Inhalable formulations of ruxolitinib, methods of manufacture and uses thereof

Abstract

There is provided inhalable formulations of ruxolitinib, manufacture, and uses thereof.

Description

FIELD This application relates to inhalable formulations of ruxolitinib and ruxolitinib salts, methods of manufacture and uses thereof. BACKGROUND Protein kinases are enzymes involved in cellular signalling, mediating the phosphorylation of target substrates. Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathways, comprising JAK1, JAK2, JAK3 and Tyrosine kinase (TYK)2. JAK1 and JAK 2 involved in type II interferon signalling and JAK3 and TYK2 are involved in type I interfering signalling. Correction of dysregulated cellular signalling is useful in treatment of diseases and disorders. Ruxolitinib is a JAK inhibitor which is selective for JAK1 and JAK2 subtypes, and which is used in the treatment of diseases and disorders wherein activation of JAK signaling is dysregulated such as autoimmune diseases, disorders, and cancer. Thus, ruxolitinib is presently used in diseases such as graft-versus-host disease (GvHD), after hematopoietic stem cell transplantation, such as pulmonary GvHD, nonsegmental vitiligo, splenomegaly, myelofibrosis, polycythemia vera and atopic dermatitis, and is being investigated for use in other treatments. Ruxolitinib use may carry side effects and adverse events such as moderate to severe thrombocytopenia, neotropenia, anemia, bruising, bleeding, dizziness, high blood pressure, and opportunistic infections and herpes zoster reactivation (shingles). Such side effects and adverse events may be dosedependent. Based on efficacy and safety, the maximum recommended daily dose of ruxolitinib is 50 mg / day as approved by the European Medicines Agency (EMA) and the Food and Drug administration (FDA). Current administrations of ruxolitinib are oral and topical on the skin, however, there is potential for use of ruxolitinib through other forms of administration to target localized diseases and disorders. Such diseases and disorders include those of the lungs and airways. SUMMARY To be able to treat diseases or disorders of the lungs and / or airways, other types of compositions or formulations of ruxolitinib than those presently available will be needed to effectively treat such diseases or disorders. An approach is to treat diseases or disorders by local administration to the respiratory tract. The present invention addresses the need for providing formulations suitable for inhalation, i.e., formulations to deliver ruxolitinib directly to the respiratory tract, e.g. lungs and airways. In its broadest aspect, the present invention relates to inhalable formulations of ruxolitinib or pharmaceutically acceptable salts thereof. The present invention relates to novel dry powder formulations suitable for inhalation comprising micronized ruxolitinib or pharmaceutically acceptable salts thereof, wherein at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% of ruxolitinib or pharmaceutically acceptable salts thereof occur in a single crystal form. In aspects of invention, ruxolitinib is in the form of ruxolitinib HCL In aspects of the invention the pharmaceutically acceptable salt of ruxolitinib is ruxolitinib phosphate. Inhalable formulations of the invention provide load-reducing benefits such as improved patient comfort, safety, and compliance by reducing the overall amount of ruxolitinib that is inhaled while still providing a therapeutically effective drug concentration in the lungs and airways, and avoiding the severe adverse effects associated with an oral route or IV route of administration. Inhalable formulations of the invention offer immediate release and extended release of ruxolitinib or pharmaceutically acceptable salts thereof. Inhalable formulations of the invention offer greater lung exposure than equivalent doses of ruxolitinib administered through conventional oral routes or by IV. While a relatively high oral dose of ruxolitinib would be required to achieve the same target lung exposure as achieved by inhalation of the inventive formulations, significantly lower dosages can be delivered using these formulations and methods. In embodiments, the ruxolitinib or pharmaceutically acceptable salts thereof used in formulations and methods of the invention can consist of entirely or almost entirely a single crystal form (e.g., 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% of a single crystal form), thereby allowing for controlled and predictable dosing and patient response. In certain embodiments, 95% or more of ruxolitinib or pharmaceutically acceptable salts thereof in the inhalable formulation may be present in a single crystal form. Various powder diffraction diagrams are provided. In certain embodiments, inhalable ruxolitinib or pharmaceutically acceptable salts thereof are provided by methods in which it may be micronized through wet or dry milling (e.g., jet milling) to achieve the desired particle size or particle size distribution for dry powder formulations for inhalation. Such particles in the particle size distribution preferably have a median particle size of 10 pm or less, such as 9 pm or less, such as 8 pm or less, such as 7 pm or less, such as 6 pm or less, such as 5 pm or less. It is desired to achieve a particle size that is suitable for inhalation. In certain embodiments, inhalable ruxolitinib or pharmaceutically acceptable salts thereof may be micronized through wet or dry milling (e.g., jet milling) to achieve the desired particle size or particle size distribution for dry powder formulations for inhalation. Such particles in the particle size distribution preferably have a median particle size less than 5 pm, such as less than 4 pm, such as less than 3 pm, such as less than 2.5 pm, such as less than 2 pm. In certain embodiments, ruxolitinib or pharmaceutically acceptable salts thereof is micronized alone or co-micronized with one or more pharmaceutically acceptable excipient(s). In certain embodiments, the dry powder formulation for inhalation comprises 1-80% w / w ruxolitinib or a pharmaceutically acceptable salt thereof, and 20-99% w / w of one or more pharmaceutically acceptable excipients. In aspects of the invention the micronized ruxolitinib or pharmaceutically acceptable salts thereof are subjected to conditioning to converting surface amorphicity into crystalline form. Such conditioning is demonstrated in the examples of the instant application. It is contemplated that after conditioning, amorphicity is reduced. In aspects of the invention, micronized ruxolitinib or pharmaceutically acceptable salts thereof is subjected to such conditioning before being mixed with one or more pharmaceutically acceptable excipients. In aspects of the invention micronization is and conditioning is carried in the same step. In aspects of the invention, the inhalable formulations comprising ruxolitinib or pharmaceutically acceptable salts thereof and one or more excipients are for use in the treatment of a disease or disorder. In aspects the invention provides methods of treatment for treating a disease or disorder. In aspects of the invention, there are provided dose regimens or dose methods for treating diseases or disorders. The use of the inhalable formulations for treatment, as well as the provided methods of treatment and dose regimens or dose methods are in particular for treating a disease or disorder in a subject affected by dysregulated JAK1 and / or JAK2 activity. In particular such diseases or disorders are of the lungs and / or airways. In aspects, methods of treatment comprise administration of a single or two daily doses of the inhalable formulation. In aspects of the invention, the total daily dosis is up to 12 mg, such as up to 11 mg, such as up to 10 mg. DETAILED DESCRIPTION The present invention relates to dry powder formulations suitable for inhalation comprising micronized ruxolitinib or pharmaceutically acceptable salts thereof, wherein the ruxolitinib or pharmaceutically acceptable salts thereof occur in a single crystal form. Inhalable formulations of the invention refer to formulations for administering ruxolitinib or pharmaceutically acceptable salts thereof via the respiratory tract. The formulation is inhaled though the nose and / or mouth and ruxolitinib and excipients and / or carriers having particle sizes about and below 10 pm travel together with ruxolitinib down the throat (pharynx) and through the larynx into the trachea. The trachea leading to the lungs, branches into bronchi and smaller bronchioles, together forming the lower respiratory tract together with the alveoli of the lungs. For effective lung deposition particle sizes of 1-5 pm (endpoints included) are ideal for reaching the lower respiratory tract. Particles larger than 5 pm may deposit in the upper airways and very small particles, i.e., smaller than 1 pm may be exhaled without being deposited. Inhaled ruxolitinib deposited to the lungs can work locally. Inhalable formulations of the invention deliver ruxolitinib directly to the site of action (lungs), providing faster and more effective treatment. Inhalable formulations of the invention require smaller doses compared to oral or injectable routes and reduce systemic side effects. The present invention relates to novel dry powder formulations suitable for inhalation ruxolitinib or pharmaceutically acceptable salts thereof. Dry powder refers to a finely milled or micronized form of ruxolitinib only or dry powder refers to a finely milled or micronized form of ruxolitinib and / or excipients and / or carriers. Dry powder formulations are a method for delivering ruxolitinib to the lungs using devices such as e.g., a dry powder inhaler. Dry powder formulations of the invention consist of micronized and / or milled ruxolitinib or pharmaceutically acceptable salts thereof and may include carriers and / or excipients to improve flowability and dispersion. Dry powder formulations of the invention consist of micronized and / or milled ruxolitinib or pharmaceutically acceptable salts thereof with the ideal particle size for lung deposition and carriers and / or excipients if any with a larger particle size to help improve flowability, dose uniformity, and dispersibility of the dry powder formulation as fine powders may have low flowability, may agglomerate, may reduce the uniformity of dosing. Flowability refers to the ability of a powder to flow freely and uniformly. For inhalable dry powders, good flowability ensure consistent dose delivery, ease of handling during manufacturing and reliable performance in devices such as e.g., dry powder inhalers. Agglomeration refers to the process by which fine particles cluster or stick together to form larger aggregates, known as agglomerates. Agglomeration occurs due to attractive forces between particles, such as van der Waals forces, electrostatic interactions or liquid bridges from moisture. In devices such as e.g., dry powder inhalers agglomeration can impact inhalation of the formulation and the efficacy of ruxolitinib. Agglomerates may not break apart during inhalation, reducing the fine particles fraction (FPF) and leading to larger particles that settle in the upper airways instead of reaching the lungs. Agglomerates may affect the dose variability of the delivery due to clumping or due to blocking of the inhalers’ delivery mechanism. Controlled agglomeration such as mild agglomeration can be beneficial, as the agglomeration improves flowability and dose uniformity by reducing excessive fines. Inhalable formulations of the invention are designed properly such that agglomerates if any can deagglomerate during inhalation. In the present invention, the particles size distribution of ruxolitinib or pharmaceutically acceptable salts thereof is controlled to reduce excessive fines that promote agglomeration. In the present invention, the dry powder formulation may comprise carriers and / or excipients with larger particles to reduce agglomeration by separating finer ruxolitinib particles if necessary, and / or ruxolitinib may be surface coated to reduce particle cohesion, and / or the dry powder formulation may be stored in low-humidity environments and / or the dry powder formulation may be properly dried after manufacturing. Inhalable formulations of the invention offer greater lung exposure than equivalent doses of ruxolitinib administered through conventional oral routes or by IV. While a relatively high oral dose of ruxolitinib would be required to achieve the same target lung exposure as achieved by inhalation of the inventive formulations, significantly lower dosages can be delivered using these formulations and methods. Thus, the present invention provides for administering to the subject a daily dose of 0.25 mg, such as 0.5 mg, such as 1 mg, such as 2 mg, such as 3 mg, such as 4 mg, such as 5 mg, such as 6 mg, such as 7 mg, such as 8 mg, such as 9 mg, such as 10 mg, such as 11 mg, such as 12 mg, such