Inhaled formulations of roscovitine, methods of making and uses thereof

Abstract

Inhalation formulations of relacorilant, their production and their use are provided.

Description

Technical Field

[0001] This application relates to inhaled formulations of ruxolitinib and ruxolitinib salts, methods of manufacturing them, and uses thereof. Background Technology

[0002] Protein kinases are enzymes involved in cell signaling and mediating the phosphorylation of target substrates. Janus kinases (JAKs) are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway, including JAK1, JAK2, JAK3, and tyrosine kinase (TYK)2. JAK1 and JAK2 are involved in type II interferon signaling, while JAK3 and TYK2 are involved in type I interferon signaling. Correcting dysregulated cell signaling can be used to treat diseases and conditions. Ruxolitinib is a JAK inhibitor selective for JAK1 and JAK2 subtypes and is used to treat diseases and conditions in which JAK signaling activation is dysregulated, such as autoimmune diseases, rabies, and cancer.

[0003] Therefore, ruxolitinib is currently used for diseases such as graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation, including pulmonary GvHD, non-segmental vitiligo, splenomegaly, myelofibrosis, polycythemia vera, and atopic dermatitis, and is being investigated for other treatments. Use of ruxolitinib may result in side effects and adverse events such as moderate to severe thrombocytopenia, neutropenia, anemia, bruising, bleeding, dizziness, hypertension, opportunistic infections, and reactivation of herpes zoster (herpes zoster). These side effects and adverse events may be dose-dependent. Based on efficacy and safety, the maximum recommended daily dose of ruxolitinib, as approved by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), is 50 mg / day. Ruxolitinib is currently administered orally and topically, but it has the potential to be used through other routes of administration to target specific diseases and conditions. These diseases and conditions include those of the lungs and airways. Summary of the Invention

[0004] In order to treat lung and / or airway diseases or conditions, there is a need to develop alternative types of compositions or formulations that differ from currently available ruxolitinib compositions or formulations for the effective treatment of such diseases or conditions. One approach is to treat the disease or condition by topical application to the respiratory tract. This invention addresses the need to provide formulations suitable for inhalation, that is, formulations that deliver ruxolitinib directly to the respiratory tract (e.g., the lungs and airways).

[0005] In its broadest aspect, the present invention relates to inhaled formulations of ruxolitinib or a pharmaceutically acceptable salt thereof. The present invention relates to novel dry powder formulations suitable for inhalation, comprising micronized ruxolitinib or a pharmaceutically acceptable salt 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 a pharmaceutically acceptable salt thereof are present in single-crystal form.

[0006] In this invention, ruxolitinib is in the form of ruxolitinib HCl.

[0007] In this invention, a pharmaceutically acceptable salt of ruxolitinib is ruxolitinib phosphate.

[0008] The inhaled formulation of the present invention provides the benefits of reduced load by reducing the total amount of ruxolitinib inhaled, such as improved patient comfort, safety and compliance, while still providing therapeutically effective drug concentrations in the lungs and airways, and avoiding serious adverse reactions associated with oral or IV administration.

[0009] The inhaled formulation of the present invention provides immediate and sustained release of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0010] The inhaled formulation of the present invention provides greater pulmonary exposure than equivalent doses of ruxolitinib administered via conventional oral routes or intravenously. While oral ruxolitinib requires relatively high doses to achieve the same target pulmonary exposure as the inhaled formulation of the present invention, the dose can be significantly reduced using these formulations and methods.

[0011] In embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof used in the formulations and methods of the present invention may consist entirely or almost entirely in 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% single-crystal form), thereby allowing for controlled and predictable dosing and patient response. In some embodiments, 95% or more of ruxolitinib or a pharmaceutically acceptable salt thereof in the inhalation formulation may be present in single-crystal form. Various powder diffraction patterns are provided.

[0012] In some embodiments, inhaled ruxolitinib or a pharmaceutically acceptable salt thereof is provided by a method wherein it is micronized by wet milling or dry milling (e.g., jet milling) to achieve the particle size or particle size distribution required for an inhaled dry powder formulation. The median particle size of such particles in the particle size distribution is preferably 10 µm or less, such as 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less.

[0013] The goal is to achieve a particle size suitable for inhalation.

[0014] In some embodiments, inhaled ruxolitinib or a pharmaceutically acceptable salt thereof may be micronized by wet milling or dry milling (e.g., jet milling) to achieve the particle size or particle size distribution required for an inhaled dry powder formulation. The median particle size of such particles in the particle size distribution is preferably less than 5 µm, such as less than 4 µm, such as less than 3 µm, such as less than 2.5 µm, such as less than 2 µm.

[0015] In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is micronized alone or co-micronized with one or more pharmaceutically acceptable excipients.

[0016] In some embodiments, the inhaled dry powder formulation comprises 1-80% w / w ruxolitinib or a pharmaceutically acceptable salt thereof, and 20-99% w / w one or more pharmaceutically acceptable excipients.

[0017] In aspects of this invention, micronized ruxolitinib or a pharmaceutically acceptable salt thereof is modified to convert surface amorphous properties into a crystalline form. This modification is demonstrated in the examples of this application. It is anticipated that the amorphous properties will decrease after modification.

[0018] In this invention, micronized ruxolitinib or a pharmaceutically acceptable salt thereof is subjected to this conditioning before being mixed with one or more pharmaceutically acceptable excipients. In this invention, micronization and conditioning are performed in the same step.

[0019] In aspects of the present invention, an inhaled formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof and one or more excipients is used to treat a disease or condition.

[0020] In this invention, a method for treating diseases or conditions is provided.

[0021] In this invention, a dosage regimen or method of administration for treating a disease or ailment is provided.

[0022] The use of therapeutic inhaled formulations, and the treatment and administration regimens or methods provided, are specifically intended for the treatment of diseases or conditions affecting subjects affected by dysregulation of JAK1 and / or JAK2 activity. Specifically, such diseases or conditions are diseases or conditions of the lungs and / or airways. In various respects, treatment methods include administration of a single or two daily doses of the inhaled formulation.

[0023] In respect of this invention, the total daily dose is up to 12 mg, such as up to 11 mg, such as up to 10 mg. Detailed Implementation

[0024] This invention relates to dry powder formulations suitable for inhalation, comprising micronized ruxolitinib or a pharmaceutically acceptable salt thereof, wherein ruxolitinib or a pharmaceutically acceptable salt thereof exists in single-crystal form.

[0025] The inhaled formulation of this invention refers to a formulation in which ruxolitinib or a pharmaceutically acceptable salt thereof is administered via the respiratory tract. The formulation is inhaled through the nose and / or mouth, with ruxolitinib and excipients and / or carriers (particle size of about 10 µm or less) passing downwards through the pharynx, across the larynx, and into the trachea. The trachea leading to the lungs branches into bronchi and even smaller bronchioles, forming the lower respiratory tract together with the alveoli of the lungs.

[0026] For effective lung deposition, particles with a size of 1–5 µm (inclusive) are ideal for reaching the lower respiratory tract. Particles larger than 5 µm can deposit in the upper airway, while very small particles, i.e., smaller than 1 µm, can be exhaled without deposition. Inhaled ruxolitinib deposited in the lungs can exert its effect locally.

[0027] The inhaled formulation of this invention delivers ruxolitinib directly to the site of action (lungs), providing faster and more effective treatment. Compared to oral or injectable routes, the inhaled formulation of this invention requires a lower dose and reduces systemic side effects.

[0028] This invention relates to novel dry powder formulations suitable for inhalation of ruxolitinib or pharmaceutically acceptable salts thereof. Dry powder refers to a finely ground or micronized form of ruxolitinib alone, or a finely ground or micronized form of ruxolitinib and / or excipients and / or carriers. A dry powder formulation is a method of delivering ruxolitinib to the lungs using a device such as, for example, a dry powder inhaler. The dry powder formulations of this invention consist of micronized and / or ground ruxolitinib or pharmaceutically acceptable salts thereof, and may contain carriers and / or excipients to improve flowability and dispersibility. The dry powder formulations of this invention consist of micronized and / or ground ruxolitinib or pharmaceutically acceptable salts thereof having an ideal particle size suitable for lung deposition, and (if applicable) larger-particle-size carriers and / or excipients to help improve the flowability, dose uniformity, and dispersibility of the dry powder formulation, as fine powders may have poor flowability, agglomerate, and reduce dose uniformity.

[0029] Flowability refers to the ability of powder to flow freely and uniformly. For inhaled dry powder, good flowability ensures consistent dosage delivery, ease of handling during manufacturing, and reliable performance in devices such as dry powder inhalers.

[0030] Aggregation refers to the process by which fine particles gather or adhere together to form larger aggregates (called agglomerates). Aggregation occurs due to interparticle attraction such as van der Waals forces, electrostatic interactions, or liquid bridging caused by moisture. In devices such as, for example, dry powder inhalers, agglomerates can affect the inhalation of the formulation and the efficacy of ruxolitinib. Agglomerates may not break down during inhalation, reducing the fine particulate fraction (FPF) and causing larger particles to settle in the upper airways instead of reaching the lungs. Agglomerates can affect the variability of the delivered dose due to clumping or by obstructing the delivery mechanism of the inhaler.

