WO2022023456A1

WO2022023456A1 - Pharmaceutical compositions comprising nano embedded microparticles and methods of use

Info

Publication number: WO2022023456A1
Application number: PCT/EP2021/071229
Authority: WO
Inventors: Ida Christina HOVDAL; Sandra Gracin; Annica Maarit JARKE; Mikael Johan Alvin BRÜLLS; Noemi GAGLIANONE; Ankur AJMERA
Original assignee: Astrazeneca Ab
Priority date: 2020-07-29
Filing date: 2021-07-28
Publication date: 2022-02-03

Abstract

Pharmaceutical compositions comprising nano embedded microparticles are provided herein, as well as methods of making said pharmaceutical compositions, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and/or non-respiratory diseases, and also kits.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING NANO EMBEDDED MICROPARTICLES AND METHODS OF USE

FIELD OF THE DISCLOSURE

[001] Pharmaceutical compositions comprising nano embedded microparticles are provided herein, as well as methods of making said pharmaceutical compositions, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and/or non-respiratory diseases, and also kits.

BACKGROUND OF THE DISCLOSURE

[002] Pulmonary delivery of active pharmaceutical ingredients (APIs) is a way to target drug delivery to the lungs with lower systemic side effects and higher local concentrations. In particular, this has been widely used for the treatment of respiratory diseases such as asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis. In recent years, there has been increased interest in pulmonary administration for systemic delivery of a variety of other drug products for other indications.

[003] For an API that is poorly soluble, lung absorption may be limited by slow dissolution, which may rate limit absorption after lung deposition and consequently influence clinical performance, such as safety, efficacy and duration of treatment. Reducing the API particle size to nanometre sizes typically of about 100-300 nm, rather than micrometre, increases the dissolution rate significantly and improves clinical performance. This is because nanoparticles can overcome biological barriers in the lung, such as pulmonary mucus and bacterial films, which are especially strong barriers in diseased states, by being able to permeate these barriers. This ability of API nano-sized particles to overcome biological barriers in the lungs is dependent on their physiochemical properties such as size, charge and hydrophobicity. Further, API nano-sized particles have been found to have reduced clearance from the lungs and can provide a sustained and controlled drug release. A sustained drug release is desired because it allows the reduction of dosing frequency and an improved API transport in mucus and biofilms in the lung reduces the required overall dose.

[004] However, there are practical challenges to deliver API nano-sized particles to the lungs due to the very strong adhesive forces between nano-sized particles, which can lead to aggregation of the nano-size particles to form larger sized particles thereby decreasing the surface area of the particles and consequently dissolution rate of the API. Further, nano-sized particles have unfavourable lung biodistribution upon inhalation because of their relatively small size and are typically exhaled, with only a small amount actually being deposited.

Microparticles, on the other hand, with an aerodynamic diameter of approximately 1-5 pm deposit to a high degree in the respiratory tract and have been studied as potential vehicles/carriers for delivering API nanoparticles into the lungs (C. A. Rugge et al., Surfaces B: Biointerfaces 139 (2016), 219-227). Pharmaceutical compositions, in particular dry powder formulations, based on such vehicles/carriers have been produced by embedding nanoparticles into microparticles and are known as nano-embedded microparticles (NEMs) or Trojan particles. [005] NEMs can be prepared by spray drying a nanosuspension of the APIs together with a matrix forming excipients, such as a bulking agent. Saccharides and/or sugar alcohols have been widely used as bulking agents due to their high aqueous solubility and low toxicity. Studies have shown that the selection of appropriate excipients, such as the bulking agent as well as dispersing agent/enhancer (e.g. leucine), can provide the desired aerodynamic properties of the NEMs and disintegration of the microparticles after deposition into the lungs, which upon re-dispersion in the lung fluid result in retention and release of the API nanoparticles into the lungs (A. Torge et al., European Journal of Pharmaceutical Sciences 104 (2017) 171-179; M. Agnoletti et al., European Journal of Pharmaceuticals and Biopharmaceuticals 120 (2017) 9-21; Arpagaus C (2018) Int J Med Nano Res 5).

[006] Further, the agglomeration/aggregation of the nanoparticles can be further prevented during preparation of the NEMs by the process of spray drying by using a surface modifier to change the charge and/or hydrophobicity of the nanoparticles to ensure an efficacious drug delivery (I. d’ Angelo et al., Colliods and Surface B: Biointerfaces 135 (2015) 717-725; C. Duret et al., International Journal of Nanomedicine 7 (2012) 5475-5489; and F. Ungaro et al., Journal of Controlled Release 157 (212) 149-159). However, presently no solution has been reported for also preventing and/or limiting an increase of the size of the API nano particles comprised within the NEMs during storage of the pharmaceutical composition, which would have a negative impact on its clinical performance.

[007] It is therefore an object of the present invention to provide pharmaceutical compositions with an increased stability, aerodynamic properties, as well as dissolution rate, re-dispersion of the nanoparticles upon delivery into the lung, and sustained drug release so as to improve drug delivery to the lungs and clinical performance. The pharmaceutical compositions described herein meet one or more of these objectives.

SUMMARY

[008] There is provided herein a pharmaceutical composition comprising nano embedded microparticles, methods of making the pharmaceutical composition, their use as medicaments, as well as kits.

[009] In one aspect, the pharmaceutical composition which is a dry powder formulation comprising microparticles, wherein said microparticles comprise a dispersing agent and nanoparticles; wherein the dispersing agent is trileucine; wherein said nanoparticles comprise an active agent and a surface modifier; and, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1 : 1 to about 20: 1 by weight.

[0010] In one aspect, there is provided a process (I) for the preparation of a pharmaceutical composition as described herein, wherein said process comprises the steps of:

(a) dissolving a surface modifier and mixing particles of an active agent in a first liquid solvent to obtain a dispersion, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1:1 to about 20:1 by weight;

(b) subjecting the dispersion of step (a) to a particle size reduction step to obtain a nanosuspension;

(c) dissolving a dispersing agent in a second liquid solvent to form a solution, wherein the dispersing agent is trileucine;

(d) mixing the solution of step (c) with the nanosuspension to obtain a feedstock suspension; and,

(e) spray drying the feedstock suspension of step (d) to form the pharmaceutical composition.

[0011] In one aspect, there is provided a process (II) for the preparation of a pharmaceutical composition as described herein, wherein said process comprises the steps of: (a) dissolving a surface modifier and a dispersing agent in a first liquid solvent and mixing particles of an active agent in the first liquid solvent to obtain a dispersion, wherein the dispersing agent is trileucine, and, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1:1 to about 20:1 by weight;

(b) subjecting the dispersion of step (a) to a particle size reduction step to obtain a nanosuspension; and,

(c) spray drying the nanosuspension of step (b) to form the pharmaceutical composition. [0012] In one aspect, there is provided a pharmaceutical composition as described herein for use in therapy.

[0013] In one aspect, there is provided a pharmaceutical composition as described herein for use in treating and/or preventing a respiratory disease and/or a non-respiratory disease.