as 13 mg, such as 14 mg, such as 15 mg ruxolitinib or a pharmaceutically acceptable salt thereof. The daily dose may be administered in one daily administration or may be administered in separate equal administrations, such as 2 daily administrations or 3 daily administrations, or even more daily administrations. Such administration may be administered to the subject for a time period as needed, or ongoing such as for at least 2 weeks, 3 weeks, 4 weeks, one month, two months, three months, four months, six months, a year or more; or may be administered as long-term chronic treatment. A subject to be treated may be suffering from a disease or disorder as discussed herein, and may be an animal, or a human. Formulations of the invention may include one or more excipients or carriers. In certain embodiments, excipients with larger particles (particles constituting a particle size distribution preferably having a median particle size D(v,0.5) of 10 pm or more) may be used to increase aerodynamic forces on the combined formulation in order to aid in delivering ruxolitinib through inhalation. In certain embodiments, excipients with smaller particles (particles constituting a particle size distribution preferably having a median particle size D(v,0.5) of 10 pm or less) may be used as fines. Fines are the smallest particles in a powder-based formulation. Fines are ruxolitinib, carrier and / or excipients. For inhalable formulations, fines refer to particles with a median particles size smaller than 10 pm. In certain embodiments, median particles size of about 5 pm or smaller than 5 pm allows particles to reach the deep lung (alveoli), making them critical for delivery ruxolitinib to the respiratory tract, in certain embodiments, median particles size of about 1-2 pm allows particles to reach even deeper penetration, such as alveolar regions where systemic absorption can occur. In certain embodiments, enhance ruxolitinib delivery, fines improve the fine particle fraction (FPF), which is the proportion of ruxolitinib that reaches the lungs. In certain embodiments, fines often adhere to larger particles but detach during inhalation due to airflow ensuring effective delivery to the lungs. Fines may be ruxolitinib alone or may include fines from excipients and / or carriers. In certain embodiments, formulations of the invention may be optimized by carefully control the quantity and particle size distribution of fines in the formulation for inhalation to maximize lung deposition (higher FPF), maintaining acceptable powder flowability and / or ensuring dose uniformity during manufacturing and use. Ruxolitinib and pharmaceutically acceptable salts Ruxolitinib has the chemical name (R)-3-(4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1 H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, the molecular formula is C17H18N6 and the molecular weight is 306.4 g / mol. Ruxolitinib also exists as the S-enantiomer, and as hydrate, dihydrate, and anhydrate. It is appreciated that pharmaceutically acceptable salts include maleate, sulfate, oxalate, hydrogen chloride (HCI), mesylate, hemifumarate, and phosphate salts of ruxolitinib. Ruxolitinib phosphate has the chemical name (R)-3-(4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1 H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate, the molecular formula is C17H21N6O4P, and the molecular weight is 404.4 g / mol. Polymorphism exists for ruxolitinib phosphate. The anhydrous crystalline Form I is the most stable solid form. Excipients Typically, ruxolitinib or pharmaceutically acceptable salts thereof are micronized and combined with a suitable carrier to form a formulation suitable for inhalation. In certain embodiments, formulations of the invention may include one or more excipients (also referred to as carriers). Excipients may include, for example, larger particles to be used as a carrier for inhalation of micronized ruxolitinib formulations. The carrier particles, with their larger size, can be used to increase aerodynamic forces on the combined ruxolitinib / carrier in order to aid in delivery through inhalation. In certain embodiments, the formulation of the invention may include one or more excipients (also referred to as carriers) as dry powder. In certain embodiments, such dry powder is a free-flowing powder that is dispersed in the lungs and airways during inhalation. In certain embodiments, the carrier particle surface (or other excipient particle surfaces) may be coated and or treated such that ruxolitinib can be effectively separated from the carrier (or other excipient surfaces) as it leaves an inhaler device and / or within the oral cavity or nasal cavity when such excipients are being used as a carrier. In order to achieve a free-flowing powder formulations suitable excipients (also referred to as carriers) may include, for example, lactose in various forms (e.g., milled, roller dried or spray dried). Other saccharides than lactose may also be used as excipients, such as disaccharides, such as e.g., sucrose, glucose, dextrose, sorbitol, polysaccharides, such as e.g., starches, such as corn starch and potato starch, cellulose, modified cellulose such as microcrystalline cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; and cellulose ethers such as hydroxypropyl cellulose (HPC). Excipients may include solvents and may be used to condition the carrier particle surface (or other excipient particle surfaces) such that ruxolitinib can be effectively separated from the carrier (or other excipient surfaces) as it leaves an inhaler device and / or within the oral cavity or nasal cavity when such excipients are being used as a carrier. Excipients such as e.g., magnesium stearate, or lecithin sorbitan oleate can be added to keep the carrier and ruxolitinib from sticking together. Excipients may be added in low and high concentrations to the formulation for various purposes, and one or more excipients / carriers may be used in a dry powder inhaler such as those mentioned above or, e.g., a-Lactose, Sucrose, a,a-Trehalose, Raffinose, Mannitol, Citrate, Acetate, Magnesium stearate, Sodium stearate, Leucine, Deleucine, Trileucine, L-leucine, L-lsoleucine, L-Phenylalanine, L-alanine, Glycine, L-arginine, L-aspartic acid, L-lysine, L-Threonine, L-Cysteine, L-Histidine, Ammonium Carbonate, Ammonium bicarbonate, Calcium Chloride, Sodium chloride, Fumaryl diketopiperazine, Cholesterol, Compritol 888, Tristearin, Dipalmitoyl phosphatidylcholine (DPPC), Distearoyl phosphatidylcholine (DSPC), Lecithin, Limonene, Polycaprolactone (PCL), Polylactic acid (PLA) and / or Polylactide-co-glycolide (PLGA). A preferred excipient is lactose. In some embodiments, lactose may be used in a quality suitable for inhalation such as, e.g. Lactohale 100, Lactohale 200, Lactohale 201, Lactohale 206, Lactohale 210, Lactohale 220, Lactohale 230, Lactohale 300, Lactohale 400, Respitose ML001, Respitose SV003, Respitose SV010, Respitose SV011 and / or Respitose SV014 (DFE Pharma, Goch, Germany). In certain embodiments, the particle size distribution of the carriers / excipients, such as e.g. lactose, may be the same or different. In certain embodiments, excipients with larger particles may be used as carriers, and excipient with smaller particles may be used as fines. In certain embodiments, the excipients may be the same or different. In certain embodiments, the excipients may be lactose. In some embodiments, lactose may be used alone and / or in combination with one or more excipient(s). A preferred combination of excipients is lactose and magnesium stearate. Another preferred combination is lactose alone. In certain embodiments, inhalable formulations may have carrienruxolitinib weight ratios of 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 75:25, 80:20, 85:15, 85.5:14.5, 86:14, 86.5:13.5, 87:13, 87.5:12.5, 88:12, 88.5:11.5, 89:11,89.5:10.5, 90:10, 90.5:9.5, 91:9, 91.5:8.5, 92:8, 92.5:7.5, 93:7, 93.5:6.5, 94:6, 94.5:5.5, 95:5, 95.5:4.5, 96:4, 96.5:3.5, 97:3, 97.5:2.5, 98:2, 98.5:1.5, 99:1 or 99.5:0.5. In certain embodiments, carriers may be larger particles used as carrier and smaller particles used as fines. In certain embodiments, the carrier may be the same or different. In certain embodiments, carrier may include a combination of all excipients used in the formulation. In certain embodiments, formulations may include ruxolitinib or salts thereof as the API (ruxolitinib or a pharmaceutically acceptable salt thereof) in concentrations of 0.5% or more, 1% or more, 2% or more, 2.5% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, or 80%. As used herein, percent is %w / w. The carrier portion of the inhalable formulations may thus comprise one or more excipients, however, the carrienruxolitinib ratio is defined as a ratio between the total weight of carrier(s) and the weight of ruxolitinib calculated as ruxolitinib phosphate. Micronization Micronization may be done using e.g. wet milling or dry milling or jet milling to achieve the desired particle size and particle size distribution for dry powder formulation for inhalation. In certain embodiments, inhalable ruxolitinib or pharmaceutically acceptable salts thereof may be micronized to achieve the desired particle size or particle size distribution for dry powder formulations for inhalation. In certain embodiments, ruxolitinib or pharmaceutically acceptable salts thereof is micronized alone or co-micronized with one or more pharmaceutically acceptable excipient(s). In certain embodiments, pharmaceutically acceptable excipients may be micronized alone or co-micronized with one or more acceptable excipients to achieve the desired particle size or particle size distribution. Such particles constituting the particle size distribution preferably have a median particle size D(v,0.5) of 10 pm or less, such as 9 pm or less, such as 8 pm or less, such as 7 pm or less, such as 6 pm or less, such as 5 pm or less. It is preferred that the median particle size D(v,0.5) in the particle size distribution is preferably 5 pm or less, such as 4 pm or less, such as 3 pm or less, such as 2.5 pm or less, such as 2 pm or less. In certain embodiments, pharmaceutically acceptable excipients may be micronized alone or co-micronized with one or more acceptable excipients to achieve the desired particle size or particle size distribution for dry powder formulations for inhalation. Such particles constituting the particle size distribution preferably have a median particle size of 300 pm or less, such as 250 pm or less, such as 200 pm or less, such as 190 pm or less, such as 180 pm or less, such as 170 pm or less, such as 160 pm or less, such as 150 pm or less, such as 140 pm or less, such as 130 pm or less, such as 120 pm or less, such as 110 pm or less, such as 100 pm or less, such as 90 pm or less, such as 80 pm or less, such as 70 pm or less, such as 60 pm or less, such as 50 pm or less, such as 40 pm or less, such as 30 pm or less, such as 25 pm or less, such as 20 pm or less, such as 15 pm or less, such as 10 pm or less, such as 9 pm or less, such as 8 pm or less, such as 7 pm or less, such as 6 pm or less, such as 5 pm or less. Particle size such as for example the median particle size D(v,0.5) and / or particle size distribution (PSD) may be measured by using laser diffraction LALLS (Low-Angle Laser Light Scattering). Laser diffraction is a widely used technique to measure the size and distribution of particles in each sample. It is based on the principle of light scattering and provides rapid, accurate, and reproducible results over a wide range of particles sizes. Laser diffraction can measure particle sizes from nanometers to millimeters and the output is typically presented as a volume-based particle size distribution showing the proportion of particles in different size ranges. Sample preparation can be in dry powder form or suspended in a liquid medium. Proper dispersion of particles is crucial to avoid agglomeration and for the measurement process. The output is typically displayed as a size distribution curve, a graph showing the particles size (x-axis) versus volume fraction (y-axis). D-values are reported as D(v, 0.1), D(v, 0.5) and D(v, 0.9), representing the particle size below which 10%, 50% and 90% of the sample volume lies. Micronization may be done using e.g. wet milling wherein the ruxolitinib or the pharmaceutically acceptable salt thereof optionally together with excipient particles are e.g., suspended in a slurry and reduced through shearing or impact with a grinding media. Micronization may be done using e.g. dry milling e.g., jet milling e.g., by using fluidized jet mill equipment where the gas pressure applied in the milling chamber causes the particles of ruxolitinib or the pharmaceutically acceptable salt thereof and / or excipients to collide with each other and with the walls producing smaller particles. Once the particles have obtained sufficiently small size, they are able to pass a classifier. Other methods for micronization