RU2795231C2 - New carrier particles for dry powder compositions for inhalation - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to carrier particles suitable for use in dry powder formulations for inhalation. Spray-frozen carrier particles based on mannitol as a carrier for dry powder formulations for inhalation, the said particles having a mass diameter in the range of 30 to 300 micrometers, the said particles having a shape factor of 0.80 to 1.15; moreover, these particles are obtained by a method including heating mannitol until complete melting; spraying the molten mannitol through the injection nozzle into the spray freezing chamber to form droplets; cooling the droplets so as to cause curing and particle formation; separating the obtained particles; and carrying out a particle conditioning step. Also a method for producing frozen spray particles, a pharmaceutical composition, a method for producing a pharmaceutical composition, an inhaler, and a package are disclosed.

EFFECT: group of inventions provides the ability to contain high amounts of micronized medicinal products while maintaining the effectiveness of the aerosol without the use of fine excipient particles and/or fine additives.

18 cl, 6 dwg, 3 tbl, 3 ex

Description

FIELD OF TECHNOLOGY

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

STATE OF THE ART TO which THE INVENTION RELATES

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

Compared to oral medications, only relatively small doses are needed for effective therapy because first pass metabolism is bypassed and/or greatly reduced.

Such small doses reduce the effect of the drug on the body and minimize side effects. Systemic adverse events are also reduced as local pulmonary delivery directs the drug directly to the site of action. Lower dosage regimens can also provide significant savings, particularly when it comes to expensive therapeutics.

Effective delivery to the lungs requires that the drug particles have a particle size in the range of a few micrometers, typically 1-5 micrometers.

Dry powder formulations are typically formulated by mixing the drug with coarse carrier particles, providing an ordered mixture where the micronized active particles adhere to the surface of the carrier particles while in the inhaler.

The carrier makes the micronized powder less sticky and improves its fluidity, making it easier to process the powder during the manufacturing process (pouring, filling, dosing, etc.). In addition, the carrier acts as an excipient when the therapeutic dose of the drug is in the microgram range.

During inhalation, the drug particles are detached from the surface of the carrier particles and penetrate into the lower lungs, while the larger particles of the carrier are mainly deposited in the oropharyngeal cavity.

Detachment of drug particles from the surface of the carrier is considered the most important factor that determines the availability of the drug to the lungs. This may depend on the mechanical stability of the powder mixture and how this is affected by the adhesion characteristics between the drug and the carrier and the external forces required to break the non-covalent bonds formed between the adherent particles. Too strong bonds between adherent particles can actually prevent the separation of micronized drug particles from the surface of the carrier particles.

In this area have been proposed various approaches aimed at modulating adhesion, to facilitate the separation of drug particles from carrier particles and, thus, increase the respirable fraction. For example, in order to achieve this goal, the addition of excipient particles and/or fine additives with lubricating or anti-adhesive properties (hereinafter collectively referred to as fine particles) has been proposed as a solution to a technical problem. As a rule, said fine particles have a size of less than 50 micrometers, preferably less than 20 micrometers.

However, since the fine particles have poor fluidity, the fluidity of the respective powder formulations tends to deteriorate as the content of the fine particles increases.

On the other hand, the inhalation route is increasingly being used to administer active ingredients in rather high single doses.

This becomes a difficult task since it is well known that the higher the dose, and thus the concentration of the active ingredient, the higher the risk of formation of rough agglomerates (i.e., micronized drug particles held together by strong cohesive forces), which are unfavorable with in terms of being able to achieve good uniformity of drug distribution in the powder mixture and thus high dose accuracy, as well as acceptable deaggregation upon inhalation by the patient. Moreover, the higher the dose and thus the concentration of the active ingredient, the higher is the amount of fine particles required for a satisfactory respirable fraction.

A high amount of micronized active ingredient and/or fine particles of excipient can adversely affect the flowability of the respective formulation, which in turn can affect the device's ability to deliver the correct dose upon activation of the inhaler.

Thus, it would be advantageous to provide carrier particles capable of accommodating fairly high amounts of micronized drugs without compromising the flowability of the respective powder formulations.

It would be even more advantageous to provide carrier particles capable of accommodating fairly high amounts of micronized drugs while maintaining good aerosol efficiency without the use of fine excipient particles and/or fine additives.

The problem is solved by the carrier particles of the present invention and methods for their preparation.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to melt-spray solidified particles (e.g., spray-frozen) made from mannitol for use as a carrier for dry powder formulations for administration by inhalation, said particles having a mass diameter in the range of 10 to 300 micrometers. , and said particles have a regular shape having a shape factor of 0.80 to 1.00, preferably 0.90 to 1.00, more preferably 0.95 to 1.00.

In a second aspect, the invention relates to the carrier particles described above obtained by a process comprising the steps of:

i) heating the mannitol until completely melted;

ii) spraying the molten mannitol through a suitable nozzle into the spray freezing chamber to form droplets;

iii) cooling the droplets so as to cause curing and particle formation,

iv) separating the obtained particles; And

v) performing a particle conditioning step.

