HK1182002A - Dry powder formulation comprising a phosphodiesterase inhibitor - Google Patents

Description

Dry powder formulations comprising phosphodiesterase inhibitors

Technical Field

The present invention relates to dry powder formulations suitable for inhalation administration by dry powder inhalers comprising a phosphodiesterase-4 inhibitor as the active substance.

The invention also relates to a process for its preparation and to its use in the prevention and/or treatment of inflammatory or obstructive airways diseases (e.g. asthma and COPD).

Background

Airway obstruction characterizes a number of serious respiratory diseases, including asthma and Chronic Obstructive Pulmonary Disease (COPD). Events leading to airway obstruction include edema of the airway wall, increased mucus production, and inflammation.

Drugs for the treatment of respiratory diseases (e.g., asthma and COPD) are currently administered by inhalation. One of the advantages of the inhalation route over the systemic route is the possibility of delivering the drug directly to the site of action, avoiding any systemic side effects, thus providing a faster clinical response and a higher therapeutic ratio.

Another class of therapeutic agents that is being investigated in view of their anti-inflammatory effects for the treatment of inflammatory respiratory diseases is represented by inhibitors of Phosphodiesterase (PDE), in particular phosphodiesterase type 4 (hereinafter referred to as PDE 4).

Various compounds have been disclosed as PDE4 inhibitors. However, the effectiveness of several PDE4 inhibitors of the first generation (e.g., rolipram and pyraclostrobin) was limited because of adverse side effects such as nausea, gastric acid secretion and vomiting due to the effect on PDE4 in the central nervous system and due to the effect on PDE4 in cells of the gut wall.

The causes of such side effects have been extensively studied.

PDE4 has been found to exist in two distinct forms representing different conformations, termed the high affinity rolipram binding site or HPDE4 (particularly in the central nervous system and parietal cells) and the low affinity rolipram binding site or LPDE4 (jacobiz, S et al, mol. Although both forms appear to exhibit catalytic activity, they differ in their sensitivity to inhibitors. In particular, compounds with higher affinity for LPDE4 are less prone to induce side effects such as nausea, vomiting and increased gastric secretion.

It would therefore be advantageous to provide selective inhibitors in the form of LPDE4 that are therapeutically effective when administered by inhalation.

Compounds having selective LPDE4 inhibitory activity are disclosed in WO 2009/018909.

Other highly potent PDE4 inhibitors are the object of co-pending application No. PCT/EP2010/000676, where it has been surprisingly found that the presence of a sulfonamide substituent on the benzoate residue significantly improves the efficacy, and that the (-) enantiomer is more potent than the corresponding (+) enantiomer and racemate.

Furthermore, it has been found that they can act in a synergistic manner in combination with long-acting β 2-agonists.

Thus, these compounds provide significant therapeutic benefits in the treatment of respiratory diseases (e.g., asthma and COPD) when administered by inhalation.

The drugs may be administered to the respiratory tract in dry powder form by means of a suitable inhaler known as a Dry Powder Inhaler (DPI).

The object of the present invention is to provide inhalable dry powder compositions comprising as active ingredient a compound of general formula (I) as PDE4 inhibitor.

Optimally, the formulation should exhibit good flow, good uniformity of active ingredient distribution, and appropriate chemical and physical stability in the device prior to use.

Should also produce a good breath fraction and deliver an accurate therapeutically active dose of the active ingredient.

Summary of The Invention

One aspect of the present invention provides a pharmaceutical formulation in the form of an inhalable dry powder comprising micronized particles of a compound of formula (I) as particles of an active ingredient and a physiologically acceptable pharmacologically inert solid carrier.

According to another aspect, the present invention provides a dry powder inhaler comprising the inhalable dry powder of the invention.

A further aspect of the invention relates to the inhalable dry powder of the invention for use in the prevention and/or treatment of inflammatory or obstructive airways diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

A further aspect of the present invention relates to a method of preventing and/or treating inflammatory or obstructive airways diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD), which comprises administering by inhalation a therapeutically effective amount of the respirable dry powder of the present invention.

Finally, the invention relates to a pharmaceutical pack comprising the inhalable dry powder formulation of the invention and a dry powder inhaler according to the invention.

Definition of

The terms "active drug", "active ingredient", "active substance", "active compound" and "therapeutic agent" are used synonymously.