[0014] In one aspect, there is provided use of a pharmaceutical composition as described herein in the manufacture of a medicament for use in treating and/or preventing a respiratory disease and/or a non-respiratory disease.

[0015] In one aspect, there is provided a method of treating and/or preventing a respiratory disease and/or a non-respiratory disease in a patient suffering from said disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as described herein.

[0016] In one aspect, there is provided a kit comprising a dry powder inhaler device and the pharmaceutical composition described herein.

PET AIT, ED DESCRIPTION

[0017] It should be appreciated that the particular aspects and examples shown and described herein are not intended to otherwise limit the scope of the present invention in any way.

[0018] There is provided a pharmaceutical composition comprising nano embedded microparticles, as well as methods of making said pharmaceutical compositions, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and/or non-respiratory conditions, and also kits. [0019] As used herein, the term “about” is used to modify, for example, the quantity of an ingredient in a composition, concentration, volume, process temperature, process time, yield, flow rate, pressure, and ranges thereof, employed in describing the disclosure. The term “about” refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrates or formulations; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of starting materials or ingredients used to carry out the methods, and other similar considerations. The term "about" also encompasses amounts that differ due to aging of a formulation with a particular initial concentration or mixture and amounts that differ due to mixing or processing a formulation with a particular initial concentration or mixture. Where modified by the term "about," the claims appended hereto include such equivalents. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0020] As used in this specification, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0021] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present application pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art.

[0022] As used herein, the terms “pharmaceutical composition “and “composition” are used interchangeably.

[0023] As used herein, the terms “pharmaceutical composition comprising nano embedded microparticles” and, “pharmaceutical composition of microparticles comprising nanoparticles”, are used interchangeably.

[0024] As used herein, the terms “active pharmaceutical ingredients (APIs)” and “active agents” are used interchangeably.

[0025] “Patient” or “subject” refers to mammals and other animals, particularly humans and the methods described herein are applicable to both human therapy and veterinary applications. In one aspect, the patient or subject is a mammal. In another aspect, the patient or subject is a human. In one aspect, the subject is suffering from a clinical condition including respiratory diseases and/or non-respiratory diseases. [0026] In one aspect, there is provided a pharmaceutical composition which is a dry powder formulation comprising microparticles, wherein said microparticles comprise a dispersing agent and nanoparticles; wherein the dispersing agent is trileucine; wherein said nanoparticles comprise an active agent and a surface modifier; and, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1 : 1 to about 20: 1 by weight.

[0027] “Trileucine” as used herein refers to the chemical compound in which three leucine molecules are linked together in a peptide, as leucine-leucine-leucine (Leu-Leu-Leu), C18H35N3O4. The chemical structure of trileucine is provided below:

[0028] Advantageously, the pharmaceutical compositions described herein may have improved dissolution rate, and/or re- dispersion and delivery of the nano-sized API particles to the lungs by preventing and/or limiting an increase in the size of the nano-sized API particles during preparation and/or storage by using trileucine as the only dispersing agent and having the active agent and the surface modifier present at a ratio of active agent: surface modifier of about 1 : 1 to about 20:1 by weight. The pharmaceutical compositions as described herein may also have the advantage of improved aerodynamic properties of the NEMs. Another advantage of the pharmaceutical compositions as described herein may have increased stability when stored at 25°C ± 2°C at 60% ± 5% at relative humidity or at 40°C ± 2°C and 75% ± 5% relative humidity for at least 6 months, preferably at least 9 months and more preferably at least 12 months.

[0029] In one aspect, the pharmaceutical composition is a dry powder formulation. As used herein a “dry powder formulation” refers to a formulation that suitably contains less than about 20% moisture, more suitably less than 10% moisture, even more suitably less than about 5-6% moisture, or less than about 3% moisture. [0030] In one aspect, the pharmaceutical composition is suitable for pulmonary administration. [0031] Pulmonary administration can be used for local and/or systemic delivery of an active pharmaceutical ingredient (API) to treat pulmonary and/or non-pulmonary diseases. In one aspect, the pharmaceutical composition described herein is administered through pulmonary administration. In one aspect, the pharmaceutical composition described herein is administered using a “dry powder inhaler”. The term “dry powder inhaler” (DPI) refers to a device for administering a dry powder into the lungs of a subject. The DPI may be "passive" or breath- actuated, or "active" where the powder is dispersed by some mechanism other than the patient's inhalation, for instance, an internal supply of compressed air., for example, a breath activated device. DPI can be classified by the number of doses the device can carry. At present, three types of passive dry powder inhalers are available: single dose, multiple unit dose or multidose (reservoir) inhalers. In one aspect, the DPI includes a single-unit dose reservoir. In one aspect, the DPI includes a multi-unit dose reservoir. In one aspect, the DPI includes a multi-dose reservoir. A variety of DPI devices are commercially available.

[0032] In one aspect, the pharmaceutical composition is a dry powder formulation suitable for pulmonary delivery, including via inhalation by a dry powder inhaler (DPI).

[0033] In one aspect, the microparticles further comprise a bulking agent. In one aspect, the bulking agent is a saccharide and/or a sugar alcohol. In one aspect, the saccharide is an amorphous saccharide. In one aspect, the saccharide comprises trehalose, lactose, sucrose, raffmose, inulin, dextran, cyclodextrin and combinations thereof. In one aspect, the sugar alcohol comprises mannitol. In one aspect, the saccharide comprises trehalose.

[0034] In one aspect, the pharmaceutical composition comprises about 1% to about 20% trileucine by weight. In one aspect, the pharmaceutical composition comprises about 1% to about 15% trileucine by weight. In one aspect, the pharmaceutical composition comprises about 1% to about 10% trileucine by weight. In one aspect, the pharmaceutical composition comprises about 2% to about 7% trileucine by weight. In one aspect, the pharmaceutical composition comprises about 2.5% to about 5% trileucine by weight. In one aspect, the pharmaceutical composition comprises about 5% trileucine by weight.

[0035] In one aspect, the surface modifier is selected from the group consisting of a polyethylene glycol-derivatized phospholipid, polyvinylpyrrolidone, an ethylene oxide-propylene oxide block copolymer, hydroxypropylmethylcellulose, dioctyl sodium sulfosuccinate, and combinations thereof. In one aspect, the surface modifier is selected from the group consisting of N-(carbonyl- methoxypolyethyleneglycol-2000)-l,2-distearoyl-sn-glycero-3- phosphoethanol-amine (MPEG- 2000-DSPE); N-(carbonyl-methoxypolyethylenglycol 2000)-l,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine (MPEG-2000-DPPE); polyvinylpyrrolidone (PVP) (such as PVP K30); poloxamer, preferably poloxamer 407; hydroxypropyl methyl cellulose (HPMC), preferably HPMC 6 cps; and, combinations thereof. In one aspect, the surface modifier is MPEG-2000- DSPE.