In a third aspect, the invention relates to the carrier particles described above obtained by a process comprising the steps of:

i) heating the mannitol until completely melted;

ii) spraying the molten mannitol through a suitable nozzle into the spray freezing chamber to form droplets;

iii) cooling the droplets so as to cause curing and particle formation,

iv) separating the obtained particles; And

v) performing a particle conditioning step.

In a fourth aspect, the invention relates to a process for preparing the claimed spray-frozen particles, said process comprising the following steps:

i) heating the mannitol until completely melted;

ii) spraying the molten mannitol through a suitable nozzle into the spray freezing chamber to form droplets;

iii) cooling the droplets so as to cause curing and particle formation,

iv) separating the obtained particles; And

v) performing a particle conditioning step.

In a fifth aspect, the invention relates to a pharmaceutical composition in the form of a dry powder for inhalation containing particles of the carrier according to the invention and one or more active ingredients.

In a sixth aspect, the invention relates to a dry powder inhaler filled with the above dry powder pharmaceutical composition.

In a seventh aspect, the invention relates to a process for the preparation of the aforementioned pharmaceutical composition comprising the step of mixing the carrier particles of the invention with one or more active ingredients in a high shear mixer.

In a further aspect, the invention also relates to a package containing a dry powder pharmaceutical formulation of the invention and a dry powder inhaler.

DEFINITIONS

Unless otherwise indicated, the terms "active drug", "active ingredient", "active" and "active substance", "active compound" and "therapeutic agent" are used as synonyms.

The term "microns" is used as a synonym for "micrometers".

In general terms, particle size is quantified by measuring the characteristic equivalent diameter of the spheres, known as the volumetric diameter, by means of laser diffraction.

Particle size can also be quantified by measuring the mass diameter using suitable devices and methods known to the person skilled in the art, such as sieving.

Volume diameter (VD) refers to mass diameter (MD) multiplied by particle density (assuming size is independent of particle density).

Alternatively, particle size can be expressed in terms of bulk diameter. In particular, the particle size distribution can be expressed in terms of: i) volume median diameter (VMD), which corresponds to the diameter of 50 percent by weight of the particles, for example, d(v0.5), and ii) volume diameter (VD) in micrometers 10 % and 90% particles, respectively, for example, d(v0.1) and d(v0.9).

The term "fine particles" refers to particles having a median volume diameter, preferably below 20 micrometers, more preferably below 15 micrometers, made from a physiologically acceptable excipient and/or made from an additive with lubricating or anti-adhesive properties, or mixtures thereof.

The term "good flow properties" refers to a formulation that is easy to process during manufacture and that is capable of providing accurate and reproducible delivery of a therapeutically effective dose.

Flow characteristics can be assessed by measuring the Carr index; a Carr index of less than 25 is generally considered to indicate good flow characteristics.

Alternatively, the flow characteristics can be evaluated by measuring the flow function coefficient (ffc) using a powder rheometer shear cell module. According to the ffc value, the powder can be classified as solid (ffc ≤ 1), highly cohesive (ffc 1-2), cohesive (ffc 2-4) to free flowing (ffc 4-10) and free flowing (ffc ≥ 10). A value above 10 is generally considered to indicate a free-flowing powder and good flow characteristics.

The term "good uniformity" refers to a formulation where, when mixed, the uniformity of the active ingredient content, expressed as relative standard deviation (RSD), is less than 5%.

The expression "physically stable in the device prior to use" refers to a formulation where the active particles do not substantially separate and/or detach from the surface of the carrier particles both during dry powder production and in the delivery device prior to use.

The expression "respirable fraction" refers to the percentage of particles of the active ingredient that can reach the deep regions of the lungs of patients. The respirable fraction, also referred to as the fine particle fraction (FPF), is usually assessed using a suitable in vitro device, typically a multi-stage cascade impactor or multi-stage liquid impinger (MLSI), rapid screening impactor (FSI) or latest generation impactor (NGI) according to with the methods described in common pharmacopoeias. It is calculated from the ratio between the inhaled dose and the delivered (released) dose.

The delivered dose is calculated from the cumulative drug deposition on the stages of the device, while the inhaled dose (fine particle dose) is calculated from the deposition on the stages corresponding to particles having a diameter of < 5.0 micrometers. One of skill in the art may use other parameters, such as inspiratory flow, in accordance with the guidance described in the commonly used pharmacopoeias.

An inhalable fraction above 30% is a sign of good inhalation efficiency.

The term "therapeutic amount" means the amount of an active ingredient which, when delivered to the lungs via a dry powder formulation as described herein, provides the desired biological effect.

"Single dose" means the amount of active ingredient administered at one time by inhalation when the inhaler is triggered.

"Firing" means the release of the active ingredient from the device through a single activation (eg, mechanical or inhalation).

The definition of "reasonably high single therapeutically effective dose" means a nominal dose equal to or greater than 800 micrograms (mcg).

The term "high shear mixer" refers to a mixer that uses a rotor or blade, together with a stationary component known as a stator, in a vessel containing the powder to be mixed to provide shear.

The term "mannitol" refers to the three polymorphs of mannitol: α, β and δ. The β form is a thermodynamically stable form at 20° C. and above. Form δ is the form with the lowest melting form of mannitol. The δ form is thermodynamically unstable and can spontaneously convert to the more thermodynamically stable β form. The polymorphic transition from δ to β can be triggered, for example, by moisture.