The term "substantially pure" means a compound having an optical purity higher than 90%, advantageously higher than 95% w/w, preferably higher than 97% w/w, more preferably higher than 97.5% w/w, based on the weight of the compound.

By "monotherapeutically effective dose" is meant the amount of active ingredient that is administered by inhalation once on actuation of the inhaler.

The dose may be delivered in one or more actuations, preferably one actuation (ejection) of the inhaler.

By "activated" is meant that the active ingredient is released from the device by a single activity (e.g., mechanical or respiratory).

In general terms, the particle size of a particle, referred to as the volume diameter, can be quantified by measuring the characteristic equivalent spherical diameter by laser diffraction.

The particle size may also be quantified by measuring the mass diameter by a suitable known means, such as, for example, a sieve analyzer.

The Volume Diameter (VD) is related to the Mass Diameter (MD) by the density of the particles (assuming a density-independent dimension for the particles).

In the present application, the particle size is expressed in terms of Mass Diameter (MD) and the particle size distribution is expressed in terms of: i) mass Median Diameter (MMD), which corresponds to the diameter of 50% by weight or volume of the particles, respectively, and ii) MD in microns for 10% and 90% of the particles, respectively.

The terms MMD and average particle size are used synonymously.

The term "good flow" refers to a formulation that is easy to handle during manufacture and that ensures accurate and repeated delivery of a therapeutically effective dose.

Flow characteristics can be evaluated by measuring the Carr's index; carr's index below 25 is usually taken to indicate good flow characteristics.

The expression "good homogeneity" refers to a formulation wherein the content homogeneity of the active ingredient expressed as the Relative Standard Deviation (RSD) at the time of mixing is lower than 7.5%, preferably equal to or lower than 5.0%.

The expression "chemically stable" refers to formulations which meet the requirements of ICH Guideline Q1A for the "new active substance (and drug) stability test".

The expression "physically stable in the device prior to use" refers to a formulation wherein the active particles do not substantially leave and/or detach from the surface of the carrier particles during the dry powder manufacturing process and in the device prior to use.

The tendency to segregation can be assessed according to Stanifforth et al, J.Pharm.Pharmacol.34, 700-706, 1982 and is considered acceptable if the distribution of the active ingredient in the powder formulation after the test, expressed as the Relative Standard Deviation (RSD), does not change significantly relative to the pre-test formulation.

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

The respirable fraction, also referred to as the fines fraction, is evaluated according to the procedures described in the general pharmacopoeia using a suitable extracorporeal device, such as a multi-stage impactor or a multi-stage liquid impactor (MLSI).

Calculated by the ratio between the delivered dose and the mass of the fines (the previous dose of fines).

The delivered dose was calculated from the cumulative deposition in the device, while the fine particle mass was calculated from the deposition from platform 3 (S3) to the filter (AF) (corresponding to particles ≦ 4.7 microns).

A respirable fraction above 30% is an index of good inhalation performance.

The expression "precise therapeutically active dose of active ingredient" refers to a formulation in which the variation between the average delivered daily dose and the average emitted dose is equal to or lower than 15%, preferably lower than 10%.

Detailed Description

The composition of the invention is a pharmaceutical formulation in the form of an inhalable dry powder comprising micronized particles of the compound of formula (I) as the (-) enantiomer,

wherein:

n is 0 or 1;

R₁and R₂May be the same or different and is selected from:

-linear or branched (C)₁-C₆) Alkyl, optionally substituted with one or more halogen atoms;

-OR₃wherein R is₃Is optionally substituted by one or more halogen atoms or (C)₃-C₇) Cycloalkyl-substituted straight or branched chain (C)₁-C₆) An alkyl group; and

-HNSO₂R₄wherein R is₄Is a straight or branched chain (C) optionally substituted by one or more halogen atoms₁-C₄) An alkyl group, a carboxyl group,

wherein R is₁And R₂Is HNSO₂R₄；

And particles of a physiologically acceptable pharmacologically inert solid carrier.

In the context of the present invention, the compounds of the general formula (I) are used in the form of the essentially pure (-) -enantiomer.

According to a preferred embodiment, the compound of general formula (I) is selected from the compounds C1, C2, C3, C4, C5 and C6 described below.

In one embodiment, a preferred compound is C1. In another embodiment, is C2. In a further preferred embodiment, the compound may be C3, C4, C5 or C6.

