Compositions and methods for modulating gp130 activity

Abstract

The disclosure also provides particulate compositions and methods useful for modulating gp130 biological activity. The disclosure also provides compositions and methods for treating disease and disorders associated with gp130 activity, particularly those associated with inflammation.

Description

COMPOSITIONS AND METHODS FOR MODULATING GP130 ACTIVITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority of U.S. provisional application no. 63 / 514,655, filed July 20, 2023, which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The disclosure provides compounds and method useful for modulating gpl30 biological activity. The disclosure also provides methods and compositions for treating disease and disorders associated with gpl30 activity, particularly those associated with inflammation.BACKGROUND

[0003] Modulators of gpl30 activity, such as JV-(4-Q?-tolyl)thiazol-2-yl)picolinamide (Compound 1) have poor solubility in water. Such poor solubility creates severe challenges for creating workable formulations such as solutions or suspensions.

[0004] Compositions and methods are needed for successful clinical outcomes for treating or ameliorating disease, disorders and conditions associated with gpl30 activity.SUMMARY OF THE DISCLOSURE

[0005] Provided herein are compositions and methods comprising / V-(4-( -tolyl)thiazol-2-yl)picol inamide (Compound 1) or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein are methods of making a solid form of Compound 1 .

[0007] In various embodiments, the disclosure provides a composition comprising: a plurality of microparticles comprising a Compound 1 or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

[0008] In various embodiments, the disclosure provides a composition consisting essentially of: a plurality of microparticles comprising a Compound 1 or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

[0009] In various embodiments, the disclosure provides a composition consisting essentially of: a plurality of microparticles consting essentially of a Compound 1 or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

[0010] In various embodiments, the disclosure provides a composition comprising: a plurality of microparticles consting essentially of a Compound 1 or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

[0011] In various embodiments, the disclosure provides a composition comprising: a plurality of microparticles comprising a Compound 1 or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 10 pm to about 100 pm.

[0012] In various embodiments, the disclosure provides a composition comprising: a plurality of microparticles comprising Compound 1, wherein the plurality of microparticles comprises a substantially uniform particle size distribution comprising a D90 of about 25 pm.

[0013] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

[0014] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

[0015] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising an aqueous solution.

[0016] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a saline solution.

[0017] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution.

[0018] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution.

[0019] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution, wherein the surfactant solution is an aqueous solution comprising one or more surfactants.

[0020] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution, wherein the surfactant solution is an aqueous solution comprising one or more surfactants, wherein the one or more surfactants is each independently a polysorbate.

[0021] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) a surfactant solution, and ii) a stabilizer.

[0022] In various embodiments, the disclosure provides a composition comprising: a suspension of a plurality of microparticles comprising Compound 1 in a pharmaceutically acceptable solution.

[0023] In various embodiments, the disclosure provides a composition consisting essentially of: a suspension of a plurality of microparticles comprising Compound 1 in a pharmaceutically acceptable solution.

[0024] In various embodiments, the disclosure provides a suspension consisting essentially of: (a) a plurality of microparticles comprising a Compound 1; and (b) a carrier.

[0025] In various embodiments, the disclosure provides a suspension comprising: (a) a plurality of microparticles comprising a Compound 1; and (b) a carrier.

[0026] In various embodiments, the disclosure provides a plurality of microparticles comprising a particle size distribution D90 of at most about 100 pm, wherein the plurality of microparticles is suspended in the carrier, wherein the carrier comprises an aqueous solution, and wherein the concentration of the compound ranges from about 0.01 mg / mL to about 2 mg / mL of suspension.

[0027] In various embodiments, the disclosure provides a suspension comprising: a) a plurality of microparticles comprising a Compound 1; and b) a carrier; wherein the carrier comprises an aqueous solution, wherein the plurality of microparticles of has a particle size distribution D90 of at most about 100 pm, where in the plurality of microparticles is suspended in the carrier, and wherein the concentration of the compound ranges from about 0.01 mg / mL to about 2 mg / mL of suspension.

[0028] In various embodiments, the disclosure provides a suspension comprising: (A) a plurality of microparticles comprising a Compound 1; and (B) a carrier; wherein the carrier comprises an aqueous solution, wherein the aqueous solution comprises a surfactant where in the plurality of microparticles is suspended in the carrier.

[0029] In various embodiments, the disclosure provides a method of treating a disorder in a subject in need thereof. In various embodiments, the disorder is an inflammatory disorder. In various embodiments, the inflammatory disorder is osteoarthritis.

[0030] In various embodiments, the disclosure provides a method of reducing activation of gpl30 in a subject in need thereof, wherein the method comprises administering to the subject Compound 1 to the subject in a pharmaceutically acceptable amount.

[0031] In various embodiments, the disclosure provides a method of reducing activation of gpl30 in a subject in need thereof, wherein the method comprises administering to the subject a plurality of microparticles comprising Compound 1 to the subject in a pharmaceutically acceptable amount.

[0032] In various embodiments, the disclosure provides a method of reducing activation of gpl30 in a subject in need thereof, wherein the method comprises administering to the subjecta plurality of microparticles consisting essentially of Compound 1 to the subject in a pharmaceutically acceptable amount.

[0033] In various embodiments, the disclosure provides a method of manufacturing a composition, wherein the composition comprises a plurality of microparticles comprising a Compound 1; said method comprising: (A) a step of jet milling; and (B) a step of sterilization by gamma radiation.

[0034] In various embodiments, the disclosure provides a method of manufacturing a composition, wherein the composition consists essentially of a plurality of microparticles comprising a Compound 1; said method comprising: (A) a step of jet milling; and (B) a step of sterilization by gamma radiation.

[0035] In various embodiments, the disclosure provides a method of manufacturing a composition, wherein the composition comprises a plurality of microparticles consisting essentially of a Compound 1; said method comprising: (A) a step of jet milling; and (B) a step of sterilization by gamma radiation.

[0036] In various embodiments, the disclosure provides a method of manufacturing a composition, wherein the composition consists essentially of a plurality of microparticles consisting essentially of a Compound 1; said method comprising: (A) a step of jet milling; and (B) a step of sterilization by gamma radiation.

[0037] The compositions and methods of the disclosure are advantageous. In one nonlimiting example, particles with low solubility allow for a slow release of a compound upon administration to a subject. In various aspects, insoluble particles enable slow release of Compound 1 into the joint space. In another non-limiting example, localized delivery of a suspension of defined particle sizes minimizes systemic exposure. In another non-limiting example, particles of Compound 1 may be formulated as solid components of saline (NaCl) to be reconstituted with sterile water.

[0038] The compositions and methods of the disclosure have several quality attributes. In a non-limiting example, the present disclosure describes compositions comprising a suspension of Compound 1 particles with a D90 lum-100 um, sterilized with gamma irradiation and suspended in saline or other aqueous solvent with or without surfactants and / or other excipients.

[0039] The plurality of microparticles disclosed herein, have good flowability.

[0040] The plurality of microparticles disclosed herein, arereadily taken up as a suspension.

[0041] The plurality of microparticles disclosed herein, has a body clearance rate that allows for sustained release of Compound 1.

[0042] In an aspect, provided is a method of treating inflammation, inflammatory disease or disorder, reducing joint pain, preventing joint degeneration or promoting cartilage regeneration in a human subject over the age of 25 in need thereof. The method includes administering to the subject an effective amount of a compound or a composition as described herein.

[0043] In an aspect, provided is a method of treating inflammation, inflammatory disease or disorder, reducing joint pain, preventing joint degeneration or promoting cartilage regeneration in a human subject over the age of 25 in need thereof. The method includes administering to the subject an effective amount of a compound or a composition as described herein.

[0044] In an aspect, provided is a method of treating a cell proliferative disease or disorder that is enhanced by gp!30 activation in a human subject in need thereof. The method includes administering to the subject an effective amount of a compound or a composition as described herein.

[0045] In an aspect, provided is a method of treating or ameliorating a pain condition that is enhanced by gpl30 activation in a human subject in need thereof. The method includes administering to the subject an effective amount of a compound or a composition as described herein. In particular, the pain condition is selected from the group consisting of: neuropathic pain, inflammatory pain, headache pain, somatic pain, visceral pain, musckulo-skeletal, craniofacial, other somatic forms of pain and referred pain.

[0046] In an aspect, provided is a method of modulating IL-6 family cytokine-mediated inflammatory responses in a cell. The method includes contacting the cell with a compound or a composition described herein. In an aspect, provided is a composition comprising a pharmaceutically acceptable carrier and a compound or a composition described herein.

[0047] In an aspect, provided is a method of treating an acute or chronic inflammatory state. The method includes administering to a subject an effective amount of a compound or a composition as described herein.

[0048] In an aspect, provided is a method of decreasing an activated inflammatory pathway in a cell. The method includes contacting the cell with a compound or a composition as described herein.

[0049] In an aspect, provided is a method of inhibiting the production or induction of pro-inflammatory genes, cytokines or mediators. The method includes contacting a cell or subject with a compound or a composition as described herein.

[0050] In an aspect, provided is a method of inhibiting the production or induction of extracellular matrix degrading enzymes comprising contacting a cell or subject with a compound or a composition as described herein.

[0051] In an aspect, provided is a method of modulating STAT3 and / or MYC levels in a cell. The method includes contacting the cell with a compound or a composition as described herein.