[0031] Controlled agglomeration (such as mild agglomeration) can be beneficial because agglomeration improves flowability and dosage uniformity by reducing excess fine powder. The inhalation formulations of the present invention are suitably designed so that any agglomerates present during inhalation can be deagglomerated. In the present invention, the particle size distribution of ruxolitinib or its pharmaceutically acceptable salts is controlled to reduce excess fine powder that promotes agglomeration. In the present invention, the dry powder formulation may contain a carrier 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 a low-humidity environment; and / or the dry powder formulation may be appropriately dried after production.

[0032] The inhaled formulation of the present invention provides greater pulmonary exposure than an equivalent dose of ruxolitinib administered via the conventional oral route or via IV. While oral ruxolitinib requires a relatively high dose to achieve the same target pulmonary exposure as the inhaled formulation of the present invention, the dose can be significantly reduced using these formulations and methods. Therefore, the present invention provides 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 of ruxolitinib or a pharmaceutically acceptable salt thereof, administered to a subject.

[0033] The daily dose can be administered once daily, or multiple times in equal amounts, such as twice or three times daily, or even more times daily.

[0034] Such administration may be given to subjects as needed for a period of time, or for a duration such as at least 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 1 year or longer; or it may be administered as a long-term chronic treatment.

[0035] Subjects receiving treatment may suffer from the diseases or conditions discussed in this article and may be animals or humans.

[0036] The formulations of the present invention may comprise one or more excipients or carriers. In some embodiments, larger excipients (preferably with a median particle size distribution D(v,0.5) of 10 µm or greater) may be used to increase the aerodynamics of the combined formulation to aid in the delivery of ruxolitinib by inhalation. In some embodiments, smaller excipients (preferably with a median particle size distribution D(v,0.5) of 10 µm or less) may be used as fine powders.

[0037] Fine powder refers to the smallest particles in a powder-based formulation. Fine powder is ruxolitinib, a carrier, and / or an excipient. For inhaled formulations, fine powder refers to particles with a median particle size of less than 10 µm. In some embodiments, a median particle size of about 5 µm or less allows the particles to reach deep into the lungs (alveoli), making it crucial for delivering ruxolitinib to the respiratory tract. In some embodiments, a median particle size of about 1–2 µm allows the particles to penetrate deeper, such as the alveolar region, where systemic absorption can occur.

[0038] In some embodiments, to enhance ruxolitinib delivery, the fine powder improves the fine particulate fraction (FPF), i.e., the proportion of ruxolitinib reaching the lungs. In some embodiments, the fine powder typically adheres to larger particles but detaches due to airflow during inhalation, thereby ensuring effective delivery to the lungs. The fine powder may be ruxolitinib only, or it may include excipients and / or carriers.

[0039] In some embodiments, the formulations of the present invention can be optimized by carefully controlling the amount and particle size distribution of fine powder in the inhaled formulation to maximize lung deposition (higher FPF), maintain acceptable powder flowability, and / or ensure dosage uniformity during production and use.

[0040] Ruxolitinib and pharmaceutically acceptable salts The chemical name of ruxolitinib is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, with the molecular formula C17H18N6 and a molecular weight of 306.4 g / mol. Ruxolitinib also exists in the form of its S-enantiomer, hydrate, dihydrate, and anhydrous form.

[0041] It should be understood that pharmaceutically acceptable salts include ruxolitinib maleate, sulfate, oxalate, hydrochloride (HCl), mesylate, hemifumarate, and phosphate.

[0042] The chemical name of ruxolitinib phosphate is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, with the molecular formula C17H21N6O4P and a molecular weight of 404.4 g / mol. Ruxolitinib phosphate exists in polymorphism. Anhydrous crystalline form I is the most stable solid form.

[0043] excipient Typically, ruxolitinib or a pharmaceutically acceptable salt thereof is micronized and combined with a suitable carrier to form a formulation suitable for inhalation. In some embodiments, the formulations of the present invention may comprise one or more excipients (also referred to as carriers). For example, the excipients may comprise larger particles to serve as a carrier for the inhalation of the micronized ruxolitinib formulation. The larger particle size of the carrier particles can be used to increase the aerodynamics of the combined ruxolitinib / carrier to aid in delivery by inhalation.

[0044] In some embodiments, the formulations of the present invention may comprise one or more excipients (also referred to as carriers) in the form of a dry powder. In some embodiments, this dry powder is a free-flowing powder that disperses in the lungs and airways during inhalation.

[0045] In some embodiments, the surface of the carrier particles (or other excipient particles) may be coated and / or treated to allow ruxolitinib to be effectively separated from the carrier (or other excipient surface) upon exiting the inhaler device and / or within the oral cavity or nasal cavity (when such excipients are used as carriers).

[0046] To obtain a free-flowing powder formulation, suitable excipients (also known as carriers) may include lactose in various forms (e.g., milled, roller-dried, or spray-dried). Besides lactose, other sugars may also be used as excipients, such as disaccharides, such as sucrose, glucose, dextrose, and sorbitol; polysaccharides, such as 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).

[0047] The excipients may include solvents and may be used to modulate the surface of the carrier particles (or other excipient particles) so that ruxolitinib can be effectively separated from the carrier (or other excipient surface) upon exiting the inhaler device and / or within the oral cavity or nasal cavity (when such excipients are used as carriers).

[0048] Excipients such as magnesium stearate or lecithin sorbitol oleate can be added to prevent the carrier and ruxolitinib from sticking together.

[0049] Excipients can be added to formulations in low or high concentrations for various purposes, and one or more excipients / carriers can be used in dry powder inhalers such as those described above, or for example, α-lactose, sucrose, α,α-trehalose, raffinose, mannitol, citrate, acetate, magnesium stearate, sodium stearate, leucine, dileucine, trileucine, L-leucine, L-isoleucine, 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, fumarodikepiperazine, cholesterol, Compritol 888, tristearate, dipalmitoylphosphatidylcholine (DPPC), distearate phosphatidylcholine (DSPC), lecithin, limonene, polycaprolactone (PCL), polylactic acid (PLA), and / or polylactic acid-glycolic acid copolymer (PLGA).

[0050] Lactose is a preferred excipient. In some embodiments, lactose may be used in a mass suitable for inhalation, such as, for example, 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 (DFEPharma, Goch, Germany). In some embodiments, the particle size distribution of the carrier / excipient, such as lactose, may be the same or different. In some embodiments, larger excipient particles may be used as a carrier, and smaller excipient particles may be used as a fine powder. In some embodiments, the excipients may be the same or different. In some embodiments, the excipient may be lactose. In some implementations, lactose may be used alone and / or in combination with one or more excipients.

[0051] A preferred combination of excipients is lactose and magnesium stearate. Another preferred combination is to use lactose alone.

[0052] In some embodiments, the carrier-to-ruxolitinib weight ratio of the inhaled formulation may be 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, or 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 some embodiments, the carrier can be larger particles used as a carrier and smaller particles used as a fine powder. In some embodiments, the carriers can be the same or different. In some embodiments, the carrier can contain a combination of all excipients used in the formulation. In some embodiments, the formulation may include ruxolitinib or a salt thereof as an API (ruxolitinib or a pharmaceutically acceptable salt thereof) at a concentration 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%. Percentages are %w / w as used herein. Therefore, the carrier portion of an inhalation formulation may contain one or more excipients; however, the carrier:ruxolitinib ratio is defined as the ratio between the total weight of the carrier and the weight of ruxolitinib as ruxolitinib phosphate.

[0053] Micronization Micronization can be performed, for example, by wet milling, dry milling, or jet milling, to achieve the desired particle size and particle size distribution for inhaled dry powder formulations. In some embodiments, inhaled ruxolitinib or a pharmaceutically acceptable salt thereof may be micronized to achieve the desired particle size or particle size distribution for inhaled dry powder formulations. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof may be micronized alone or co-micronized with one or more pharmaceutically acceptable excipients. In some 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. The median particle size D(v, 0.5) of such particles constituting the particle size distribution is preferably 10 µm or less, such as 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less. Preferably, the median particle size D(v,0.5) in the particle size distribution is 5 µm or lower, such as 4 µm or lower, such as 3 µm or lower, such as 2.5 µm or lower, such as 2 µm or lower.

[0054] In some implementations, pharmaceutically acceptable excipients may be micronized alone or co-micronized with one or more acceptable excipients to achieve the particle size or particle size distribution required for inhalation dry powder formulations. Such particles constituting the particle size distribution preferably have a median particle size of 300 µm or less, such as 250 µm or less, such as 200 µm or less, such as 190 µm or less, such as 180 µm or less, such as 170 µm or less, such as 160 µm or less, such as 150 µm or less, such as 140 µm or less, such as 130 µm or less, such as 120 µm or less, such as 110 µm or less, such as 100 µm or less, such as 90 µm or less, such as 80 µm or less, such as 70 µm or less, such as 60 µm or less, such as 50 µm or less, such as 40 µm or less, such as 30 µm or less, such as 25 µm or less, such as 20 µm or less. Less than 15 µm or lower, such as 10 µm or lower, such as 9 µm or lower, such as 8 µm or lower, such as 7 µm or lower, such as 6 µm or lower, such as 5 µm or lower.

[0055] Particle size, such as median particle size D(v, 0.5) and / or particle size distribution (PSD), can be measured using laser diffraction (LALLS, low-angle laser scattering). Laser diffraction is a widely used technique for measuring particle size and distribution in each sample. Based on the principle of light scattering, it provides rapid, accurate, and repeatable results over a wide range of particle sizes.