The composition according to the invention comprises an amount of active ingredient such that, in the case of administration by inhalation from an inhaler, a therapeutically effective single dose (hereinafter referred to as single dose) of the compound of formula (I) is advantageously from 10 μ g to 2000 μ g, more advantageously from 20 μ g to 1000 μ g, preferably from 50 μ g to 800 μ g, more preferably from 80 to 700 μ g, even more preferably from 100 to 600 μ g.

According to a preferred embodiment, the single dose may be from 100 to 300 μ g, while according to another preferred embodiment, the single dose is from 200 to 800 μ g, more preferably from 300 to 600 μ g.

In other embodiments, the single dose may be 100 μ g, 200 μ g, 400 μ g, or 600 μ g.

The single dose will depend on the kind and severity of the disease and the condition of the patient (body weight, sex, age) and will be administered one or more times a day, preferably once a day.

The daily dose of the pharmaceutical composition comprising the compound of formula (I) should be in the range of 100 μ g to 1600 μ g, preferably 200 μ g to 800 μ g, more preferably 200 μ g to 600 μ g.

In one embodiment, the daily dose may be achieved by a single or double administration.

In another preferred embodiment, the daily dose can be achieved by a single administration and one actuation of the inhaler.

In another preferred embodiment, the daily dose can be achieved by a single administration and multiple (preferably two) actuation deliveries from the inhaler.

In another preferred embodiment, the daily dose may be achieved by two administrations and one actuation delivery of the inhaler.

In another preferred embodiment, the daily dose may be achieved by two administrations and multiple (preferably two) actuation deliveries of the inhaler.

The particles of the compound of formula (I) in the formulation according to the invention must be in finely divided (micronized) form, i.e. their mass median diameter should generally be equal to or less than 10 microns, preferably less than 6 microns, more preferably from 1 to 6 microns.

In a particular embodiment of the invention, the particle size may meet the following requirements:

i) no more than 10% of the particles have a mass diameter of less than 0.8 micron;

ii) no more than 50% of the particles have a mass diameter of less than 1.7 microns, preferably from 1.8 to 2.5 microns; and

iii) at least 90% of the particles have a mass diameter of less than 6 microns.

Known methods, such as milling, direct precipitation, spray drying, freeze drying or supercritical fluids, can be used to produce the active ingredient of the desired particle size.

The carrier particles may be made of any physiologically acceptable pharmacologically inert material or combination of materials suitable for inhalation use.

For example, the carrier particles may be composed of one or more materials selected from the group consisting of: a sugar alcohol; 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; and other organic compounds such as urea, polysaccharides, e.g. starch and its derivatives; oligosaccharides, such as cyclodextrins and dextrins.

Advantageously, the carrier particles are made from crystalline sugars, for example, monosaccharides, such as glucose or arabinose, or disaccharides, such as maltose, sucrose, dextrose or lactose.

Preferably, the carrier particles are made from lactose, more preferably, from alpha-lactose monohydrate.

In one embodiment of the invention, the powder formulation may be in the form of agglomerated spherical particles, also known as soft pellets, in which the particles of the compound of formula (I) and the particles of the carrier are both in finely divided form, i.e. they have a mass median diameter generally less than 10 microns, preferably from 1 to 6 microns.

The formulations may be prepared according to known methods.

Generally, the method comprises the steps of:

i) micronizing the active ingredient and the carrier together;

ii) subjecting the obtained co-micronised mixture to granulation and spheronization.

Alternatively, the method comprises the steps of:

i) separately micronizing the active ingredient and the carrier;

ii) mixing the micronized ingredients; and

iii) subjecting the resulting mixture to granulation and spheronization.

In another embodiment of the invention, the formulation comprises a coarse-grained carrier and a drug in finely divided form, a type of formulation known in the art as an ordered mixture (ordered mixture).

Advantageously, the coarse carrier particles have a Mass Diameter (MD) of at least 50 microns, more advantageously greater than 80 microns. Preferably, the MD is 90 to 500 microns.

In particular embodiments of the present invention, the MD may be 90 to 150 microns.

In other embodiments, the MD may be 150 to 400 microns, preferably with an MMD greater than 175 microns, and more preferably the MD may be 210 to 355 microns.

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

When the MD is 150 to 400 microns, the coarse carrier particles preferably have a relatively high fractured surface, i.e., there are crevices and depressed bottoms and other recessed areas thereon, collectively referred to herein as fractures.

