Pharmaceutical formulations of NLRP3 inhibitors and methods of using the same

Abstract

The present invention relates to compositions, capsules, or formulations comprising isopropyl (R)- 2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), for the treatment of NLRP3 related disease and disorders, and the processes for the preparation of such compositions, capsule, or formulations.

Description

[0001] NOD-C-P3911PCT

[0002] PHARMACEUTICAL FORMULATIONS OF NLRP3 INHIBITORS AND METHODS OF USING THE SAME

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to compositions, capsules, or formulations comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), for the treatment of NLRP3 related disease and disorders, and the processes for the preparation of such compositions, capsule, or formulations.

[0005] BACKGROUND OF THE INVENTION

[0006] Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system like dendritic cells. IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Masters, S. L., et. al., Annu. Rev. Immunol. 2009. 27:621-68).

[0007] In humans, 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with inflammasome formation.

[0008] Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability activate in response to endogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers of NLRP3 activation. Similarly, cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators led to IL-1 and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders.

[0009] Accordingly, it is an object of the present invention to provide compositions, capsules, or formulations comprising an NLRP3 inhibitor (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.NOD-C-P3911PCT

[0010] Accordingly, it is an object of the present invention to provide compositions, capsules, or formulations comprising an NLRP3 inhibitor (e.g., Compound 1).

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides compositions comprising NLRP3 inhibitors.

[0013] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0014] N O'

[0015] H

[0016]

[0017] (Compound 1),

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2- (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0020] N

[0021] N O''

[0022] H

[0023]

[0024] (Compound 1).

[0025] In some embodiments, the present invention provides a composition comprising:

[0026] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0027] (ii) a non-ionic surfactant;

[0028] (iii) a co-surfactant and solubilizer; and

[0029] (iv) a polymer.NOD-C-P3911PCT

[0030] In some embodiments, the present invention provides a composition comprising:

[0031] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0032] (ii) a non-ionic surfactant;

[0033] (iii) a co-surfactant and solubilizer; and

[0034] (iv) a polymer.

[0035] In some embodiments, the present invention provides a suspension composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0036] N

[0037] N O'

[0038] H

[0039]

[0040] (Compound 1),

[0041] or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the present invention provides a suspension composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0043] N

[0044] N O''

[0045] H

[0046]

[0047] (Compound 1).

[0048] In some embodiments, the present invention provides a suspension composition comprising:

[0049] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0050] (ii) a non-ionic surfactant;

[0051] (iii) a co-surfactant and solubilizer; and

[0052] (iv) a polymer.NOD-C-P3911PCT

[0053] In some embodiments, the present invention provides a suspension composition comprising:

[0054] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0055] (ii) a non-ionic surfactant;

[0056] (iii) a co-surfactant and solubilizer; and

[0057] (iv) a polymer.

[0058] In some embodiments, the present invention provides a capsule comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0059] N

[0060] N O'

[0061] H

[0062]

[0063] (Compound 1),

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the present invention provides a capsule comprising isopropyl (R)-2- (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0066] N

[0067] N O''

[0068] H

[0069]

[0070] (Compound 1).

[0071] In some embodiments, the present invention provides a capsule comprising:

[0072] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0073] (ii) a non-ionic surfactant;

[0074] (iii) a co-surfactant and solubilizer; and

[0075] (iv) a polymer.NOD-C-P3911PCT

[0076] In some embodiments, the present invention provides a capsule comprising:

[0077] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0078] (ii) a non-ionic surfactant;

[0079] (iii) a co-surfactant and solubilizer; and

[0080] (iv) a polymer.

[0081] In some embodiments, the present invention provides a pharmaceutical formulation comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0082] N

[0083] N O'

[0084] H

[0085]

[0086] (Compound 1),

[0087] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the present invention provides a pharmaceutical formulation comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0089] N

[0090] N O''

[0091] H

[0092]

[0093] (Compound 1).

[0094] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0095] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0096] (ii) a non-ionic surfactant;

[0097] (iii) a co-surfactant and solubilizer; and

[0098] (iv) a polymer.NOD-C-P3911PCT

[0099] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0100] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0101] (ii) a non-ionic surfactant;

[0102] (iii) a co-surfactant and solubilizer; and

[0103] (iv) a polymer.

[0104] In some embodiments, the present invention provides a method of treating an NLRP3 related disease or disorder in a subject, comprising administering to a subject a composition, capsule, or formulation as described herein.

[0105] In some embodiments, the present invention provides a method of treating an inflammatory disorder, an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject, comprising administering a composition, capsule, or formulation as described herein.

[0106] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation as described herein by:

[0107] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[0108] (ii) adding a polymer to the mixture of step (i); and

[0109] (iii) adding Compound 1 to the mixture of step (ii).

[0110] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.NOD-C-P3911PCT

[0111] Other features and advantages of the invention will be apparent from the following detailed description and claims.

[0112] BRIEF DESCRIPTION OF THE FIGURES

[0113] Figure 1: Depicts the Compound 1 drug product capsule (F1) bulk mix preparation process.

[0114] Figure 2: Depicts the Compound 1 drug product capsule (F1) manufacture process. Figure 3: Depicts the PK profile of Compound 1 of suspension formulation (F2) in blood, cerebrospinal fluid (CSF), and unbound plasma.

[0115] Figure 4: Depicts the PK profile of Compound A of suspension formulation (F2) in blood, CSF, and unbound plasma.

[0116] DETAILED DESCRIPTION OF THE INVENTION

[0117] Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system like dendritic cells, involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Masters, S. L. et al., Annu. Rev. Immunol. 2009. 27:621-68).