[0052] In an aspect, provided is a topical formulation including a compound as described herein.

[0053] In an aspect, provided is a method of reducing or preventing inflammaging in a target tissue of a human subject in need thereof. The method includes contacting the target tissue with an effective amount of the topical formulation as described herein.

[0054] Other aspects of the invention are disclosed infra.

[0055] All publications, patent applications, patents and other reference material mentioned are incorporated by reference in their entirety. In addition, the materials, methods and examples are only illustrative and are not intended to be limiting. The citation of references herein is not to be construed as an admission that the references are prior art to the present invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG. l is a histogram illustrating a particle size distribution profile of micronized Compound 1. The X-axis denotes pm (micrometres).

[0058] FIG. 2 depicts a process schematic for the preparation of a suspension of Compound 1.

[0059] FIG. 3 is an XRPD pattern for Form A of Compound 1.

[0060] FIG. 4 is a schematic illustrating the synthesis of Compound 1.

[0061] DETAILED DESCRIPTION OF THE DISCLOSURE

[0062] Disclosed herein are compositions and methods of using modulators of the gpl30 signaling pathway and / or downstream pathway members such as STAT-3 and NF-KB.

[0063] Also disclosed herein are compositions and methods for treating a subject in need thereof, wherein the subject has a disorder that is modulated by the gpl30 signaling pathway and / or downstream pathway members such as STAT-3 and NF-KB.

[0064] Also disclosed herein are compositions and methods for treating a subject in need thereof, wherein the subject has an inflammatory disorder that is modulated by the gpl30 signaling pathway and / or downstream pathway members such as STAT-3 and NF-KB.

[0065] The disclosure also provides a method of modulating IL-6-mediated inflammatory responses in a cell comprising contacting the cell with a compound as described herein and above. In one embodiment, the cell is a chondrocyte.

[0066] The disclosure also provides a method of treating an acute of chronic inflammatory state comprising contact a subject with a compound or pharmaceutical as described herein and above.

[0067] The disclosure also provides a method of decreasing an activated inflammatory pathway in a cell comprising contact the cell with a compound or pharmaceutical as described herein and above.

[0068] The disclosure provides a method of inhibiting the production or induction of pro- inflammatory genes, cytokines or mediators comprising contacting a cell or subject with a compound or pharmaceutical as described herein and above.

[0069] The disclosure provides a method of inhibiting the production or induction of extracellular matrix-degrading enzymes comprising contacting a cell or subject with a compound or pharmaceutical as described herein and above.

[0070] In another embodiment, the compound modulates STAT3 and MYC signaling. In one embodiment, the compound does not stimulate STAT3 and MYC signaling. In another embodiment, the compound stimulates STAT3 and MYC signaling.

[0071] The disclosure also provides a method of treating an inflammatory disease or disorder or cell-proliferative disease or disorder comprising contacting a subject with a compound as described herein and above. In one embodiment, the inflammatory disease or disorder or cell proliferative disease or disorder is selected from the group consisting of stroke; heart disease; cartilage degeneration; hair loss; wound healing; arthritis; neurodegenerative disorders; aging; diseases known to be associated with low-grade chronic inflammation; immune disorders including psoriasis, rosacea, lupus, rheumatoid arthritis, inflammatory bowel disease; and cancer.

[0072] Also disclosed herein are compositions and methods for treating a subject in need thereof, wherein the subject has a proliferative disorder. In embodiments, the proliferative disorder is cancer.

[0073] In some embodiments, the proliferative disorder is a cancer that is modulated by the gpl30 signaling pathway and / or downstream pathway members such as STAT-3 and NF-KB. In some embodiments, the proliferative disorder is a skin cancer.

[0074] Also disclosed herein are methods and compositions suitable for cosmetically treating a subject with mild to moderate photodamage on human skin cells, e.g., facial skin cells, by applying a novel cream formulation comprising one or more modulators of the gpl30 signaling pathway and / or downstream pathway members such as STAT-3 and NF-KB.

[0075] Osteoarthritis (OA) is a degenerative disease of joints, characterized by progressive loss of cartilage which causes stiffness, swelling and pain. Nearly 10% of the world'spopulation suffers from OA, making it the most common form of arthritis and one of the most common pathological conditions. In the United States, there are over 27 million people affected by OA, with this number projected to climb steeply due to a rapidly aging population and increases in obesity rates. Each year, over $185 billion is spent to treat OA globally, establishing this disease as a major burden on global health and economics.

[0076] Currently, there are no disease modifying agents available on the market for the treatment of osteoarthritis. Treatment modalities are focused on lifestyle modifications, pain management and improving joint viscosity, with the overall goal to delay joint replacement surgery. Initial therapies for those with mild osteoarthritis include weight loss, physical therapy and pain management using over-the-counter non-steroidal anti-inflammatory drugs (NSATDs). As the condition progresses to a moderate stage, opioid-based pain control is introduced, while continuing physical therapy and other exercises. If the disease progresses to a severe stage, intraarticular injections, such as hyaluronic acid, are used to increase joint viscosity. Finally, if none of the previous treatments are able to mitigate pain, total joint replacement surgery is considered. There are over 1 million knee and hip replacements performed each year in the U.S, at a cost of over $50 billion.

[0077] These glaring statistics, and the lack of effective treatments that address the causes rather than the symptoms of OA, have not escaped notice by clinicians and researchers. The most effective treatments for cartilage lesions thus far include four main surgical procedures: microfracture, osteochondral autologous transplantation (OATS), autologous chondrocyte implantation (ACI) and fresh osteochondral allograft (FOA). Each of these procedures has major disadvantages that preclude widespread adoption and implementation. Microfracture is technically easy, but is prone to subsequent degeneration in comparison to the other methods, and mostly results in the formation of biomechanically inferior fibrocartilage. OATS is technically difficult, and donor site morbidity increases with the number and size of the osteochondral plugs that are removed for transplantation. ACI is by far the most expensive cartilage defect treatment, and recovery biopsies still display fibrocartilaginous content in place of hyaline cartilage. FOA is also expensive due to specific instrumentation required for the procedure, limited availability of tissue and short shelf-life of material for transplantation (less than 6 weeks). Critically, all of these techniques require surgery in order to be implemented; thisfact, in combination with the unconvincing data surrounding their efficacy, has limited the broad implementation of these therapies.

[0078] Newer efforts in cell therapy are focusing on transplantation of chondrocytes from other sources or mesenchymal stem cells into the joint. Many groups are optimizing strategies to generate articular-like chondrocytes from pluripotent stem cells for use in cartilage repair. This approach, although promising, will face many of the same hurdles that impede the adoption of existing cell therapies: integration of transplanted cells with existing cartilage, inflammation and graft survival. Other groups are pursuing a strategy similar to microfracture, in that they are attempting to promote the adoption of an articular cartilage fate by mesenchymal stem cells isolated from a variety of sources. Because the starting material for these procedures can be expanded in culture and applied allogeneically, several groups have reached Phase 2 clinical trials with their work in this area. However, as with microfracture, concerns over the ability of the cells to generate true articular cartilage (vs. fibrocartilage) that substantially integrates with surrounding tissue loom.

[0079] Traditionally, cartilage has been considered to be a static tissue, with little to no cellular turnover or capacity for repair following injury. However, detailed analysis of articular cartilage tissues from a variety of species has identified a primitive stem / progenitor chondrocyte population located within the layer of cartilage closest to the joint space, termed the superficial zone. These cells are capable of proliferating and producing hyaline matrix, and mouse lineage tracing studies show these cells maintain cartilage throughout life, but it is clear that they lack sufficient capacity to effect substantive regeneration in most injury contexts. Moreover, there is a paucity of information on how to positively identify these cells in humans and understand their biology. Finally, pro-inflammatory signaling that often accompanies cartilage injury is a major inhibitor of proliferation while also driving apoptosis.

[0080] The pathogenesis of osteoarthritis (OA) often begins from an injury to articular cartilage, which establishes chronic, low-grade inflammation mediated by interleukin-6 / gly coprotein 130 (IL-6 / gpl30) and other factors that promote matrix degradation over time and eventual destruction of cartilage. IL-6 signaling through IL-6R / gpl30 suppresses chondrocyte proliferation, promotes mineralization in articular cartilage, downregulation of matrix proteins and increases expression of matrix-degrading proteases. Moreover, blockade of IL-6 in vivo inmouse models of OA has been shown to be chondroprotective. Importantly, higher serum levels of IL-6 have been correlated with the development of OA in humans, and a monoclonal antibody against IL-6R is currently in Phase III clinical trials for the treatment of hand OA (NCT02477059). Signaling downstream of IL-6 / gpl30 is mediated by multiple pathways, including signal transducer and activator of transcription 3 (STAT3). STAT3 has been demonstrated to have pleiotropic effects during chondrogenesis and in articular chondrocytes. During chondrogenic differentiation of multipotent mesenchymal stem cells, IL-6 / STAT3 signaling promotes chondrocyte commitment and matrix production. Similarly, loss of STAT3 during limb formation results in increased hypertrophy, premature ossification and decreases in expression of the master regulator of chondrocyte identity SOX9. In contrast, in adult articular chondrocytes inhibition of STAT3 downstream of IL-6 is chondroprotective, reducing the severity of OA-like pathology in a mouse model. Together, these data indicate that IL-6 / STAT3 signaling can drive matrix loss and development of OA in vivo in both mouse models and humans.