A "relatively high fractured" grit may be defined in terms of a fracture index or roughness factor, as described in WO01/78695 and WO01/78693, incorporated herein by reference, and may be characterized according to the description set forth therein.

The carrier kibbles can also be characterized according to bulk density or total intrusion volume measured as described in WO 01/78695.

The bulk density of the coarse support particles is advantageously less than 0.8g/cm³Preferably 0.8 to 0.5g/cm³。

The total invasion volume is at least 0.8cm³Preferably at least 0.9cm³。

When the formulation of the invention is in the form of an ordered mixture as described above, it may be advantageous to include an additive material capable of promoting release of the active particles from the carrier particles upon actuation of the inhaler device, and thus capable of increasing the respirable fraction.

The additive material, preferably bound to the surface of the coarse particles of the carrier, is a different material than the carrier particles.

Advantageously, the additive material is an amino acid, preferably selected from leucine, isoleucine, lysine, valine, methionine and phenylalanine. The additive may be a salt of an amino acid derivative, for example aspartame or acesulfame K.

In one embodiment of the invention, the additive particles consist essentially of leucine, advantageously L-leucine.

Alternatively, the additive material may comprise or consist of one or more water-soluble surface-active materials, for example lecithin, in particular soya lecithin.

In particular embodiments of the invention, the additive material may include or consist of one or more lubricants selected from stearic acid and salts thereof (such as magnesium stearate), sodium lauryl sulfate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate.

Other possible additive materials include talc, titanium dioxide, aluminum dioxide, and silicon dioxide.

Advantageously, the additive particles have a starting average particle size of less than 35 microns. Preferably, they have an average particle size of no more than 15 microns, more preferably no more than 10 microns.

The optimum amount of additive material should depend on the chemical composition and other characteristics of the additive material.

Generally, the content of additives should not exceed 10% by weight, based on the total weight of the formulation.

However, it is believed that for most additives, the content of additive material should not exceed 5%, preferably not exceed 2%, or even not exceed 1% by weight or not exceed 0.5%, based on the total weight of the formulation. Typically, the additive material is present in an amount of at least 0.01% based on the total weight of the formulation.

In a preferred embodiment of the invention, the additive material is magnesium stearate.

The amount of magnesium stearate is generally 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.

In some embodiments, the magnesium stearate may cover the surface of the carrier particles in such a way that the degree of molecular surface coverage is at least 5%, preferably more than 10%, more preferably more than 15%, even more preferably equal to or more than 25%.

The degree of molecular surface coverage, which represents the percentage of total surface of carrier particles covered by magnesium stearate, can be determined by the water contact angle measurement method described in WO00/53157 or co-pending application No. ep 10158951.3.

For very high degrees of surface coverage, i.e. above 60%, this coverage can be achieved using the method described in the above-cited co-pending application No. ep 10158951.3.

The extent to which the magnesium stearate covers the surface of the lactose particles can also be determined by Scanning Electron Microscopy (SEM) by common analytical techniques well known in the art.

Such a microscope may be equipped with an EDX analyzer (electron diffusion X-ray analyzer) which can produce images selective to a particular type of atom (e.g., magnesium atoms). In this way a clear data set of the distribution of magnesium stearate over the surface of the carrier particles can be obtained.

Alternatively, SEM can be used in conjunction with IR or Raman spectroscopy to determine the degree of coverage according to known procedures.

Another analysis technique that can be advantageously used is X-ray photoelectron spectroscopy (XPS), by which it has been possible to calculate simultaneously the degree and depth of coverage of the magnesium stearate film around the lactose particles.

XPS measurements can be performed using commercially available tools, such as the Axis-Ultra tool from Kratos Analytical (Manchester UK), typically using monochromatic A1K alpha radiation according to known procedures.

The formulation of the invention in the form of an ordered mixture may also comprise fine particles of a physiologically acceptable pharmacologically inert material having a Mass Median Diameter (MMD) equal to or less than 15 microns, preferably equal to or less than 10 microns, even more preferably equal to or less than 6 microns.

The percentage of fine particles of physiologically acceptable pharmacologically inert material is advantageously between 0.1 and 40% of the total amount of the formulation.

Preferably, the coarse and fine particles are composed of the same physiologically acceptable pharmacologically inert material.