[0036] In one aspect, the active agent and the surface modifier are present in the pharmaceutical composition at a ratio of active agent: surface modifier of about 2: 1 to about 10:1 by weight. In one aspect, the active agent and the surface modifier are present in the pharmaceutical composition at a ratio of active agent: surface modifier of about 2: 1 to about 8: 1 by weight. In one aspect, the active agent and the surface modifier are present in the pharmaceutical composition at a ratio of active agent: surface modifier of about 5: 1 to about 8: 1 by weight. In one aspect, the active agent and the surface modifier are present in the pharmaceutical composition at a ratio of active agent: surface modifier of about 8:1 by weight.

[0037] In one aspect, the pharmaceutical composition comprises about 0.1% to about 30% of the active agent by weight. In one aspect, the pharmaceutical composition comprises at least 1%,

5%, 10%, 15%, 20%, 25%, 30% of the active agent by weight.

[0038] In one aspect, the pharmaceutical composition is typically stable under long term storage conditions. As used herein, “stable” means that there is no observable change, for example, less than about 10%, 9%, 8%. 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% change, in one or more physical properties of the pharmaceutical composition and drug product performance parameters, for example, as determined by X-ray powder diffraction (XRPD) or chemical degradation by UPLC analysis of organic impurities and as determined of mass median aerodynamic diameter (MMAD), fine particle dose (FPD) and/or fine particle fraction (FPF), and after about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months or 1 year. In one aspect, the pharmaceutical composition is stable under long term storage conditions, for example, when stored at 25°C ± 2°C and 60% ± 5% or at 40°C ± 2°C and 75% ± 5% relative humidity for at least about 6 months, at least about 7 months, or at least about 12 months.

[0039] In one aspect, the active agent is typically a small molecule. As used herein, the term small molecule” refers to a chemically synthesized, low molecular-weight pharmaceutical, therapeutic and/or diagnostic agent (examples of the latter being markers, dyes, etc.), that generally has a molecular weight of less than about 10 kD, suitably less than about 5000 Daltons, and more suitably less than about 1000 Daltons, for example about 100 to about 900 Daltons, about 200 to about 800 Daltons, about 300 to about 700 Daltons, about 400 to about 600 Daltons, or about 500 Daltons, as well as salts, esters, and other pharmaceutically acceptable forms of such compounds.

[0040] In one aspect, the active agent is a biologic. As used herein, the term “biologic” refers to an isolated or synthetically produced natural product, including nucleic acids, amino acids, peptides, polypeptides, and proteins, and suitably includes antibodies, antigen binding fragments, and the like.

[0041] In one aspect, the active agent is typically a poorly soluble drug having an equilibrium water solubility concentration of <1 mM as determined after a period of about 24 hours at a pH of about 7.4, a pressure of about 101.325 kPa (i.e. 1 atm) and a temperature of about 25 ⁰ Celsius. [0042] In one aspect, the active agent is typically selected from the group consisting of inhaled corticosteroids (ICS), long-acting beta agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting anti-muscarinics (LAMA), cromones, short- acting beta agonist (SABA), Janus kinase (JAK) inhibitors, selective glucocorticoid receptor modulators (SGRMs), cytokines including interleukins, hormones, interferons, tissue growth factors, endothelial growth factors, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, single or dual kinase inhibitors (such as a RI3Kdg), anti-inflammatory and/or bronchodilatory compounds, glucocorticoid receptor agonists (steroidal or non-steroidal), selective b2 adrenoceptor agonists, dual b2 adrenoceptor agonist/antimuscarinic agents, p38 antagonists, phosphodiesterase (PDE) inhibitors (including a PDE4 inhibitor or an inhibitor of the isoform PDE4D), modulators of chemokine receptor function, bisphosponates, macrolides, antibiotics, fluoroquinolones, aminoglycosides, polymixins, antifungal agents and/or carbapenems.

[0043] In one aspect, the active agent is a dual phosphatidylinositol 3-kinase delta (PI3K6) and phosphatidylinositol 3 -kinase gamma (RI3Kg) inhibitor.

[0044] In one aspect, the active agent is 2-[(lS)-l-cyclopropylethyl]-5-(4-methyl-2-{[6-(2- oxopyrrolidin-l-yl)pyri din-2 -yl]amino}-l,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-l//- isoindol-l-one, also known as AZD8154,

[0045] In one aspect, the active agent is a JAK inhibitor.

[0046] In one aspect, the active agent is N2-(3,4,5-trimethylphenyl-5-methyl-N4-(2-oxo-2,3- dihydro-l,3-benzoxazol-5-yl)-2,4-pyrimidinediamine, also known as AZD0449,

[0047] In one aspect, the active agent is a selective glucocorticoid receptor modulator. [0048] In one aspect, the active agent is 3-{5-[(lR,2S)-2-(2,2-difluoropropanamido)-l-(2,3- dihydro-l,4-benzodioxin-6-yl)propoxy]-lH-indazol-l-yl}-N-[(3R)-tetrahydro-3- furanyl]benzamide, also known as AZD7594,

[0049] In one aspect, there is provided a pharmaceutical composition which is a dry powder formulation comprising microparticles, wherein said microparticles comprise a dispersing agent and nanoparticles; wherein the dispersing agent is trileucine; wherein preferably the pharmaceutical composition comprises about 1% to about 15% trileucine by weight; wherein said nanoparticles comprise an active agent and a surface modifier; wherein the surface modifier is MPEG-2000-DSPE; wherein the active agent is selected from

2-[(lS)-l-cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxopyrrolidin-l-yl)pyridin-2-yl]amino}-l,3- thiazol-5 -yl)-7-(m ethyl sulfonyl)-2, 3 -dihydro- 1 H- i soindol- 1 -one;

2-(3,4,5-trimethylphenyl-5-methyl-N4-(2-oxo-2,3-dihydro-l,3-benzoxazol-5-yl)-2,4- pyrimidinediamine; and

3-{5-[(lR,2S)-2-(2,2-difluoropropanamido)-l-(2,3-dihydro-l,4-benzodioxin-6-yl)propoxy]-lH- indazol-l-yl}-N-[(3R)-tetrahydro-3-furanyl]benzamide; and wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 5:1 to about 8:1 by weight, preferably about 8:1 by weight. [0050] In one aspect, the nanoparticles have a d50 of about 10 nm to about 500 nm, preferably about 50 nm to about 400 nm, more preferably about 100 nm to about 300 nm, and most preferably about 100 nm to about 250 nm. [0051] In one aspect, the nanoparticles have a d90 of about 100 nm to about 500 nm, preferably about 150 nm to about 450 nm, and more preferably 200 nm to about 400 nm.

[0052] In one aspect, the microparticles have a d50 of about 1 pm to about 5 pm, preferably a d50 of about 1.5 pm to about 3 pm.

[0053] For particle size distributions, d50 values may refer to the median particle size distribution and can be determined by known methods, for example, by laser diffraction. In another embodiment, d90 values may refer, for examples, volume distribution in which 90% of the particle size distribution lies below the d90 value. Alternatively, d90 may refer to, for instance, the numeric distribution in which 90% of the particle size distribution lies below the d90 value.