[0056] 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 within different size ranges. Sample preparation can be in dry powder form or suspended in a liquid medium. Proper particle dispersion is crucial to avoid agglomeration and for the measurement process. The output is usually displayed as a size distribution curve, which shows the relationship between particle size (x-axis) and volume fraction (y-axis). D values ​​are reported as D(v, 0.1), D(v, 0.5), and D(v, 0.9), representing 10%, 50%, and 90% of the sample volume of particles smaller than that size.

[0057] Micronization can be carried out, for example, by wet milling, in which ruxolitinib or a pharmaceutically acceptable salt thereof (optionally together with excipient particles) is suspended in a slurry, for example, and reduced in size by shearing or impact with the grinding media.

[0058] Micronization can be performed, for example, by dry milling, or by jet milling, such as using a fluidized bed mill, where the gas pressure applied in the milling chamber causes particles of ruxolitinib or its pharmaceutically acceptable salts and / or excipients to collide with each other and with the walls, thereby producing smaller particles. When the particles achieve a sufficiently small size, they can pass through a classifier. Other micronization methods are known in the art.

[0059] Adjustment (converting surface amorphousness into crystalline form) The advantage of the compounds and methods of this invention lies in the ability to remove all or most of the amorphous ruxolitinib from the formulation, even after micronization. Methods for reducing or eliminating amorphous ruxolitinib from the formulation are called conditioning. Conditioning is the restoration of surface amorphousness to a crystalline form. Conditioning involves treating the micronized ruxolitinib with elevated or high relative humidity (RH) and / or elevated or high relative ethanol activity (RE). If surface amorphousness is present due to micronization, it can potentially be reversed by controlling the conversion of the surface amorphousness to a crystalline form using elevated RH or RE. This treatment, also known as excitation, results in the complete or substantial crystallization of the amorphous structure, including the surface amorphousness. It should be understood that elevated (i.e., higher) RH generally leads to faster crystallization.

[0060] Surface amorphism refers to the amorphous (disordered) nature of the surface layer of particles, such as ruxolitinib, while the core of the material remains crystalline. Surface amorphism is common in finely ground or micronized powders because grinding and micronization produce disordered surface structures. Grinding and micronization disrupt the ordered crystalline structure of the surface, creating an amorphous layer. For the inhaled formulations of this invention, surface amorphism can play a crucial role in affecting formulation stability because amorphous layers are less stable than crystalline bulk materials.

[0061] The amorphous layer may recrystallize during storage, thereby affecting the performance of ruxolitinib, such as its solubility. The amorphous layer may also affect the performance of the formulation by creating adhesion and / or interaction with ruxolitinib and / or the carrier / excipient, thus altering the flowability of the formulation due to interparticle interactions or cohesion.

[0062] Micronization followed by conditioning (i.e., activation) produces ruxolitinib particles with a crystalline surface, suitable for dry powder inhalation formulations. This conditioning involves treating micronized ruxolitinib or a pharmaceutically acceptable salt thereof with 50% to 80%, such as 53% to 75%, elevated or high relative ethanol activity (RE), or with 50% to 86%, such as 53% to 75%.

[0063] Sufficient conditioning duration may be required to convert the surface amorphous state into a crystalline form. This conditioning duration is preferably 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, or 1 hour or less.

[0064] The conditioning process for converting the surface amorphous state into a crystalline form can be carried out at a temperature of about 15°C to about 50°C. Such conditioning temperatures are preferably about 50°C or lower, 45°C or lower, 40°C or lower, 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, such as about 15°C.

[0065] It should be understood that, in order to minimize the tendency of ruxolitinib to aggregate, a process with mild conditions is usually applied, such as, for example, about 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, such as 25°C / 75 RH.

[0066] X-ray powder diffraction can be used to determine the crystal form and purity.

[0067] Crystallization purity can be estimated using, for example, X-ray powder diffraction (XRPD).

[0068] X-ray powder diffraction (XRPD) is a powerful analytical technique used to identify the crystalline structure of materials. It works by directing X-rays onto a powder sample of the material and analyzing how the X-rays are scattered or diffracted by the sample's atoms. The result is a diffraction pattern showing the X-ray intensity relative to the diffraction angles (2Θ, 2θ). This pattern acts like a "fingerprint" of the material's crystal structure. Amorphous materials exhibit a broad and featureless pattern. X-rays are rapid and non-destructive, allowing for the analysis of complex mixtures, and require very small sample preparations.

[0069] The 2θ (2Θ) value can be used to identify and characterize the published crystalline forms of ruxolitinib.

[0070] The peaks of the X-ray powder diffraction spectra of ruxolitinib hydrochloride in crystalline form-R are expressed as degrees (2θ) at approximately 8.2, 9.6, 11.7, 12.0, 13.7, 14.7, 15.2, 15.6, 16.5, 17.9, 18.7, 19.3, 19.8, 20.4, 20.8, 22.0, 22.4, 22.8, 23.5, 24.8, 25.4, 26.4, 27.7, 28.1, 30.4, 33.3, and 37.6 ± 0.2 θ.

[0071] The peaks of the X-ray powder diffraction spectra of crystalline form-M ruxolitinib phosphate are expressed as degrees (2θ) 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 θ.

[0072] The peaks of the X-ray powder diffraction spectra of crystalline form-S ruxolitinib phosphate are expressed as degrees (2θ) 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 θ.

[0073] The peaks of the X-ray powder diffraction spectra of crystalline N-ruxolitinib phosphate are expressed as degrees (2θ) 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 θ.

[0074] The peaks of the X-ray powder diffraction spectra of crystalline form-I ruxolitinib phosphate are expressed as degrees (2θ) 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 θ.

[0075] In some embodiments, the peaks of the X-ray powder diffraction spectra of crystalline form-I ruxolitinib phosphate are expressed as degrees (2θ) at approximately 4.0, 7.6, and 9.5 ± 0.2 θ, which are commonly used for the identification of form-I. An X-ray image of the crystalline form-I of ruxolitinib phosphate is shown below. Figure 1 and Figure 2 .

[0076] The preferred form is ruxolitinib phosphate in crystalline form I.

[0077] preparation In some embodiments, the formulations of the present invention have been developed.

[0078] In some embodiments, a representative pharmaceutical formulation for a dry powder formulation suitable for inhalation comprises lactose and a micronized form of ruxolitinib. In some embodiments, a dry powder formulation for a dry powder inhaler comprises lactose and micronized ruxolitinib. In some embodiments, such a dry powder formulation can be prepared, for example, by combining dry-milled lactose with micronized ruxolitinib or a pharmaceutically acceptable salt thereof, and then dry-mixing the components. In some embodiments, such a dry powder formulation is then typically sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule, for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler.

[0079] In some embodiments, the dry powder formulation is then optionally sieved and filled into individual capsules. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is micronized and optionally adjusted. Thus, the excipient portion of the dry powder formulation may contain one or more excipients; however, the excipient:ruxolitinib ratio is defined as the ratio between the total weight of the excipients and the weight of ruxolitinib as ruxolitinib phosphate.

[0080] In some embodiments, a dry powder formulation is prepared by blending micronized ruxolitinib or a pharmaceutically acceptable salt thereof with excipients having the same or different particle size distributions. In some embodiments, one excipient may be used, but it may have two or more different particle size distributions. In some embodiments, two or more excipients may be used, but these excipients have the same particle size distribution. In some embodiments, the excipient may be lactose. In some embodiments, lactose may be used alone and / or in combination with one or more excipients. In some embodiments, lactose may be used with one particle size distribution or with 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.

[0081] In some embodiments, a dry powder formulation is prepared by blending 10% micronized and optionally conditioned ruxolitinib or a pharmaceutically acceptable salt thereof with 90% excipients / carrier. The blend is then sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler. In some embodiments, a dry powder formulation is prepared by blending 10% micronized and optionally conditioned ruxolitinib or a pharmaceutically acceptable salt thereof with 90% lactose carrier. The blend is then sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler. In some embodiments, such as those discussed above, ruxolitinib or a pharmaceutically acceptable salt thereof is micronized and optionally conditioned, and then blended with excipients. Lactose:Ruxolitinib ratio is defined as the ratio between the total weight of lactose and the weight of ruxolitinib phosphate, regardless of whether ruxolitinib phosphate is used.

[0082] In some embodiments, a dry powder formulation is prepared by blending 2% micronized and optionally regulated ruxolitinib or a pharmaceutically acceptable salt thereof with 98% excipients / carrier. The blend is then sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule, for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler.

[0083] In some embodiments, the dry powder formulation is prepared by first blending 2% micronized and optionally conditioned ruxolitinib or a pharmaceutically acceptable salt thereof with 8% excipient / carrier (with a particle size close to that of ruxolitinib), and then adding 90% excipient / carrier (with a particle size greater than 50 µm) to the blend. The blend is then sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler. In some embodiments, this dry powder formulation is then optionally sieved and loaded into individual capsules. Thus, the excipient portion of the dry powder formulation may contain one or more excipients; however, the excipient:ruxolitinib ratio is defined as the ratio between the total weight of the excipients and the weight of ruxolitinib as ruxolitinib phosphate. In some embodiments, the dry powder formulation is prepared by first blending 2% micronized and optionally conditioned ruxolitinib or a pharmaceutically acceptable salt thereof with 8% lactose (with a particle size close to that of ruxolitinib), and then adding 90% lactose (with a particle size greater than 50 µm) to the blend. The blend is then sieved and loaded into a dry powder dispenser, or into an inhalation cartridge or capsule for use with a dry powder delivery device. In some embodiments, the dry powder delivery device is a dry powder inhaler. In some embodiments, this dry powder formulation is then typically sieved and loaded into individual capsules. The lactose:ruxolitinib ratio is defined as the ratio between the total weight of lactose and the weight of ruxolitinib as ruxolitinib phosphate.