In a preferred embodiment of the invention, in particular when the active ingredient is present in a single dose of equal to or less than 300. mu.g, preferably equal to or less than 200. mu.g, the formulation is in the form of hard pellets according to the teaching of WO 01/78693.

The formulation comprises:

i) particles of a compound of formula (I) in micronized form

ii) a particulate fraction consisting of a mixture comprising particles of a physiologically acceptable pharmacologically inert material and particles of an additive material, said particulates having an MMD equal to or less than 10 microns, preferably equal to or less than 6 microns; and

iii) a particulate fraction of a physiologically acceptable pharmacologically inert material having a high fracture surface and a Mass Diameter (MD) of from 150 to 400 microns, preferably from 212 to 355 microns.

Advantageously, the particulate fraction comprises 90 to 99.5% by weight of physiologically acceptable pharmacologically inert material and 0.5 to 10% by weight of additive material, and the ratio between the particulate fraction and the coarse fraction is 1:99 to 40:60% by weight, preferably 5:95 to 30:70% by weight, even more preferably 10:90 to 20:80% by weight.

Preferably, the physiologically acceptable inert material is alpha-lactose monohydrate and the additive material is magnesium stearate.

In a more preferred embodiment, the particulate fraction comprises 98 to 99% by weight of alpha-lactose monohydrate and 1 to 2% by weight of magnesium stearate, and the ratio between the particulate fraction and the coarse fraction made from alpha-lactose monohydrate is 10:90% by weight, respectively.

The amount of magnesium stearate in the final formulation is advantageously from 0.01 to 1.0% by weight, preferably from 0.05 to 0.5% by weight, more preferably from 0.1 to 0.4% by weight, based on the total weight of the formulation.

The preparation according to the invention in the form of an ordered mixture can be prepared according to known methods.

The method comprises the steps of mixing together coarse carrier particles, optionally fine carrier particles and additive particles, and finally adding the finely divided pharmaceutically active compound to the resulting mixture.

Particularly preferred formulations according to the invention may be prepared according to the methods described in WO 01/78693.

In the process described herein, the formulation is preferably prepared according to a process comprising the steps of:

a) preparing microparticles consisting of a mixture comprising particles made of a physiologically acceptable pharmacologically inert material and particles of an additive, and first mixing together the inert material and the additive and then co-micronizing;

b) mixing the microparticles of step a) with a kibble of a physiologically acceptable pharmacologically inert material such that the microparticles adhere to the surface of the kibble;

c) adding to the particles of step b) by mixing the active particles in micronized form.

The co-micronization step may be carried out by known methods, for example as described in WO 02/00197.

Advantageously, said step is carried out by grinding, more preferably by using a jet mill according to the conditions described in WO 01/78693.

In a particular embodiment, the microparticles of step a) obtained by co-micronization may be subjected to a conditioning step according to the conditions disclosed in co-pending application n.ep 10160565.7.

Advantageously, during step a), the additive may be embedded in the formed microparticles, or alternatively, in the case of a lubricant such as magnesium stearate, the additive may cover the surface of the carrier particles in such a way that the degree of molecular surface coverage is at least 5%, preferably more than 10%, more preferably more than 15%, even more preferably more than 35%.

The degree of molecular surface coverage indicates the percentage of the total surface of the carrier particles covered by magnesium stearate.

The presence of the embedded additive in the microparticles can be detected according to known methods, for example by scanning electron microscopy in combination with microcalorimetry.

Instead, as noted above, the degree of molecular surface coverage can be determined by the water contact angle measurement method described in WO00/53157 or other known means.

The formulations of the invention may further comprise other therapeutic agents useful in the prevention and/or treatment of respiratory diseases, e.g., beta₂Agonists such as albuterol, salmeterol and vilanterol, corticosteroids such as fluticasone propionate or furoate, flunisolide, mometasone furoate, rofleponide and ciclesonide, anticholinergic or antimuscarinic agents such as ipratropium bromide, oxitropium bromide, tiotropium bromide, oxybutynin, and combinations thereof.

The dry powder formulations disclosed herein can be used in all common dry powder inhalers, such as single or multi-dose inhalers.

For example, the formulations of the invention may be filled into hard gelatin capsules and subsequently loaded into a single dose inhaler, such as an Aerolyzer^TM. Alternatively, the formulation may be loaded as a powder into a multidose inhaler comprising a powder reservoir, as described in WO 2004/012801.

