8 cm ³ , preferably at least 0.9 cm ³ .

The ratio between the fine particle fraction a) and the coarse particle fraction b) is 1:99 to 30:70% by weight, preferably 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 drum mixer such as a Turbula ^™ , a rotary mixer or an instant mixer such as a Diosna ^™ for at least 5 minutes, preferably at least 30 minutes, more preferably at least 2 hours. In a general manner, a person skilled in the art will adjust the mixing time and the rotation speed of the mixer to obtain a homogeneous mixture.

In case 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 totality of the micronized particles of beclomethasone dipropionate (BDP) is characterized by a selected, narrow and well-defined particle size distribution such that: i) no more than 10% of the particles have a diameter below 0.6 microns, preferably equal to or below 0.7 microns; ii) no more than 50% of the particles have a diameter between 1.5 microns and 2.0 microns, preferably between 1.6 and 1.9 microns; and iii) at least 90% of the particles have a diameter equal to or below 4.7 microns, preferably equal to or below 4.0 microns, more preferably equal to or below 3.8 microns.

Particular BDP size distributions are characterized by d(v0.1) of 0.8 to 1.0 microns, preferably 0.85 to 0.95 microns; d(v0.5) of 1.5 to 2.0 microns, preferably 1.6 to 1.9 microns, and d(v0.9) of 2.5 to 4.7 microns, preferably 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, which corresponds to [d(v, 0.9) - d(v, 0.1)] / d(v, 0.5) according to Chew et al. J Pharm Pharmaceut Sci 2002, 5, 162-168.

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

The size of the particulate active is determined by measuring the characteristic equivalent spherical diameter (called volume diameter) by laser diffraction. In the reported examples, the volume diameter has been determined using 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 specific surface area of 5.5 to 7.0 ^m2 /g, preferably 5.9 to 6.8 ^m2 /g.The specific surface area is determined by the Brunauer-Emmett-Teller (BET) nitrogen adsorption method according to procedures known in the art.

All 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 of less than 5.0 microns. In a particular embodiment, the particle size distribution is such that: i) no more than 10% of the particles have a volume diameter of less than 0.8 microns, ii) no more than 50% of the particles have a volume diameter of less than 1.7 microns; and iii) at least 90% of the particles have a volume diameter of less than 5.0 microns. The micronized formoterol fumarate dihydrate used in the formulation of the present invention is also advantageously characterized by a specific surface area of 5 to 7.5 ^m2 /g, preferably 5.2 to 6.5 ^m2 /g, and more preferably 5.5 to 5.8 ^m2 /g.

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 using a conventional fluid energy mill, such as a commercially available jet mill micronizer having milling chambers of varying diameters. Depending on the equipment type and batch size, one skilled in the art will appropriately 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 BDP, it is highly advantageous to use a jet mill 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 α-lactose monohydrate particles and 2% by weight of magnesium stearate, said mixture having a mass median diameter equal to or lower than 6 μm;

b) a fraction of coarse particles consisting of α-lactose monohydrate having a mass diameter of 212 to 355 μm, and a ratio of fine particles to coarse particles of 10:90% by weight; and

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

The present invention also relates to a process for the preparation of the dry powder formulation disclosed herein, comprising the steps of mixing a fine particle fraction a), a coarse particle fraction b) and two micronized active ingredients.

The carrier particles comprising the fine particle fraction and the coarse particle fraction can be prepared by mixing in a suitable apparatus known to the skilled person, for example a Turbula ^™ stirrer. The two fractions are preferably mixed in a Turbula ^™ stirrer, which is operated at a rotation speed of 16 rpm for a period of 30 to 300 minutes, preferably 150 to 240 minutes.

The carrier particles can be mixed with the active ingredient particles by mixing the components in a suitable apparatus known to the skilled person, such as a Turbula ^™ mixer, 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 screen, and then additional active ingredient and the remaining portion of the carrier particles are blended with the screened mixture; and finally the resulting mixture is screened through a filter and mixed again.

The technician will select the mesh size of the filter based on 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 dosage required.

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

For example, the formulation is suitable for delivering 6-12 μg formoterol (as fumarate dihydrate) per actuation, in particular 6 μg or 12 μg per actuation, and 50-200 μg beclomethasone dipropionate per actuation, in particular 50, 100 or 200 μg per actuation.

The therapeutically effective daily dose may be 6 μg to 24 μg of formoterol and 50 μg to 800 μg of BDP.

The dry powder formulations of the present invention can be used with any dry powder inhaler.

Dry powder inhalers (DPIs) can be divided into two basic types: i) single-dose inhalers, used to administer single sub-divided doses of the active compound; each single dose is usually filled into a capsule;

ii) Multidose inhalers, pre-loaded with an amount of active ingredient sufficient for a longer treatment period.