are known in the art. Conditioning (converting surface amorphicity into crystalline form) An advantage of the compounds and methods of the invention is the ability to exclude all or most of amorphous ruxolitinib from the formulation, even after micronization. A method for reducing or excluding amorphous ruxolitinib from the formulation is referred to as conditioning. Conditioning is restoring surface amorphicity into crystalline form. Conditioning comprises treating the micronized ruxolitinib with elevated or high Relative Humidity (RH) and / or elevated or high Relative Ethanol activity (RE). It is possible to revert the surface amorphicity resulting from the micronization, if present, by converting surface amorphicity into crystalline form in a controlled manner using elevated RH or RE. Such treatment is also referred to as provocation, and results in complete or substantial crystallization of amorphic structures including surface amorphicity. It is appreciated that elevated (i.e., higher) RH generally results in a faster crystallization. Surface amorphicity refers to the amorphous (disordered) nature of the surface layer of a particle such as e.g. ruxolitinib, while the core of the material may remain crystalline. Surface amorphicity is common in finely milled or micronized powders where milling and micronization can create a disordered surface structure. Milling and micronization disrupt the orderly crystalline structure at the surface resulting in an amorphous layer. For inhalable formulations of the invention surface amorphicity can play a critical role in influencing the stability of the formulation, as the amorphous layer is less stable than the crystalline bulk. The amorphous layer may recrystallize during storage and therefor affecting the performance of ruxolitinib, performance such as e.g., the dissolution properties of ruxolitinib. The amorphous layer may also affect the performance of the formulation by creating adhesion to and / or interaction with ruxolitinib and / or carriers / excipients which changes the flowability of the formulation due to interaction or cohesion between the particles. Micronization followed by conditioning (i.e., provocation) produces ruxolitinib particles with a crystalline surface suitable for dry powder inhalable formulations. Such conditioning comprising treating micronized ruxolitinib or pharmaceutically acceptable salts thereof with elevated or high RH between 50% to 80%, such as 53% to 75% or with elevated or high Relative Ethanol activity (RE) between 50% to 86%, such as 53% to 75%. A sufficient duration of the conditioning procedure to converting surface amorphicity into crystalline form may be required. Such duration of the conditioning preferable has a duration of 48 hours or less, 36 hours or less, 24 hours or less, 16 hours or less, 8 hours or less, 4 hours or less, 2 hours or less, 1 hour or less. The conditioning procedure to converting surface amorphicity into crystalline form may be performed at a temperature between about 15°C to about 50°C. Such temperature of the conditioning preferable is about 50°C or less, 45°C or less, 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, such as about 15°C. It is appreciated to minimise agglomeration tendency of ruxolitinib and therefor generally conditioning processes using mild conditions are applied, such as e.g. around 25°C / 50 RH, such as 25°C / 53 RH, such as 25°C / 55 RH, such as 25°C / 60 RH, such as 25°C / 65 RH, such as 25°C / 70 RH, 25°C / 75 RH. To determine the crystal form and crystal purity, X-ray powder diffraction may be used. Crystalline purity can be estimated using, for example X-ray powder diffraction (XRPD). X-ray powder diffraction (XRPD) is a powerful analytical technique used to identify the crystalline structure of materials. It works by directing X-rays at a powdered sample of the material and analyzing the way the X-rays are scattered, or diffracted, by the sample’s atoms. The result is a diffraction pattern of X-ray intensity versus diffraction angle (2 theta 29). This pattern acts like a “fingerprint” of the material’s crystal structure. Amorphous material gives broad and featureless patterns. X-rays is fast and non-destructive, can analyze complex mixtures and requires minimal sample preparation. 2 theta (20) values can be used for identification and characterization of disclosed crystalline forms of ruxolitinib. Ruxolitinib hydrochloride acid in crystalline form-R has an X-ray powder diffraction spectrum with peaks expressed in degrees (29) at approximately 8.2, 9.6, 11.7, 12.9, 13.7, 14.7, 15.2, 15.6, 16.5, 17.9, 18.7, 19.3, 19.8, 29.4, 29.8, 22.9, 22.4, 22.8, 23.5, 24.8, 25.4, 26.4, 27.7, 28.1,39.4, 33.3 and 37.6 ± 9.2 theta. Ruxolitinib phosphate salt in crystalline form-M has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 4.0, 12.3, 14.0, 15.2, 15.8, 16.4, 17.8, 20.6, 22.0 and 26.0 ± 0.2 theta. Ruxolitinib phosphate salt in crystalline form-S has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 3.7, 7.5, 11.4, 13.7, 15.2, 15.5, 18.0, 18.8, 19.0, 20.1,23.5, 23.8, 24.8, 25.3 and 27.4 ± 0.2 theta. Ruxolitinib phosphate salt in crystalline form-N has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 4.1,4.8, 12.3, 14.1, 15.0, 15.2, 15.9, 16.0, 16.4, 17.4, 17.9, 18.7, 19.6, 20.6,21.1,21.9, 22.1 and 23.1 ±0.2 theta. Ruxolitinib phosphate salt in crystalline form-l has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 4.0, 7.6, 8.2, 9.5, 12.0, 14.4, 14.7, 15.8, 16.6, 17.5, 18.7, 18.9,20.1,21.6, 22.7,23.1,23.4, 23.7, 24.8,25.1 and 26.2 ± 0.2 theta. In certain embodiments, Ruxolitinib phosphate salt in crystalline form-l has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 4.0, 7.6 and 9.5 ± 0.2 theta, the peaks normally used for identification of form-l. An X-ray diagram for form-l crystal form of ruxolitinib phosphate is shown in Figure 1 and 2. It is preferred that ruxolitinib is ruxolitinib phosphate in crystal form I. Formulation In certain embodiments, formulations of the invention are developed. In certain embodiments, a representative pharmaceutical formulation for use in a dry powder formulation suitable for inhalation comprises lactose and ruxolitinib in micronized form. In certain embodiments, a dry powder formulation for use in a dry powder inhaler comprises lactose and micronized ruxolitinib. In certain embodiments, such a dry powder formulation can be made, for example, by combining dry milled lactose with micronized ruxolitinib or pharmaceutically acceptable salts thereof and then dry blending the components. In certain embodiments, such dry powder formulation is then typically sieved and loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, such dry powder formulation is then optionally sieved and loaded into individual capsules. In certain embodiments, ruxolitinib or pharmaceutically acceptable salts thereof are micronized and optionally conditioned. The excipients portion of the dry powder formulations may thus comprise one or more excipients, however, the excipient:ruxolitinib ratio is defined as a ratio between the total weight of excipient(s) and the weight of ruxolitinib calculated as ruxolitinib phosphate. In certain embodiments, a dry powder formulation is prepared by blending micronized ruxolitinib or pharmaceutically acceptable salts thereof with excipient(s) having the same or different particle size distributions. In certain embodiments, one excipient may be used but have two or more different particle size distributions. In certain embodiments, two or more excipients may be used but have the same particle size distribution. In certain embodiments, the excipients may be lactose. In some embodiments, lactose may be used alone and / or in combination with one or more excipient(s). In some embodiments, lactose may be used with one particle size distribution or different particle size distributions. In some embodiments, lactose may be used with one particle size distribution. In some embodiments, lactose may be used with two different particle size distributions. In certain embodiments, a dry powder formulation is prepared by blending 10% micronized and optionally conditioned ruxolitinib or pharmaceutically acceptable salts thereof with 90% excipient(s) / carrier. The blended mixture is then sieved, and loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, a dry powder formulation is prepared by blending 10% micronized and optionally conditioned ruxolitinib or pharmaceutically acceptable salts thereof with 90% lactose carrier. The blended mixture is then sieved, and loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, such dry powder formulation is then typically sieved and loaded into individual capsules. In certain embodiments, such as those discussed above, ruxolitinib or pharmaceutically acceptable salts thereof are micronized and optionally conditioned before being blended with excipient(s). The lactose:ruxolitinib ratio is defined as a ratio between the total weight of lactose and the weight of ruxolitinib calculated as ruxolitinib phosphate, regardless of whether ruxolitinib phosphate is used. In certain embodiments, a dry powder formulation is prepared by blending 2% micronized and optionally conditioned ruxolitinib or pharmaceutically acceptable salts thereof with 98% excipient(s) / carrier. The blended mixture is then sieved, and loaded into dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, a dry powder formulation is prepared by first blending 2% micronized and optionally conditioned ruxolitinib or pharmaceutically acceptable salts thereof with 8% excipient(s) / carrier having a particle size close to the particle size of ruxolitinib and then adding 90% excipient(s) / carrier having a median particle size larger than 50 pm to the blend. The blended mixture is then sieved, and loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, such dry powder formulation is then optionally sieved and loaded into individual capsules. The excipients portion of the dry powder formulations may thus comprise one or more excipients, however, the excipient:ruxolitinib ratio is defined as a ratio between the total weight of excipient(s) and the weight of ruxolitinib calculated as ruxolitinib phosphate.In certain embodiments, a dry powder formulation is prepared by blending first 2% micronized and optionally conditioned ruxolitinib or pharmaceutically acceptable salts thereof with 8% lactose having a particle size close to the particle size of ruxolitinib and then adding 90% lactose having a median particle size larger than 50 pm to the blend. The blended mixture is then sieved, and loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. In certain embodiments, the dry powder delivery device is a dry powder inhaler. In certain embodiments, such dry powder formulation is then typically sieved and loaded into individual capsules. The lactose:ruxolitinib ratio is defined as a ratio between the total weight of lactose and the weight of ruxolitinib calculated as ruxolitinib phosphate. In certain embodiments, formulations of the invention such as a representative pharmaceutical formulation for use in a dry powder formulation suitable for inhalation comprises a dose of 0.1 mg, such as 0.25 mg, such as 0.5 mg, such as 0.75 mg, such as 1 mg, such as 1.25 mg, such as 1.5 mg, such as 1.75 mg such as 2 mg, such as 2.25 mg, such as 2.5 mg, such as 2.75 mg such as 3 mg, such as 3.25 mg, such as 3.5 mg, such as 3.75 mg, such as 4 mg, such as 4.25 mg, such as 4.5 mg, such as 4.75 mg such as 5 mg, such as 5.25 mg, such as 5.50 mg, such as 5.75 mg, such as 6 mg, such as 6.25 mg, such as 6.50 mg, such as 6.75 mg, such as 7 mg, such as 7.25 mg, such as 7.50 mg, such as 7.75 mg, such as 8 mg, such as 8.25 mg, such as 8.50 mg, such as 8.75 mg, such as 9 mg, such as 9.25 mg, such as 9.50 mg, such as 9.75 mg, such as 10 mg, such as 10.25 mg, such as 10.50 mg, such as 10.75 mg, such as 11 mg, such as 11.25 mg, such as 11.50 mg, such as 11.75 mg such as 12 mg, ruxolitinib or a pharmaceutically acceptable salt thereof. In certain embodiments, formulations of the invention such as a representative pharmaceutical formulation for use in a dry powder formulation suitable for inhalation has a homogeneity below or equal to 5% relative standard deviation (RSD), such below or equal to 4.5% RSD, below or equal to 4% RSD, below or equal to 3.5% RSD, below or equal to 3% RSD, below or equal to 2.5% RSD, below or equal to 2% RSD, below or equal to 1.5% RSD, below or equal to 1 % RSD, below or equal to 0.5% RSD, below or equal to 0.4% RSD, below or equal to 0.3% RSD, below or equal to 0.2% RSD and below or equal to 0.1% RSD. In certain embodiments, formulations of the invention such as a representative pharmaceutical formulation for use in a dry powder formulation suitable for inhalation has a fine particle fraction (FPF) more than and equal to 30%, such as more than 35%, such as more than 40%, such as more than 45%, such as more than 50%, such as more than 55%, such as more than 