[0081] Recent studies have shown that Bone Morphogenetic Protein receptor IB (BMPR1B) marks superficial chondrocytes throughout human ontogeny and also in rodent joints. As described herein these cells can also be identified by their high level of IL-6 coreceptor gpl30 expression and activity. Based on the known role of IL-6 / gpl30 signaling in hypertrophy and OA pathogenesis, a small molecule screen was performed to identify potential agents to manipulate gp!30 signaling. These studies revealed Regulator of Cartilage Growth and Differentiation 423 (RCGD 423), a small molecule modulator of gpl30.Definitions

[0082] Compound 1 is represented by the following structural formula:(Compound 1)

[0083] Compound 1 is also known by the chemical names A-(4-(p-tolyl)thiazol-2-yl)picolinamide or A-(4-(4-methylphenyl)-2-thiazolyl)-2-pyridine carboxamide. Compound 1 is also known as B805 in WO 2019 / 169135 (PCT / US2019 / 020058) the contents of which is hereby incorporated by reference in its entirety. Compound 1 is also known as B805 in WO 2022 / 082071 (PCT / 2021 / 055317), the contents of which is hereby incorporated by reference in its entirety.

[0084] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this disclosure is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. Definitions of common terms can be found in Singleton et al., Dictionary of Microbiology and Molecular Biology 3rd ed., J. Wiley & Sons New York, NY (2001); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 5th ed., J. Wiley & Sons New York, NY (2001); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012); Jon Lorsch (ed.) Laboratory Methods in Enzymology: DNA, Elsevier, (2013); Frederick M. Ausubel (ed.), Current Protocols in Molecular Biology (CPMB), John Wiley and Sons, (2014); John E. Coligan (ed.), Current Protocols in Protein Science (CPPS), John Wiley and Sons, Inc., (2005); and Ethan M Shevach, Warren Strobe, (eds.) Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, John Wiley and Sons, Inc., (2003); each of which provide one skilled in the art with a general guide to many of the terms used in the present application.

[0085] As used herein, the singular forms "a," "an," and "the" include the plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "achondrocyte" includes a plurality of such chondrocytes and reference to "an antagonist" includes reference to one or more antagonists or equivalents thereof known to those skilled in the art, and so forth.

[0086] The term "about" indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term "about" indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term "about" indicates the designated value(s) ± one standard deviation of that value(s).Particle size Distribution

[0087] Particle size distribution may be reported using a variety of approaches. See, 9276-2:2001 : Representation of results of particle size analysis - Part 2: Calculation of average particle sizes / diameters and moments from particle size distributions; ASTM E 799-03 Standard Practice for Determining Data Criteria and Processing for Liquid Drop Size Analysis; TNI 54, Particle Size Result Interpretation: Number vs. Volume Distributions; ISO 13320-1 Particle size analysis - Laser diffraction method; and ISO 13322-2 Particle size analysis - Image analysis methods - Part 2: Dynamic image analysis methods

[0088] As used herein, the "D90 particle size" means the particle size at the 90% percentile. In other words, "D90" describes a diameter where 90 % of the particles have a smaller particle diameter than the stated value. The term "90 % cumulative particle diameter in particle size distribution" is synonymous with "D90."

[0089] As used herein, the "D10 particle size" means the particle size at the 10% percentile. In other words, "D10" describes a diameter where 10 % of the particles have a smaller particle diameter than the stated value. The term " 10 % cumulative particle diameter in particle size distribution" is synonymous with "D10."

[0090] As used herein, the "D50 particle size" means the particle size at the 50% percentile. In other words, "D50" describes a diameter where 50 % of the particles have a smaller particle diameter than the stated value. The term "50 % cumulative particle diameter in particle size distribution" is synonymous with "D50."

[0091] As used herein, the "span" and the "relative span" of the particle size distribution are statistical parameters describing the width of the particle size distribution. Mathematically, the span is the difference between the D90 and the DIO values (D90-D10). The relative span is described as follows: Relative span=(D90-D10) / D50.

[0092] As used herein, the "D(3,2)" of the particle size distribution are statistical parameters describing the "Surface Mean Distribution" of the particle size distribution.

[0093] As used herein, the "D(4,3)" of the particle size distribution are statistical parameters describing the "Volume Mean Diameter" of the particle size distribution.

[0094] As used herein the "Di value" of the particle size distribution are statistical parameters describing the "Geometric Mean" of the particle size distribution.

[0095] Standard deviation and Variance may also be used.

[0096] As used herein the " Specific Surface Area" of the particle size distribution are statistical parameters describing the the total surface area of a material per unit of mass (units of m2 / kg) or m2 / g).

[0097] The term, "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.Disorder

[0098] The terms "disorder," "disease," or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the compounds / molecules or methods provided herein. "Disease," as used herein, may refer to inflammatory diseases and disorders and immune diseases and disorders such as cartilage degenerative diseasejoint surface injury or arthritis (including rheumatoid arthritis), psoriasis, inflammatory bowel disease, aging, lupus, rosacea, fibrosis and the like.

[0099] The term "gpl30" as used herein refers to glycoprotein 130, a cell surface receptor that is expressed ubiquitously in the body and is designated by the gene name IL6ST. Activation of gpl30 is essential for several physiological functions, including but not limited to, acute-phase response to injury and infection, fertility, metabolism, haematopoiesis, neuroprotection, antiangiogenesis, and melanoma and tumor cell suppression. Gpl30 is activated by a ligand from the IL-6 family of cytokines, including but not limited to, IL-6, IL-11, leukemia inhibitory factor (LIF). Oncostatin M (OSM) , ciliary neurotrophic factor (CNTF) , cardiotrophin-1 (CT-1) and cardiotrophin-like cytokine (CLC) . Activation of gpl30 signaling generally occurs by binding of the ligand to another cell surface receptor, which forms a complex with gpl30, thereby activating it. LIF, CT-1, CNTF, OSM and CLC form heterodimers of gpl30 and LIFR, whereas OSM may also form a heterodimer of gpl30 and OSMR; IL-11 and IL-6 promote formation of heterodimers of gp!30 and IL-1 IRa and IL-6R, respectively. Therefore, LIF, CT-1, CNTF, OSM and CLC may activate gpl30 signaling directly, by binding gpl30 first, or indirectly, by binding LIFR / OSMR and then recruiting gpl30 to the complex. The ligands of the IL-6 cytokine family trigger the JAK / STAT pathway, the first event of which is the ligand-induced homo- or heterodimerization of signal -transducing receptor subunits. All IL-6-type cytokines recruit gpl30 to their receptor complexes. They either signal via gpl30 alone or in combination with LIFR, OSMR, IL- 1 IRa or IL-6R, which are all able to activate Jaks and to recruit STAT proteins.

[0100] The terms "gpl30 receptor," "gpl30," gpl30 protein," "IL6ST receptor, " "IL6ST" or "IL6ST protein" are here used interchangeably and according to their common, ordinary meaning (e.g., transmembrane protein "glycoprotein 130") and refer to proteins of the same or similar names and functional fragments and homologs thereof.

[0101] The term "effective amount" refer to an amount of a compound, formulation, material, or composition, as described herein, effective to achieve a particular cosmetic result.

[0102] The term "topical" administration of a formulation disclosed herein refers to application of a formulation to skin of a patient. For purposes of applying a formulation, topical application to the skin shall include application to the stratum corneum. The topical formulation described herein is able to facilitate delivery of an active ingredient through the epidermis by carrying the component having an active ingredient activity past the cells of the epidermis and through the basement membrane into the dermis.

[0103] The term "subject" is intended to include living organisms in which an application of the compositions and methods disclosed herein is beneficial in abrogating at least one sign of aging or at least one medical skin condition.

[0104] The term "cosmetic" refers to cosmetic preparations which are used to improve looks or the way a person feels about themselves; cosmetic products must deliver visible results without side effects and should appear natural.

[0105] The term "chelator" or "chelating agent" refers to any molecule or moiety that is capable of forming a complex (i.e., "chelates") with a metal ion. In certain exemplary embodiments, a chelator refers to any molecule or moiety that "binds" to a metal ion, in solution, making it unavailable for use in chemi cal / enzymatic reactions. Chelators generally have two or more unshared electron pairs that can be used to donate to a metal ion. Metal ions are usually coordinated to the chelator by two or more pairs of electrons.

[0106] The term "prophylaxis" as used herein means the prevention of or protective treatment for a disease or disease state.

[0107] The term, "therapeutically effective amount," refers to an amount of a compound, molecule or composition of the disclosure that reduces a symptom or symptoms (and grammatical equivalents of this phrase) or the severity of or frequency of the symptom(s), or elimination of the symptom (s) associated with a disease or disorder to be treated.

[0108] The term, "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992) ; Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed. , Lippincott, Williams & Wilkins).

[0109] Throughout this disclosure, various aspects of the present disclosure can be presented in a range formats. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98% or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98% and 98-99% identity. This applies regardless of the breadth of the range.

[0110] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule relative to the absence of the modulator.[0011 1] In one embodiment, the term "modulation" refers to increase and / or induction and / or promotion and / or activation. In an alternative embodiment, the term "modulation" refers to reduction and / or reduction and / or inhibition.