FIGURES

1 is a schematic diagram of a spray freezing device.

Figure 2 - SEM images of mannitol particles.

Fig.3 -pattern WAXS for spray-frozen mannitol for 6 months (stability test).

Fig.4 -pattern WAXS for spray-frozen mannitol after production and after conditioning.

Fig.5 -pattern WAXS for spray-frozen mannitol after production and after conditioning (zoom).

Fig.6 - Images obtained using optical microscopy.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to spray-frozen particles made from mannitol for use as a carrier for dry powder formulations for inhalation.

Spray freezing, also known as spray cooling, is a solvent-free process that converts the melt into well-defined spherical particles.

A representative schematic diagram of the spray freezing apparatus is shown in Fig. 1:

The molten sample is fed from the heated liquid container (1) to the heated nozzle (2) which atomizes the sample into the freezing chamber (3). The heated nozzle and the heated container are connected to compressed gas supply lines (4) and (5). Air is supplied to the top of the freezing chamber (3) through an inlet HEPA filter (high efficiency air filter) (6) connected to a heat exchanger (7) and a cooling element (8). The air from the chamber (3) is expelled through the HEPA outlet filter (9) and fan (10) to the outlet (11).

The dry particles are withdrawn from the bottom of the freezing chamber (3) through an outlet pipe (12) into which compressed gas is supplied from the gas supply lines (13) and (14).

You can use another similar device that works on the same principles.

Mannitol is used in view of the fact that, in contrast to other sugars such as lactose, there is no degradation during melting.

All particles have a particle size, expressed as a mass or volume diameter, in the range of 10 to 300 micrometers, preferably 20 to 280 micrometers, more preferably 30 to 250 micrometers.

In a preferred embodiment of the invention, when the size is expressed as a volume diameter, the particle size distribution of the support satisfies the following parameters: d(v,0.1) ranging from 25 to 45 micrometers, d(v,0.5) ranging from 70 and 110 micrometers, and d(v,0.9) ranging from 150 to 220 micrometers.

The particle size distribution range for said carrier particles, expressed as a range, can advantageously be from 1.3 to 2.2, preferably from 1.6 to 2.0. According to Chew et al. J Pharm Pharmaceut Sci 2002, 5, 162-168, the range is [d(v,0.9) - d(v,0.1)]/d(v,0.5).

The shape factor is used to characterize the shape of the carrier particles of the invention.

The carrier particles of the invention thus have a shape factor of 0.80 to 1.00, preferably 0.90 to 1.00, more preferably 0.95 to 1.00.

The shape factor can be determined from the following equation described in Kumar S et al Curr Appl. Phys. Influence of metal powder shape on drag coefficient in a spray jet, 2009, 9, 678-682

SF=1/RN

Where:

RN indicates the roundness of particles and is calculated using the following formula:

where p and A are the average perimeter and area, respectively, for ten spherical particles as determined on images obtained by scanning electron microscopy (SEM).

Alternatively, the average perimeter and area can be determined using an optical microscope.

In Kumar S et al. it is described that the shape factor (SF) of the circle is 1.00. It also describes that deviation from unity results in particle irregularity, but particles with an SF value greater than 0.8 can be considered to be spherical.

In a typical embodiment, the resulting carrier particles exhibited an aspect ratio of 0.986 as measured by Malvern Morphology G3 Ver. 8.12 (Malvern Instruments Inc, Pennsylvania, USA).

Scanning electron (SEM) or optical microscopy can also be used to quantify the characteristics of the powder microparticles of the invention, such as particle shape and surface morphology.

The carrier particles of the invention exhibit improved fluidity which can be measured, for example, using an FT4 powder rheometer (Freeman Technology, Tewkesbury, UK). The carrier particles of the invention thus have an ffc value above 10, typically between 14 and 16.

Also, several other methods can be used to characterize the carrier particles of the invention, such as true density, apparent and bulk density, and specific surface area.

The true density of the particles according to the invention can be determined using helium pycnometry (pycnometer: AccuPyc II 1340, Micromeritics, Norcross, GA, USA) according to the following procedure: blowing 20 times at 19.5 psi. inch (134.5 kPa) and five analytical runs at 19.5 psi. inch (134.5 kPa) at a trim rate of 0.0050 psi. in/min (34.5 Pa/min). The volume of the particles was determined, allowing the calculation of the density of the particles.

As a rule, the true density is from 1.3 to 1.6 g/cm ³ , preferably from 1.4 to 1.5 g/cm ³ .

Apparent and bulk density can be determined by known methods.

For example, the sample was placed in a 10 ml cylinder until 70-90% volume was reached (the exact mass and height of the cylinder were recorded).

The apparent bulk density (ABD) was determined by the formula

ABD=M/V0 (expressed in g/ml)

where M is the mass of the sample and V0 is the initial volume of the sample in the cylinder.

Typically, the apparent bulk density is between 0.55 and 0.75 g/ml, preferably between 0.6 and 0.7 g/ml.