60%, such as more than 65%, such as more than 70%, such as more than 75%, such as more than 80%, such as more than 85%, such as more than 90%, such as more than 95%. Delivery methods Dry powder formulations can be delivered by using inhalers such as dry powder inhalers for oral inhalation or nasal inhalation. Dry powder formulation can be delivered as single dose or multiple doses by dividing the dry powder formulation into individual capsules or other formats, compatible with the dry powder inhaler used. The dry powder inhaler applied for the dry powder formulations of ruxolitinib can be designed with one, two, three, four, five or multiple of the following features such as delivery of dry powder formulations of ruxolitinib or pharmaceutically acceptable salts thereof by capsule based inhaler, inhaler easy to handle, inhaler with no loose parts, inhaler with user-friendly design, inhaler with ergonomic design, inhaler designed with integrated mouthpiece cover with or without integrated hinge, inhaler with screw-on cover and integrated desiccant, inhaler with low flow resistance or customized to a flow resistance of choice, inhaler with flexible dosing, inhaler with number of doses designed for standard size capsules or adapted for smaller or lager capsule sizes, inhaler with number of doses designed for smaller or lager reservoirs, inhaler with flexible single or multi-doses, inhaler with feedback features, inhaler excellent for maintenance treatment, inhaler pre-filled with multiple doses, inhaler with exact dose counter, inhaler with visual inhalation feedback, inhaler designed for fully automatic assembly and inhaler designed for low cost manufacturing. In certain embodiments, delivery device such as a dry powder inhaler is preferred. In one embodiment, the delivery device is a low resistance dry powder inhaler. In one embodiment, the delivery device is a dry powder inhaler for oral inhalation and in another embodiment, the delivery device is a dry powder inhaler for nasal inhalation. In certain embodiments, a delivery device is a capsule based dry powder inhaler. In certain embodiments, when preparing a dose, a capsule is placed in the delivery device, pierced and then ruxolitinib or pharmaceutically acceptable salts thereof is ready to be inhaled. In certain embodiments, capsules with ruxolitinib formulation are packed separately. In one embodiment, capsules are packed in blisters. In another embodiment, bulk is packed in bottles. In certain embodiments, a delivery device is a multi-dose dry powder inhaler. In certain embodiments, the delivery device is pre-filled with doses, ruxolitinib is ready to be inhaled. In certain embodiments, the delivery device has an exact dose counter. In one embodiment, the dose counter displays how many doses are left and, in another embodiment, the dose counter displays how many doses are used. Dry powder inhaler delivery devices such dry powder inhalers suitable for administering ruxolitinib by inhalation are described in the art and examples of such devices are commercially available. Predispensed dose, delivered dose and fine particle dose are critical in context of inhalation drug delivery systems such as e.g., dry powder inhalers. Predispensed dose, delivered dose and fine particle dose help quantify the efficiency of the device and the dry powder formulation in delivering ruxolitinib to the lungs. Predispensed dose is the total amount of ruxolitinib that is initially loaded into the inhaler for a single dose intended to be delivered to the patient. The dose as labelled on the product packing. However, due to losses during device actuation, not all the predispensed dose reaches the patients respiratory system due to retention of powder in the capsule and / or inhaler, ruxolitinib particles adhering to the inner walls of the device and / or inefficient deagglomeration of the powder formulation during inhalation. Delivered dose is also called the emitted dose and indicates the efficiency of the inhaler device in releasing ruxolitinib from the formulation. Some of the delivered dose may still be lost in the mouth and throat meaning it does not reach the lungs. Typically delivered dose is measured in the laboratory setting by connecting the inhaler to a sampling device (e.g., a Next Generation Impactor) that captures ruxolitinib particles and formulation exiting the device. Fine particle dose (FPD) is the portion of the delivered dose consisting of particles small enough to penetrate deep into the lungs. Particles with a median particles size of about 5 pm or smaller than 5 pm. It is the dose that is respirable and likely to deposit in the lower respiratory tract such as the bronchioles and alveoli. The fine particle dose (FPD) is the most clinically relevant dose because particles within this size range can reach the site of action in the lungs (particles with a median particles size of about 5 pm or smaller than 5 pm). Particles larger than 5 pm are typically deposited in the mouth or throat and are eventually swallowed and reducing therapeutic efficacy. Fine particle dose (FPD) is like delivered dose measured by an Inhaler testing equipmentwhich separate particles based on their diameter. Dry powder inhaler delivery devices such dry powder inhalers suitable for administering ruxolitinib or pharmaceutically acceptable salts thereof by inhalation has a delivered dose not less than 50 % of the metered dose (MD). Dry powder inhaler delivery devices such dry powder inhalers suitable for administering ruxolitinib by inhalation has a delivered dose not less than 50 % of the fine particle fraction (FPF). To characterize the aerodynamic particle size distribution of inhalable formulations different inhaler testing equipment exist. Next generation impactor (NGI) is a widely used instrument in the pharmaceutical industry to characterize the aerodynamic particle size distribution of inhaled drug products and to evaluate the performance of dry powder inhalers. Inhaler testing equipment is used to simulate the deposition of inhaled particles in different regions of the respiratory tract. Inhaler testing equipment measures particle size by analyzing how particles behave as they pass through various stages of the impactor. Each stage has a specific cutoff diameter, determined by the aerodynamic properties of the particles. The stages are arranged so that smaller particles are captured in progressively deeper stages. The dry powder formulation is introduced into the Inhaler testing equipment at a controlled flow rate, as particles pass through the stages, they are separated based on inertia. Larger, heavier particles deposit on earlier stages, while smaller particles move to later stages. The deposited ruxolitinib on each stage is collected and its quantity is quantified using analytical high-performance liquid chromatography (HPLC) method. Diseases and disorders Diseases and disorders of the lungs and airways may be treated using the inhalable ruxolitinib formulations of the invention. Such diseases may be referred to as pulmonary diseases and may be primary or secondary diseases. After lung transplant or allogenic stem cell transplantation, the transplantee may develop bronchiolitis obliterans syndrome (BOS) mediated by cytokine signaling and which may be considered a form of graft-versus-host disease (GvHD), after hematopoietic stem cell transplantation, such as pulmonary GvHD, if occurring after an allogenic stem cell transplantation or a host-versus-graft disease if occurring after a lung transplantation. Treatment of chronic rejection after lung transplantation such as chronic lung allograft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as gost-transplant BOS), chronic lung allograft dysfunction-restrictive allograft syndrome (CLAD-RAS). Ruxolitinib may be used in the treatment of BOS, especially in the form of an inhalable formulation as disclosed herein. Other pulmonary diseases for which the inhalable ruxolitinib formulations may preferably be used include obstructive pulmonary diseases such as asthma and chronic obstructive pulmonary disease; and interstitial lung diseases such as sarcoidosis, pneumoconiosis, berylliosis, coal worker’s disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrosing phenotype ILD (PF-ILD), hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythomatosis-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, Granulomatosis with polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, Idiopathic eosinophilic pneumonia, Pulmonary Langerhans cell histiocytosis, bronchiolitis obliterans organising pneumonia (BOOP), also known as cryptogenic organizing pneumonia (COP). Inhalable ruxolitinib formulations as disclosed may also be used for treating pulmonary hypertension, including pulmonary arterial hypertension, pulmonary veno-occlusive disease, or pulmonary hypertension associated with a lung disease including pulmonary hypertension associated with interstitial lung disease. Inhalable ruxolitinib formulations as disclosed may also be used for treating cancers of or in the lungs and / or airways, especially cancers wherein activation of JAK signalling is dysregulated. Such cancers include but are not limited to those where the tumorigenesis is mediated by inflammation, and / or where a mutation in a JAK gene or in a signalling molecule upstream of JAK activation occurs, leading to dysregulation of JAK activity. Such dysregulation may e.g., be due to mutations in oncogenes such as RAS rendering the cancer being driven by an overactive or constitutively active RAS; or may be driven by other mechanisms. Lung cancers include but are not limited to lung adenocarcinoma and non-small-cell lung cancer. Inhalable ruxolitinib formulation as disclosed may also be used for treating nasal polyps, allergic rhinitis, non-allergic rhinitis, eosinophilic rhinitis, nasal vasculitis, also known as granulomatosis with polyangiitis located in the nose, post-infectious olfactory dysfunction, chronic nasal inflammation associated with autoimmune diseases, this include Sjogren’s syndrome or lupus erythematosus, The development of an inhaled form of ruxolitinib or pharmaceutically acceptable salts thereof offers a promising solution. By delivering ruxolitinib directly to the lungs, this targeted approach aims to maximize therapeutic benefits while minimizing systemic exposure and associated toxicities. Inhalation has the potential to significantly reduce haematologic side effects such as severe cytopenias, including anemia, thrombocytopenia, and neutropenia, and gastrointestinal symptoms such as diarrhea and nausea, thus improving overall patient outcomes. Furthermore, the localized delivery of ruxolitinib could enhance the efficacy in treating such as for example bronchiolitis obliterans syndrome (BOS) by ensuring higher drug concentrations at the site of disease activity. In certain embodiments, a dry powder formulation may be developed for inhalation of ruxolitinib or pharmaceutically acceptable salts thereof. In certain embodiment, development of inhaled ruxolitinib for treatment of chronic progressive pulmonary sarcoidosis and several other rare and severe lung disease. In certain embodiment for treatment of fibrotic lung diseases. In certain embodiments, inhaled ruxolitinib will be developed to treat sarcoidosis, pneumoconiosis, chronic hypersensitivity pneumonitis (CHP), connective tissue disorder ILD (CTD-ILD). In certain embodiments, treatment of graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation, such as pulmonary GvHD. In certain embodiments, treatment of chronic rejection after lung transplantation such as chronic lung allograft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as post-transplant BOS), chronic lung allograft dysfunction-restrictive allograft syndrome (CLAD-RAS). In certain embodiments, treatment of asthma. In certain embodiments, treatment of chronic obstructive pulmonary disease. In certain embodiments, treatment of sarcoidosis. In certain embodiments, treatment of pneumoconiosis. In certain embodiments, treatment of berylliosis. In certain embodiments, treatment of coal worker’s disease. In certain embodiments, treatment of silicosis. In certain embodiments, treatment of progressive fibrosing phenotype ILD (PF-ILD). In certain embodiments, treatment of hypersensitivity pneumonitis. In certain embodiments, treatment of systemic sclerosis-associated ILD (Ssc-ILD). In certain embodiments, treatment of Idiopathic pulmonary fibrosis (IPF). General It should be understood that any feature and / or aspect discussed above in connection with the compounds according to the invention apply by analogy to the methods described herein. The term ruxolitinib is to intended to include ruxolitinib having the CAS registry number 941678-49-5, 1 H-Pyrazole-1 -propanenitrile, p-cyclopentyl-4-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)-, (PR)-(PR)-p-Cyclopentyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazole-1 -propanenitrile; (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-o(]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]propanenitrile; (R)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]-3-cyclopentylpropanenitrile; or a pharmaceutically acceptable salt thereof. Trade names include Jakafi, Jakavi, and Opzelura. The terms “a” and “an” are intended to mean “one or more”; “the” preceding an element do not exclude the presence of a plurality of such elements. The terms "comprising", “comprise” or “comprises” does not exclude the presence of other elements or steps than those listed. It should be noted that the use of “or” means “and / or” unless stated otherwise. The term “up to” is intended to include the endpoint. The following figures and examples are provided below to illustrate the present invention. They are intended to be illustrative and are not to be construed as limiting in any way. BRIEF DESCRIPTION OF THE FIGURES Figure 1. X-ray Powder Diffraction (XRPD) diffractogram of ruxolitinib phosphate, batch RH0030223 (full view) is presented and shows that the material is highly crystalline by showing characteristics peaks. Peaks expressed in degrees (20) at approximately 4.0, 7.6 and 9.5 ± 0.2 theta are the peaks normally used for identification of form-1 Figure 2. X-ray Powder Diffraction (XRPD) diffractogram of ruxolitinib phosphate, batch RH0030223 (zoomed view) is presented and shows that the material is highly crystalline Figure 3A. X-ray Powder Diffraction (XRPD) diffractogram of micronized ruxolitinib phosphate, PR-469-4 (zoomed-in view) before (top (green) curve at the position of the arrow) and after provocation with 86 %RE (lower (pink) curve for 1 day. The micronized ruxolitinib phosphate contains surface amorphicity post-micronization, which disappears post-high RE treatment Figure 3B. X-ray Powder Diffraction (XRPD) diffractogram of micronized ruxolitinib phosphate, PR-469-4 (full view) before (top (green) curve at the position of the arrow) and after provocation with 86 %RE (lower (pink) curve for 1 day. The micronized ruxolitinib phosphate contains surface amorphicity post-micronization, which disappears post-high RE treatment Figure 4A. X-ray Powder Diffraction (XRPD) diffractogram of micronized ruxolitinib phosphate, PR-469-4 (zoomed-in view) before (top (pink) curve at the position of the arrow) and after provocation with 94 %RH (lower (blue) curve for 1 day. Also, in this case it is quite clear that recrystallisation takes place Figure 4B. X-ray Powder Diffraction (XRPD) diffractogram of micronized ruxolitinib phosphate, PR-469-4 (full view) before (top (pink) curve at the position of the arrow) and after provocation with 94 %RH (lower (blue) curve for 1 day. Also, in this case it is quite clear that recrystallisation takes place Figure 5. Isothermal microcalorimetry thermogram from provocation with 75 %RH of micronized ruxolitinib phosphate shows there is a clear recrystallisation event (double peak) taking place after the initial sorption phase Figure 6. Isothermal microcalorimetry thermogram from provocation with 53 %RH of micronized ruxolitinib phosphate shows there is no clear crystallization peak, but the total integrated enthalpy is close to the value from 75 %RH (note the different time scale in this figure, a very extended event). Hence there is slow, continuous crystallization taking place Figure 7. Comparison of particle size distribution (PSD) curves for micronized batches after external sonication in beaker (immediate full dispersion method), PR-469-1, PR-4692, PR-469-3 and PR-469-4. The four batches have been micronized by applying different settings see Table 1 Figure 8. Particle size distribution (PSD) curves for batch PR-469-4 after different conditioning treatments, stirrer dispersion: untreated micronized start, TAM 53 %RH, TAM 75 %RH and after conditioning in 25 °C / 75 %RH and storage at 25 °C / 60 %RH for 4 weeks Figure 9. Particle size distribution (PSD) curves for batch PR-469-4 after different conditioning treatments, after sonic 20 % power for 1 minute: untreated micronized start, TAM 53 %RH, TAM 75 %RH and after conditioning in 25 °C / 75 %RH and storage at 25 °C / 60 %RH for 4 weeks Figure 10. Particle size distribution (PSD) curves for batch PR-469-4 after different conditioning treatments, after additional sonic 90 % power for 1 minute: untreated micronized start, TAM 53 %RH, TAM 75 %RH and after conditioning in 25 °C / 75 %RH and storage at 25 °C / 60 %RH for 4 weeks Figure 11. Particle size distribution (PSD) curves for batch PR-469-4 after different conditioning treatments, after additional sonic 90 % power for 5 minutes: untreated micronized start, TAM 53 %RH, TAM 75 %RH and after conditioning in 25 °C / 75 %RH and storage at 25 °C / 60 %RH for 4 weeks Figure 12. Ratios between free drug exposure following 2.5 mg (ruxolitinib phosphate) inhaled and 2.5 mg (ruxolitinib phosphate) given as oral immediate release (biopharmaceutical in silico assessment). BB = tracheobronchial (large airways), bb = bronchiolar (small airways) and Al = alveolar interstitial (lung parenchyma) Figure 13. Ratios between free drug exposure following 5 mg (ruxolitinib phosphate) inhaled and 5 mg (ruxolitinib phosphate) given as oral immediate release (biopharmaceutical in silico assessment). BB = tracheobronchial (large airways), bb = bronchiolar (small airways) and Al = alveolar Figure 14. The amount of active pharmaceutical ingredient (API) - ruxolitinib - measured on filters in relation to Wright Dust Feed (WDF) speed from a dry run test of the aerosolization of the formulation in an inhalation tower set-up showing a linear relationship between API (ruxolitinib) on filters and WDF speed. The dry run was performed prior to the rat pharmacokinetic study Figure 15. Tissue concentration (Ct) data normalized by dose and by bioavailability (BA) for ruxolitinib levels in parenchyma after inhaled (inh) and intravenous (iv) single dose of ruxolitinib from the rat pharmacokinetic study, showing a 5.5 times higher concentration in parenchyma after inhaled administration compared to iv administration (based on area under the curve - AUC). Figure 16. Tissue concentration (Ct) data normalized by dose and by bioavailability (BA) for ruxolitinib levels in airways after inhaled (inh) and intravenous (iv) single dose of ruxolitinib from the rat pharmacokinetic study, showing a 12.0 times higher concentration in parenchyma after inhaled administration compared to iv administration (based on area under the curve - AUC). Examples Example 1 Micronization and restoration of crystallinity of ruxolitinib phosphate Ruxolitinib phosphate batch RH0030223 from MSN Laboratories Private Limited in India, which according to the Certificate of Analysis has the crystalline Form-1, was micronized in a fluidized jet mill equipment (Airfilco 2.5” jet mill by Technoprog). The gas pressure applied in the milling chamber causes the particles to collide with each other and with the 5 walls producing smaller particles. Once the particles have obtained a sufficiently small size, they were able to pass the classifier and were then collected in a glass jar. The feed material was micronized in small amounts (1 g) applying different settings to decide upon final settings for the bulk amount (5 g). Different pressures were applied during 3 screening runs prior to bulk micronization. The conditions and results are shown 10 in Table 1. Table 1. Milling parameters applied Sample Amount 1 g Milling pressure 1 Bar Ejector pressure 1 Bar Yield 1 % PR-469-1 1 2.2 5.0 N.A. PR-469-2 1 1.6 4.0 N.A. PR-469-3 1 1.0 3.0 N.A. PR-469-4 5 2.0 4.0 91 N.A. = not applicable Based on the initial particle size distribution it was decided to apply the settings for the 5 g 15 batch (PR-469-4) as set forth in Table 2 to obtain a particle size distribution in the lower part of the interval between 2-3 pm, see Example 2 for particle size distribution results. Table 2. Milling parameters for batch PR-469-4 Parameter Value Inner surface material Titanium nitride coating Feeder Vibrating chute Feed rate Ca 1 g / min Milling gas Nitrogen Ejector pressure 4 bar Milling pressure 2 bar Initial compound amount 5g Crystallinity was measured by X-ray Powder Diffraction (XRPD) using the instrument PanAlytical X’Pert Pro. Sample was prepared by approximately 15-20 mg sample and was smeared out on zero background wafers of silicon, producing a flat powdered surface. The settings for the XRPD measurement are found in Table 3. Table 3. XRPD measurement parameters Parameter Value Instrument geometry Theta-2Theta X-Ray tube Cu-anode (Cu K a) Power 45 kV / 40 mA Monochromator Johansson (1.540598 A) Incident beam optics Programmable divergency slit Diffracted beam optics Anti-scatter Shield Detector Pixcel 2-Theta range 2-35° Scan speed 0.03 7s Step size 0.013° Sample rotation 7.5 rpm X-ray Powder Diffraction (XRPD) was recorded before and after exposing the micronized material to high Relative Humidity (RH) and high Relative Ethanol activity (RE). The XRPD diffractogram of ruxolitinib phosphate (RH0030223) is presented in Figure 1 (full view) and in Figure 2 (zoomed view). The XRPD diffractogram of micronized ruxolitinib phosphate (PR-469-4), before and after provocation with 86 % relative ethanol activity (RE) for 1 day, is presented in Figure 3A (zoomed view) and Figure 3B (full view). The micronized material contains surface amorphicity post micronization, which disappears post high RE treatment. The corresponding XRPD diffractogram of micronized ruxolitinib phosphate, before and after provocation with 94 % Relative Humidity (RH) for 1 day, is presented in Figure 4A (zoomed view) and Figure 4B (full view). Also, in this case it is quite clear that recrystallisation is taking place. It is possible to use either elevated Relative Humidity RH or elevated ethanol activity (RE) to convert the induced amorphicity to crystalline phase again, also referred to as conditioning or provocation. Example 2 Suitable conditions for conditioning (restoration of crystallinity) of micronized ruxolitinib phosphate To find suitable conditions for conditioning micronized ruxolitinib phosphate to obtain crystalline ruxolitinib phosphate, two different high Relative Humidity RHs were further selected for use in microcalorimetrical crystallization experiments. An Isothermal microcalorimetry (TAM III) from TA Instruments with multichannel calorimeter units was applied and samples were prepared by filling a sample into a 4 mL glass vial. The prepared sample vial and the hygrostat were pre-equilibrated separately at 25 °C before adding the hygrostat tube to the sample vial and sealing the vial. The closed vial was immediately introduced into the thermostating position of a calorimeter channel, equilibrated for a predefined time of 15 minutes before lowering into the measuring positions. The settings for the Isothermal microcalorimetry measurement are found in Table 4. Table 4. Isothermal microcalorimetry (TAM) measurement parameters Parameter Value Sample weight 300 mg ± 10 mg Sample preparation conditions 20-30 %RH, 21-24 °C Instrument temperature 25 °C Hygrostat solvent Water Hygrostat salt MgNOs or NaCI Hygrostat relative humidity 53 or 75 %RH, respectively Hygrostat restriction N.A. Measurement end condition N.A. Integration method Against baseline at 0 pW Conditioning at an RH of 53% and 75%, respectively was followed by microcalorimetry (TAM). Conditioning occurs in both conditions and considerably faster at the higher RH. Figure 5 shows the results from 25 °C and 75 %RH and there is a clear recrystallisation event (double peak) taking place after the initial sorption phase. Sorption phase refers to the process or conditions during which micronized ruxolitinib or pharmaceutically acceptable salts thereof interacts with relative humidity and undergoes changes from amorphous to crystalline form as it captures water. In Figure 6, the corresponding results from 25 °C and 53 %RH are shown. In this case there is no clear crystallization peak, but the total integrated enthalpy is close to the value from 75 %RH (Note the different time scale in Figure 6 with a very extended event). Hence there is slow, continuous crystallization taking place. Next, the particle size distribution (PSD) by LALLS (Low-Angle Laser Light Scattering) were evaluated on sample before and after conditioning. A Malvern Mastersizer 3000 instrument, equipped with a 300 mm reverse Fourier lens and Hydro MV sample cell and stirrer were applied. Sample preparation for primary particle size check after micronization: a few mg of solid sample was introduced into a 10 ml beaker with a sonication rod inserted while sonicating at power level 2 (of 7 steps) at 100% duty cycle. After 1 minute of sonication, the resulting suspension was introduced directly to the Hydro HV unit. Measurement was thereafter performed during stirring dispersion. Sample preparation for conditioning check: a few mg of solid sample was introduced directly to the Hydro HV unit. Measurement was performed during stirring 1 minute after addition, and after several steps of internal sonication. The settings for the particle size measurement are found in Table 5. Table 5. Particle size measurement parameters Parameter Value Background measurement time 10s Sample measurement time 10s Blue light measurement time 10s Number of measurements 3 Delay between measurements 0 s Obscuration, lower limit 2 % Obscuration, higher limit 20 % Dispersant medium n-para C10-C13 Dispersant refractive index 1.42 Analysis model General purpose, non-spherical, normal sensitivity Particle refractive index 1.6 Absorption 1 Stirrer speed 2500 rpm Sonication No sonication, then 1 minute at 20% power followed by 1 minute at 90% power, and finally 5 minutes at 90% power Results from the particle size distribution (PSD) analysis are presented in Figure 7 -Figure 11 and in Table 6 - Table 10. 