The dry powder formulation is particularly suitable for multidose DPIs containing a reservoir from which individual therapeutic doses can be withdrawn on demand by actuation of the device, as described, for example, in WO 2004/012801. Other multidose devices that can be used are, for example, GlaxoSmithKline's DISKUS ^™ , AstraZeneca's TURBOHALER ^™ , Schering's TWISTHALER ^™ , and Innovata's CLICKHALER ^™ . Examples of marketed single-dose devices include GlaxoSmithKline's ROTOHALER ^™ and Boehringer Ingelheim's HANDIHALER ^™ .

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

Where moisture ingress into the formulation is to be avoided, it may be desirable to package the DPI in a flexible package which is resistant to moisture ingress, such as those disclosed in EP 1 760 008 .

Administration of the formulations of the present invention may be indicated for 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 severities.

Other respiratory disorders characterized by obstruction of the peripheral airways due to inflammation and the presence of mucus, such as chronic obstructive bronchiolitis and chronic bronchitis, may also benefit from such formulations.

The present invention is illustrated in detail with the aid of the following examples.

Example

Example 1 - Preparation of different batches of micronized particles of beclomethasone dipropionate

Different batches of beclomethasone dipropionate were milled in a Jet Mill Micronizer MC (Jetpharma Sa, Switzerland) with a milling chamber diameter of 300 mm.

Characterize the particle size distribution and specific surface area of micronized batches.

Particle size was determined by laser diffraction using a Malvern instrument. The parameters considered were the micrometer diameters (VD) of the 10%, 50%, and 90% percentile 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 particle size is independent of 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 Coulter SA3100 instrument as the average of three measurements.

The relevant data are reported in Table 1.

Table 1 - Particle size distribution and specific surface area (SSA) of micronized beclomethasone dipropionate from different batches

Example 2 - Preparation of the fine particle fraction a)

About 40 kg of co-micronized granules were produced.

A fine particle fraction a) was obtained by co-micronizing α-lactose monohydrate particles having a particle size of less than 250 μm (Meggle D30, Meggle) and magnesium stearate particles having a particle size of less than 35 μm in a ratio of 98:2 wt% by milling in a jet mill operated under nitrogen.

At the end of the treatment, the co-micronized particles had a mass median diameter (MMD) of approximately 6 microns.

Example 3 - Preparation of "Carrier" [Fraction a) + Fraction b)]

A sample of the fine granules of Example 1 was mixed with fractured coarse granules of lactose monohydrate obtained by sieving and having a mass diameter of 212-355 microns in a ratio of 90:10% by weight.

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

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

Example 4 - Preparation of dry powder formulation

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

The micronized beclomethasone dipropionate (BDP) batch 1 or 4 obtained as in Example 1 and the remainder of the "vehicle" were blended in a Turbula blender at 16 r.p.m. for 60 minutes and the mixture was sieved to obtain the final formulation.

The ratio of active ingredient to 10 mg of "vehicle" is 6 μg FF dihydrate (theoretical delivered dose 4.5 μg) and 100 μg BDP.

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

The evaluation of aerosol potency was performed using an Andersen Cascade Impactor (ACI) according to the conditions reported in European Pharmacopoeia ^6th Ed 2008, par 2.9.18, pages 293-295.

After aerosolization of three doses, the ACI device was disassembled and the amount of drug deposited on the stage was recovered by washing with a solvent mixture and then quantified by high performance liquid chromatography (HPLC). The following parameters were calculated: i) delivered dose, which is the amount of drug delivered from the device that was recovered in the impactor; ii) fine particle mass (FPM), which is the amount of drug delivered with a particle size equal to or less than 5.0 microns; iii) fine particle fraction (FPF), which is the percentage of fine particle dose; iv) MMAD.

The results (mean ± S.D.) are reported in Table 2.

Table 2 - Aerosol Efficacy

^a) GSD, which is the geometric standard deviation

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

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

Example 5 - Therapeutic equivalence of FF/BDP dry powder formulations of the present invention to corresponding pMDI formulations currently on the market

The study was designed to show that the FF/BDP dry powder formulation delivered via the DPI disclosed in WO 2004/012801 is therapeutically equivalent to the corresponding pMDI formulation on the market.

Study Design:

A 5-way crossover, double-blind, double-dummy clinical study.

69 pre-diagnosed asthmatic patients with FEV1 60% to 90% were randomized. The five single doses tested were: 24/400 μg FF/BDP via DPI or pMDI, 6/100 μg FF/BDP via DPI or pMDI, and placebo.

Main objectives:

_{FEV1 AUC0-12h} , which is the area under the forced expiratory volume curve for the time interval 0 to 12 hours.