An increasing number of taps were used: 10, 40, 50, 100, 300, 250 and 500 and the corresponding bulk volume was recorded. The assay was terminated at a total of 1250 taps if the pitch did not change between 250 and 500 taps: if a change was observed an additional 1250 taps were added until equilibrium was reached.

Bulk bulk density (TBD) was measured using the following formula:

TBD=M/Vt (expressed in g/ml)

where M is the mass of the sample and Vt is the final volume of the sample in the cylinder.

Typically, the bulk density is 0.7 to 0.9 g/ml, preferably 0.75 to 0.85 g/ml.

From IBD and TBD, the Carr index can be calculated using the following formula:

Carr Index=100×(TBD-IBD)/TBD (expressed in %)

Values have generally been found to be well below 25, indicating that the carrier particles of the invention are endowed with good flow characteristics.

The specific surface area can be determined by the Brunauer-Emmett-Teller (BET) nitrogen adsorption method according to a known technique.

The specific surface area of the carrier particles according to the invention is from 0.09 to 0.26 m ² /g, preferably from 0.10 to 0.20 m ² /g.

Surprisingly, pharmaceutical formulations containing carrier particles of the invention can provide good aerosol performance without the use of excipient particles and/or finely divided additives.

Moreover, if mixing takes place in a high shear mixer for a short mixing time (equal to 20 minutes or less), these formulations show good uniformity of the active ingredients to be delivered at fairly high doses, for example 800 micrograms per inhaler actuation.

However, good uniformity can also be achieved by subjecting the powder to longer mixing times using conventional mixers.

These optimum characteristics are the result of the process used to obtain the carrier particles.

Thus, the invention relates to a process for preparing carrier particles according to the invention, the process comprising the following steps:

i) heating the mannitol until completely melted;

ii) spraying the molten mannitol through a suitable nozzle (2) into the chamber (3) to freeze the spray to form droplets;

iii) cooling the droplets to induce curing and particle formation,

iv) separating the obtained particles;

v) carrying out a particle conditioning step.

Mannitol is commercially available and can be used in each of its crystalline polymorphic forms (α, β and δ form) and/or mixtures thereof, as well as in amorphous and/or crystalline form, as well as mixtures thereof.

A spray freezing device is commercially available from, for example, ProCepT (Zelzate, Belgium).

Advantageously, in step i) the mannitol is heated to a temperature of at least 185°C, preferably 190 to 200°C under vacuum.

In step ii), a two-fluid nozzle can be used as a suitable nozzle.

Alternatively, other types of nozzles such as an ultrasonic atomizer and a rotary atomizer can advantageously be used.

Parameters regarding the type of nozzle, its internal diameter, pressure and spray rate, can be changed by a person skilled in the art depending on the batch size.

Typically, to obtain carrier particles of the stated particle size, the internal diameter of the two-fluid nozzle is 1.2 mm and the spray rate is adjusted to a range of 18.3 to 21.5 g/min. The air in the nozzle is adjusted to 5 l/min, which corresponds to a pressure of 0.44 bar.

Cooling of the droplets in step iii) can be achieved by ambient temperature or by using cooling air during spraying at a temperature of at least -10 to -20°C.

In some devices it is possible to solidify the particles by melt spraying by pouring droplets into liquid nitrogen.

In step iv) the particles are separated from the gas stream, for example in a cyclone and/or a filter bag.

Since the formation of the metastable δ form of mannitol occurs during curing, the particles in step v) are subjected to a conditioning step to convert the metastable form to the stable β form.

Advantageously, the conditioning step is carried out by exposing the powder at room temperature in a closed chamber with a relative humidity of 90-97%, preferably 93%, for 12-48 hours, preferably 24 hours.

Desired humidity environments can be achieved with a brine solution of potassium sulfate or potassium nitrate, preferably potassium nitrate.

Monitoring of the transition from the δ-form to the β-form can be carried out by analysis of DSC and or WAXS in accordance with techniques known to the person skilled in the art.

After converting the entire δ-form to more stable polymorphs, no further changes are observed.

Wide Angle X-Ray Scattering (WAXS) can be used to determine the crystallinity and polymorphs of powder samples. The measurement should be carried out at room temperature using the S3 point focus camera system - MICRO camera (Bruker AXS GmbH, Germany). Samples should be filled into glass capillaries with a diameter of 2 mm and analyzed with constant rotation (9 rpm) for 600 s at 30 pulses/s.

WAXS results after conditioning may show the disappearance of the characteristic δ-form Bragg peak at approximately 22° and the appearance of the most pronounced Bragg peak for the β-form at approximately 23°. In this case, it can be concluded that the chosen conditioning technique was successful in achieving the desired transition from the δ to the β polymorph.

Alternatively, a differential scanning calorimeter (DSC 204F1 Phoenix®, Netzsch GmbH, Selb, Germany) can be used for solid phase characterization with the following parameters.

- Mass of samples 10-12 mg (n=3)

- closed aluminum containers with perforated lids

- heating from 25 to 200°C at a heating rate of 10°C/min using pure nitrogen as purge gas at a flow rate of 20 ml/min.

The mannitol particles are present in substantially crystalline form.