The administration of the formulation of the invention may be indicated for the prevention and/or treatment of mild, moderate or severe acute or chronic symptoms or for the prophylactic treatment of inflammatory or obstructive airways diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

Other respiratory diseases characterized by peripheral airway obstruction as a result of inflammation and the presence of mucus, such as chronic obstructive bronchiolitis and chronic bronchitis, may also benefit from the formulations of the present invention.

The invention is better illustrated by the following examples.

Examples

Example 1 inhalable Dry powder formulation comprising Compound C2 (formulation 1)

The powder formulation according to the invention has the composition described in table 1:

TABLE 1

A 1kg batch size dry powder formulation was prepared as described below.

The active substance in the form of particles having a typical particle size suitable for inhalation is prepared by micronization of crystalline (-) -3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -2- (3, 5-dichloro-1-oxo-pyridin-4-yl) -ethyl ester (compound C2) by methods known in the art.

Particles of alpha-lactose monohydrate having an average particle size of less than 250 microns and magnesium stearate particles having an average particle size of less than 35 microns in a 98:2 weight percent ratio were micronized by milling in a jet mill operated under nitrogen to obtain a co-micronized particle fraction expressed as co-micronized particles.

The co-micronised particles were mixed with coarse alpha-lactose monohydrate particles having a mass diameter of 212-355 microns and obtained by sieving, in a 90:10 weight percent ratio.

Mixing was carried out in a Turbula mixer for 4 hours.

To a portion of the resulting mixture, micronized compound C2 was added and the resulting mixture was sieved through a 250 μm sieve.

The remaining portion of the above mixture was added and mixed in a Turbula mixer at 32r.p.m. for 90 minutes to obtain the final formulation.

The final formulation was filled into hard gelatin capsules and loaded into Aerolyzer^TMIn an inhaler.

The aerosol performance was evaluated using a multi-stage liquid impactor (MSLI) according to the procedure described in the european pharmacopoeia, 2 nd edition, 1995, section v.5.9.1, pages 15-17.

The results regarding Delivered Dose (DD), Fine Particle Mass (FPM), Fine Particle Fraction (FPF) and Mass Median Aerodynamic Diameter (MMAD) are reported in table 2.

TABLE 2

It is recognized that a formulation comprising C2 as an active ingredient is capable of producing excellent respirable particles (FPF).

In a similar manner, compounds comprising compound C1, C3, C4, C5 or C6 were prepared.

Example 2 inhalable Dry powder formulation comprising Compound C2 (formulation 2)

A powder formulation having a similar composition to example 1, but with a unit composition, i.e. the composition of each ejection of the inhaler, is prepared, as described in table 3.

TABLE 3

The formulations were loaded into a multi-dose dry powder inhaler as described in WO 2004/012801.

The aerosol performance was measured as described in example 1.

The results are set forth in Table 4.

TABLE 4

Also in this case, FPF appears to be excellent, indicating that the formulation of the kind described provides good aerosol performance regardless of which inhaler is used.

Example 3 inhalable Dry powder formulations containing Compound C2 (formulations 3, 4, 5 and 6)

Powder formulations having similar compositions as in example 1 or example 2 were prepared using different intensities and percentages of co-micronised particles.

The composition is set forth in table 5.

The final formulation was filled into hard gelatin capsules and loaded into Aerolyzer^TMIn an inhaler.

Similarly, powder formulations having the same relative percentage composition but with a unit dose of 10mg were prepared and loaded into a multi-dose dry powder inhaler as disclosed in WO 2004/012801.

In a similar manner, formulations comprising compound C1, C3, C4, C5, or C6 were prepared.

Example 4 inhalable Dry powder formulations containing Compound C2 (formulations 7 and 8)

Further powder formulations according to the invention were prepared with the compositions reported in tables 6 and 7.

TABLE 6

TABLE 7

In a similar manner, formulations comprising compound C1, C3, C4, C5, or C6 were prepared.

EXAMPLE 5 evaluation of anti-inflammatory Activity of Compound C2

According to Eur J Pharmacol2002, 2 months and 22 days; 437(3) 187-94, the efficacy of one of the preferred compounds of the invention was evaluated in vivo in an acute model of pneumonia with minor modifications.