5 Table 6. Particle size distribution results for samples micronized at different conditions, after external sonication in beaker (immediate full dispersion method) Sample D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm <2pm(%) <10pm(%) PR-469-1 0.703 2.00 4.45 50 98 PR-469-2 1.08 2.83 5.43 29 100 PR-469-3 1.17 2.99 5.63 26 100 PR-469-4 0.741 1.74 3.16 61 100 Table 7. Particle size distribution results for PR-469-4, recrystallized at different conditions, after 1 minute stirrer dispersion Condition D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm <2pm(%) <10pm(%) Noconditioning 1.30 3.86 55.8 22 70 TAM 53 %RH 1.45 4.42 23.5 17 79 TAM 75 %RH 1.76 7.24 66.9 12 58 Conditioned and stores for 4w at 25°C / 60%RH 2.16 11 92.8 9 48 Table 8. Particle size distribution results for PR-469-4, recrystallized at different conditions, after sonication 20 % power for 1 minute Condition D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm <2pm(%) <10pm(%) Noconditioning 0.978 2.53 5.20 35 99 TAM 53 %RH 1.11 3.06 6.44 27 99 TAM 75 %RH 1.20 3.60 8.55 22 94 Conditioned and stores for 4w at 25°C / 60%RH 1.27 3.97 9.43 20 92 5 Table 9. Particle size distribution results for PR-469-4, recrystallized at different conditions, after additional sonication 90 % power for 1 minute compared to PR-469-4 subjected to sonication, but not conditioning - see Figure 10 Condition D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm <2pm(%) <10pm(%) Noconditioning 0.933 2.25 4.17 42 100 TAM 53 %RH 0.978 2.36 4.34 39 100 TAM 75 %RH 1.00 2.57 5.07 34 100 Conditioned and stored for 4w at 25°C / 60%RH 1.05 2.66 5.24 32 100 Table 10. Particle size distribution results for PR-469-4, recrystallized at different 10 conditions, after additional sonication 90 % for 5 minutes Condition D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm <2pm(%) <10pm(%) Noconditioning 0.871 1.96 3.48 52 100 TAM 53 %RH 0.860 1.93 3.38 53 100 TAM 75 %RH 0.891 2.00 3.52 50 100 Conditioned and stored for 4w at 25°C / 60%RH 0.920 2.02 3.53 49 100 For the final micronized material PR-469-4 the external immediate dispersion methodology results in a somewhat lower PSD than the gradual internal methodology, (Table 6 and Table 10). The gradual dispersion methodology shows the lowest presence of larger agglomerates at stirrer dispersion for the material from 53 %RH. Otherwise, the main peaks are slightly shifted towards higher particle size distributions with higher exposure to moisture (Figure 8 - Figure 10 & Table 7 - Table 9). The result, after prolonged internal sonication, provides as good as identical primary particle size results for all conditions, see Figure 11, Table 10). Particle size distribution on sample before and after conditioning shows a slight increase of particles sizes after conditioning and more pronounced at higher RH. This is probably due to agglomeration since almost no difference between samples are seen after prolonged sonication. 4 weeks storage at 25 °C and 60 %RH exhibit a slight tendency of increased agglomeration. Example 3 The biopharmaceutical in silica assessment The objective of the biopharmaceutical assessment was to compare the pharmacokinetic (PK)-profiles for oral vs inhaled administration specifically with regards to the lung tissue concentration of ruxolitinib. The biopharmaceutical assessment was made in silico using the Mimetikos Preludium™ software with physiology-based biopharmaceutical models with systemic PK and molecular parameters for ruxolitinib. All chemical and physiological attributes for ruxolitinib applied in the model were found in the literature. A lung deposition of 50% of the Delivered Dose was assumed, with inhalation parameters and Aerodynamic Particle Size Distribution as expected for a powder inhaler. JackG Shi et al. ,(J Clin Pharmacol. 2011 Dec;51 (12):1644-54.), have described a two-compartment model based on three studies. This model was successfully applied in Preludium to generate systemic PK concentration-time profiles and AUCinf and Cmax values well aligned with observations. Two scenarios were modelled: 2.5 mg of ruxolitinib phosphate given orally (po) or inhaled (inh) 5 mg of ruxolitinib phosphate given orally (po) or inhaled (inh) For both scenarios the free drug concentration in the lung, the levels in plasma and levels in tissue were modelled. BB = tracheobronchial (large airways), bb = bronchiolar (small airways), Al = alveolar interstitial (lung parenchyma). The free drug concentration vs time suggests that there is an initial higher drug concentration in the lung airway tissue in comparison to an equivalent oral dose. The difference is highest for the 2.5 mg ruxolitinib phosphate (6-10 x higher), see Table 11 and Figure 12, and lowest for the 5 mg ruxolitinib phosphate (2-6 x higher), see Table 12 and Figure 13. Table 11. PK parameters for the 2.5 mg ruxolitinib phosphate Region Tissue BB Tissue bb Tissue Al Plasma Route po AUCt (ng*h / mL) 10.2 10.2 10.2 10.2 Cmax (ng / mL) 3.0 3.0 3.0 3.0 Tmax (hours) 0.75 0.75 0.75 0.75 Route inh AUCt (ng*h / mL) 12.80 10.37 10.13 10.13 Cmax (ng / mL) 8.04 4.15 2.82 2.82 Tmax (hours) 0.33 0.08 0.75 0.75 Ratio inh / po AUCt (ng*h / mL) 1.26 1.02 1.00 1.00 Cmax (ng / mL) 2.64 1.36 0.93 0.93 Tmax (hours) 0.44 0.11 1.00 1.00 AUCt = area under the curve to last administration; Cmax = maximal plasma concentration; Tmax = time to maximal plasma concentration Table 12. PK parameters for the 5 mg ruxolitinib phosphate Region Tissue BB Tissue bb Tissue Al Plasma Route po AUCt (ng*h / mL) 20.3 20.3 20.3 20.3 Cmax (ng / mL) 6.1 6.1 6.1 6.1 Tmax (hours) 0.75 0.75 0.75 0.75 Route inh AUCt (ng*h / mL) 24.77 20.69 20.20 20.20 Cmax (ng / mL) 10.87 8.32 5.53 5.53 Tmax (hours) 0.50 0.08 1.00 1.00 Ratio inh / po AUCt (ng*h / mL) 1.22 1.02 0.99 0.99 Cmax (ng / mL) 1.79 1.37 0.91 0.91 Tmax (hours) 0.67 0.11 1.33 1.33 5 AUCt = area under the curve to last administration; Cmax = maximal plasma concentration; Tmax = time to maximal plasma concentration However, in terms of local PK parameters (AUCt and Cmax), inhalation results only in a minor advantage in the BB and bb tissue (max 2.7) and none in Al tissue or plasma. Only minor advantages of inhaled delivery could be anticipated as judged from this in 10 silico assessment, with a transient higher concentration of ruxolitinib in the lung tissues when given pulmonary compared to orally. These assessments are preliminary as the current model does not include effects that are difficult to assess without experimental data, e.g., a significant tissue / target drug retention which could increase lung tissue retention and the link between pharmacodynamic and PK. The recommendation is therefore to test the compound in a preclinical PK and PD model setup. Example 4 Preparation of ruxolitinib formulation for the rat PK study The formulation and preparation methods applied to prepare the formulation for the PK study are described below. Choice of pharmaceutically acceptable excipient, excipient quality, formulation and process of preparation can and / or will be different for formulations to be applied going forward in clinical studies and for final dry powder formulations suitable for inhalation. 10% w / w micronized and conditioned crystalline ruxolitinib phosphate (PR-469-4) and 90% w / w lactose (Lactohale 200 from DFE Pharma - Table 13) were manually sieved together in a 0.5 mm sieve 5 times to achieve a powder that could be handled in the equipment used in the rat PK study. The batch size of the dry powder blend was 8 grams. Table 13. Particle size distribution of Lactohale 200 Batch Number D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm 103ZXKW 10 71 146 Example 5 In vivo ruxolitinib rat PK study The formulation described in Example 4 was developed to optimize dosing and a dry run was used to estimate achievable dose and aerodynamic particle size distribution from the applied administration equipment. A Wright Dust Feeder (WDF) was used to generate controlled aerosol. An aerodynamic particle sizer (APS) was used to follow the particle flow during each run in real-time. A 7-stage Marple impactor was connected in one of the runs to obtain a more accurate mass median aerodynamic diameter (MMAD) determination. A dry run was performed to test the relationship between active pharmaceutical ingredient (API) amount on filters in relation to WDF speed. The amount of API measured on filters in dry runs in relation to WDF speed is shown in Figure 14 and the mass median aerodynamic diameter (MMAD) for a WDF speed 0.15 rpm is shown in Table 14. Table14. the mass median aerodynamic diameter (MMAD) for a WDF speed 0.15 rpm 0.15 rpm Impactor stage Cut-off (pm) Cumulative undersize (%) #3 13.86 98 #4 8.49 97 #5 4.95 94 #6 2.19 73 #7 1.32 37 #8 0.73 11 MMAD (pm) 1.59 The rat PK-study was designed with inhaled (inh) and intravenous (iv) single dose administration of ruxolitinib applying the formulation described in Example 4. The study was a single-dose study with inhaled and iv administration of ruxolitinib to male Sprague-Dawley rats. The target doses were 5 mg / kg inhaled and 2 mg / kg iv, and 12 rats were included in each dosing group. The lower iv dose was due to solubility limitations. Animals were given a charcoal block prior to inhalation to remove the contribution from a potential swallowed dose. Animals were terminated at 30 mins, 2 hours, 6 hours and 24 hours after dosing (3 animals per timepoint). Terminal blood and broncho-alveolar lavage (BAL) was taken, lungs were perfused with saline via the heart apex to clear out residual blood. Lungs were excised, weighed, and separated into airways and parenchyma. Bioanalysis was performed by LC-MS (Liquid Chromatography - Mass Spectrometry). Biopharmaceutical modelling was performed using the Mimetikos Software (Physiological based pharmacokinetic (PBPK) model). Results were compared to a non-compartmental model in the software PK solver. Table 15. The rat PK data Parenchyma inh Parenchyma Iv Parenchyma inh / iv ratio Airway inh Airway iv Airway inh / iv ratio AUCt (ng*h / mL) 158.4 29.0 5.5 915.0 76.4 12.0 Cmax (ng / mL) 45.9 22.6 2.0 813.1 95.0 8.6 Tmax (h) 0.8 0.6 1.3 0.8 0.6 1.3 AUCt = area under the curve to last administration; Cmax = maxima plasma concentration; Tmax = time to maximal plasma concentration All tissue concentration (Ct) data was normalized by the bioavailable dose and for intravenous (iv) this was the nominal dose. The airway tissue concentrations were higher than parenchymal tissue concentrations after inhalation (inh). To a lesser extent this was also seen following intravenous (iv) dosing, see Table 15 and Figure 15-16. The relation between intravenous (iv) and inhalation (inh) suggest that inhalation (inh) could provide similar lung drug concentration at a roughly 5 to 10 fold lower systemic exposure compared to a systemic treatment or as it was shown here - a 5 to 10 fold higher local concentration at same systemic exposure. Example 6 Preparation of an inhalable dry powder formulation The formulation and preparation methods applied to prepare an inhalable dry powder formulation are described below. Choice of pharmaceutically acceptable excipient, excipient quality, formulation and process of preparation can and / or may be different for formulations to be applied going forward in clinical studies and for final dry powder formulations suitable for inhalation. The components of a dry powder formulation of 10% w / w micronized and conditioned crystalline ruxolitinib phosphate (RH0030224) with 90% w / w lactose (Respitose SV003 from DFE Pharma) have the particle size distribution as disclosed in Table 16. Table 16. Particle size distribution Composition D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm ruxolitinib phosphate 0.733 1.71 3.31 Respitose SV003 31 61 95 Micronized and conditioned crystalline ruxolitinib phosphate and lactose were mixed in a 0.25 liter mixing vessel for 20 minutes in a Diosna high shear mixer. The batch size of the dry powder blend was 60 grams having the batch number PR556D. 5 The final formulation was kept overnight and then manually filled into hydroxypropyl methyl cellulose (HPMC) capsules size 3. The HPMC capsules load was 40 ± 1 mg. Two doses were tested in a Next Generation Impactor (NGI) with an ICOcap device (configuration number 00101R3) with a flow of 100L / min and a pressure at 3.6 kPa. ICOcap is a capsule based dry powder inhaler available off-the-shelf and used for oral 10 inhalation. The deposited formulation at each stage was collected and ruxoulitinib was quantified using analytical high-performance liquid chromatography (HPLC-UV) method. Table 17. Result for batch PR556D Batch PR556D Average delivered mass (mg) 39.2 Ruxolitinib content (pg / mg) 95.9 Homogeneity (RSD%) 0.6 Sum / Delivered Dose (DD) NGI (pg / dose) 2203.7 Fine Particle Dose < 5 pm, (pg) 1652.5 Sd (pg) 94.2 Fine Particle Fraction < 5 pm %DD 75.0 Standard deviation (sd) 1.1 Fine Particle Fraction < 3 pm % DD 65.1 Fine Particle Fraction < 1 pm % DD 15.8 MMAD, pm 1.76 GSD 1.69 ^SD = Relative standard deviation; NGI = next generation impactor; SD = standard deviation; DD = delivered dose; MMAD = mean measured aerodynamic diameter; GSD = geometric standard deviation. The data show a dry powder formulation suitable for inhalation. The formulation has a low ruxolitinib loss (4.1 %) during manufacture of the formulation, a high fine particle fraction (FPF) of 75% of the delivered dose, and a formulation with very good homogeneity as RSD was only 0.6%. ITEMS I 1. A dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib or a micronized pharmaceutically acceptable salt thereof, wherein at least 95% w / w is in a single crystal form, and wherein the ruxolitinib particles have a median particle size of 10 pm or less measured by laser diffraction, and 20-99% w / w of one or more pharmaceutically acceptable excipient(s). 