[0084] In some embodiments, the formulations of the present invention, such as representative pharmaceutical formulations for use in inhaled dry powder formulations, contain 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. ruxolitinib or its pharmaceutically acceptable salts in doses of 1 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.

[0085] In some embodiments, the homogeneity of the formulations of the present invention (such as representative pharmaceutical formulations for use in inhaled dry powder formulations) is less than or equal to 5% relative standard deviation (RSD), such as less than or equal to 4.5% RSD, less than or equal to 4% RSD, less than or equal to 3.5% RSD, less than or equal to 3% RSD, less than or equal to 2.5% RSD, less than or equal to 2% RSD, less than or equal to 1.5% RSD, less than or equal to 1% RSD, less than or equal to 0.5% RSD, less than or equal to 0.4% RSD, less than or equal to 0.3% RSD, less than or equal to 0.2% RSD, and less than or equal to 0.1% RSD. In some embodiments, the fine particulate fraction (FPF) of the formulations of the present invention (such as representative pharmaceutical formulations for use in inhaled dry powder formulations) is greater than or equal to 30%, such as greater than 35%, such as greater than 40%, such as greater than 45%, such as greater than 50%, such as greater than 55%, such as greater than 60%, such as greater than 65%, such as greater than 70%, such as greater than 75%, such as greater than 80%, such as greater than 85%, such as greater than 90%, such as greater than 95%.

[0086] delivery method Dry powder formulations can be delivered using an inhaler, such as a dry powder inhaler for oral or nasal inhalation. Dry powder formulations can be delivered as a single dose or multiple doses, wherein multiple doses are delivered by dividing the dry powder formulation into individual capsules or other forms compatible with the dry powder inhaler used.

[0087] Dry powder inhalers for ruxolitinib dry powder formulations can be designed to have one, two, three, four, five, or more of the following functions, such as delivering ruxolitinib dry powder formulations or their pharmaceutically acceptable salts via the following inhalers: capsule-based inhalers, easy-to-operate inhalers, inhalers without loose parts, inhalers with user-friendly designs, inhalers with ergonomic designs, inhalers with integrated mouthpiece caps with or without integrated hinges, inhalers with screw caps and integrated desiccants, inhalers with low flow resistance or customized for selective flow resistance, inhalers with flexible dosing, inhalers with dosing quantities designed according to standard-size capsules or suitable for smaller or larger capsule sizes, inhalers with dosing quantities designed according to smaller or larger reservoirs, inhalers that allow flexible single or multiple dose administration, inhalers with feedback functionality, inhalers ideally suited for maintenance therapy, pre-filled multi-dose inhalers, inhalers with accurate dose counters, inhalers with visual inhalation feedback, inhalers designed for fully automated assembly, and inhalers designed for low-cost manufacturing.

[0088] In some embodiments, a delivery device such as a dry powder inhaler is preferred. In one embodiment, the delivery device is a low-resistance dry powder inhaler.

[0089] In one embodiment, the delivery device is a dry powder inhaler for oral inhalation; in another embodiment, the delivery device is a dry powder inhaler for nasal inhalation.

[0090] In some embodiments, the delivery device is a capsule-based dry powder inhaler. In some embodiments, when preparing a dose, a capsule is placed in the delivery device, the capsule is punctured, and ruxolitinib or a pharmaceutically acceptable salt thereof is ready to be inhaled. In some embodiments, capsules containing the ruxolitinib formulation are individually packaged. In one embodiment, the capsules are packaged in blister packs. In another embodiment, the bulk material is packaged in bottles.

[0091] In some implementations, the delivery device is a multi-dose dry powder inhaler.

[0092] In some embodiments, the delivery device is pre-charged with a dose, and ruxolitinib is ready to be inhaled. In some embodiments, the delivery device has a precise dose counter. In one embodiment, the dose counter displays the number of doses remaining; in another embodiment, the dose counter displays the number of doses used.

[0093] Dry powder inhaler delivery devices, such as dry powder inhalers, have been described in the art for administration of ruxolitinib by inhalation, and examples of such devices are commercially available.

[0094] Pre-dispensed dose, delivery dose, and fine particle dose are crucial for inhaled drug delivery systems such as dry powder inhalers. These parameters help quantify the efficiency with which the device and dry powder formulation deliver ruxolitinib to the lungs.

[0095] The pre-dispensed dose refers to the total amount of ruxolitinib initially loaded into the inhaler for a single dose intended to be delivered to the patient. The dosage is as indicated on the label on the product packaging. However, not all pre-dispensed doses reach the patient's respiratory system due to losses during device actuation, such as powder retention in the capsule and / or inhaler, ruxolitinib particles adhering to the inner walls of the device, and / or low deagglomeration efficiency of the powder formulation during inhalation.

[0096] The delivery dose, also known as the jet dose, indicates the efficiency with which the inhaler device releases ruxolitinib from the formulation. Some of the delivery dose may still be lost in the mouth and throat, meaning it does not reach the lungs. Delivery dose is typically measured in a laboratory setting by connecting the inhaler to a sampling device (e.g., a next-generation impactor) that captures the ruxolitinib particles and formulation leaving the device.

[0097] Fine particulate dose (FPD) is the portion of the delivered dose consisting of particles small enough to penetrate deep into the lungs. The median particle size is approximately 5 µm or smaller. This is an inhalable dose that may deposit in the lower respiratory tract, such as the bronchioles and alveoli.

[0098] Fine particle dose (FPD) is the most clinically relevant dose because particles in this size range can reach the site of action in the lungs (median particle size is approximately 5 µm or smaller). Particles larger than 5 µm typically deposit in the mouth or throat and are eventually swallowed, thus reducing therapeutic efficacy. Fine particle dose (FPD) is like the delivered dose measured by an inhaler testing device that separates particles based on their diameter.

[0099] The delivery dose of a dry powder inhaler delivery device (such as a dry powder inhaler suitable for administration of ruxolitinib or its pharmaceutically acceptable salts by inhalation) shall not be less than 50% of the dose (MD). The delivery dose of a dry powder inhaler delivery device (such as a dry powder inhaler suitable for administration of ruxolitinib by inhalation) shall not be less than 50% of the fine particulate fraction (FPF).

[0100] Different inhaler testing devices exist to characterize the aerodynamic particle size distribution of inhaled formulations. The next-generation impactor (NGI) is a widely used instrument in the pharmaceutical industry for characterizing the aerodynamic particle size distribution of inhaled drug products and evaluating the performance of dry powder inhalers. Inhaler testing devices simulate the deposition of inhaled particles in different regions of the respiratory tract. The device measures particle size by analyzing the behavior of particles as they pass through each stage of the impactor. Each stage has a specific cutoff diameter determined by the aerodynamic characteristics of the particles. The stages are designed so that smaller particles are captured in progressively deeper stages. The dry powder formulation is introduced into the inhaler testing device at a controlled flow rate, and as the particles pass through each stage, they separate based on inertia. Larger, heavier particles deposit in earlier stages, while smaller particles move to later stages. The ruxolitinib deposited at each stage is collected and quantified using analytical high-performance liquid chromatography (HPLC).

[0101] Diseases and symptoms The inhaled ruxolitinib formulation of this invention can be used to treat lung and airway diseases and conditions. Such diseases may be termed lung diseases and can be primary or secondary. Following lung transplantation or allogeneic stem cell transplantation, recipients may develop bronchiolitis obliterans syndrome (BOS), mediated by cytokine signaling, which can be considered a form of graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation, such as pulmonary GvHD if it occurs after allogeneic stem cell transplantation; or host-versus-graft disease if it occurs after lung transplantation. Treatment of chronic rejection after lung transplantation, such as chronic lung allogeneic graft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as… transplant Post-BOS, chronic lung allograft dysfunction-restrictive allograft syndrome (CLAD-RAS). Ruxolitinib can be used to treat BOS, especially in the form of an inhaled formulation as disclosed herein.

[0102] Inhaled ruxolitinib formulations may be preferentially used for other lung diseases including obstructive lung diseases such as asthma and chronic obstructive pulmonary disease; and interstitial lung diseases such as sarcoidosis, pneumoconiosis, beryllium poisoning, coal worker's disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrotic phenotype ILD (PF-ILD), hypersensitivity pneumonia, rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythematosus-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated interstitial lung disease, granulomatous polyangiitis, lymphangiomyomatosis, pulmonary vasculitis, idiopathic eosinophilic pneumonia, pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organizing pneumonia (BOOP), also known as cryptogenic organizing pneumonia (COP).

[0103] The disclosed inhaled ruxolitinib formulation can also be used to treat pulmonary hypertension, including pulmonary arterial hypertension, pulmonary venous occlusive disease, or pulmonary hypertension associated with lung disease, including pulmonary hypertension associated with interstitial lung disease.

[0104] The disclosed inhaled ruxolitinib formulation may also be used to treat lung and / or airway cancers, particularly those in which JAK signaling activation is dysregulated. Such cancers include, but are not limited to, those in which tumorigenesis is mediated by inflammation, and / or those in which mutations in the JAK gene or upstream signaling molecules that activate JAK result in dysregulation of JAK activity. For example, this dysregulation may be due to mutations in oncogenes such as RAS, leading to cancer driven by an overactive or constitutively active RAS; or it may be driven by other mechanisms. Lung cancer includes, but is not limited to, lung adenocarcinoma and non-small cell lung cancer.