Advantageously, the degree of crystallinity, expressed as mass % of crystalline particles relative to the total mass of particles, is greater than 90%, preferably greater than 95%.

Crystallinity and its degree can be determined using X-ray powder diffraction or other methods known to those skilled in the art such as differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) or microcalorimetry.

The conditioned carrier particles appear to be physically stable for at least 6 months at room temperature, making it possible to provide stable pharmaceutical formulations.

Thus, the invention also relates to a pharmaceutical composition in the form of a dry powder for inhalation, containing particles of the carrier according to the invention in a physical mixture with one or more active ingredients.

The active ingredient can be virtually any pharmaceutically active compound that can be administered by inhalation in the form of a dry powder.

For the active substance to be inhalable, i. e. could pass into deep regions of the lung, such as terminal and respiratory bronchioles and alveolar ducts and sacs, it should be in the form of particles having an average particle diameter (measured as a mass mean diameter) of no more than about 10 micrometers, for example, from 1 to 10 micrometers, and preferably 1 to 6 micrometers. Such micronized particles can be prepared in a manner known per se, for example by micronization, controlled precipitation from certain solvents, spray drying, supercritical fluids, or according to the methods described in WO 2004/073827, WO 2008/155570, WO 2008/114052 and WO 2010/007447.

The therapeutic amount of the active substance may vary over a wide range depending on the nature of the active substance, the type and severity of the condition being treated and the condition of the patient in need of treatment.

In general, the active substance particles are added to the carrier particles of the invention by mixing using known techniques, preferably in a high shear mixer.

Typical high shear mixers are P 100 and P 300 (Diosna GmbH, Germany), Roto Mix (IMA, Italy) and Cyclomix ^TM (Hosokawa Micron Group Ltd, Japan).

In particular, the mixer rotation speed and mixing time can be adjusted by one skilled in the art to achieve a highly uniform distribution of the active ingredient in the formulation.

Typically, excellent uniformity of active ingredient distribution is achieved in a high shear mixer using a mixing time of at least 5 minutes and a speed of 100-500 rpm, preferably 20 minutes at a speed of 100-250 rpm.

As an example, the active ingredients can be selected from short acting and long acting beta ₂ agonists such as terbutaline, reproterol, salbutamol, salmeterol, formoterol, carmoterol, milveterol, indacaterol, olodaterol, fenoterol, clenbuterol, bambuterol, broxaterol, epinephrine, isoprenaline. or hexoprenaline or their salts and/or solvates; short acting and long acting anticholinergics such as tiotropium, ipratropium, oxitropium, oxybutynin, aclidinium, trospium, glycopyrronium or the compounds known under the codes GSK 573719 and GSK 1160274, in the form of their salts and/or solvates; bifunctional muscarinic receptor beta 2 agonist antagonist (MABA) compounds for inhalation, such as GSK 961081; neutrophil elastase inhibitors such as ONO-6818 and MK0339; p38 map kinase inhibitors such as VX-702, SB-681323 and GW-856553; short acting and long acting corticosteroids such as butixocart, rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its ester, i.e. furoate, flucatisone and its ester, i. e. propionate and furoate, beclomethasone and its ester, i.e. propionate, loteprednol or triamcinolone acetonide and its solvates; leukotriene antagonists such as andolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; phosphodiesterase inhibitors such as filaminast, piclamylast or roflumilast; a PAF inhibitor such as apafant, rorapafant or israpafant; pain relievers such as morphine, fentanyl, pentazocine, buprenorphine, pethidine, tilidine or methadone; potency-enhancing agents such as sildenafil, alprostadil, or phentolamine; or a pharmaceutically acceptable derivative or salt of any of the above compounds or classes of compounds. When any of these compounds possess chiral centers, the compounds may be used in optically pure form, or they may be presented as diastereomeric mixtures or racemic mixtures.

Dry powder formulations may also contain as active ingredients antibiotics such as ciprofloxacin, levofloxacin and colistin, tobramycin, amikacin and gentamicin; proteins such as insulin and α1-antitrypsin; antivirals such as zanamivir and ribavirin; antifungals such as itraconazole; and phosphodiesterase (PDE)-5 inhibitors such as sildenafil and tadalafil. Preferably, dry powder formulations for inhalation comprising the carrier particles of the invention and one or more active ingredients selected from the bifunctional compound classes of muscarinic beta 2 receptor antagonists (MABAs), neutrophil elastase inhibitors, p38 map kinase inhibitors, short acting corticosteroids and long-acting and phosphodiesterase inhibitors.

The concentration of the active ingredient in the powder formulation depends on the weight of the portion of the formulation delivered upon actuation of the inhaler.

For example, given an anticipated single dose of 800 micrograms, if the delivery weight of the composition upon actuation of the inhaler is 10 mg, this would correspond to an active ingredient concentration of 8% w/w.

Similarly, for a 20 mg serving weight, the active ingredient concentration is 4% w/v.

In a preferred embodiment, dry powder formulations containing carrier particles of the invention are particularly suitable for administering the active ingredients to be delivered in single doses per inhaler actuation in the range of 800 micrograms to 1 mg.