[0054] In one aspect, the nanoparticles have a Z-average particle size of about 10 nm to about 500 nm, preferably about 50 nm to about 400 nm, more preferably about 100 nm to about 300 nm, and most preferably about 100 nm to about 250 nm.

[0055] The Z-average particle size or Z-average mean can be determined by known methods, for example, dynamic light scattering. Typically, the Z-average particle size is as defined in ISO 13321 and more recently ISO 22412, which defines this mean as the ‘harmonic intensity averaged particle diameter’ .

[0056] As used herein, the term “mass median aerodynamic diameter” or “MMAD” is a measure of the aerodynamic size of a dispersed microparticle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior and is the diameter of a unit density sphere having the same settling velocity, in air, as the microparticle. The aerodynamic diameter encompasses particle shape, density and physical size of a microparticle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction, unless otherwise indicated. Suitably the microparticles of the pharmaceutical compositions provided herein typically have a mass median aerodynamic diameter (MMAD) of about 1 pm to about 10 pm, more suitably about 1 pm to about 8 pm, about 2 pm to about 7 pm, about 2 pm to about 6 pm, about 2 pm to about 5 pm, about 2 pm to about 4 pm, or about 2 pm to about 3 pm.

[0057] The “fine particle dose” (FPD) is the total mass of API emitted dose (ED) from a dry powder inhaler device following actuation which is present in an aerodynamic particle size smaller than a defined limit, is generally less than about 5 pm, about 4 pm, about 3 pm, about 2 pm or about 1 mih and can also be referred to as the “respirable fraction,” i.e., the percentage of API which can reach the deep lungs in a patient. The FPD can be measured using known techniques, including, for example, using an impactor or impinger, such as a twin stage impinger (TSI), multistage impinger (MSI), Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI). Suitably, the fine particle dose is at least about 50 pg, 100 pg, 250 pg, 500 pg, 750 pg, 1000 pg, 1100 pg, 1200 pg, 1300 pg, 1400 pg, 1500 pg, 1600 pg, 1700 pg, 1800 pg, 1900 pg, 2000 pg, or 2100 pg.

[0058] Suitably, the “fine particle fraction” is the fraction of fine particles emitted from an inhalation device having an aerodynamic particle diameter of less than 5 pm of the pharmaceutical compositions described herein is > 30%, more suitably > 40%, > 50%, even more suitably > 60%, most suitably > 70%, and in particular > 80%.

[0059] Suitably, the “% retention in capsule and device” of the pharmaceutical compositions being suitably of less than 30 %, suitably less than 20%, suitably less than 15%, less than 10%, or less than 5%, remaining in the capsule and the dry powder inhaler device following actuation of the device.

[0060] In one aspect, processes for preparing the pharmaceutical composition are provided. [0061] In one aspect, there is provided a process (I) for the preparation of a pharmaceutical composition as described herein, wherein said process comprises the steps of:

(a) dissolving a surface modifier and mixing particles of an active agent in a first liquid solvent to obtain a dispersion, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1 : 1 to about 20: 1 by weight;

(e) spray drying the feedstock suspension of step (d) to form the pharmaceutical composition. [0062] In one aspect, there is provided a process (II) for the preparation of a pharmaceutical composition as described herein, wherein said process comprises the steps of:

(a) dissolving a surface modifier and a dispersing agent in a first liquid solvent and mixing particles of an active agent in the first liquid solvent to obtain a dispersion, wherein the dispersing agent is trileucine, and, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1:1 to about 20:1 by weight;

(c) spray drying the feedstock suspension of step (d) to form the pharmaceutical composition. [0063] In one aspect, step (c) of the process (I) described herein further comprises dissolving a bulking agent in the second liquid solvent to form the solution.

[0064] In one aspect, the process (II) for the preparation of a pharmaceutical composition comprises a step of dissolving a bulking agent in the second liquid solvent to form a solution and mixing the solution with the nanosuspension obtained in step (b) prior to the spray drying in step

(c)·

[0065] In one aspect, step (a) of the processes (I) and (II) described herein may comprise dissolving the surface modifier in the first liquid solvent prior to, together with or following the mixing of the particles of the active agent in the first liquid solvent.

[0066] In one aspect, the particle size reduction of step (b) of the processes (I) and (II) described herein comprises (ultra)sonicating, microfluidizing, high pressure homogenizing, (bead)milling or a combination thereof. In one aspect, the particle size reduction of step (b) of the process described herein comprises (bead)milling.

[0067] In one aspect, the first and second liquid solvent is water.

[0068] In one aspect, the pharmaceutical composition described herein is used in therapy.

[0069] In one aspect, the pharmaceutical composition described is used to treat or prevent a respiratory disease and/or a non-respiratory disease.

[0070] Non-limiting examples of respiratory diseases include, but are not limited to: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; alpha- 1 antitrypsin deficiency; EGPA (Eosinophilic Granulocytic with Polyangiitis, also known as Churg-Strauss syndrome or allergic granulomatosis); ABPA (Allergic Broncopulmonary Aspergillosis); MGA (mixed granulocytic asthma); CEP (Chronic Eosinophilic Pneumonia); farmer’s lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, and idiopathic pulmonary fibrosis (IPF), idiopathic interstitial pneumonias, fibrosis complicating anti -neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adenovirus, acute lung injury, adult respiratory distress syndrome (ARDS), as well as exacerbations of each of the foregoing respiratory tract disease states, and in particular exacerbations of all types of asthma or COPD.

[0071] In one aspect, the respiratory disease is asthma.

[0072] In one aspect, the respiratory disease is chronic obstructive pulmonary disease (COPD). [0073] In one aspect, the respiratory disease is idiopathic pulmonary fibrosis (IPF).

[0074] Non-limiting examples of non-respiratory diseases include, but are not limited to: cancers (e.g., a breast cancer, a uterine cancer, an ovarian cancer, a prostate cancer, a testicular cancer, a lung cancer, a leukemia, a lymphoma, a colon cancer, a gastrointestinal cancer, a pancreatic cancer, a bladder cancer, a kidney cancer, a bone cancer, a neurological cancer, a head and neck cancer, a skin cancer, a sarcoma, an adenoma, a carcinoma and a myeloma); infectious diseases (e.g., bacterial diseases, fungal diseases, parasitic diseases and viral diseases (such as a viral hepatitis, a disease caused by a cardiotropic virus; HIV/AIDS, and the like)); genetic disorders (e.g., anemia, neutropenia, thrombocytopenia, hemophilia, dwarfism and severe combined immunodeficiency disease (“SCID”); inflammatory and autoimmune disorders (e.g., psoriasis, systemic lupus erythematosus and rheumatoid arthritis and atopic dermatitis) and neurodegenerative disorders (e.g., various forms and stages of multiple sclerosis, Creutzfeldt- Jakob Disease, Alzheimer's Disease, and the like).

[0075] In one aspect, the non-respiratory disease is cancer.