[0105] For example, the publicly available inhaled ruxolitinib formulation can also be used to treat nasal polyps, allergic rhinitis, non-allergic rhinitis, eosinophilic rhinitis, nasal vasculitis (also known as nasal granuloma with polyangiitis), post-infectious olfactory dysfunction, and chronic nasal inflammation associated with autoimmune diseases, including Sjögren's syndrome or lupus.

[0106] The development of ruxolitinib or its pharmaceutically acceptable saline inhaled form offers a promising solution. This targeted approach, by delivering ruxolitinib directly to the lungs, aims to maximize therapeutic benefit while minimizing systemic exposure and associated toxicities. Inhalation therapy has the potential to significantly reduce hematological side effects, such as severe cytopenia (including anemia, thrombocytopenia, and neutropenia), and gastrointestinal symptoms such as diarrhea and nausea, thereby improving overall patient outcomes. Furthermore, local delivery of ruxolitinib can improve the efficacy of treatments for conditions such as, for example, bronchiolitis obliterans syndrome (BOS) by ensuring higher drug concentrations at sites of disease activity.

[0107] In some embodiments, a dry powder formulation of ruxolitinib or a pharmaceutically acceptable salt thereof may be developed for inhalation. In some embodiments, inhaled ruxolitinib is developed for the treatment of chronic progressive pulmonary sarcoidosis and several other rare and serious lung diseases. In some embodiments, it is used to treat fibrotic lung disease. In some embodiments, inhaled ruxolitinib will be developed to treat sarcoidosis, pneumoconiosis, chronic hypersensitivity pneumonia (CHP), and connective tissue disorder ILD (CTD-ILD). In some embodiments, it is used to treat graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation, such as pulmonary GvHD. In some embodiments, it is used to treat chronic rejection after lung transplantation, such as chronic lung allogeneic graft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as post-transplant BOS), and chronic lung allogeneic graft dysfunction-restrictive allogeneic graft syndrome (CLAD-RAS). In some embodiments, it is used to treat asthma. In some embodiments, it is used to treat chronic obstructive pulmonary disease. In some embodiments, it is used to treat sarcoidosis. In some embodiments, it is used to treat pneumoconiosis. In some embodiments, it treats beryllium poisoning. In some embodiments, it treats coal worker's disease. In some embodiments, it treats silicosis. In some embodiments, it treats progressive fibrotic phenotype ILD (PF-ILD). In some embodiments, it treats hypersensitivity pneumonia. In some embodiments, it treats systemic sclerosis-associated ILD (Ssc-ILD). In some embodiments, it treats idiopathic pulmonary fibrosis (IPF).

[0108] Overview It should be understood that any features and / or aspects of the compound discussion above in connection with the present invention are applicable by analogy to the methods described herein.

[0109] The term ruxolitinib is intended to include ruxolitinib, which has CAS registration number 941678-49-5, 1 H -pyrazole-1-propionitrile, β-cyclopentyl-4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-, (β) R )-(β R )-β-cyclopentyl-4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H - Pyrazole-1-propionitrile; (3R)-3-cyclopentyl-3-[4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H [-pyrazole-1-yl]propionitrile; ( R)-3-[4-( 7H -pyrrolo[2,3- d [Pyrimidin-4-yl]-1H-pyrazol-1-yl]-3-cyclopentylpropionitrile; or a pharmaceutically acceptable salt thereof. Trade names include Jakafi, Jakavi, and Opzelura.

[0110] The terms “a” and “an” are intended to mean “one or more”; the “the” preceding an element does not exclude the existence of multiple such elements.

[0111] The terms “comprising,” “including,” or “constituting” do not exclude the presence of other elements or steps besides those listed.

[0112] It should be noted that, unless otherwise stated, the use of "or" means "and / or".

[0113] The term "at most" is intended to include endpoints.

[0114] The following figures and embodiments are provided to illustrate the present invention. These embodiments are intended to be illustrative and should not be construed as limiting in any way. Attached Figure Description

[0115] Figure 1 The X-ray powder diffraction (XRPD) pattern (full view) of ruxolitinib phosphate (batch RH0030223) is shown, and the characteristic peaks indicate that the material is highly crystalline. The peaks, expressed in degrees (2θ) at approximately 4.0, 7.6, and 9.5 ± 0.2 θ, are those commonly used for form-I identification. Figure 2 The X-ray powder diffraction (XRPD) pattern (magnified view) of ruxolitinib phosphate (batch RH0030223) is shown, indicating that the material is highly crystalline. Figure 3A X-ray powder diffraction (XRPD) patterns of micronized ruxolitinib phosphate PR-469-4 before excitation (top (green) curve at the arrow position) and after excitation with 86% RE (bottom (pink) curve after 1 day) (magnified view). Micronized ruxolitinib phosphate exhibits surface amorphism after micronization, which disappears after high RE treatment.

[0116] Figure 3B X-ray powder diffraction (XRPD) patterns of micronized ruxolitinib phosphate PR-469-4 before excitation (top (green) curve at the arrow position) and after excitation with 86% RE (bottom (pink) curve after 1 day) (full view). Micronized ruxolitinib phosphate exhibits surface amorphism after micronization, which disappears after high RE treatment.

[0117] Figure 4A X-ray powder diffraction (XRPD) patterns of micronized ruxolitinib phosphate PR-469-4 before excitation (top (pink) curve at the arrow position) and after excitation with 94% RE (bottom (blue) curve after 1 day) (magnified view). Furthermore, recrystallization is clearly evident in this case. Figure 4B X-ray powder diffraction (XRPD) patterns (full view) of micronized ruxolitinib phosphate PR-469-4 before excitation (top (pink) curve at the arrow position) and after excitation with 94% RE (bottom (blue) curve after 1 day). Moreover, recrystallization is clearly evident in this case. Figure 5 Isothermal microcalorimetric thermography using micronized ruxolitinib phosphate at 75% RH showed a distinct recrystallization event (bimodal) after the initial adsorption stage. Figure 6 Isothermal microcalorimetry thermography using micronized ruxolitinib phosphate excited at 53% RH showed no obvious crystallization peaks, but the total integral enthalpy was close to that at 75% RH (note the different time scales in this figure; this is a very long-term event). Therefore, slow, continuous crystallization occurred. Figure 7 A comparison of particle size distribution (PSD) curves of micronized batches PR-469-1, PR-469-2, PR-469-3, and PR-469-4 after external ultrasonic treatment in beakers (immediate complete dispersion method). These four batches were micronized using different settings, see Table 1.

[0118] Figure 8 Particle size distribution (PSD) curves of batch PR-469-4 material after different conditioning treatments and agitator dispersion: untreated micronization at onset, TAM 53%RH, TAM 75%RH, and after conditioning at 25℃ / 75%RH and storage at 25℃ / 60%RH for 4 weeks. Figure 9 Particle size distribution (PSD) curves of batch PR-469-4 material after different conditioning treatments and ultrasonic treatment at 20% power for 1 minute: untreated micronization at the beginning, TAM 53%RH, TAM 75%RH, and after conditioning at 25℃ / 75%RH and storage at 25℃ / 60%RH for 4 weeks. Figure 10Particle size distribution (PSD) profiles of batch PR-469-4 material after different conditioning treatments and an additional 1 minute of ultrasonic treatment at 90% power: untreated micronization at onset, TAM 53%RH, TAM 75%RH, and after conditioning at 25°C / 75%RH and storage at 25°C / 60%RH for 4 weeks. Figure 11 Particle size distribution (PSD) profiles of batch PR-469-4 material after different conditioning treatments and an additional ultrasonic treatment at 90% power for 5 minutes: untreated micronization at onset, TAM 53%RH, TAM 75%RH, and after conditioning at 25°C / 75%RH and storage at 25°C / 60%RH for 4 weeks. Figure 12 The ratio of free drug exposure after inhalation of 2.5 mg (ruxolitinib phosphate) to that after oral immediate-release administration of 2.5 mg (ruxolitinib phosphate) (biopharmaceutical computer simulation assessment). BB = tracheobronchial duct (large airway), bb = bronchiolar duct (small airway), AI = alveolar interstitium (lung parenchyma). Figure 13 The ratio of free drug exposure after inhalation of 5 mg (ruxolitinib phosphate) to that after oral immediate-release administration of 5 mg (ruxolitinib phosphate) (biopharmaceutical computer simulation assessment). BB = tracheobronchial ducts (large airways), bb = bronchioles (small airways), AI = alveoli Figure 14 In a dry run test of formulation aerosolization in the inhalation tower unit, the amount of the active pharmaceutical ingredient (API) – ruxolitinib – was measured at the filter in relation to the Wright dust feed (WDF) rate, showing a linear relationship between the API (ruxolitinib) at the filter and the WDF rate. The amount of the active pharmaceutical ingredient (API) – measured at the filter relative to the Wright dust feed (WDF) rate – was derived from a dry run test of formulation atomization in the inhalation tower assembly. The dry run was performed prior to the rat pharmacokinetic studies.

[0119] Figure 15 For ruxolitinib levels in the parenchyma following single inhalation (inh) and intravenous (iv) doses in rat pharmacokinetic studies, tissue concentration (Ct) data normalized to dose and bioavailability (BA) showed that the parenchymal concentrations after inhalation were 5.5 times higher than those after iv administration (based on area under the curve – AUC).