Although not necessary to achieve good aerosol performance, the powder formulation may further comprise a fine particle fraction having a median volume diameter of less than 20 micrometers, more preferably less than 15 micrometers, preferably less than 10 micrometers.

Said fine particles may be made from a physiologically acceptable excipient as defined above and/or may be made from an additional material selected from the class of anti-adhesives such as amino acids such as leucine and isoleucine, or from the class of lubricants such as magnesium stearate; sodium stearyl fumarate, stearyl alcohol, stearic acid and sucrose monopalmitate.

In a specific embodiment, the fine particles may be composed of physiologically acceptable excipient particles and additive particles in any ratio and are prepared as described in WO 01/78695.

In another embodiment, the fine particles may consist of a mixture of 90 to 99.5 percent by weight of alpha-lactose monohydrate particles and 0.5 to 10 percent by weight of magnesium stearate, wherein at least 90% of said particles have a volume diameter of less than 12 micrometers, and the volume median diameter of these particles is from 4 to 6 micrometers.

These fine particles can be added to the composition and mixed by known methods.

The dry powder formulation for inhalation containing the carrier particles of the invention may be used with any dry powder inhaler.

Dry powder inhalers can be generally classified into: i) single dose (single dose) inhalers, for administering single divided doses of the active compound; ii) multi-dose metered dose inhalers or reservoir inhalers pre-loaded with quantities of the active substance sufficient for longer courses of treatment.

Dry powder formulations may be provided in unit dosage form. Dry powder formulations for topical delivery to the lungs via inhalation may be provided in capsules and cassettes, eg gelatin, or blisters, eg aluminum foil laminates, for use in an inhaler or insufflator.

The dry powder inhalation formulation of the invention is particularly suitable for multi-dose dry powder inhalers containing a reservoir from which individual therapeutic doses can be withdrawn as needed by actuating the device.

A preferred multi-dose device is the inhaler described in WO 2004/012801, in particular from page 1, first line to page 39, last line.

Other multi-dose devices that can be used are, for example, ELLIPTA ^TM or DISKUS ^TM from GlaxoSmithKline, TURBOHALER ^TM from AstraZeneca, TWISTHALER ^TM from Schering and CLICKHALER ^TM from Innovata.

As commercially available examples of single dose devices, mention may be made of ROTOHALER ^TM from GlaxoSmithKline and HANDIHALER ^TM from Boehringer Ingelheim.

The following examples illustrate the invention in detail.

Example 1 - Preparation of carrier particles based on mannitol according to the invention

Mannitol Pearlitol 300DC was purchased from Roquette (France).

A spray freezer available from ProCepT (Belgium) was used.

Received three different samples (60 g, 2×500 g, containing 4 times 125 g).

The mannitol was heated at 200°C under vacuum until completely melted and sprayed through a two-fluid nozzle with an inner diameter of 1.2 mm using cooling air in a chamber at a temperature of -7°C to -10°C (cooler with a set temperature of -20° C) into the freezing chamber.

The resulting particles (yield: approximately 45%) were separated from the gas stream in a cyclone.

The formation of δ-mannitol during spray freezing raised concerns about the stability of the final particles. In fact, the δ form is a metastable polymorph of mannitol that has 2 stable polymorphs (α and β). A one month stability test on a selected spray frozen batch showed that the δ form was detectable after WAXS conversion to the stable β or α form over time (FIG. 3). However, the δ-form can be successfully converted to stable β-mannitol using a post-spray freeze conditioning step (24 h at 93% RH set using brine potassium nitrate in a closed chamber) (FIGS. 4 and 5). The conditioned material is stable up to 6 months (FIG. 3).

Particle morphology was examined using a scanning electron microscope (SEM) (Zeiss Ultra 55, Zeiss, Oberkochen, Germany) operating at 5 kV. Samples before analysis were placed on a carbon tape and they were sputtered with gold-palladium (figure 2).

Shape factor analysis was performed as follows. A sample of the spray-frozen powder was isolated with a graduated spatula (19 mm ³ sample), an aliquot was placed in a Morphology G3 sample holder (imaging analysis system using optical microscopy, Malvern Morphology G3 Ver. 8.12) and spread on a specialized glass slide under controlled pressure (1 bar ) using a specialized distribution chamber. Image analysis was performed using a 5x objective on a selected area (rounded area with a radius of 25 mm) to ensure that at least 20,000 particles were measured. Measurement parameters were set to obtain individual particles for shape analysis and any sampling anomalies, i.e. many particles have been removed by the software filter.

Roundness ratio (RN) was determined using the equation RN=p2/4πA, where p is the perimeter and A is the area. Particle shape factor (PSF) was calculated using Morphology software using the 1/RN equation (this factor is called HS Circularity according to Malvern Morphology terminology). The powder had a uniform spherical morphology demonstrated by optical microscopy and SEM images (FIGS. 2 and 6). Particle Shape Factor (PSF) determined by image analysis of ~40,000 individual particles provided an average value of 0.986 and confirmed the spherical morphology of the particles.

The physical state was examined by WAXS at room temperature using a camera system with a point focusing S3 - MICRO camera (Bruker AXS GmbH, Germany). The samples were filled into glass capillaries 2 mm in diameter and analyzed at constant rotation (9 rpm) for 600 s at 30 pulses/s.