Briefly, male Brown-Norway rats (150-200 g) were sensitized by intraperitoneal injection of a suspension containing ovalbumin (OVA, 1 mg/rat) in 1mL saline for 3 consecutive days. After two-three weeks, airway inflammation was induced by inhaled antigen (OVA, 1% in saline). Vehicle control treated animals were exposed to a saline aerosol. Aerosol challenge with OVA resulted in a statistically significant increase in the concentration of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage fluid (BALF), all of which are markers of acute ongoing pulmonary inflammation. To examine the inhibitory efficacy, micronized compound C2 was mixed with lactose at different concentrations and administered as a single dose by the intratracheal route 2 hours prior to the antigen aerosol.

A dose-response curve was performed to test the inhibitory effect of compounds on OVA-induced eosinophilia in BALF, and the ED50 dose of compound C2 was taken as a measure of efficacy in this bioassay. The ED50 dose value of compound C2 was 0.028. mu. mol/kg (0.016-0.051) of body weight, which should correspond to a human dose of 100-.

Claims (22)

1. An inhalable dry powder formulation comprising particles of a compound of formula (I) as the (-) enantiomer,

wherein:

n is 0 or 1;

R₁and R₂May be the same or different and is selected from:

-straight chainOr branched (C)₁-C₆) Alkyl, optionally substituted with one or more halogen atoms;

-OR₃wherein R is₃Is optionally substituted by one or more halogen atoms or C₃-C₇Cycloalkyl-substituted straight or branched chain (C)₁-C₆) An alkyl group; and

-HNSO₂R₄wherein R is₄Is a straight or branched chain (C) optionally substituted by one or more halogen atoms₁-C₄) An alkyl group, a carboxyl group,

wherein R is₁And R₂Is HNSO₂R₄；

And carrier particles made of a physiologically acceptable pharmacologically inert material.

2. The inhalable powder according to claim 1, wherein the compound of general formula (I) is administered in a single dose of 10 μ g to 2000 μ g.

3. The inhalable powder according to claim 2, wherein the single dose is between 20 μ g and 1000 μ g.

4. The inhalable powder according to claim 3, wherein the single dose is between 50 μ g and 800 μ g.

5. The inhalable powder according to claim 4, wherein the single dose is between 100 μ g and 600 μ g.

6. The inhalable powder according to claim 5, wherein the single dose is 100 μ g or 200 μ g, 400 μ g or 600 μ g.

7. The inhalable powder according to any one of claims 1 to 6, wherein the carrier comprises a crystalline sugar selected from glucose, arabinose, maltose, sucrose, dextrose and lactose or a polyol selected from mannitol, maltitol, lactitol and sorbitol.

8. The inhalable powder according to claim 7, wherein the sugar is lactose.

9. The inhalable powder according to claim 8, wherein the sugar is alpha-lactose monohydrate.

10. The inhalable powder according to any one of claims 1 to 9, wherein the carrier is in the form of finely divided particles having a Mass Median Diameter (MMD) equal to or less than 10 microns.

11. The inhalable powder according to any one of claims 1 to 9, wherein the carrier is in the form of coarse particles having a mass diameter of at least 50 micron.

12. The inhalable powder according to claim 11, wherein the mass diameter is greater than 80 microns.

13. The inhalable powder according to claim 12, wherein the mass diameter is between 150 and 400 microns.

14. The inhalable powder according to any one of claims 1 to 9, wherein the carrier comprises a mixture of coarse particles having a mass diameter of 150 to 400 microns and fine particles having an MMD equal to or less than 10 microns.

15. The inhalable powder according to any one of claims 10 to 14, further comprising one or more additive materials selected from the group consisting of amino acids, water-soluble surfactants, lubricants and glidants.

16. The inhalable powder according to claim 15, wherein the additive material is a lubricant.

17. The inhalable powder according to claim 16, wherein the additive material is magnesium stearate.

18. The inhalable powder according to claim 17, wherein magnesium stearate is present in an amount of 0.01 to 2% by weight, based on the total weight of the formulation.

19. The inhalable powder according to claim 18, wherein the magnesium stearate is present in an amount of 0.02 to 1% w/w.

20. A dry powder inhaler comprising an inhalable dry powder formulation according to any one of claims 1 to 19.

21. The inhalable dry powder formulation according to any one of claims 1 to 19, for use in the prevention and/or treatment of respiratory diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

22. A pharmaceutical pack comprising an inhalable dry powder formulation according to any one of claims 1 to 19 and a dry powder inhaler.