2. The dry powder formulation according to item 1, wherein the ruxolitinib particles have a median particle size of 10 pm or less, such as 9 pm or less, such as 8 pm or less, such 7 pm or less, such than 6 pm or less, such as 5 pm or less. 3. The dry powder formulation according to item 1 or 2, wherein the ruxolitinib particles have a median particle size of less than 4 pm, such than 3 pm or less. 4. The dry powder formulation according to any one of items 1 to 3, wherein the micronized ruxolitinib is a micronized pharmaceutically acceptable salt and is selected from the group comprising ruxolitinib maleate, ruxolitinib sulfate, ruxolitinib oxalate, ruxolitinib hydrogen chloride (HCI), ruxolitinib mesylate, ruxolitinib hemifumarate, and the phosphate salt of ruxolitinib 5. The dry powder formulation according to item 4 wherein micronized pharmaceutically acceptable salt of ruxolitinib is ruxolitinib HCI. 6. The dry powder formulation according to item 4, wherein the micronized pharmaceutically acceptable salt of ruxolitinib is ruxolitinib phosphate. 7. A method of manufacturing a dry powder suitable for inhalation comprising a. Micronizing ruxolitinib particles or particles of a pharmaceutically acceptable salt of ruxolitinib. b. mixing the micronized ruxolitinib particles with one or more pharmaceutically acceptable excipients, 8. The method according to item 7 wherein step a. is followed by a step of conditioning the micronized ruxolitinib particles before the mixing is carried out in step b. 9. The method according to item 7 wherein step a. of micronizing ruxolitinib particles further comprises concurrent or substantially concurrent conditioning of the ruxolitinib particles. 10. A method of treating a disease comprising administering to a subject a pharmaceutically effective amount of a dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib in a single crystal form, wherein the ruxolitinib particles have a median particle size of 10 pm or less measured by laser diffraction and a 20-99% w / w of one or more pharmaceutically acceptable excipient(s). 11. The method according to item 10 wherein the ruxolitinib particles have a median particle size of as 9 pm or less, such as 8 pm or less, such 7 pm or less, such than 6 pm or less, such as 5 pm or less, such as 4 pm or less, such than 3pm or less. 12. A method of treating a disease comprising administering to a subject a pharmaceutically effective amount of a dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib HCI in a single crystal form, wherein the ruxolitinib HCI particles have a median particle size of 10 pm or less measured by laser diffraction and a 20-99% w / w of one or more pharmaceutically acceptable excipient(s). 13. The method according to item 12 wherein the ruxolitinib HCI particles have a median particle size of as 9 pm or less, such as 8 pm or less, such 7 pm or less, such than 6 pm or less, such as 5 pm or less, such as 4 pm or less, such than 3pm or less. 14. A method of treating a disease comprising administering to a subject a pharmaceutically effective amount of a dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib phosphate in a single crystal form, wherein the ruxolitinib phosphate particles have a median particle size of 10 pm or less measured by laser diffraction and a 20-99% w / w of one or more pharmaceutically acceptable excipient(s). 15. The method according to item 14 wherein the ruxolitinib phosphate particles have a median particle size of as 9 pm or less, such as 8 pm or less, such 7 pm or less, such than 6 pm or less, such as 5 pm or less, such as 4 pm or less, such than 3pm or less. 16. The method according to any one of item 10 to 15 wherein the disease is a pulmonary disease. 17. The method according to any one of items 10 to 16 wherein the pulmonary disease is selected from the group consisting of bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary venoocclusive disease, pulmonary hypertension associated with a lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, Chronic obstructive pulmonary disease (COPD), lung cancer, and an interstitial lung disease (ILD). 18. The method according to any item 17 wherein the interstitial lung disease (ILD) is selected from the group consisting of sarcoidosis, pneumoconiosis, berylliosis, coal worker’s disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrosing phenotype ILD (PF-ILD), hypersensitivity pneumonitis, chronic hypersensitivity pneumonitis (CHP), rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythomatosis-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, connective tissue disorder pulmonitis ILD (CTD-ILD), Granulomatosis with polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, Idiopathic eosinophilic pneumonia, Pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organising pneumonia (BOOP, also known as cryptogenic organising pneumomia (COP). 19. The method according to item 16 wherein the pulmonary disease is selected from the group comprising graft-versus-host-disease (GvHD), pulmonary GvHD, chronic rejection after lung transplantation, chronic lung allograft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as gost-transplant BOS), chronic lung allograft dysfunction-restrictive allograft syndrome (CLAD-RAS). and chronic lung allograft dysfunction-restrictive allograft syndrome- bronchiolitis obliterans syndrome (CLAD-BOS). 20. The method according to any one of items 12 to 19 wherein the method comprises administering to the subject a daily dose up to 5 mg ruxolitinib. 21. The method according to item 20 wherein the daily dose is administered in separate administrations of 2 equal doses daily. 22. The method according to any one of the items 20 or 21, wherein the daily dose is administered to the subject for at least 12 weeks. 23. The method according to any one of items 20 to 22 wherein ruxolitinib is administered to the subject for long term chronic treatment. 24. A dry powder formulation according to any one of items 1 to 6 for use in inhalation as a medicine. 25. A dry powder formulation according to any one of items 1 to 6 for use in a method of treating a disease as defined in any one of items 12 to 20, wherein said formulation is administered in a single daily dose of up to 10 mg. 26. A dry powder formulation according to any one of items 1 to 6 for use in a method of treating a disease as defined in any one of items 12 to 18 or item 21, wherein said formulation is administered twice daily to a total dose of up to 10 mg. 27. The dry powder formulation according to item 5 wherein the ruxolitinib phosphate salt is in crystalline form-l 28. The dry powder formulation according to item 27 characterized in that the ruxolitinib phosphate salt has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 3.9, 7.5, 8.2, 9.4. 29. The dry powder formulation according to item 6 characterized in that the ruxolitinib HCI has an X-ray powder diffraction spectrum with peaks expressed in degrees (20) at approximately 8.2, 9.6, 11.7, 12.0. ITEMS II 1. A dry powder formulation suitable for inhalation comprising 2-80 % w / w micronized ruxolitinib or a micronized pharmaceutically acceptable salt thereof, wherein at least 95% w / w is in a single crystal form, and wherein the ruxolitinib particles have a particle size of 10 pm or less, and 20-98% w / w of one or more pharmaceutically acceptable excipient(s). 2. The dry powder formulation according to item 1, wherein the ruxolitinib particles have a median particle size less than 5 pm. 3. The dry powder formulation according to item 1 or 2, wherein the ruxolitinib particles have a median particle size less than 3 pm. 4. A method of manufacturing a dry powder suitable for inhalation comprising a. micronizing ruxolitinib particles b. conditioning the ruxolitinib particles c. mixing the conditioned ruxolitinib particle with one or more pharmaceutically acceptable excipients. 5. The method according to item 4 wherein the micronized ruxolitinib particles have a median particle size less than 5 pm. 6. A method of treating a disease, the method comprising administering to a subject a pharmaceutically effective amount of a dry powder formulation suitable for inhalation comprising 2-80 % w / w micronized ruxolitinib in a single crystal form, wherein the ruxolitinib particles have a particle size of 10 pm or less and a 20-98% w / w of one or more pharmaceutically acceptable excipient(s). 7. The method according to item 6 wherein the disease is a pulmonary disease. 8. The method according to item 7 wherein the pulmonary disease is selected from the group consisting of bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary veno-occlusive disease, pulmonary hypertension associated with a lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, Chronic obstructive pulmonary disease (COPD), lung cancer, and an interstitial lung disease (ILD). 9. The method according to item 8 wherein the interstitial lung disease (ILD) is selected from the group consisting of sarcoidosis, pneumoconiosis, berylliosis, coal worker’s disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrosing phenotype ILD (PF-ILD), hypersensitivity pneumonitis, chronic hypersensitivity pneumonitis (CHP), rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythomatosis-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, connective tissue disorder pulmonitis ILD (CTD-ILD) Granulomatosis with polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, Idiopathic eosinophilic pneumonia, Pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organising pneumonia (BOOP, also known as cryptogenic organising pneumomia (COP). 10. The method according to item 7 wherein the pulmonary disease is selected from the group comprising graft-versus-host-disease (GvHD), pulmonary GvHD, chronic rejection after lung transplantation such as chronic lung allograft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as ^ost-transplant BOS), chronic lung allograft dysfunction-restrictive allograft syndrome (CLAD-RAS)., and chronic lung allograft dysfunction-restrictive allograft syndromebronchiolitis obliterans syndrome (CLAD-BOS). 11. The method according to any one of items 6 to 10 wherein the method comprises administering to the subject a daily dose up to 5 mg ruxolitinib. 12. The method according to item 10 wherein the daily dose is administered in separate administrations of 2 equal doses daily. 13. The method according to any one of the items 11 or 12, wherein the daily dose is administered to the subject for at least 12 weeks. 14. The method according to any one of items 11 to 13 wherein ruxolitinib is administered to the subject for long term chronic treatment. 15. A dry powder formulation according to item 1 for use in inhalation as a medicine. 5 16. A dry powder formulation suitable for inhalation comprising 2-80 % w / w micronized ruxolitinib wherein at least 95% w / w is in a single crystal form and wherein the ruxolitinib particles have a particle size of 10 pm or less, and 20-98% w / w of one or more pharmaceutically acceptable excipient(s) for use in a method of treating a 10          disease as defined in any one of items 7 to 9, wherein said formulation is administered twice daily in a daily dose of up to 5 mg.