WAXS results indicate that the conditioned sample peak pattern found corresponds to a mixture of α and β polymorphs (δ-mannite gives rise to β-mannite), predominantly α (Burger at al., Journal of Pharmaceutical Science, 2000, Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol).

Characterization of the properties of fine particles was carried out in accordance with the following methods.

The particle size was determined by laser diffraction using an R1 lens (Sympatec HELOS). A sample of the powder was dispensed for two measurement conditions using an air pressure of 0.5 and 3 bar, respectively (Sympatec RODOS) and sampled at a speed of 5 m/s from a temperature and humidity controlled dosing element (Sympatec ASPIROS). Mean values d[v.10], d[v.50], d[v.90] were measured by measuring in triplicate.

The span was calculated using the following equation:

Range= [d(v, 0.9) - d(v,0.1)]/d(v,0.5)

The specific surface area of mannitol particles was studied using a Micromeritics Tristar II 3020 (Norcross, USA). All samples were vacuum dried for two days at 25°C using a Micromeritics VacPrep 061 degassing element (Norcross, United States). The measurement was carried out using isotherms of adsorption and desorption of nitrogen at the temperature of liquid N ₂ (-196°C); Brunauer, Emmett and Teller (BET) adsorption theory (Emmett, 1936) was used to calculate the specific surface area, using a pressure range of 0.05-0.30 normalized to the saturation pressure of the adsorbate.

1.5 g of powder was used, which resulted in BET correlation coefficients above 0.999, indicating the applicability of the method. Each measurement was carried out in triplicate.

True density was determined by helium pycnometry (AccuPyc II 1340, Micromeritics, USA). Powder samples were accurately weighed and their volume measured over five consecutive runs using 20 gas purges at 19.5 psi. inch (134.5 kPa) and a trim rate of 0.005 psi. in/min (34.5 Pa/min). The particle density was calculated as the ratio of the mass and volume of the samples.

The characteristics of the three parties are presented in table 1.

Table 1

Batch Scale 60g Batch 500 g n.1 Lot 500 g n.2 Specific surface area (m ² /g) 0.1621 0.1467 0.1173 True density (g / cm ³ ) 1.4373 1.4533 1.4569 PSD (X ₁₀ - µm) 31.07 32.0 31.2 PSD (X ₅₀ - µm) 94.08 89.0 88.3 PSD (X ₉₀ - µm) 208.20 189.6 184.1 PSD (SPAN - µm) 1.8 1.8 1.7

Example 2 - Preparation of compositions containing particles of the carrier according to the invention

Compound 1-(S)-1-[(3-cyclopropylmethoxy-4-difluoromethoxy)phenyl]-2-[(3,5-dichloro-1-oxy)-4-pyridinyl]ethyl ester 3-cyclopropylmethoxy-4-[ (methanesulfonyl)-amino]benzoic acid, hereinafter referred to as CHF 6001, was obtained by the method described in WO 2010/089107.

Mannitol particles were prepared as described in Example 1.

Compositions CHF 6001 (batch size 25 g), containing 4% wt./mass. The drug was obtained by mixing in a high shear mixer (Hosokawa Lab Cyclomix, Japan) for 20 min at 100 rpm or 250 rpm.

The homogeneity of the obtained mixtures was checked at the end of the mixing procedure. For each composition, ten samples (from 20 to 60 mg each) were collected from different points of the powder layer. Each sample was dissolved in 50 ml of the appropriate solvent (CH ₃ CN/water, 60:40 v/v solution) and the drugs were quantified by HPLC-UV.

Homogeneity was taken as a coefficient of variation (calculated as a percentage of the ratio of the standard deviation to the mean for ten measurements) below 5%. The result of the analysis is expressed as a % relative to the theoretical claimed content.

The results are presented in table 2.

Table 2 .

The consignment Mixing time (min) Mixing speed (rpm) Analysis (%) RSD (%) Party 1 20 100 96.6 3.9 Party 2 20 250 97.0 1.5 Party 3 20 250 96.8 0.9

Example 3 - Aerodynamic performance in vitro

The powder formulation of Example 3 was characterized in terms of aerosol characteristics after being loaded into the multi-dose dry powder inhaler described in WO 2004/012801 and known as the ^NEXThaler® . The average ejection mass of the composition depends on the density of the powder, and for this composition it is approximately 20 mg. The nominal dosage in the tested formulation (drug loading 4% w/w) corresponds to 800 µg/20 mg burst.

In vitro aerodynamic evaluation was performed using a Next Generation Impactor (NGI, Copley Scientific, UK) equipped with a USP induction port, a pre-separator, seven compaction stages, and a micro-perforated final manifold.

After completion of assembly, the NGI was connected to a vacuum pump (and the flow rate through the impactor was measured using a mass flow meter).

The critical flow (P ₃ /P ₂ ratio) was ≤ 0.5 at a sampling flow rate of 60 ml/min.

After connecting the device to the impactor through an airtight rubber tube, the vacuum pump was activated at a flow rate of 60 l/min for 4 seconds, so that 4 l of air according to Ph. Eur. 8.0, 2.9.18.