[0120] Figure 16For ruxolitinib levels in the airway after single inhalation (inh) and intravenous (iv) doses in rat pharmacokinetic studies, tissue concentration (Ct) data normalized to dose and bioavailability (BA) showed that the concentration in the parenchyma was 12.0 times higher after inhalation than after iv (based on area under the curve – AUC).

[0121] Example Example 1 Micronization and Crystallinity Restoration of Ruxolitinib Phosphate The ruxolitinib phosphate batch RH0030223 from MSN Laboratories Private Limited, India, was found to be in crystalline form I according to the inspection report and was micronized in a fluidized bed mill (Technoprog's Airfilco 2.5'' jet mill). The gas pressure within the milling chamber caused the particles to collide with each other and with the walls, resulting in even smaller particles. Once the particles reached a sufficiently small size, they passed through a classifier and were then collected in glass jars.

[0122] The feed material was micronized in small quantities (1 g), and different settings were applied to determine the final settings for the bulk material quantity (5 g). Different pressures were applied during three screening runs prior to the micronization of the bulk material. The conditions and results are shown in Table 1.

[0123] Table 1. Grinding parameters used

[0124] NA = Not applicable Based on the initial particle size distribution, the setting of 5 g batch (PR-469-4) as shown in Table 2 was adopted to obtain the particle size distribution in the lower part of the 2-3µm range. The particle size distribution results are shown in Example 2.

[0125] Table 2. Grinding parameters for batch PR-469-4

[0126] Crystallinity was measured using X-ray powder diffraction (XRPD) with a PanAlytical X'Pert Pro instrument. Sample preparation involved applying approximately 15-20 mg of sample onto a zero-background silicon wafer to create a flat, powdery surface. XRPD measurement settings are shown in Table 3.

[0127] Table 3. XRPD Measurement Parameters

[0128] X-ray powder diffraction (XRPD) was recorded before and after the micronized material was exposed to high relative humidity (RH) and high relative ethanol activity (RE).

[0129] The XRPD diffraction pattern of ruxolitinib phosphate (RH0030223) is shown below. Figure 1 (Full view) and Figure 2 (Enlarged view)

[0130] XRPD diffraction patterns of micronized ruxolitinib phosphate (PR-469-4) before and after one day of excitation with 86% relative ethanol activity (RE) are shown below. Figure 3A (Enlarged view) and Figure 3B (Full view). Micronized materials exhibit surface amorphism after micronization, which disappears after high RE treatment.

[0131] The corresponding XRPD diffraction patterns of micronized ruxolitinib phosphate before and after excitation at 94% relative humidity (RH) for 1 day are shown below. Figure 4A (Enlarged view) and Figure 4B (Full view). Furthermore, recrystallization is clearly occurring in this case.

[0132] It is possible to use increased relative humidity (RH) or increased ethanol activity (RE) to revert the induced amorphous phase back to the crystalline phase, also known as regulation or excitation.

[0133] Example 2 Suitable conditions for the regulation (crystallinity restoration) of micronized ruxolitinib phosphate In order to find suitable conditions to adjust the micronized ruxolitinib phosphate to obtain crystalline ruxolitinib phosphate, two different high relative humidity (RH) values ​​were further selected for microthermal crystallization experiments.

[0134] A TA Instruments isothermal microcalorimeter (TAM III) equipped with a multi-channel calorimeter unit was used. Samples were prepared as follows: Samples were placed in 4 mL glass sample vials. Before adding the humidifier tube to the vial and sealing it, the prepared vial and humidifier were pre-equilibrated at 25°C. The sealed vial was immediately introduced into the isothermal position of the calorimeter channel and equilibrated for a predetermined time of 15 minutes, then lowered to the measurement position. The settings for isothermal microcalorimetry measurements are shown in Table 4.

[0135] Table 4. Measurement parameters of isothermal microcalorimetry (TAM)

[0136] Conditioning was performed at 53% and 75% RH, respectively, followed by microcalorimetry (TAM). Conditioning occurred under both conditions, but was much faster at higher RH.

[0137] Figure 5 Results were shown at 25°C and 75%RH, with a distinct recrystallization event (doublet) occurring after the initial adsorption phase. The adsorption phase refers to the process or conditions under which micronized ruxolitinib or its pharmaceutically acceptable salt interacts with relative humidity and transforms from an amorphous to a crystalline form in the process of capturing moisture.

[0138] exist Figure 6 The results for 25 °C and 53 %RH are shown in the figure. No obvious crystallization peaks are observed in this case, but the total integral enthalpy is close to the value at 75 %RH (note...). Figure 6 (This is a very long-term event, occurring on different timescales). Therefore, slow, continuous crystallization occurs.

[0139] Next, the particle size distribution (PSD) of the sample before and after adjustment was evaluated using LALLS (low-angle laser scattering).

[0140] The instrument used was a Malvern Mastersizer 3000 equipped with a 300 mm inverted Fourier lens and a Hydro MV sample cell, and a stirrer was applied.

[0141] Sample preparation for initial particle size analysis after micronization: A few mg of solid sample was introduced into a 10 ml beaker fitted with an ultrasonic treatment rod and ultrasonicated simultaneously at power level 2 (out of 7 steps) and 100% duty cycle. After ultrasonication for 1 minute, the resulting suspension was directly introduced into the Hydro HV device. Measurements were then taken during stirring and dispersion.

[0142] Sample preparation for conditioning tests: A few mg of solid sample was directly introduced into the Hydro HV device. Measurements were taken after several internal sonication steps, with stirring for 1 minute following addition. The particle size measurement setup is shown in Table 5.

[0143] Table 5. Particle size measurement parameters

[0144] The results of the particle size distribution (PSD) analysis are shown below. Figure 7 - Figure 11 And Tables 6-10.

[0145] Table 6. Particle size distribution of samples micronized under different conditions after external ultrasonic treatment (immediate complete dispersion method) in beakers.

[0146] Table 7. Particle size distribution of PR-469-4 recrystallized under different conditions after 1 minute of agitation.

[0147] Table 8. Particle size distribution of PR-469-4 recrystallized under different conditions after 1 minute of ultrasonic treatment with 20% power.

[0148] Table 9. Particle size distribution of PR-469-4 recrystallized under different conditions after ultrasonic treatment for 1 minute with an additional 90% power, compared to PR-469-4 that has only undergone ultrasonic treatment without conditioning – see Figure 10 .

[0149] Table 10. Particle size distribution of PR-469-4 recrystallized under different conditions after 90% additional ultrasonic treatment for 5 minutes.

[0150] For the final micronized material PR-469-4, the PSD obtained by the external immediate dispersion method was slightly lower than that obtained by the progressive internal dispersion method (Tables 6 and 10).

[0151] Progressive dispersion showed that for materials with 53% RH, the presence of larger agglomerates was lowest under stirred dispersion. Otherwise, with higher moisture exposure, the main peak shifted slightly towards higher particle size distributions. Figures 8-10 (See Tables 7-9). After prolonged internal sonication, the results provided as good as those under the same primary particle size conditions (see Tables 7-9). Figure 11 (Table 10).

[0152] The particle size distribution of the samples before and after conditioning showed a slight increase in particle size after conditioning, which was more pronounced at higher RH levels. This is likely due to agglomeration, as there was almost no difference between samples after prolonged sonication.

[0153] After being stored at 25°C and 60%RH for 4 weeks, it showed a slight increasing tendency to aggregate.

[0154] Example 3 Computer simulation evaluation of biopharmaceuticals The goal of biopharmaceutical evaluation is to compare the pharmacokinetic (PK) characteristics of oral administration versus inhalation, particularly the concentration of ruxolitinib in lung tissue.

[0155] Biopharmaceutical evaluation of ruxolitinib was performed using Mimetikos Preludium™ software with a physiology-based biopharmaceutical model, employing computer simulations of systemic PK and molecular parameters. All chemical and physiological properties of ruxolitinib used in the model are referenced.

[0156] Assuming 50% lung deposition of the delivered dose, the inhalation parameters and aerodynamic particle size distribution are consistent with those expected for powder inhalers.

[0157] Jack G. Shi et al. (J Clin Pharmacol. Dec 2011; 51(12):1644-54.) described a two-compartment model based on three studies. This model has been successfully applied to Preludium to generate systemic PK concentration-time curves, as well as AUCinf and Cmax values, that are highly consistent with observations.

[0158] Two scenarios were modeled: Administer 2.5 mg of ruxolitinib phosphate orally (po) or by inhalation (inh). 5 mg ruxolitinib phosphate administered orally (po) or by inhalation (inh) For both scenarios, models were developed for the concentration of free drug in the lungs, in plasma, and in tissues.

[0159] BB = trachea and bronchi (large airways) bb = bronchioles (small airways) AI = alveolar interstitium (lung parenchyma).

[0160] Free drug concentrations compared to time indicate that initial drug concentrations in lung airway tissues are higher than equivalent oral doses.

[0161] The 2.5 mg ruxolitinib phosphate dose showed the greatest variation (6-10 times higher), see Table 11 and Figure 12 The difference was minimal (2-6 times higher) with 5 mg ruxolitinib phosphate, see Table 12 and Figure 13 .

[0162] Table 11.2.5 mg ruxolitinib phosphate PK parameters

[0163] AUCt = Area under the curve before the last dose; Cmax = Maximum plasma concentration; Tmax = Time to reach maximum plasma concentration. Table 12.5 mg ruxolitinib phosphate PK parameters

[0164] AUCt = Area under the curve before the last dose; Cmax = Maximum plasma concentration; Tmax = Time to reach maximum plasma concentration. However, in terms of local PK parameters (AUCt and Cmax), inhalation only showed a slight advantage (maximum 2.7) for BB and bb tissues, but no advantage for AI tissues or plasma.