Claims

1. A dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib or a micronized pharmaceutically acceptable salt thereof, wherein at least 95% w / w is in a single crystal form, and wherein the ruxolitinib particles have a median particle size of 10 pm or less measured by laser diffraction, and 20-99% w / w of one or more pharmaceutically acceptable excipient(s).

2. The dry powder formulation according to claim 1, wherein the ruxolitinib particles have a median particle size less than 5 pm.

3. The dry powder formulation according to claim 1 or 2, wherein the ruxolitinib particles have a median particle size less than 3pm.

4. A method of manufacturing a dry powder suitable for inhalation comprisinga. Micronizing ruxolitinib particlesb. mixing the micronized ruxolitinib particles with one or more pharmaceutically acceptable excipients, optionally wherein step a. is followed by a step of conditioning the micronized ruxolitinib particles before the mixing is carried out in step b.

5. A method of treating a disease comprising administering to a subject a pharmaceutically effective amount of a dry powder formulation suitable for inhalation comprising 1-80 % w / w micronized ruxolitinib in a single crystal form, wherein the ruxolitinib particles have a median particle size of 10 pm or less measured by laser diffraction and a 20-99% w / w of one or more pharmaceutically acceptable excipient(s).

6. The method according to claim 5 wherein the disease is a pulmonary disease.

7. The method according to claim 6 wherein the pulmonary disease is selected from the group consisting of bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary veno-occlusive disease, pulmonary hypertension associated with a lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, Chronic obstructive pulmonary disease (COPD), lung cancer, and an interstitial lung disease (ILD).

8. The method according to claim 7 wherein the interstitial lung disease (ILD) is selected from the group consisting of sarcoidosis, pneumoconiosis, berylliosis, coal worker’s disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrosing phenotype ILD (PF-ILD), hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythomatosis-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, Granulomatosis with polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, Idiopathic eosinophilic pneumonia, Pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organising pneumonia (BOOP), also known as cryptogenic organising pneumomia (COP).

9. The method according to any one of claims 5 to 8 wherein the method comprises administering to the subject a daily dose up to 5 mg ruxolitinib.

10. The method according to claim 9 wherein the daily dose is administered in separate administrations of 2 equal doses daily.

11. The method according to any one of the claims 9 or 10, wherein the daily dose is administered to the subject for at least 12 weeks.

12. The method according to any one of claims 9 to 2 wherein ruxolitinib is administered to the subject for long term chronic treatment.

13. A dry powder formulation according to any one of claims 1 to 3 for use in inhalation as a medicine.

14. A dry powder formulation according to any one of claims 1 to 3 for use in a method 5          of treating a disease as defined in any one of claims 6 to 8, wherein saidformulation is administered in a daily dose of up to 10 mg.

15. A dry powder formulation according to claim 14 for use in a method of treating a disease as defined in any one of claims 6 to 8, wherein said formulation is10          administered twice daily to a total dose of up to 10 mg.

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