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

result

For FEVi _AUC0-12h , non-inferiority was demonstrated between formulations _at both the low and high doses.

Both doses were significantly better than placebo. Both formulations showed superiority of the high dose over the low dose in _FEV1 AUC _0-12h , reaching statistical significance for DPI. Safety and tolerability were good and comparable.

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

The study objective was to test the efficacy of a 6/100 μg FF/BDP dry powder formulation delivered via a DPI disclosed in WO 2004/012801 (hereafter FF/BDP DPI) versus the same dose of a corresponding marketed pMDI formulation (hereafter FF/BDP pMDI) and a marketed 100 μg BDP DPI formulation (hereafter BDP DPI).

Study Design:

A phase III, 8-week, multinational, multicenter, randomized, double-blind, triple-dummy, active-controlled, 3-arm, parallel-group clinical trial was conducted in adult patients with asthma.

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

Main objectives:

demonstrated that FF/BDP DPI was non-inferior to FF/BDP pMDI in mean predose morning peak expiratory flow (PEF) from baseline to the entire treatment period.

PEF is a person's peak expiratory velocity and is measured with a peak flow meter (a small handheld device used to monitor a person's ability to exhale air.) It measures airflow through the bronchi and thus the degree of obstruction in the airways.

Secondary objectives:

To evaluate the superiority of FF/BDP DPI over BDPDPI in terms of mean pre-dose morning PEF from baseline to the entire treatment period;

To evaluate the effects of FF/BDP DPI on other lung function parameters and on clinical outcome measures, and safety and tolerability.

result:

Non-inferiority of the FF/BDP DPI relative to the FF/BDP pMDI in primary efficacy parameters was demonstrated.

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

No significant differences between treatments were observed 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 was comparable to the FF/BDP pMDI in terms of safety and tolerability.

Claims (12)

1. A dry powder formulation for use in a dry powder inhaler, comprising: a) Fine particles of a certain fraction, which are prepared from a mixture of 98% by weight α-lactose monohydrate particles and 2% by weight magnesium stearate, said mixture having a median mass diameter of less than 20 micrometers. b) A fraction of coarse particles composed of physiologically acceptable excipients, having a mass diameter of 200-400 micrometers, wherein the ratio of fine particles to coarse particles is 10:90% by weight; and c1) is formoterol fumarate dihydrate in microparticle form, with a therapeutic dose of 6 or 12 μg each time the inhaler is activated; c2) is beclomethasone dipropionate in microparticle form, with a therapeutic dose of 100 or 200 μg each time the inhaler is activated; Wherein i) no more than 10% of the BDP particles have a volume diameter of less than 0.6 micrometers; ii) no more than 50% of the particles have a volume diameter of 1.5 to 2.0 micrometers; and iii) at least 90% of the particles have a volume diameter of less than 4.7 micrometers; and The aforementioned formulation is therapeutically equivalent to a corresponding formulation for use in a pressurized metered inhaler containing the aforementioned active ingredient dissolved in a mixture of ethanol and HFA134a propellant. The beclomethasone dipropionate particles have a particle size range of 1.2 to 2.2 micrometers. The beclomethasone dipropionate particles were further characterized by a specific surface area of 5.5 to 7.0 ^m² /g. 2. The formulation according to claim 1, wherein the beclomethasone dipropionate particles have a particle size range of 1.3 to 2.1 micrometers. 3. The formulation according to claim 2, wherein the beclomethasone dipropionate particles have a particle size range of 1.6 to 2.0 micrometers. 4. The formulation according to claim 1, wherein the specific surface area is 5.9 to 6.8 ^m² /g. 5. The formulation according to any one of claims 1-4, wherein i) not more than 10% of the formoterol fumarate dihydrate particles have a volume diameter of less than 0.8 micrometers, ii) not more than 50% of the particles have a volume diameter of less than 1.7 micrometers; and iii) at least 90% of the particles have a volume diameter of less than 5.0 micrometers. 6. The formulation according to claim 5, wherein the formoterol fumarate dihydrate particles are further characterized by a specific surface area of 5 to 7.5 ^m² /g. 7. The formulation according to claim 6, wherein the specific surface area is 5.2 to 6.5 ^m² /g. 8. The formulation according to any one of claims 1-4 and 6-7, wherein the fraction of fine particles a) has a median diameter equal to or less than 10 micrometers. 9. A dry powder inhaler filled with the dry powder formulation of any one of claims 1-8. 10. A multi-dose dry powder inhaler filled with the dry powder formulation of any one of claims 1-8. 11. Use of the dry powder formulation according to any one of claims 1-8 for the preparation of a medicament for the prevention and/or treatment of inflammatory or obstructive airway diseases. 12. The use according to claim 11, wherein the disease is asthma or chronic obstructive pulmonary disease.