[0165] Based on this computer simulation assessment, only minor advantages of inhaled delivery can be expected, as the concentration of ruxolitinib in lung tissue will temporarily increase when administered to the lungs compared to oral administration.

[0166] These assessments are preliminary because the current model does not include effects that are difficult to assess without experimental data, such as potentially increased lung tissue retention and significant tissue / target drug retention that could link pharmacodynamics and PK. Therefore, it is recommended that the compound be tested in preclinical PK and PD model settings.

[0167] Example 4 Preparation of ruxolitinib formulation for rat pharmacokinetic studies The following describes the formulations and preparation methods used in the preparation of PK investigational formulations. For formulations intended for use in clinical studies and for ultimately suitable inhalation dry powder formulations, the selection of pharmaceutically acceptable excipients, excipient quality, formulation, and preparation process may and / or will be different.

[0168] 10% w / w micronized and conditioned crystalline ruxolitinib phosphate (PR-469-4) and 90% w / w lactose (DFE Pharma's Lactohale 200 – Table 13) were manually sieved five times through a 0.5 mm sieve to obtain a powder that could be processed in equipment used for rat PK studies. The batch size of the dry powder blend was 8 grams.

[0169] Table 13. Particle size distribution of Lactohale 200

[0170] Example 5 In vivo ruxolitinib rat pharmacokinetic study The formulation described in Example 4 was developed to optimize dosage, and the no-load run was used to estimate the dosage and aerodynamic particle size distribution achievable with the applied application equipment. A Wright dust feeder (WDF) was used to generate the controlled aerosol. An aerodynamic particle size analyzer (APS) was used to track the particle flow in real time during each run. In one run, a 7-stage Marple impactor was connected to obtain a more accurate mass median aerodynamic diameter (MMAD) measurement.

[0171] A no-load run was performed to test the relationship between the amount of active pharmaceutical ingredient (API) on the filter and the WDF speed.

[0172] The relationship between the API quantity measured on the filter and the WDF speed during no-load operation is shown in [reference needed]. Figure 14 The median mass aerodynamic diameter (MMAD) at WDF speed of 0.15 rpm is shown in Table 14.

[0173] Table 14. Median aerodynamic diameter (MMAD) of mass at WDF speed of 0.15 rpm

[0174] The rat pharmacokinetic (PK) study was designed to administer ruxolitinib via inhalation (inh) and intravenous (iv) single doses, using the formulation described in Example 4. This was a single-dose study in which male Sprague-Dawley rats were administered ruxolitinib via inhalation and iv. The target doses were 5 mg / kg inhalation and 2 mg / kg iv, with 12 rats in each administration group. The lower iv dose was due to solubility limitations. Activated charcoal blocks were administered to the animals prior to inhalation to eliminate the effect of possible ingestion. Animals were sacrificed at 30 min, 2 h, 6 h, and 24 h post-administration (3 animals at each time point). Terminal blood and bronchoalveolar lavage fluid (BAL) were collected, and physiological saline was infused into the lungs via the apex of the heart to remove residual blood. The lungs were removed, weighed, and separated into airways and lung parenchyma. Bioanalysis was performed by LC-MS (liquid chromatography-mass spectrometry).

[0175] Biopharmaceutical modeling was performed using Mimetikos software (physiology-based pharmacokinetic (PBPK) model). The results were compared with non-compartmental models in the software's PK solver.

[0176] Table 15. Rat PK data

[0177] AUCt = Area under the curve before the last dose; Cmax = Maximum plasma concentration; Tmax = Time to reach maximum plasma concentration. All tissue concentration (Ct) data were normalized to the bioavailable dose, which is the nominal dose for intravenous (iv) administration. After inhalation, airway tissue concentrations are higher than those in parenchymal tissues. This phenomenon was also observed to a lesser extent after intravenous (iv) administration, see Table 15 and... Figure 15-16 .

[0178] The relationship between intravenous (iv) and inhalation (inh) suggests that inhalation (inh) can provide similar pulmonary drug concentrations with approximately 5 to 10 times lower systemic exposure compared to systemic therapy, or, as shown in this paper, local concentrations can be increased 5 to 10 times at the same systemic exposure.

[0179] Example 6 Preparation of inhaled dry powder formulations The following describes the formulations and preparation methods used in the preparation of inhaled dry powder formulations. The pharmaceutically acceptable excipients, excipient quality, formulation, and preparation process choices may differ and / or may vary for formulations intended for use in clinical studies and for dry powder formulations ultimately suitable for inhalation.

[0180] The dry powder formulation of 10% w / w micronized and regulated crystalline ruxolitinib phosphate (RH0030224) and 90% w / w lactose (DFEPharma's Respitose SV003) has the particle size distribution disclosed in Table 16.

[0181] Table 16. Particle Size Distribution

[0182] Micronized and conditioned crystalline ruxolitinib phosphate and lactose were mixed in a 0.25-liter mixing container using a Diosna high-shear mixer for 20 minutes. The batch size of the dry powder blend was 60 grams, lot number PR556D.

[0183] The final formulation was left to stand overnight and then manually filled into No. 3 hydroxypropyl methylcellulose (HPMC) capsules. The HPMC capsules contained 40 ± 1 mg of the drug.

[0184] In the New Generation Inhaler (NGI), two doses were tested using an ICOcap device (configuration number 00101R3) at a flow rate of 100 L / min and a pressure of 3.6 kPa. ICOcap is a commercially available capsule-based dry powder inhaler for oral inhalation. Formulation deposits from each stage were collected, and ruxolitinib was quantified using analytical high-performance liquid chromatography (HPLC-UV).

[0185] Table 17. Results of batch PR556D

[0186] RSD = Relative Standard Deviation; NGI = Next Generation Impactor; SD = Standard Deviation; DD = Delivered Dose; MMAD = Mean Measured Aerodynamic Diameter; GSD = Geometric Standard Deviation.

[0187] Data shows that the dry powder formulation is suitable for inhalation. During the manufacturing process, the formulation exhibits low ruxolitinib loss (4.1%), a high fine particle size fraction (FPF) delivering 75% of the dose, and excellent formulation homogeneity with an RSD of only 0.6%.

[0188] Project I 1. A dry powder formulation for inhalation comprising 1-80% w / w micronized ruxolitinib or a micronized pharmaceutically acceptable salt thereof, wherein at least 95% w / w is in single-crystal form, and wherein the median particle size of the ruxolitinib particles, as measured by laser diffraction, is 10 µm or less, and 20-99% w / w one or more pharmaceutically acceptable excipients.

[0189] 2. The dry powder formulation according to Project 1, wherein the median particle size of the ruxolitinib particles is 10 µm or less, such as 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less.

[0190] 3. The dry powder formulation according to Project 1 or Project 2, wherein the median particle size of the ruxolitinib particles is less than 4 µm, such as 3 µm or lower.

[0191] 4. The dry powder formulation according to any one of items 1 to 3, wherein the micronized ruxolitinib is a micronized pharmaceutically acceptable salt selected from ruxolitinib maleate, ruxolitinib sulfate, ruxolitinib oxalate, ruxolitinib hydrochloride, ruxolitinib mesylate, ruxolitinib hemifumarate, and ruxolitinib phosphate.

[0192] 5. The dry powder formulation according to Project 4, wherein the micronized pharmaceutically acceptable salt of ruxolitinib is ruxolitinib HCl.

[0193] 6. The dry powder formulation according to Project 4, wherein the micronized pharmaceutically acceptable salt of ruxolitinib is ruxolitinib phosphate.

[0194] 7. A method for preparing a dry powder suitable for inhalation, comprising: a. Micronize ruxolitinib granules or pharmaceutically acceptable salts of ruxolitinib.

[0195] b. Mix the micronized ruxolitinib particles with one or more pharmaceutically acceptable excipients. 8. The method according to Project 7, wherein step a is followed by a conditioning step of micronized ruxolitinib particles, and then mixing is performed in step b.

[0196] 9. The method according to Project 7, wherein step a of micronizing ruxolitinib particles further includes simultaneously or substantially simultaneously adjusting the ruxolitinib particles.

[0197] 10. A method of treating a disease, comprising administering to a subject a pharmaceutically effective amount of an inhalation-compatible dry powder formulation, said dry powder formulation comprising 1-80% w / w micronized ruxolitinib in single-crystal form, wherein the ruxolitinib particles have a median particle size of 10 µm or less as measured by laser diffraction, and 20-99% w / w one or more pharmaceutically acceptable excipients.

[0198] 11. The method according to Item 10, wherein the median particle size of the ruxolitinib particles is 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less, such as 4 µm or less, such as 3 µm or less.

[0199] 12. A method of treating a disease, comprising administering to a subject a pharmaceutically effective amount of an inhalation-compatible dry powder formulation, said dry powder formulation comprising 1-80% w / w micronized ruxolitinib HCl in single-crystal form, wherein the ruxolitinib HCl particles have a median particle size of 10 µm or less as measured by laser diffraction, and 20-99% w / w one or more pharmaceutically acceptable excipients.

[0200] 13. The method according to Item 12, wherein the median particle size of the ruxolitinib HCl particles is 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less, such as 4 µm or less, such as 3 µm or less.