CHF 6001 drug deposited in each impactor cell was recovered from the NGI using CH ₃ CN:H ₂ O solvent (60:40% v/v) fed into the induction port (including -50 ml nozzle) , pre-separator (100 ml) and each well (10 ml). All samples were analyzed by HPLC-UV.

The aerodynamic particle size distribution was based on 2 triggers from the ^NEXThaler® , the multi-dose device described in WO 2004/012801, and in particular from page 1, first line to page 39, last line), in each case sampling carried out in 4 liters of air (equivalent to an inhalation time of 4 s).

Aerodynamic characteristics were evaluated by calculating:

- the delivered dose (ED), obtained as the sum of the parts of the drug extracted in all parts of the impactor, expressed in μg, and its percentage relative to the nominal dose;

- fine particle mass (FPM), namely the amount of drug with a threshold diameter below 5 µm, calculated by interpolation according to the European Pharmacopoeia (Ph. Eur. 8.0, 2.9.18.) and expressed in µg;

- fine particle fraction (FPF), calculated as the ratio of FPM to ED, expressed as a percentage;

- mean mass aerodynamic diameter (MMAD), calculated as the median value of the mass distribution of airborne particles relative to the aerodynamic diameter.

Aerosol characterization results are presented in Table 3.

Table 3

The consignment Mixing time (min) Mixing speed (rpm) Theoretical dose, mcg ED, µg ED% FPM, mcg FPF % MMAD
(µm) Party 1 20 100 800 770.8 96.35 320.5 41.6 2.1 Party 2 20 250 800 768.1 96.01 322.2 41.9 2.0

As can be appreciated, good aerosol performance was achieved for all formulations, with FPF well above 40%.

Excellent values have been achieved in terms of percentages of doses emitted.

Similar results regarding the percentage of dose emitted were achieved by replacing CHF 6001 with beclomethasone dipropionate at the same nominal dose per release (800 µg/20 mg).

Claims (29)

1. Spray-frozen carrier particles based on mannitol as carrier for dry powder formulations for inhalation, said particles having a mass diameter in the range of 30 to 300 micrometers, said particles having a shape factor of 0.80 to 1.15 ; moreover, these particles are obtained by a method including: i) heating the mannitol until completely melted; ii) spraying the molten mannitol through the injection nozzle (2) into the chamber (3) to freeze the spray to form droplets; iii) cooling the droplets so as to cause curing and particle formation; iv) separating the obtained particles; And v) carrying out a particle conditioning step. 2. Spray-frozen mannitol-based carrier particles according to claim 1, wherein the aspect ratio is from 0.90 to 1.10. 3. Spray-frozen mannitol-based carrier particles according to claim 1 or 2, wherein the aspect ratio is from 0.95 to 1.05. 4. Spray-frozen mannitol-based carrier particles according to any one of claims 1 to 3, wherein the mass diameter is from 30 to 280 micrometers. 5. Spray-frozen mannitol-based carrier particles according to claim 4, wherein the mass diameter is from 30 to 250 micrometers. 6. Spray-frozen mannitol carrier particles according to any one of the preceding claims, having a specific surface area of 0.09 to 0.26 m ² /g. 7. Spray-frozen mannitol carrier particles according to any one of the preceding claims, having a true density of 1.3 to 1.6 g/cm ³ . 8. The spray-frozen mannitol-based carrier particles of claim 1, wherein the conditioning step is carried out by exposing the powder, at room temperature in a closed chamber, to 90-97% relative humidity conditions for 12-48 hours. 9. A method for producing spray-frozen mannitol-based carrier particles having a mass diameter in the range of 30 to 300 micrometers and characterized by a shape factor of 0.80 to 1.15, comprising the following steps: i) heating the mannitol until completely melted; ii) spraying the molten mannitol through the injection nozzle (2) into the chamber (3) to freeze the spray to form droplets; iii) cooling the droplets so as to cause curing and particle formation; iv) separating the obtained particles; And v) performing a particle conditioning step. 10. The method of claim 9, wherein the conditioning step is carried out by exposing the powder, at room temperature in a closed chamber, to conditions of 90-97% relative humidity for 12-48 hours. 11. A pharmaceutical composition in the form of a dry powder for inhalation, comprising spray-frozen particles of a mannitol-based carrier according to any one of claims 1 to 8 in a physical mixture with one or more active ingredients. 12. A method for preparing a pharmaceutical composition according to claim 11, comprising the step of mixing the spray-frozen particles with one or more active ingredients in a high shear mixer. 13. Dry powder inhaler filled with the dry powder pharmaceutical composition of claim 11. 14. A package containing the dry powder pharmaceutical formulation of claim 11 and a dry powder inhaler. 15. Spray-frozen mannitol-based carrier particles according to any one of claims 1 to 8, wherein said particles consist of mannitol. 16. Spray-frozen mannitol-based carrier particles according to any one of claims 1 to 8, wherein said particles consist essentially of mannitol. 17. The method of claim 9, wherein the particles consist of mannitol. 18. The method of claim 9, wherein the particles consist essentially of mannitol.

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