[0076] In one aspect, the pharmaceutical composition as described herein may be used in treating and/or preventing a respiratory disease and/or a non-respiratory disease. In one aspect, the pharmaceutical composition as described herein may be used in treating and/or preventing asthma. In one aspect, the pharmaceutical composition as described herein may be used in treating and/or preventing chronic obstructive pulmonary disease (COPD). In one aspect, the pharmaceutical composition as described herein may be used in treating and/or preventing idiopathic pulmonary fibrosis (IPF). In one aspect, the pharmaceutical composition as described herein may be used in treating and/or preventing cough.

[0077] In one aspect, there is provided use of the pharmaceutical composition described herein in the manufacture of a medicament for use in treating and/or preventing a respiratory disease and/or a non-respiratory disease. In one aspect, there is provided use of the pharmaceutical composition described herein in the manufacture of a medicament for use in treating and/or preventing asthma. In one aspect, there is provided use of the pharmaceutical composition described herein in the manufacture of a medicament for use in treating and/or preventing chronic obstructive pulmonary disease (COPD). In one aspect, there is provided use of the pharmaceutical composition described herein in the manufacture of a medicament for use in treating and/or preventing idiopathic pulmonary fibrosis (IPF). In one aspect, there is provided use of the pharmaceutical composition described herein in the manufacture of a medicament for use in treating and/or preventing cough.

[0078] In one aspect, there is provided a method of treating and/or preventing a respiratory disease and/or a non-respiratory disease, in a patient suffering from said disease, which comprises administering to the patient a therapeutically effective amount of the pharmaceutical composition described herein. In one aspect, there is provided a method of treating and/or preventing asthma. In one aspect, there is provided a method of treating and/or preventing chronic obstructive pulmonary disease (COPD). In one aspect, there is provided a method of treating and/or preventing idiopathic pulmonary fibrosis (IPF). In one aspect, there is provided a method of treating and/or preventing cough.

[0079] In one aspect, the method comprises administration of the pharmaceutical composition described herein to treat and/or prevent a respiratory disease and/or a non-respiratory disease. In one aspect, the method comprises administration of the pharmaceutical composition described herein to treat and/or prevent asthma. In one aspect, the method comprises administration of the pharmaceutical composition described herein to treat and/or prevent chronic obstructive pulmonary disease (COPD). In one aspect, the method comprises administration of the pharmaceutical composition described herein to treat and/or prevent idiopathic pulmonary fibrosis (IPF). In one aspect, the method comprises administration of the pharmaceutical composition described herein to treat and/or prevent cough.

[0080] In one aspect, there is provided a kit comprising a dry powder inhaler device and the pharmaceutical composition described herein. In one aspect, the kit further comprising instructions for administration and/or storage. In one aspect, the dry powder inhaler is a multi dose dry powder inhaler. In one aspect, the dry powder inhaler is a single dose inhaler.

[0081] All references cited herein, including patents, patent applications, papers, text books and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety.

WORKING EXAMPLES

[0082] The following physical powder characteristics of (i) Residual Moisture Content using Oven KF; and, (ii) d50 Particle Size Distribution using either (1) Sympatec or (2) Malvern Mastersizer 3000, were tested for all the pharmaceutical compositions described in the following Examples.

Example 1 (Reference). Pharmaceutical composition comprising 30 w/w% Compound A, MPEG-2000-DSPE, Leucine and Trehalose and a ratio of Compound A:MPEG-2000- DSPE of 5:1

[0083] Crystalline 2-[(lS)-l-cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxopyrrolidin-l-yl)pyridin- 2-yl]amino}-l,3-thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-l//-isoindol-l-one (Compound A) was prepared essentially as described in Example 1 of W02018/055040. A dispersion was prepared of Compound A as the active agent and MPEG-2000-DSPE (Corden Pharma in Switzerland) as the surface modifier in a ratio of 5: 1 in water at a concentration of approximately 200 mg/ml and 40 mg/ml, respectively. The dispersion was milled in Dynomill-RL to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of leucine as the dispersing agent instead of trileucine and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The feed suspension was spray dried in a Mini Biichi b-290 spray dryer, using an outlet temperature of 70°C, feedstock feed rate, 2.5 ml/min; atomizer air, 1800 liters/hr; and drying gas flow, 25 kg/hr. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 0.47% and (ii) a d50 particle size distribution 2.08 pm⁽¹⁾. The composition of the resulting formulation is shown in Table 1 below.

Table 1: Composition of formulation

Example 2 (Reference). Pharmaceutical composition comprising 30 w/w% Compound A, MPEG-2000-DSPE, Trileucine, Leucine and Trehalose and a ratio of Compound A:MPEG- 2000-DSPE of 5:1

[0084] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 5: 1 in water at a concentration of approximately 200 mg/ml and 40 mg/ml, respectively. The dispersion was milled in Dynomill-RL to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent, leucine as an additional dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension in water. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.13% and (ii) a d50 particle size distribution 1.65 pm⁽¹⁾. The composition of the resulting formulation is shown in Table 2 below.

Table 2: Composition of formulation

Example 3. Pharmaceutical composition comprising 30 w/w% Compound A, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound A:MPEG-2000-DSPE of 5:1

[0085] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 5: 1 in water at a concentration of approximately 200 mg/ml and 40 mg/ml, respectively. The dispersion was milled in Dynomill-RL to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.35% and (ii) a d50 particle size distribution 1.68 pm⁽¹⁾. The composition of the resulting formulation is shown in Table 3 below.

Table 3: Composition of formulation

Example 4. Pharmaceutical composition comprising 20 w/w% Compound A, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound A:MPEG-2000-DSPE of 5:1

[0086] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 5: 1 in water at a concentration of approximately 200 mg/ml and 40 mg/ml respectively. The dispersion was milled in the Fritsch mill to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 60 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.75% and (ii) a d50 particle size distribution 2.07 pm⁽²⁾. The composition of the resulting formulation is shown in Table 4 below. Table 4: Composition of formulation

Example 5. Pharmaceutical composition comprising 20 w/w% Compound A, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound A:MPEG-2000-DSPE of 8:1

[0087] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 200 mg/ml and 25 mg/ml, respectively. The dispersion was milled in the Fritsch mill to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 60 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.77% and (ii) a d50 particle size distribution 2.07 pm⁽²⁾. The composition of the resulting formulation is shown in Table 5 below.

Table 5: Composition of formulation

Example 6. Pharmaceutical composition comprising 10 w/w% Compound A, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound A:MPEG-2000-DSPE of 8:1

[0088] A Pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 200 mg/ml and 25 mg/ml, respectively. The dispersion was milled in the Dynomill-RL to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 60 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.09% and (ii) a d50 particle size distribution 1.95 pm⁽²⁾. The composition of the resulting formulation is shown in Table 6 below.