[0201] 14. A method of treating a disease, comprising administering to a subject a pharmaceutically effective amount of an inhalation-compatible dry powder formulation, said dry powder formulation comprising 1-80% w / w micronized ruxolitinib phosphate in single-crystal form, wherein the ruxolitinib phosphate particles have a median particle size of 10 µm or less as measured by laser diffraction, and 20-99% w / w one or more pharmaceutically acceptable excipients.

[0202] 15. The method according to Item 14, wherein the median particle size of the ruxolitinib phosphate particles is 9 µm or less, such as 8 µm or less, such as 7 µm or less, such as 6 µm or less, such as 5 µm or less, such as 4 µm or less, such as 3 µm or less.

[0203] 16. The method according to any one of items 10 to 15, wherein the disease is a lung disease.

[0204] 17. The method according to any one of items 10 to 16, wherein the lung disease is selected from bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary venous occlusive disease, pulmonary hypertension associated with lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and interstitial lung disease (ILD).

[0205] 18. The method according to any item 17, wherein the interstitial lung disease (ILD) is selected from sarcoidosis, pneumoconiosis, beryllium poisoning, coal worker's disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrotic phenotype ILD (PF-ILD), hypersensitivity pneumonia, chronic hypersensitivity pneumonia (CHP), rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythematosus-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, connective tissue disease pulmonary inflammatory ILD (CTD-ILD), granulomatous polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, idiopathic eosinophilic pneumonia, pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organizing pneumonia (BOOP, also known as cryptogenic organizing pneumonia (COP)).

[0206] 19. The method according to Item 16, wherein the lung disease is selected from graft-versus-host disease (GvHD), pulmonary GvHD, chronic rejection after lung transplantation, chronic lung allogeneic graft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as post-transplant BOS), chronic lung allogeneic graft dysfunction-restrictive allogeneic graft syndrome (CLAD-RAS), and chronic lung allogeneic graft dysfunction-restrictive allogeneic graft syndrome-bronchiolitis obliterans syndrome (CLAD-BOS).

[0207] 20. The method according to any one of items 12 to 19, wherein the method comprises administering a daily dose of up to 5 mg of ruxolitinib to the subject.

[0208] 21. The method according to item 20, wherein the daily dose is administered by administering two equal doses separately each day.

[0209] 22. The method according to any one of items 20 or 21, wherein the daily dose is administered to the subject for at least 12 weeks.

[0210] 23. The method according to any one of items 20 to 22, wherein ruxolitinib is administered to the subject for long-term chronic treatment.

[0211] 24. A dry powder formulation according to any one of items 1 to 6, for use as a drug inhalation.

[0212] 25. A dry powder formulation according to any one of items 1 to 6, for the treatment of a disease as defined in any one of items 12 to 20, wherein the formulation is administered in a single daily dose of up to 10 mg.

[0213] 26. A dry powder formulation according to any one of items 1 to 6, for the treatment of a disease as defined in any one of items 12 to 18 or 21, wherein the formulation is administered twice daily at a total dose of up to 10 mg.

[0214] 27. The dry powder formulation according to Project 5, wherein the ruxolitinib phosphate salt is in crystalline form -I 28. The dry powder formulation according to item 27, characterized in that the peaks of the X-ray powder diffraction spectrum of the ruxolitinib phosphate are expressed in degrees (2θ) at approximately 3.9, 7.5, 8.2, and 9.4.

[0215] 29. The dry powder formulation according to Item 6, characterized in that the peaks of the X-ray powder diffraction spectrum of the ruxolitinib HCl are expressed in degrees (2θ) at approximately 8.2, 9.6, 11.7, and 12.0.

[0216] Project II 1. A dry powder formulation for inhalation comprising 2-80% w / w micronized ruxolitinib or a micronized pharmaceutically acceptable salt thereof, wherein at least 95% w / w is in single crystal form, and wherein the ruxolitinib particles have a particle size of 10 µm or less, and 20-98% w / w one or more pharmaceutically acceptable excipients.

[0217] 2. The dry powder formulation according to Project 1, wherein the median particle size of the ruxolitinib particles is less than 5 µm.

[0218] 3. The dry powder formulation according to Project 1 or 2, wherein the median particle size of the ruxolitinib particles is less than 3 µm.

[0219] 4. A method for preparing a dry powder suitable for inhalation, comprising: a. Micronizing ruxolitinib particles b. Adjustment of ruxolitinib granules c. Mix the adjusted ruxolitinib granules with one or more pharmaceutically acceptable excipients.

[0220] 5. The method according to Project 4, wherein the median particle size of the micronized ruxolitinib particles is less than 5 µm.

[0221] 6. A method of treating a disease, the method comprising administering to a subject a pharmaceutically effective amount of an inhalation-compatible dry powder formulation, the dry powder formulation comprising 2-80% w / w micronized ruxolitinib in a single-crystal form, wherein the median particle size of the ruxolitinib particles is 10 µm or less, and 20-98% w / w one or more pharmaceutically acceptable excipients.

[0222] 7. The method described in Project 6, wherein the disease is a lung disease.

[0223] 8. The method according to Item 7, wherein the lung disease is selected from bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary venous occlusive disease, pulmonary hypertension associated with lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and interstitial lung disease (ILD).

[0224] 9. The method according to Item 8, wherein the interstitial lung disease (ILD) is selected from sarcoidosis, pneumoconiosis, beryllium poisoning, coal worker's disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrotic phenotype ILD (PF-ILD), hypersensitivity pneumonia, chronic hypersensitivity pneumonia (CHP), rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythematosus-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, connective tissue disease pulmonary inflammatory ILD (CTD-ILD), granulomatous polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, idiopathic eosinophilic pneumonia, pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organizing pneumonia (BOOP, also known as cryptogenic organizing pneumonia (COP)).

[0225] 10. The method according to Item 7, wherein the lung disease is selected from graft-versus-host disease (GvHD), pulmonary GvHD, chronic rejection after lung transplantation such as chronic lung allogeneic graft dysfunction (CLAD), bronchiolitis obliterans syndrome (BOS) (also known as post-transplant BOS), chronic lung allogeneic graft dysfunction-restrictive allogeneic graft syndrome (CLAD-RAS), and chronic lung allogeneic graft dysfunction-restrictive allogeneic graft syndrome-bronchiolitis obliterans syndrome (CLAD-BOS).

[0226] 11. The method according to any one of items 6 to 10, wherein the method comprises administering a daily dose of up to 5 mg of ruxolitinib to the subject.

[0227] 12. The method according to item 10, wherein the daily dose is administered by administering two equal doses separately each day.

[0228] 13. The method according to any one of items 11 or 12, wherein the daily dose is administered to the subject for at least 12 weeks.

[0229] 14. The method according to any one of items 11 to 13, wherein ruxolitinib is administered to the subject for long-term chronic treatment.

[0230] 15. The dry powder formulation according to Project 1, for use as a drug inhalation.

[0231] 16. A dry powder formulation suitable for inhalation comprising 2-80% w / w micronized ruxolitinib, wherein at least 95% w / w is in single-crystal form and wherein the ruxolitinib particles have a particle size of 10 µm or less, and 20-98% w / w one or more pharmaceutically acceptable excipients, for the treatment of a disease as defined in any one of items 7 to 9, wherein said formulation is administered twice daily at a dose of up to 5 mg.

Claims

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

2. The dry powder formulation according to claim 1, wherein the median particle size of the ruxolitinib particles is less than 5 µm.

3. The dry powder formulation according to claim 1 or 2, wherein the median particle size of the ruxolitinib particles is less than 3 µm.

4. A method for preparing a dry powder suitable for inhalation, comprising: a. Micronizing ruxolitinib particles b. Mix the micronized ruxolitinib particles with one or more pharmaceutically acceptable excipients, optionally wherein a conditioning step of the micronized ruxolitinib particles is performed after step a, and then the mixing is performed in step b.

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

6. The method of claim 5, wherein the disease is a lung disease.

7. The method of claim 6, wherein the lung disease is selected from bronchiolitis obliterans syndrome (BOS), pulmonary hypertension, pulmonary arterial hypertension, pulmonary venous occlusive disease, pulmonary hypertension associated with lung disease, pulmonary hypertension associated with interstitial lung disease, asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and interstitial lung disease (ILD).

8. The method according to claim 7, wherein the interstitial lung disease (ILD) is selected from sarcoidosis, pneumoconiosis, beryllium poisoning, coal worker's disease, silicosis, asbestosis, talcosis, idiopathic pulmonary fibrosis (IPF), progressive fibrotic phenotype ILD (PF-ILD), hypersensitivity pneumonia, rheumatoid arthritis-associated ILD (RA-ILD), systemic sclerosis-associated ILD (Ssc-ILD), systemic lupus erythematosus-associated ILD (SLE-ILD), dermatomyositis (polymyositis)-associated ILD, granulomatous polyangiitis, lymphangioleiomyomatosis, pulmonary vasculitis, idiopathic eosinophilic pneumonia, pulmonary Langerhans cell histiocytosis, and bronchiolitis obliterans organizing pneumonia (BOOP, also known as cryptogenic organizing pneumonia (COP)).

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

10. The method of claim 9, wherein the daily dose is administered by administering two equal doses separately each day.

11. The method according to any one of 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. The dry powder formulation according to any one of claims 1 to 3, for use as a drug inhalation.

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

15. The dry powder formulation of claim 14, for treating a disease as defined in any one of claims 6 to 8, wherein the formulation is administered twice daily at a total dose of up to 10 mg.

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