[0112] In one embodiment, the term "modulate" refers to upregulation. In an alternative embodiment, the term "modulate" refers to downregulation.

[0113] The term "Inflammation" refers to a complex biological response of a body to a stimulus (e.g., a pathogen, cellular damage or an irritant) . Inflammation, when prolonged, can lead to an inflammatory disease or disorder. Factors elicited during an inflammatory reaction include pro-inflammatory cytokines (e.g., TNF-a, IL-1, IFN-gamma, MCP-1, IL-6), cellular migration (e.g., monocytes, macrophages, lymphocytes, plasma cells) and serum proteins (e.g., serum amyloid A (SAA) and serum amyloid P (SAP)). Inflammation can be local (e.g., vascular inflammation) or systemic.

[0114] "Inflammatory disorder" or "inflammatory disease" refers to a condition characterized by inflammation in a cell, tissue or body. Inflammatory diseases and disorders include, but are not limited to, hypersensitivities (e.g., allergies), asthma, autoimmune disease (e.g., rheumatoid and osteoarthritis, lupus, multiple sclerosis), cancer, diabetes, inflammatory bowel disease (IBD) or cardiovascular disease (e.g., atherosclerosis), NAFLD, NASH, hepatitis, fibrosis, and cirrhosis.

[0115] "Inflammaging" as described herein refers to inflammation, particularly of skin, as a biological response of a body tissue to both environmental challenges such as sun and wind, and internal drivers such as diet, alcohol consumption and smoking, and other potentially harmful stimuli, that promotes detrimental biological responses that result in visible signs of aging such as the appearance of fine lines and wrinkles, hyperpigmentation and increased laxity. The harmful stimuli can include but are not limited to pathogens, bacteria, viruses, fungi, damaged cells and other irritants that are known to those skilled in the art. While inflammation can be a protective immune response that can involve, for example, immune cells, white blood cells, blood vessels, molecular mediators, and other small molecules. Signs of inflammation can include but is not limited to pain, heat, swelling, and / or loss of function. Inflammation can be acute or chronic.

[0116] The term "pharmaceutically acceptable" as in pharmaceutically acceptable salt or pharmaceutically acceptable counter ion, refers to compounds, salts, or ions that are tolerated by a subject for topical, or internal use.

[0117] The term "pharmaceutically acceptable salt" refers to making a salt formation of a compound disclosed herein. Salt formation can be used as a means of varying the properties of the compounds disclosed herein, for example, to increase or decrease solubility of thecompounds, to improve stability of the compounds, to reduce toxicity of the compounds, and / or to reduce the hygroscopicity of the compounds. There are a wide range of chemically diverse acids and bases, with a range of pKa values, molecular weights, solubilities and other properties, that can used for making pharmaceutically acceptable salts of the compounds disclosed herein. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate , acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'- methylene-bis- (2-hydroxy-3 -naphthoate) ) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For additional examples of pharmaceutical salts that can used to practice this disclosure, see P.H. Stahl and C.G. Wermuth (eds.), Pharmaceutical Salts: Properties, Selection, and Use (2d ed. 2011) Wiley and Sons Publisher, ISBN: 978-3-90639-051-2.

[0118] The term "pharmaceutically acceptable counter ion" either refers to pharmaceutically acceptable cations including, but not limited to, alkali metal cations (e.g., Li+, Na+, K+), alkaline earth metal cations (e.g., Ca2+, Mg2+), non-toxic heavy metal cations and ammonium (NH4+) and substituted ammonium (N(R')4+, where R' is hydrogen, alkyl, or substituted alkyls, i.e., including, methyl, ethyl, or hydroxyethyl, specifically, trimethyl ammonium, triethyl ammonium, and triethanol ammonium cations); or pharmaceutically- acceptable anions including, but not limited to, halides (e.g., Cl", Br"), sulfate, acetates (e.g., acetate, trifluoroacetate), ascorbates, aspartates, benzoates, citrates, and lactate.

[0119] A "subject" generally refers to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Animals include all vertebrates, e.g., mammals and non-mammals, such as sheep, dogs, cows, chickens, amphibians, and reptiles.

[0120] The term "substantially" as used to modify a term means that the modified term includes minor variations in size, purity, structure and the like by only a minor amount.Accordingly, "substantially homogenous in size" means that the material does not vary by more than 1%, 5%, 10%, 20% or 30% (or any value there between) in size from an average size.

[0121] The term "pain," as used here, means any unpleasant sensory experience, usually associated with a physical disorder. The physical disorder may or may not be apparent to a clinician. Pain is of two types: chronic and acute. An "acute pain" is a pain of short duration having a sudden onset. One type of acute pain, for example, is cutaneous pain felt on injury to the skin or other superficial tissues, such as caused by a cut or a burn. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. "Chronic pain" is a pain other than an acute pain. Chronic pain includes neuropathic pain, inflammatory pain, headache pain, somatic pain visceral pain and referred pain.

[0122] It should be understood many of the reagents and starting materials used in the Schemes presented herein are readily available from various commercial suppliers, such as Sigma-Aldrich, Alfa Aesar, Tokyo Chemical Industry Co., LTD, etc. Moreover, many of these same reagents and starting materials can be modified to incorporate additional functional groups by using standard organic synthesis reactions.

[0123] In various embodiments, Compound 1 is synthesized using methods described in U.S. Patent No. 11,420,964, "Compositions and Methods for Modulating Inflammatory and Degenerative Disorder."Pharmaceutical Compositions

[0124] In some aspects, provided herein is a pharmaceutical composition comprising particles comprising a crystalline form of Compound 1 of the disclosure, and a pharmaceutically acceptable carrier or diluent.

[0125] In some aspects, provided herein is a pharmaceutical composition comprising a plurality of microparticles comprising Compound 1 of the disclosure, and a pharmaceutically acceptable carrier or diluent.

[0126] In some aspects, provided herein is a pharmaceutical composition comprising Compound 1 prepared by a method of the disclosure, and a pharmaceutically acceptable carrier or diluent.

[0127] In some aspects, provided herein is a pharmaceutical composition comprising a plurality of microparticles comprising Compound 1 prepared by a method of the disclosure, and a pharmaceutically acceptable carrier or diluent.

[0128] In embodiments of the pharmaceutical compositions, the compound, or pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount.

[0129] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration.

[0130] Examples of routes of administration include parenteral, e.g., intra-articular injection, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration.

[0131] In various embodiments, a composition comprising Compound 1 is injected into a joint of a subject. In various embodiments, a composition comprising Compound 1 is injected into the knee of a subject.

[0132] Suspensions or solutions or used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with buffers, acids or bases, such as hydrochloric acid or sodium hydroxide.

[0133] In various embodiments, the saline solution is an isotonic solution. An isotonic solution may also be referred to as physiological saline or as physiologically normal solution. An isotonic may be approximately isotonic to blood serum. In various embodiments, the isotonic solution has minimal hypotonicity or hypertonicity. In various embodiments, the isotonic solution has good fluid balance. In various embodiments, the saline solution comprises about 0.9% w / v NaCl. In various embodiments, the saline solution comprises about 9 g of NaCl per litre solution. In various embodiments, the saline solution comprises about 0.9mg NaCl in ImL H2O.

[0134] Sterile injectable solutions can be prepared by incorporating the active compound, e.g., Compound 1, disclosed herein, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization, or radiation. In various embodiments, Compound 1 is sterilized by radiation. In various embodiments, the radiation is gamma radiation.

[0135] Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient.Carrier

[0136] In a particular embodiment, one or more compounds of the disclosure are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations should be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.Liposomal suspensions (including liposomes targeted to cells with monoclonal antibodies) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4, 522, 811.

[0137] In some embodiments, the pharmaceutical composition comprising Compound 1 is provided in solid form. In some embodiments, the pharmaceutical composition comprising Compound 1 is administered in solid form. Some preferred, but non-limiting examples of such forms include powders and dispersible granules. In some embodiments, the pharmaceutical composition comprises compound of Compound 1 and a solid carrier. A solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In various embodiments, the carrier is sodium chloride, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

[0138] In powders, the carrier may be a finely divided solid in a mixture with the finely divided active component.

[0139] The powders may contain from about 0.01% to about 75% of the active compound.

[0140] In various embodiments, the pharmaceutical composition comprises a powder formulation wherein Compound 1 is present in an amount ranging from about 0.01% to about 50% by mass of the power.Surfactants

[0141] A surfactant solution is an aqueous solution comprising one or more surfactants. A surfactant may also be referred to as a detergent.

[0142] Any suitable surfactant may be used. In various embodiments, the one or more surfactants is each independently an ionic surfactant or a non-ionic surfactant.

[0143] In various embodiments, the surfactant is a non-ionic surfactant. In various embodiments, the non-ionic surfactant is selected from the group consisting of a poloxamer, and a polysorbate. In various embodiments, the non-ionic surfactant is a polysorbate. In various embodiments the polysorbate is polysorbate 80, polysorbate 60, polysorbate 40, or polysorbate 20. Examples of suitable commercially available polysorbates include, but are not limited to, Tween 80 and Tween 20.