Table 6: Composition of formulation

Example 7. Pharmaceutical composition comprising 1 w/w% Compound A, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound A:MPEG-2000-DSPE of 8:1

[0089] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound A as the active agent and MPEG- 2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 200 mg/ml and 25 mg/ml, respectively. The dispersion was milled in the Dynomill-RL to produce a nanosuspension having a particle size with a d50 of approximately 130 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 60 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound A nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.05% and (ii) a d50 particle size distribution 1.87 pm⁽²⁾. The composition of the resulting formulation is shown in Table 7 below.

Table 7: Composition of formulation

Example XI. Pharmaceutical composition comprising 1 w/w% Compound B, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound B:MPEG-2000-DSPE of 10:1 [0090] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound B as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 200 mg/ml and 25 mg/ml, respectively. The dispersion was milled in the Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound B nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.77% and (ii) a d50 particle size distribution 1.40 pm(l). The composition of the resulting formulation is shown in Table XI below. Table XI: Composition of formulation

Example X2. Pharmaceutical composition comprising 30 w/w% Compound B, MPEG- 2000-DSPE, Trileucine and Trehalose and a ratio of Compound B:MPEG-2000-DSPE of 8:1

[0091] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound B as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 200 mg/ml and 25 mg/ml, respectively. The dispersion was milled in Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound B nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.58% and (ii) a d50 particle size distribution 1.55 pm(l). The composition of the resulting formulation is shown in Table X2 below.

Table X2: Composition of formulation

Example X3. Pharmaceutical composition comprising 1 w/w% Compound C, MPEG-2000- DSPE, Trileucine and Trehalose and a ratio of Compound C:MPEG-2000-DSPE of 10:1 [0092] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound C as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 10: 1 in water at a concentration of approximately 300 mg/ml and 35 mg/ml, respectively. The dispersion was milled in the Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound C nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.77% and (ii) a d50 particle size distribution 1.40 pm(l). The composition of the resulting formulation is shown in Table X3 below.

Table X3: Composition of formulation

Example X4. Pharmaceutical composition comprising 30 w/w% Compound C, MPEG- 2000-DSPE, Trileucine and Trehalose and a ratio of Compound C:MPEG-2000-DSPE of 8:1

[0093] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound C as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 8:1 in water at a concentration of approximately 300 mg/ml and 35 mg/ml, respectively. The dispersion was milled in Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound C nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.58% and (ii) a d50 particle size distribution 1.55 pm(l). The composition of the resulting formulation is shown in Table X4 below.

Table X4: Composition of formulation

Example X5. Pharmaceutical composition comprising 30 w/w% Compound C, MPEG- 2000-DSPE, Trileucine and Trehalose and a ratio of Compound C:MPEG-2000-DSPE of 8:1

[0094] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound C as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 8:1 in water at a concentration of approximately 300 mg/ml and 35 mg/ml, respectively. The dispersion was milled in Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound C nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.58% and (ii) a d50 particle size distribution 1.55 pm(l). The composition of the resulting formulation is shown in Table X5 below. Table X5: Composition of formulation

Example X6. Pharmaceutical composition comprising 30 w/w% Compound C, MPEG- 2000-DSPE, Leucin and Trehalose and a ratio of Compound C:MPEG-2000-DSPE of 8:1

[0095] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound C as the active agent and MPEG-2000-DSPE as the surface modifier in a ratio of 8: 1 in water at a concentration of approximately 300 mg/ml and 35 mg/ml, respectively. The dispersion was milled in Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound C nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.58% and (ii) a d50 particle size distribution 1.55 pm(l). The composition of the resulting formulation is shown in Table X6 below.

Table X6: Composition of formulation

Example X7. Pharmaceutical composition comprising 20 w/w% Compound C, Pluronic F127:PVP K30: AOT, Trileucine and Trehalose and a ratio of Compound C: (Pluronic

F127:PVP:AOT) of 8.4:1

[0096] A pharmaceutical composition was prepared according to the method as described in Example 1, except the dispersion prepared was of Compound C as the active agent and Pluronic F127: PVP:AOT (1.95%: 1.3%:0.065%) as the surface modifier in a ratio of 8.4:1 in water at a concentration of approximately 300 mg/ml and 35 mg/ml, respectively. The dispersion was milled in Fritsch Pulverisette to produce a nanosuspension having a particle size with a d50 of approximately 120 nm, as determined by laser diffraction using a Malvern Mastersizer 2000. A feed stock suspension was prepared at a total concentration of solids at approximately 30 mg/mL by first preparing a solution of trileucine as the dispersing agent and trehalose as the bulking agent in water and then adding the Compound C nanosuspension. The parameters were selected to achieve an acceptable water content and particle properties for a pharmaceutical composition intended for inhalation, having (i) a residual moisture content of 1.58% and (ii) a d50 particle size distribution 1.55 pm(l). The composition of the resulting formulation is shown in Table X7 below.

Table X7: Composition of formulation

Example 8. Aerosol Performance Characteristics Studies

[0097] The aerosol performance characteristics were determined using cascade impaction testing of all the Examples using a dry powder inhaler device. All aerosol performance characterization studies were completed using a Monodose RS01 device, with one size 3 HPMC capsule containing 10 mg of the pharmaceutical composition. [0098] Cascade impaction testing was performed as per EiSP <601> using a Next Generation Impactor (NGI; USP41, Chapter <601>). One size 3 HPMC capsule containing 10 mg of the pharmaceutical composition of Examples 1-5, and two size 3 HPMC capsules containing 10 mg of the pharmaceutical composition of Examples 6-7, XI- X7, and 3 size 3 HPMC capsules containing 10 mg of the pharmaceutical composition of Examples X3, X4, X6, were dispersed from the dry powder inhaler device and delivered into the NGI under a vacuum pulled at 60 L/min as per USP methodology. Samples from each stage of the NGI were recovered and assayed for the active agent content.

[0099] The results of the initial aerosol analysis of the pharmaceutical compositions, compound A, are summarized in Table 8.

Table 8: Results of initial aerosol characterization

[00100] Aerosol performance characteristics were also determined for selected Examples by filling HPMC capsules with the respective pharmaceutical compositions and storing individually in a sealed aluminium pouch at the following climate conditions (i) 25°C ± 2°C and 60% ± 5% relative humidity or (ii) 40°C ± 2°C and 75% ± 5% relative humidity. Examples 1, 2, 3 were stored for 7 months for both climate conditions (i) and (ii). Examples 4 and 5 were stored for 6 months both climate conditions (i) and (ii). Examples 6 and 7 were stored for 12 months at climate condition (i) and for 6 months at climate condition (ii).

[00101] The results of the aerosol analysis of the stored pharmaceutical compositions are summarized in Tables 9 and 10.