[0144] In various embodiments, the surfactant is an ionic surfactant. In various embodiments, the ionic surfactant is sodium lauryl sulfate.Stabilizers

[0145] In some embodiments, the composition comprises a stabilizer. In some embodiments, the stabilizer is a heat stabilizer.

[0146] Heat stabilizers, include but are not limited to, polyethylene glycol (PEG), (Povidone((PVP), and and (Polyvinyl alcohol(PVA).

[0147] In various embodiments, the stabilizer is PEG (Polyethylene glycol) PVP (Povidone), PVA (Polyvinyl alcohol), captisol, cellulose, HPMC (Hypromellose, hydroxypropylmethylcellulose), HPC (Hydroxypropyl cellulose), HEC (Hydroxyethyl cellulose), CMC (carboxymethylcellulose), NaCMC (Carboxymethylcellulose sodium), SD (Docusate sodium), SLS (Sodium lauryl sulfate), PEI (Polyehtylene imine), TPGS (D- a - tocopheryl polyethylene glycol succinate), PEO (Polyethylene oxide) or PPO (Polypropylene oxide).

[0148] In various embodiemnts, the stabilizer comprises carboxymethylcellulose. In various embodiments, the carboxymethylcellulose comprizes a molecular weight ranging from about 50kDa to about 800kDa.

[0149] In various embodiemnts, the stabilizer comprises sodium carboxymethylcellulose. In various embodiments, the carboxymethylcellulose comprizes a molecular weight ranging from about 45kDa to about lOOOkDa. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight ranging from about 50kDa to about 800kDa. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight ranging from about 45kDa to about 250kDa. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight ranging from about 50kDa to about lOOkDa. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight ranging from about 80kDa to about lOOkDa. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight ranging from about 90kDa to about lOOkDa.

[0150] In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 49,000 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 90,000 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 90,500 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 100,000 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 250,000 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 395,000 g / mol. In various embodiments, the sodium carboxymethylcellulose comprizes a molecular weight of about 725,000 g / mol.

[0151] In various embodiments, the sodium carboxymethylcellulose comprises a viscosity (millipascal seconds) of about 25-50 mPa • S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 50-200 mPa • S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 400-800 mPa • S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 800-3, 100 mPa - S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 1,500-3,100 mPa - S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 1000-2,800 mPa • S. In various embodiments, the sodium carboxymethylcellulose comprises a viscosity of about 1,500-3,000 mPa • S.

[0152] In some embodiments, heat stabilizers include for example, but are not limited to, polyethylene glycol (PEG).

[0153] In some embodiments, the polyethylene glycol is a high molecular weight PEG. In some embodiments, the polyethylene glycol is a low molecular weight PEG. In some embodiments, the polyethylene glycol is PEG 300PEG 400, or PEG 500.

[0154] In some embodiments, the suspension comprises a physiological pH.

[0155] In some embodiments, the suspension comprises a pH ranging from about 4 to about 10, about 5 to about 9, about 6 to about 8, about 6.5 to about 7.5.

[0156] In some embodiments, the suspension comprises a pH of about 5.0, about 5.5, about 6.0, about 6.5, about 7.0 about 7.5, or about 8.0, or about 7.0.Solid Unit dosage Form

[0157] In some embodiments, the pharmaceutical composition is in a solid unit dosage form. In some embodiments, the pharmaceutical composition is an oral unit dosage form. In some embodiments, the pharmaceutical composition is in the form of a powder.

[0158] The present disclosure also relates to a solid pharmaceutical composition comprising a plurality of microparticles comprising Compound 1 (e.g., in the form of crystalline particles or amorphous particles) and one or more pharmaceutically acceptable excipients. 1Solid Form of Compound 1

[0159] In various aspects, Compound 1 comprises a solid form. In various embodiments, Compound 1 comprises a crystalline form. In various embodiments, Compound 1 comprises an amorphous form.

[0160] In various embodiments, solid forms of Compound 1 are identifiable on the basis of characteristic peaks in an X-ray powder diffraction analysis. X-ray powder diffraction, also referred to as XRPD, is a scientific technique using X-ray, neutron, or electron diffraction on powder, microcrystalline, or other solid materials for structural characterization of the materials.

[0161] In various embodiments, XRPD patterns are generated using a Bruker 08 Advance X-Ray Powder Diffractometer with Copper (Cu) tube material; voltage of 40kV; and current of 40mA.

[0162] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0163] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having one or two characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0164] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having two or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0165] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having three or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0166] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having four or more characteristic peaks expressed in degrees 2-theta (“20”),selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0167] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having five or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0168] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having six or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0169] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having seven or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0170] In some embodiments, the Compound 1 Form A exhibits an X-ray powder diffraction pattern having one or two characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

[0171] In some embodiments, Compound 1 Form A exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta, selected from the group consisting of 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, and 27.8 + / - 0.3.

[0172] In some embodiments, Compound 1 Form A exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2-theta, of 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, and 27.8 + / - 0.3.

[0173] In some embodiments, Compound 1 Form A exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta, selected from the group consisting of 15.4 + / - 0.3, and 15.9 + / - 0.3.

[0174] In some embodiments, Compound 1 Form A exhibits an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2-theta, of 15.4 + / - 0.3, and 15.9 + / - 0.3.Particle Size Distribution

[0175] In some embodiments, Particle Size Distribution is measured by any suitable method in the art. In some embodiments, Particle Size Distribution is measured using a Mastersizer 3000 by Malvern Panalytical, Malvern Instruments, Ltd. v3.81 software. In some embodiments, Particle Size Distribution is measured by laser diffraction.

[0176] In various aspects, Compound 1 is in powder form. In various embodiments, the powdered form of Compound 1 comprises a substantially uniform particle morphology. In various aspects, the solid form of Compound 1 is an off-white solid.

[0177] In various aspects, the present disclosure provides a solid form of Compound 1 comprising a plurality of microparticles.

[0178] In various embodiments, the plurality of microparticles comprises a particle size distribution, wherein the particle size distribution is substantially uniform.PSD - D90

[0179] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 10 pm to about 50 pirn. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 20 pun to about 40 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 20 pm to about 30 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 24 pm to about 26 pm.

[0180] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of about 25 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 90 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 80 pm. In various embodiments, the plurality ofmicroparticles comprises a particle size distribution comprising a D90 of at most about 30 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 25 pm.

[0181] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of about 20 pm, about 21 pm, about 22 pm, about 23 pm, about 24 pm, about 25 pm, about 26 pm, about 27 pm, about 28 pm, about 29 pm, about 30 pm, about 31 pm, about 32 pm, about 33 pm, about 34 pm, or about 35 pm.

[0182] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of about 33.9 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D90 of about 30.1 pm.PSD - D10

[0183] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 ranging from about 0.1 pm to about 10 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 ranging from about 1 pm to about 10 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 ranging from about 5 pm to about 10 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of about 10 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of at least about 1 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of at least about 5 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of at least about 10 pm.

[0184] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of about 1 pm, 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, or 10 pm.

[0185] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of about 5.5 pm. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of about 5.46 pm. Invarious embodiments, the plurality of microparticles comprises a particle size distribution comprising a D10 of about 5.9 pm.PSD - Span

[0186] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a span of about 20 pm or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a span of about 10 pm or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 5 or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 4 or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 3 or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2 or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 3 or less. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 3. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2.5. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2.2. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2.1. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of 2.15.

[0187] In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of 2.14. In various embodiments, the plurality of microparticles comprises a particle size distribution comprising a relative span of about 1.82.

[0188] In various embodiments, the plurality of microparticles comprises a D[3,2] of about 9.4 micrometers. In various embodiments, the plurality of microparticles comprises a D[3,2] of about 9.8 micrometers.

[0189] In various embodiments, the plurality of microparticles comprises a D[4,3] of about 17.7 micrometers. In various embodiments, the plurality of microparticles comprises a D[4,3] of about 16.3 micrometers.

[0190] In various embodiments, the plurality of microparticles comprises a uniformity of about 0.7. In various embodiments, the plurality of microparticles comprises a uniformity of about 0.6.Preparation of Suspension

[0191] A suspension may be prepared by any suitable method in the art. In some embodiments, the suspension may be prepared by methods including but not limited to ultrasound (sonication), mechanical stirring, or homogenization, mixingPreparation of particlesMilling of Particles

[0192] In various aspects, microparticles of the present disclosure are produced by any suitable particle size reduction techniques known in the art.

[0193] In various embodiments, the microparticles are prepared using wet milling. Any suitable apparatus for wet milling may be used. In various aspects, the microparticles of the present disclosure are prepared using any suitable milling techniques known in the art. In various embodiments, the microparticles are prepared using dry milling. Any suitable apparatus for dry milling may be used.

[0194] In various embodiments, the microparticles are prepared using jet milling. Any suitable apparatus for jet milling may be used. Examples of jet milling apparatus include, but are not limited to, MC DecJet 30® Micronizer (Dec Group), Spiral Jet Mill (Epic Power), and Alpine TFG Fluidized Bed Jet Mill (Hosokawa Micron Powder Systems).Kits

[0195] For use in the therapeutic applications described herein, kits, and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

[0196] For example, the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0197] A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Nonlimiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0198] A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0199] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

[0200] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprisingSodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

[0201] In various embodiments, the particle size distribution of microparticles comprising a Compound 1 is the same as the the particle size distribution of the microparticles of NaCl.