Table 9: Results of aerosol characterization of the stored pharmaceutical compositions at

25°C ± 2°C and 60% ± 5% relative humidity

Table 10: Results of aerosol characterization of the stored pharmaceutical compositions at

40°C ± 2°C and 75% ± 5% relative humidity

Tables 9 and 10 show that the pharmaceutical compositions of Examples 3 to 7 were stable in terms of MMAD for at least 6 months when stored at both 25°C ± 2°C and 60% ± 5% relative humidity and 40°C ± 2°C and 75% ± 5% relative humidity. These results show the advantage of using trileucine as the only dispersing agent in the pharmaceutical compositions of Examples 3 to 7 over the Reference Examples 1 and 2 of having improved stability. Tables 9 and 10 also show that the pharmaceutical compositions of Examples 5 to 7 were stable in terms of MMAD, FPD and FPF <5 pm for at least 6 months when stored both at 25°C ± 2°C and 60% ± 5% relative humidity and 40°C ± 2°C and 75% ± 5% relative humidity. These results show a further advantage of the pharmaceutical compositions of Examples 5 to 7 of also having the active agent and the surface modifier present at a ratio of active agent: surface modifier of about 8: 1 by weight.

[00102] The results of the initial aerosol analysis of the pharmaceutical compositions, compound B, are summarized in Table 11 . Table 11 Results of initial aerosol characterization

[00103] Aerosol performance characteristics were also determined for selected Examples by filling HPMC capsules with the respective pharmaceutical compositions and storing individually in a sealed aluminium pouch at the following climate conditions (i) 25°C ± 2°C and 60% ± 5% relative humidity or (ii) 40°C ± 2°C and 75% ± 5% relative humidity. Examples XI and X2 were stored for 6 months for both climate conditions (i) and (ii).

[00104] The results of the aerosol analysis of the stored pharmaceutical compositions are summarized in Tables 12 and 13.

Table 12: Results of aerosol characterization of the stored pharmaceutical compositions at 25°C ± 2°C and 60% ± 5% relative humidity

Table 13: Results of aerosol characterization of the stored pharmaceutical compositions at 40°C ± 2°C and 75% ± 5% relative humidity

[00105] Tables 12 and 13 show that the pharmaceutical compositions of Examples XI and X2 were stable in terms of MMAD, FPD and FPF <5 pm for at least 6 months when stored at both 25°C ± 2°C and 60% ± 5% relative humidity and 40°C ± 2°C and 75% ± 5% relative humidity.

[00106] The results of the initial aerosol analysis of the pharmaceutical compositions, compound C, are summarized in Table 14.

Table 14 Results of initial aerosol characterization

[00107] Aerosol performance characteristics were also determined for selected Examples by filling HPMC capsules with the respective pharmaceutical compositions and storing individually in a sealed aluminium pouch at the following climate conditions (i) 25°C ± 2°C and 60% ± 5% relative humidity or (ii) 40°C ± 2°C and 75% ± 5% relative humidity. Examples X, X4, X4 and X7 were stored for 6 months for both climate conditions (i) and (ii). Example X5 was stored for 4 months for both climate conditions (i) and (ii).

[00108] The results of the aerosol analysis of the stored pharmaceutical compositions are summarized in Tables 15 and 16.

Table 15: Results of aerosol characterization of the stored pharmaceutical compositions at

25°C ± 2°C and 60% ± 5% relative humidity

Table 16: Results of aerosol characterization of the stored pharmaceutical compositions at

40°C ± 2°C and 75% ± 5% relative humidity

Tables 15 and 16 show that the pharmaceutical compositions of Examples X3, X4, X6, X7 were stable in terms of MMAD, FPD and FPF <5 pm for at least 6 months when stored at 25°C ± 2°C and 60% ± 5% relative humidity, Example X5 when stored for at least 4 months. Table 40/75 shows that the pharmaceutical compositions of Examples X3, X5 and X7 were stable in terms of MMAD, FPD and FPF <5 pm for at least 4 months and 6 months respectivley when stored both at 25°C ± 2°C and 60% ± 5% relative humidity and 40°C ± 2°C and 75% ± 5% relative humidity.

Example 9. Re-dispersion Studies of the API nanoparticles

[00109] The re-dispersion of the API nanoparticles embedded in the microparticles of all the Examples of the pharmaceutical compositions were tested by storing in a glass bottle in a sealed aluminium pouch at 25°C ± 2°C and 60% ± 5% relative humidity or 40°C ± 2°C and 75% ± 5% relative humidity for set periods of time as indicated in the table below. Prior to testing the pharmaceutical compositions were redispersed by adding an amount of the pharmaceutical compositions in water to obtain a final concentration of the active agents used in the respective pharmaceutical compositions of Compound A. The particle size distribution was measured with laser diffraction (Malvern Mastersizer 2000) or Dynamic light scattering (Zetasizer) and the particle size distribution is compared with the nanosuspension that was added to the feed stock before spray drying to determine the d50/d90 particle size distribution or Z-average particle sizes, respectively. No change in solid state of the API in the formulation was determined by X- ray powder diffraction (XRPD) and chemical degradation by UPLC analysis of organic impurities was within acceptable limits according to International Council for Harmonisation (ICH) guidelines. The results of the re-dispersion studies are shown in Table 17 below.

Table 17: Results of Re-dispersion Studies of the API Nanoparticles

⁽¹⁾ d50/d90 (pm) measured with wet Malvern2000 (Laser Diffraction)

⁽²⁾ Z-average (pm) measured with Zetasizer (Dynamic Light Scattering)

Table 17 shows that the size of the API nanoparticles comprised in the pharmaceutical compositions of Examples 3 to 7 changed less than those of Reference Examples 1 and 2, when stored at 40°C ± 2°Cand 75% ± 5% relative humidity for at least 6 months. These results indicate that the pharmaceutical compositions of Examples 3 to 7, which only have trileucine as the dispersing agent, would have improved dissolution rate, and/or re- dispersion and drug delivery to the lungs due to the size of the API nanoparticles (i.e. d50/d90 or z-average particle size) not increasing during storage, which would lead to an improved clinical performance of the pharmaceutical composition.

Example 10. Re-dispersion Studies of the API nanoparticles

[00110] The re-dispersion of the API nanoparticles embedded in the microparticles of all the Examples of the pharmaceutical compositions were tested by storing in a glass bottle in a sealed aluminium pouch at 25°C ± 2°C and 60% ± 5% relative humidity or 40°C ± 2°C and 75% ± 5% relative humidity for set periods of time as indicated in the table below. Prior to testing the pharmaceutical compositions were redispersed by adding an amount of the pharmaceutical compositions in water to obtain a final concentration of the active agents used in the respective pharmaceutical compositions of Compound B . The particle size distribution was measured with laser diffraction (Malvern Mastersizer 2000) or Dynamic light scattering (Zetasizer) and the particle size distribution is compared with the nanosuspension that was added to the feed stock before spray drying to The results of the re-dispersion studies are shown in Table 18 below.

Table 18: Results of Re-dispersion Studies of the API Nanoparticles

^(1, d50/d90 (mpi) measured with wet Malveni2000 (Laser Diffraction)

^<2) Z-average (gm) measured with Zetasizer (Dynamic Light Scattering)

Table 18 shows that the size of the API nanoparticles comprised in the pharmaceutical compositions of Examples XI and X2 do not change in d50 stored at 40°C ± 2°Cand 75% ± 5% relative humidity for at least 6 months. These results indicate that the pharmaceutical compositions would have improved dissolution rate, and/or re- dispersion and drug delivery to the lungs due to the size of the API nanoparticles (i.e. d50/d90 or z-average particle size) not increasing during storage, which would lead to an improved clinical performance of the pharmaceutical composition.