[0202] Ratios of Compound 1 and NaCl are expressed as mass:mass (w / w) ratio (e g., mg:mg).

[0203] In various embodiments, the mass ratio of NaCl and Compound 1 ranges from about 200:1 to about 1 : 1 (NaCl:Compound 1). In various embodiments, the mass ratio of Compound 1 and NaCl ranges from about 90: 1 to about 20: 1. In various embodiments, the mass ratio of Compound 1 and NaCl ranges from about 81 : 1 to about 27: 1 (NaCl: Compound 1).

[0204] In one embodiment, the mass ratio of NaCl and Compound 1 is about 100:1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 200: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 80: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 70: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 60: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 50: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 40: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 30: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 20: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 10:1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 5: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 5: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 4: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 3: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 2: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 1 : 1.

[0205] In one embodiment, the mass ratio of NaCl and Compound 1 is about 81 :1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 2: 1. In one embodiment, the mass ratio of NaCl and Compound 1 is about 27: 1.

[0206] In preferred embodiments, the mass ratio of NaCl and Compound 1 is about 187: 1. In preferred embodiments, the mass ratio of NaCl and Compound 1 is about 186: 1. Inpreferred embodiments, the mass ratio of NaCl and Compound 1 is about 66:1 . In preferred embodiments, the mass ratio of NaCl and Compound 1 is about 21 : 1.Concentrations of surfactant

[0207] Concentrations of surfactant are expressed as mass percent (mass per lOOmL of solution). For example, a concentration of 0. 1% is O.lmg per lOOmL solution.

[0208] In various embodiments, the concentration of surfactant ranges from about 0.01 to about 2.5%. In one embodiment, the the concentration of surfactant is about 0.1%.

[0209] In various embodiments, the concentration of polysorbate 80 ranges from about 0.01 to about 2.5%. In one embodiment, the the concentration of polysorbate 80 is about 0.1%.Concentrations of stabilizer

[0210] Concentrations of stabilizers are expresses as mass percent (mass per 100mL of solution).

[0211] In various embodiments, the concentration of stabilizer ranges from about 0.1 to about 2%. In one embodiment, the the concentration of stabilizer is about 0.5%.

[0212] In various embodiments, the concentration of carboxymethylcellulose ranges from about 0.1 to about 2%. In one embodiment, the the concentration of carboxymethylcellulose is about 0.5%.

[0213] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising an aqueous solution.

[0214] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a saline solution.

[0215] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution.

[0216] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution.

[0217] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution, wherein the surfactant solution is an aqueous solution comprising one or more surfactants.

[0218] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising a surfactant solution, wherein the surfactant solution is an aqueous solution comprising one or more surfactants, wherein the one or more surfactants is each independently a polysorbate.

[0219] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distributionD90 ranging from about 10 pm to about 100 pm; and (B) a container comprising an aqueous solution comprising i) a surfactant, and ii) a stabilizer.

[0220] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80, and ii) carboxymethyl cellulose.

[0221] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80 at a concentration ranging from about 0.01% to about 2.5%, and ii) carboxymethyl cellulose at a concentration ranging from about 0.1% to about 2%.

[0222] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80 at a concentration ranging from about 0.05% to about 0.15%, and ii) carboxymethyl cellulose at a concentration ranging from about 0.1% to about 1.0%.

[0223] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprisingSodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80 at a concentration of about 0.1%, and ii) sodium carboxymethyl cellulose at a concentration ranging from about 0.5%.

[0224] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80 at a concentration of about 0.1%, and ii) sodium carboxymethyl cellulose comprising an average molecular weight of about 90,000 g / mol to abput 100,000 g / mol, at a concentration ranging from about 0.5%.

[0225] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm, and ii) a plurality of microparticles comprising Sodium chloride (NaCl) wherein the plurality of microparticles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and (B) a container comprising and aqueous solution comprising i) polysorbate 80 at a concentration of about 0.1%, and ii) sodium carboxymethyl cellulose, comprising an average molecular weight of about 90,500 g / mol, at a concentration ranging from about 0.5%.

[0226] In various embodiments, the disclosure provides a kit comprising: (A) a container comprising i) a plurality of microparticles comprising a Compound 1, or a pharmaceutically acceptable salt thereof, at a mass of about 1 microgram(pg) to about 10,000mg.

[0227] In one embodiment, the container comprises about Ipg to l,000pg of Compound 1. In one embodiment, the container comprises about lOpg to l,000pg of Compound 1. In one embodiment, the container comprises about lOOpg to l,000pg of Compound 1.

[0228] In one embodiment, the container comprises about Img to l,000mg of Compound 1. In one embodiment, the container comprises about Img to lOOmg of Compound 1. In one embodiment, the container comprised about Img to lOmg of Compound 1.

[0229] In one embodiment, the container comprises about Ipg of Compound 1. In one embodiment, the container comprised about lOpg of Compound 1. In one embodiment, the container comprised about lOOpg of Compound 1.

[0230] In one embodiment, the container comprises about Img of Compound 1. In one embodiment, the container comprises about lOmg of Compound 1. In one embodiment, the container comprised about lOOmg of Compound 1. In one embodiment, the container comprises about l,000mg of Compound 1.Incorporation by Reference

[0231] All references cited herein are incorporated by reference in their entirety as though fully set forth.EXAMPLESExample 1. Synthesis

[0232] Compound 1 was prepared using the following methods

[0233] A synthesis scheme for Compound 1 is illustrated in Figure 4.

[0234] Step 1

[0235] Charge SMI (1.7 Kg, l.Oeq. LOX) into 1 L Jacket flask (R4150) with a thermometer and a mechanic stirrer, protected by N2. Charge EtOH (6.52kg) into R4150. Adjust temperature to 10-20°C. Charge Thiourea (0.68kg) at 10-20°C. Adjust temperature to 75-85 °C. Stir for 3h at 75-85 °C under N2 protection. Adjust to 20-40oC. Stir flask at 0-10°C for 0.5-lh.IPC (Purity of wet cake: 99.8%; Residual in mother liquor: 0.6%). Filtrate the mixture. Rinse the cake with EtOH (2.52kg) at 0-10°C. IPC (Residual in mother liquor: 0.6%). IPC (Purity of wet cake: 100.0%). Charge the wet cake into flask. Add H2O (7kg). Adjust to 15-25oC. Adjust pH to 9-10 with 10% Na2CO3 aqueous (5kg) at 15-25oC. Stir for 3h at 15-25 °C under N2 protection. IPC (Purity of wet cake: 100.0%; Residual in mother liquor: 0.03%). Filtrate the mixture. Rinsethe cake with H2O(4.5kg). IPC (Purity of wet cake: 100.0%; Residual in mother liquor: 0.01%). Dry the wet cake at 45-55 °C under vacuum for 12h. IPC (Residual of EtOH: 0.0%. Water content: 18.9%). Dry the wet cake at 45-55 °C under vacuum for 12h. IPC (Water content: 0.6%). Obtain 1.36kg of INT-A. IPC (Purity: 100.0%;

[0236] Step 2

[0237] Charge INT-A (1 ,34kg) into Flask under N2. Charge SM2 (1 ,30kg) into R1. Charge DMF (7.0kg) into R1 under N2. Stir at 20-30 °C for 10-30min. Charge DMAP (1.30kg). Adjust the temperature to 5-15 °C. Stir at 5~15 °C for 10-30min. Charge EDCI (2.08kg) into in portions. Degas and purge with N2 for three times. Stir at 5-15 °C for 20 hr. IPC (A / B = 0.2% spec^2.0%). Charge H2O (6.1kg) drop-wise at 5-15oC. Adjust the temperature to 20-30 °C. Charge 2-MeTHF (17.0kg) into Rl. Stir the mixture in at 20-30oC for 0.5-lh. Settle for 0.5-lh and separate the mixture at 20-3 OoC. Charge water layer into Rl . Extract water phase with 2- MeTHF (6.0kg). Stir the mixture in Rl at 20-30oC for 0.5-lh. Settle for 0.5-lh and separate the mixture at 20-30oC. IPC(residual B in water phase: 0.07%). Combine the organic layer and charge into Rl. Wash the organic layer with H2O (6.9kg). Settle for 0.5-lh and separate the mixture at 20-30oC. IPC (Residual DMF in organic layer: 1.6%). IPC(residual B in water phase: 0.006%). Concentrate R4146 to 1-3V under 50oC. Charge IP Ac (6.5kg). Concentrate to 1-3V under 50oC. Charge IP Ac (3.5kg) into R4146. IPC(residual 2-MeTHF: 0.3%). Adjust Rl to 50- 60oC. Stir at 50-60oC for 2h. Cool to 5~15oC in 5h. Stir for 2-5h at 5~15oC. IPC(Purity of fdter cake: 99.3%, Residual B in filtrate: 3.1%). Filter. Wash cake with IP Ac (1.8kg). IPC(Purity of filter cake:99.7%). IPC (Residual B in filtrate: 3.0%). Dry at 45-55oC under vacuum for 15h. IPC: Residual Solvents (IP Ac : 0.1%; 2-MeTHF: 0.0%; DMF: < 0.04%; KF: 0.3%). Obtain 1.78kg of final product (Purity of B: 100.0%; assay of B: 98.1%)

[0238] Step 3

[0239] Charge INT-B (1 ,78kg) into Flask. Charge 2-MeTHF (14kg) into Rl . Stir at 15~25oC for 10~20min. Decolor with 0.2X CUNO for 6~8h. Wash the CUNO with 2-MeTHF (14kg). Concentrate to 4-5V below 50oC. Charge EtOH (11kg). Adjust to 70-80oC. Stir the mixture at 70-80oC for 1 -3h. Cool the mixture to 62-72 oC. Charge crystal seed (18g). Stir the mixture at 62-72 oC for 2~5h. Cool the mixture to 0-10 oC during 4h-6h. Stir the mixture at 0~10oC for 5~8h. IPC (Purity of cake: 99.8%). Filter and Wash the cake with EtOH (2.7kg). IPC(Purity of cake: 100%. Dry under vacuum at 55~60oC for 13h. (Residual of 2-MeTHF: 659ppm; Residual of EtOH: 1406ppm; Residual of DMF: <442ppm; Residual of IP Ac: ^99ppm; Residual of EtOAc: ^99ppm; KF of B: 0.1%). Weigh of product (1.40kg).Example 2. Micronization - Jet Milling

[0240] Compound 1 (63g) is added to anAlpine TFG Fluidized Bed Jet Mill (Hosokawa Micron Powder Systems), jet milling apparatus. The following parameters for the milling were set: Venturi pressure: 0.8-0.9 MPa, Ring pressure: 0.7-0.8 MPa. Material was jet milled two times. Milled product is passed through a 60-mesh sieve. NaCl is ground using a mortar and pestle and then passed through a 60-mesh sieve.

[0241]

[0242] Particle Size Disctribution (PSD) testing showed the following PSD: (D10: 5pm, D50: 11 pm, D90: 25pm). A histogram illustrating the particle size distribution profile of milled Compound 1 is shown in Figure 1. The Y-axis denotes volme density percentage (%) The X-axis denotes micrometres (pm).

[0243] Particle Size Disctribution (PSD) upon release testing showed the following PSD: (D10: 5.7pm, D50: 13.3pm, D90: 32.0pm). Milled material (48.3g) was discharged.Example 3. Solid Form Analysis

[0244] XRPD patterns were generated using a Bruker 08 Advance X-Ray Powder Diffractometer with Copper (Cu) tube material; voltage of 40kV; and current of 40mA. Figure 3 illustrates a XRPD pattern of Compound 1. Table 1 provides a list of 2-theta peaks.Table 1.Example 4. Kit

[0245] Container A: 5 mL single-dose vial to deliver 0.24 mg of Compound 1 and 44.8 mg NaCl supplied as a sterile, white to off-white powder in a cerium glass (clear) vial with a rubber stopper and an aluminum seal with a gray plastic cap.

[0246] Container B: 5 mL single-dose vial supplied as a sterile, clear H2O solution containing 0.5% w / v sodium carboxymethylcellulose (90,500 g / mol, 25-50 mPa S) (Aquaion™, Ashland), and 0.1% w / w polysorbate-80 in a glass vial with a rubber stopper, aluminum seal and white plastic cap.Example 5. Kit

[0247] Container A: 5 mL single-dose vial to deliver 1 mg of Compound 1 and 27mg NaCl supplied as a sterile, white to off-white powder in a cerium glass (clear) vial with a rubber stopper and an aluminum seal with a gray plastic cap.

[0248] Container B: 5 mL single-dose vial supplied as a sterile, clear H2O solution containing 0.5% w / v sodium carboxymethylcellulose (90,500 g / mol, 25-50 mPa S) (Aquaion™, Ashland), and 0.1% w / w polysorbate-80 in a glass vial with a rubber stopper, aluminum seal and white plastic cap.Example 6. Kit

[0249] Container A: 5 mL single-dose vial to deliver 0.33 mg of Compound 1 and 27mg NaCl supplied as a sterile, white to off-white powder in a cerium glass (clear) vial with a rubber stopper and an aluminum seal with a gray plastic cap.

[0250] Container B: 5 mL single-dose vial supplied as a sterile, clear H2O solution containing 0.5% w / v sodium carboxymethylcellulose (90,500 g / mol, 25-50 mPa S) (Aquaion™, Ashland), and 0.1% w / w polysorbate-80 in a glass vial with a rubber stopper, aluminum seal and white plastic cap.Example 7. Formulation

[0251] Microparticles of Compound 1 (approximately 2mg) is mixed in a vial with microparticles of NaCl (approximately 45mg) with similar D90. A solution of water (5mL) containing 0.50% NaCMC (90.5 kDa) and 0.1% polysorbate 80 is added to the vial creating a 0.9% saline solution and suspension of Compound 1 in situ.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising: a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

2. A composition comprising: a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 10 pm to about 100 pm.

3. A composition comprising: a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of about 25 pm.

4. The composition of claim 1, wherein the composition is in powder form.

5. The composition of claim 1 wherein the particle size distribution comprises a substantially uniform particle morphology.

6. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution, wherein the particle size distribution is substantially uniform.

7. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 10 pm to about 50 pm.

8. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 20 pm to about 40 pm.

9. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 20 pm to about 30 pm.

10. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 ranging from about 24 pm to about 26 pm.

11. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of about 20 pm, about 21 pm about 22 pm about 23 pm about 24 pm about 25 pm about 26 pm about 27 pm about 28 pm about 29 pm about 30 pm.

12. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of about 25 pm.

13. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 90 pm.

14. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 80 pm.

15. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 30 pm.

16. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D90 of at most about 25 pm.

17. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D10 ranging from about 0.1 pm to about 10 pm.

18. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D10 ranging from about 1 pm to about 10 pm.

19. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a DIO ranging from about 5 pm to about 10 pm.

20. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a DIO of about 10 pm.

21. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a DIO of at least about 1 pm.

22. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a DIO of at least about 5 pm.

23. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a DIO of at least about 10 pm.

24. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 20 pm or less.

25. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 10 pm or less.

26. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 5 or less.

27. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 4 or less.

28. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 3 or less.

29. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2 or less.

30. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2. 12.

31. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a relative span of about 2.2.

32. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a specific surface area ranging from about 100 m2 / kg to about 1000 m2 / kg.

33. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a specific surface area ranging from about 100 m2 / kg t o about500 m2 / kg.

34. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a specific surface area of about 512 m2 / kg.

35. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D(3,2) (Surface Mean distribution) ranging from about 5 pm to about 20 pm.

36. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D(3,2) (Surface Mean distribution) of about 11.7 pm.

37. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising a D(4,3) (Volume Mean Diameter) ranging from about 10 pm to about 20 pm.

38. The composition of claiml, wherein the plurality of microparticles comprises a particle size distribution comprising a D(4,3) (Volume Mean Diameter) of about 16.5 pm.

39. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising uniformity ranging from about 0.1 to about 1.0.

40. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising uniformity ranging from about 0.1 to about 0.9.

41. The composition of claim 1, wherein the plurality of microparticles comprises a particle size distribution comprising uniformity of about 0.4.

2. A composition comprising: a suspension of a plurality of microparticles comprising(Compound 1), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable solution.

43. A suspension comprising: a. a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof; and b. a carrier wherein the plurality of microparticles of has a particle size distribution D90 of at most about 100 pm, wherein the plurality of microparticles is suspended in the carrier, wherein the carrier comprises an aqueous solution, and wherein the concentration of the compound ranges from about 0.01 mg / mL to about 2 mg / mL of suspension.

44. A suspension comprising: a. a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, and b. a carrier; wherein the carrier comprises an aqueous solution, wherein the plurality of microparticles of has a particle size distribution D90 of at most about 100 pm, wherein the plurality of microparticles is suspended in the carrier, and wherein the concentration of the compound ranges from about 0.01 mg / mL to about 2 mg / mL of suspension.

45. A suspension comprising: a. a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, and b. a carrier; wherein the carrier comprises an aqueous solution, wherein the aqueous solution comprises an anionic surfactant, and wherein the plurality of microparticles is suspended in the carrier.

46. The suspension of claim 43, wherein the concentration of Compound 1 ranges from about 0.01 mg / mL to about 1.0 mg / mL of suspension.

47. The suspension of claim 43, wherein the concentration of Compound 1 ranges from about 0.5 mg / mL to about 1.0 mg / mL of suspension.

48. The suspension of claim 43, wherein the carrier comprises a saline solution.

49. The suspension of claim 43, wherein the carrier comprises a 0.9% saline solution.

50. The suspension of claim 43, wherein the suspension further comprises a surfactant.

51. The suspension of claim 43, wherein the surfactant is a non-ionic surfactant.

52. The suspension of claim 43, wherein the non-ionic surfactant is selected from the group consisting of a poloxamer, and a polysorbate.

53. The suspension of claim 43, wherein the non-ionic surfactant is selected from the group consisting of polysorbate 80, and polysorbate 20.

54. The suspension of claim 43, wherein the surfactant is an anionic surfactant.

55. The suspension of claim 43, wherein the anionic surfactant is is sodium lauryl sulfate.

56. The suspension of claim 43, wherein the surfactant is present at a concentration of about 0.1% to about 1%.

57. The suspension of claim 43, wherein the surfactant is present at a concentration of about 0.2%.

58. The suspension of claim 43, wherein the suspension further comprises a buffer.

59. The suspension of claim 43, wherein the suspension further comprises one or more of an emulsifier.

60. The suspension of claim 43, wherein the emulsifier comprised one or more emulsifiers selected from the group consisting of carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl and cellulose.