Example 11. Re-dispersion Studies of the API nanoparticles

[00111] The re-dispersion of the API nanoparticles embedded in the microparticles of all the Examples of the pharmaceutical compositions were tested by storing in a glass bottle in a sealed aluminium pouch at 25°C ± 2°C and 60% ± 5% relative humidity or 40°C ± 2°C and 75% ± 5% relative humidity for set periods of time as indicated in the table below. Prior to testing the pharmaceutical compositions were redispersed by adding an amount of the pharmaceutical compositions in water to obtain a final concentration of the active agents used in the respective pharmaceutical compositions of Compound C . The particle size distribution was measured with laser diffraction (Malvern Mastersizer 2000) or Dynamic light scattering (Zetasizer) and the particle size distribution is compared with the nanosuspension that was added to the feed stock before spray drying to determine the d50/d90 particle size distribution or Z-average particle sizes, respectively. -The results of the re-dispersion studies are shown in Table 19 below.

Table 19: Results of Re-dispersion Studies of the API Nanoparticles

^(1, d50/d90 (mpi) measured with wet Malveni2000 (Laser Diffraction)

^<2) Z-average (gm) measured with Zetasizer (Dynamic Light Scattering)

Table 19 shows that the size of the API nanoparticles comprised in the pharmaceutical compositions of Examples X3, X4, X5 and X7 changed less than those of Reference Example X6, when stored at 40°C ± 2°Cand 75% ± 5% relative humidity for at least 6 months and 4 months respectively. These results indicate that the pharmaceutical compositions of Examples X3, X4, X5 and X7, which only have trileucine as the dispersing agent, would have improved dissolution rate, and/or re- dispersion and drug delivery to the lungs due to the size of the API nanoparticles (i.e. d50/d90 or z-average particle size) not increasing during storage, which would lead to an improved clinical performance of the pharmaceutical composition.

Claims

1. A pharmaceutical composition which is a dry powder formulation comprising microparticles, wherein said microparticles comprise a dispersing agent and nanoparticles; wherein the dispersing agent is trileucine; wherein said nanoparticles comprise an active agent and surface modifier; and, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 1:1 to about 20:1 by weight.

2. A pharmaceutical composition according to claim 1, wherein said composition is suitable for pulmonary administration.

3. A pharmaceutical composition according to any one of claims 1-2, wherein said microparticles further comprise a bulking agent.

4. The pharmaceutical composition according claim 3, wherein the bulking agent is a saccharide and/or a sugar alcohol.

5. The pharmaceutical composition according to claim 4, wherein the bulking agent comprises trehalose.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the surface modifier comprises N-(carbonyl-methoxypolyethyleneglycol-2000)-l,2-distearoyl-sn-glycero-3- phosphoethanol-amine (MPEG-2000-DSPE); N-(carbonyl-methoxypolyethylenglycol 2000)- 1,2- dipalmitoyl-sn-glycero-3-phosphoethanolamine (MPEG-2000-DPPE); polyvinylpyrrolidone (PVP); poloxamer; hydroxypropyl methyl cellulose (HPMC); dioctyl sodium sulfosuccinate; and combinations thereof.

7. The pharmaceutical composition according to claim 6, wherein the surface modifier comprises MPEG-2000-DSPE.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the active agent and the surface modifier are present at a ratio of active agent: surface modifier of about 2:1 to about 10:1 by weight, preferably 2:1 to about 8:1 by weight, even more preferably about 5:1 to about 8: 1 by weight, and most preferably about 8: 1 by weight.

9. The pharmaceutical composition according to any one of claims 1-8, wherein said composition comprises about 1% to about 20% trileucine be weight.

10. The pharmaceutical composition according to any one of claims 1-9, wherein said composition comprises about 0.1% to about 30% of the active agent by weight.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the active agent is a poorly soluble drug having an equilibrium water solubility concentration of <1 mM as determined after a period of about 24 hours at a pH of about 7.4, a pressure of about 101.325 kPa and a temperature of about 25 ⁰ Celsius.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the active agent is selected from the group consisting of:

2-[(lS)-l-cyclopropylethyl]-5-(4-methyl-2-{[6-(2-oxopyrrolidin-l-yl)pyridin-2-yl]amino}-l,3- thiazol-5-yl)-7-(methylsulfonyl)-2,3-dihydro-l /7-isoindol-l -one

N2-(3,4,5-trimethylphenyl-5-methyl-N4-(2-oxo-2,3-dihydro-l,3-benzoxazol-5-yl)-2,4- pyrimidinediamine

and 3-{5-[(lR,2S)-2-(2,2-difluoropropanamido)-l-(2,3-dihydro-l,4-benzodioxin-6-yl)propoxy]- lH-indazol-l-yl}-N-[(3R)-tetrahydro-3-furanyl]benzamide

13. The pharmaceutical composition according to any one of claims 1-12, wherein the nanoparticles have a d50 of about 10 nm to about 500 nm; wherein the nanoparticles have a d90 of about 100 nm to about 500 nm; and, wherein the microparticles have a d50 of about 1 pm to about 5 pm.

14. Process (I) for the preparation of a pharmaceutical composition according to any one of claims l-kl3, wherein said process comprises the steps of:

(d) mixing the solution of step (c) with the nanosuspension to obtain a feedstock suspension; and, (e) spray drying the feedstock suspension of step (d) to form the pharmaceutical composition.

15. Process according to claim 14, wherein step (c) further comprises dissolving a bulking agent in the second liquid solvent to form the solution.

16. Process (II) for the preparation of a pharmaceutical composition according to any of claims 1 to 13, wherein said process comprises the steps of:

(c) spray drying the nanosuspension of step (b) to form the pharmaceutical composition.

17. Process according to claim 16, wherein said process comprises a step of dissolving a bulking agent in the second liquid solvent to form a solution and mixing the solution with the nanosuspension obtained in step (b) prior to the spray drying in step (c).

18. Process according to any one of claims 14-17, wherein the particle size reduction of step (b) comprises (ultra)sonicating, microfluidizing, high pressure homogenizing, (bead)milling or a combination thereof.

19. Process according to any one of claims 14-18, wherein the first and second liquid solvent is water.

20. A pharmaceutical composition as claimed in any one of claims 1 to 13 for use in therapy.

21. A pharmaceutical composition as claimed in any one of the claims 1 to 13 for use in treating and/or preventing a respiratory disease and/or a non-respiratory disease.

22. A method of treating and/or preventing a respiratory disease and/or a non-respiratory disease in a patient suffering from said disease, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as claimed in any one of claims 1-13.

23. A kit comprising a dry powder inhaler device and the pharmaceutical composition according to any one of claims 1-13.