61. The suspension of claim 43, wherein the emulsifier is present at a concentration of about 0.1% to about 20%.

62. The suspension of claim 43, wherein the emulsifier is present at a concentration of about 0.25%.

63. The suspension of claim 62, wherein the emulsifier is sodium carboxymethyl cellulose.

64. The suspension of claim 63, wherein the sodium carboxymethyl cellulose comprises an average molecular weight of about 90,500 g / mol.

65. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.

66. A pharmaceutical composition comprising a suspension of the composition of claim 1 and a pharmaceutically acceptable excipient.

67. A suspension comprising Compound 1 and a diluent.

68. The suspension of claim 67, wherein the Compound 1 is present at a concentration ranging from about 0.01 mg / mL to about 1.0 mg / mL.

69. The suspension of claim 67, wherein the Compound 1 is present at a concentration ranging from about 0.02 mg / mL to about 0.2 mg / mL.

70. The suspension of claim 67, wherein the Compound 1 is present at a concentration ranging from about 0.02 mg / mL.

71. The suspension of claim 67, wherein the Compound 1 is present at a concentration ranging from about 0.2 mg / mL.

72. The suspension of claim 67, wherein the Compound 1 is present at a concentration ranging from about 0.06 mg / mL73. The suspension of claim 67, wherein the Compound 1 is present at a concentration of about 0.048 mg / mL.

74. The suspension of claim 67, wherein the Compound 1 is present at a concentration of about 0.134 mg / mL.

75. The suspension of claim 67, wherein the Compound 1 is present at a concentration of about 0.404 mg / mL.

76. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, a therapeutically effective amount of the composition of claim 1.

77. The method of claim 76, wherein the disorder is an inflammatory disorder.

78. The method of claim 76, wherein the inflammatory disorder is osteoarthritis.

79. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of(a) mixing the composition of claim 1 with a saline solution to form a suspension; and(b) administering the suspension to the subject.

80. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the suspension of claim 43, wherein the composition further comprises a concentration ranging from 100 pg / mL to about 500 pg / mL.

81. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the suspension of claim 43, wherein the composition further comprises a concentration of 333 pg / mL.

82. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, a therapeutically effective amount of the suspension of claim 43, wherein the therapeutically effective amount comprises a range of about ImL to about lOmL of the composition.

83. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, a composition comprising Compound 1 at a dose ranging from about 100 microgams / kg to about lOOmg / Kg.

84. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose ranging from about 0.01 mg to about 10 mg of Compound 1.

85. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose ranging from about 0.1 mg to about 1 mg of Compound 1.

86. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose of about 0.1 mg of Compound 1.

87. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose of about 0.3 mg of Compound 1 .

88. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose of about 1 mg of Compound 1.

89. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose ranging from about about 0.0006 mg / kg to about 0.025 mg / Kg.

90. A method of treating a disorder in a subject in need thereof, wherein the method comprises the steps of administering to the subject, the composition of claim 1, at a dose of about 100 mg / kg of Compound 1.

91. A method of reducing activation of gp 130 in a subject in need thereof, wherein the method comprises administering to the subject the composition of claim 1 to the subject in a pharmaceutically acceptable amount.

92. A method of manufacturing a composition, wherein the composition comprises a plurality of microparticles comprising a Compound 1; said method comprising:(A) a step of jet milling; and(B) a step of sterilization by gamma radiation.

93. A method of manufacturing a composition, wherein the composition comprises a plurality of microparticles comprising Compound 1; said method comprising:(A) a step of jet milling; and(B) a step of sterilization by gamma radiation.

94. A method of manufacturing a composition, wherein the composition consists essentially of a plurality of microparticles comprising Compound 1; said method comprising:(A) a step of jet milling; and(B) a step of sterilization by gamma radiation.

95. A method of manufacturing a composition, wherein the composition consists essentially of a plurality of microparticles consisting essentially of Compound 1; said method comprising:(A) a step of jet milling; and(B) a step of sterilization by gamma radiation.

96. A kit comprising:(Aja container comprising a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

97. A kit comprising:(A) a container comprising: i) a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and ii) a plurality of microparticles comprising sodium chloride wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm.

98. A kit comprising:(A) a container comprising a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and(B) a container comprising an aqueous solution.

99. A kit comprising:(A) a container comprising a plurality of microparticles consisting essentially of a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and(B) a container comprising an aqueous solution.

100. A kit comprising:(A) a container comprising: a container comprising: i) a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10pm to about 100 pm; and ii) a plurality of microparticles comprising sodium chloride wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; wherein Compound 1 and sodium chloride are present at a ratio of about 1 : 100 to about 1 : 1 w / w Compound 1 to sodium chloride; and(B) a container comprising aqueous solution comprising: i) polysorbate 80 at a concentration ranging from about 0.01% to about 2.5%, and ii) carboxymethyl cellulose at a concentration ranging from about 0.1% to about 2%.

101. A kit comprising:(A) a container comprising: i) a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and ii) a plurality of microparticles comprising sodium chloride wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; wherein Compound 1 and sodium chloride are present at a ratio of about 1 : 100 to about 1: 1 w / w Compound 1 to sodium chloride; and(B) a container comprising aqueous solution comprising: i) polysorbate-80 at a concentration of about 0.1%, and ii) sodium carboxymethyl cellulose at a concentration of about 0.5%, wherein the sodium carboxymethyl cellulose comprises an average molecular weight of about 90,500g / mol.

102. A kit comprising:(A)a container comprising a plurality of microparticles comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and(B) a container comprising a saline solution.

103. A kit compri si ng :(A) a container comprising a plurality of microparticles consisting essentially of a Compound 1, or a pharmaceutically acceptable salt thereof, wherein the plurality of particles has a particle size distribution D90 ranging from about 10 pm to about 100 pm; and(B) a container comprising a saline solution.

104. A kit comprising:(A) a first container comprising a plurality of microparticles consisting essentially of a Compound 1, and sodium chloride; and(B) a second container comprising a diluent.

105. The kit of claim 104, wherein the first container comprises about 0.1 mg to about 1.0 mg of Compound 1.

106. The kit of claim 104, wherein the first container comprises about 0.3 mg of Compound 1.

107. The kit of claim 104, wherein, the first container comprises about 1.0 mg of Compound 1.

108. The kit of claim 104, wherein, the first container comprises about 0.24 mg of Compound 1.

109. The kit of claim 104, wherein, the first container comprises about 0.67 mg of Compound 1.

110. The kit of claim 104, wherein, the first container comprises about 2.02 mg of Compound 1.

111. The kit of claim 104, wherein, the first container comprises about 45 mg of NaCl.

112. The kit of claim 104, wherein, the first container comprises about 44.76 mg of NaCl.

113. The kit of claim 104, wherein, the first container comprises about 44.34 mg of NaCl.

114. The kit of claim 104, wherein, the first container comprises about 42.98 mg of NaCl.

115. The kit of claim 104, wherein, the first container comprises about 0.24 mg of Compound 1 and about 44.76 mg of NaCl.

116. The kit of claim 104, wherein, the first container comprises about 0.67 mg of Compound 1 and about 44.34 mg of NaCl.

117. The kit of claim 104, wherein, the first container comprises about 2.02 mg of Compound 1 and about 42.98 mg of NaCl.

118. The kit of claim 104, wherein, the first container comprises a NaCl to Compound 1 ratio of about 187:1.

119. The kit of claim 104, wherein, the first container comprises a NaCl to Compound 1 rationof about 66: 1.

120. The kit of claim 104, wherein, the first container comprises a NaCl to Compound 1 ratio of about 21:1.

121. A solid form comprising a compound of formula:(Compound 1), wherein the solid form exhibits an X- ray powder diffraction pattern comprising one or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

122. The solid form of Claim 121, wherein the the solid form exhibits an X-ray powder diffraction pattern comprising two or more characteristic peaks expressed in degrees 2-theta (“20”), selected from the group consisting of 9.7 + / - 0.3, 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, 23.2 + / - 0.3, 27.8 + / - 0.3, 30.1 + / - 0.3, and 15.4 + / - 0.3.

123. A solid form comprising a compound of formula:(Compound 1), wherein the solid form exhibits an X- ray powder diffraction pattern comprising one or more characteristic peaks expressed in degrees 2-theta, selected from the group consisting of 15.4 + / - 0.3, 15.9 + / - 0.3, 20.4 + / - 0.3, and 27.8 + / - 0.3.

124. A solid form comprising a compound of formula:(Compound 1), wherein the solid form exhibits anX-ray powder diffraction pattern comprising one or more characteristic peaks expressed in degrees 2-theta, selected from the group consisting of 15.4 + / - 0.3, and 15.9 + / - 0.3.

125. A composition consisting essentially of: a plurality of microparticles comprising a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

126. A composition comprising: a plurality of microparticles consisting essentially of a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

127. A composition consisting essentially of: a plurality of microparticles consisting essentially of a compound of formula:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plurality of microparticles comprises a substantially uniform particle size distribution.

Images