[0118] Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system like dendritic cells, involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Masters, S. L., et al. Annu. Rev. Immunol. 2009. 27:621-68).

[0119] Cytokines from the IL-1 family are highly active and, as important mediators of inflammation, primarily associated with acute and chronic inflammation (Sims, J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). The overproduction of IL-1 is considered to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterised by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0120] Proinflammatory cytokines of the IL-1 superfamily include IL-1α, IL-1β, IL-18, and IL-36α, β, λ and are produced in response to pathogens and other cellular stressors as part of a host innateNOD-C-P3911PCT

[0121] immune response. Unlike many other secreted cytokines, which are processed and released via the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack leader sequences required for endoplasmic reticulum entry and thus are retained intracellularly following translation. In addition, IL-1β, IL-18, and IL-36α, β, λ are synthesised as procytokines that require proteolytic activation to become optimal ligands for binding to their cognate receptors on target cells.

[0122] In the case of IL-1ct, IL-1 p and IL-18, it is now appreciated that a multimeric protein complex known as an inflammasome is responsible for activating the proforms of IL-1β and IL-18 and for release of these cytokines extracellularly. An inflammasome complex typically consists of a sensor molecule, such as an NLR (Nucleotide-Oligerimisation Domain (NOD)-like receptor), an adaptor molecule ASG (Apoptosis-associated speck-like protein containing a CARD (Caspase Recruitment Domain)) and procaspase-1. In response to a variety of “danger signals”, including pathogen-associated molecule patterns (PAMPs) and danger associated molecular patterns (DAMPs), subunits of an inflammasome oligomerise to form a supramolecular structure within the cell. PAMPs include molecules such as peptidoglycan, viral DNA or RNA and bacterial DNA or RNA. DAMPs, on the other hand, consist of a wide range of endogenous or exogenous sterile triggers including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals and aggregates of beta-amyloid peptide. Assembly of an inflammasome platform facilitates autocatalysis of procaspase-1 yielding a highly active cysteine protease responsible for activation and release of pro-IL-1β and pro-IL-18. Thus, release of these highly inflammatory cytokines is achieved only in response to inflammasome sensors detecting and responding to specific molecular danger signals.

[0123] In humans, 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with inflammasome formation including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12 and NLRC4 (IPAF).

[0124] Two other structurally distinct inflammasome structures containing a PYHIN domain (pyrin and HIN domain containing protein) namely Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 201313(6) 397-311) serve as intracellular DNA sensors.NOD-C-P3911PCT

[0125] Pyrin (encoded by the MEFV gene) represents another type of inflammasome platform associated with proIL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0126] Requiring assembly of an inflammasome platform to achieve activation and release of IL-1β andIL-18 from monocytes and macrophages ensures their production is carefully orchestrated via a 2-step process. First, the cell must encounter a priming ligand (such as the TLR4 receptor ligand LPS, or an inflammatory cytokine such as TNFa) which leads to NFkB dependent transcription of NLRP3, pro-IL-1β and pro-IL-18. The newly translated procytokines remain intracellular and inactive unless producing cells encounter a second signal leading to activation of an inflammasome scaffold and maturation of procaspase-1.

[0127] In addition to proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin-D. Pyroptosis allows the mature forms of IL-1β and IL-18 to be externalised along with release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity) such as high mobility group box 1 protein (HMGB1), IL-33, and IL-1 a.

[0128] Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability activate in response to endogenous and exogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers of NLRP3 activation. Similarly, cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators led to IL-1β and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders.

[0129] A link to human disease is best exemplified by discovery that mutations in the NLRP3 gene which lead to gain-of-function confer a range of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and Neonatal onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat. Genet. 29(3) (2001) 301-305). Likewise, sterile mediator-induced activation of NLRP3 has been implicated in a wide range of disorders including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic (type 2 diabetes,NOD-C-P3911PCT

[0130] atherosclerosis, hypertension), Central Nervous System (Alzheimer’s Disease, Parkinson’s disease, multiple sclerosis), gastrointestinal (Crohn’s disease, ulcerative colitis), lung (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis) and liver (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). It is further believed that NLRP3 activation promotes kidney inflammation and thus contributes to chronic kidney disease (CKD).

[0131] Current treatment options for diseases where IL-1 is implicated as a contributor to pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and IL-1 receptor accessory protein (rilonacept) and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is licensed for CAPS, Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS) / Mevalonate Kinase Deficiency (MKD), Familial Mediterranean Fever (FMF) and gout.

[0132] Some small molecules have been reported to inhibit function of the NLRP3 inflammasome. Glyburide, for example, is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations which are unlikely attainable in vivo. Non-specific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene are reported to impair NLRP3 activation but are expected to possess limited therapeutic utility due to their sharing of a common structural feature consisting of an olefin activated by substitution with an electron withdrawing group; this can lead to undesirable formation of covalent adducts with protein-bearing thiol groups. A number of natural products, for example β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, also are reported to suppress NLRP3 activation. Likewise, numerous effectors / modulators of other molecular targets have been reported to impair NLRP3 activation including agonists of the G-protein coupled receptor TGR5, an inhibitor of sodium-glucose co-transport epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate nonsteroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol. Utility of these molecules as therapeutics for the chronic treatment of NLRP3-dependent inflammatory disorders remains to be established.

[0133] The invention relates to compositions, capsules, or formulations useful for the specific modulation of NLRP3-dependent cellular processes. In particular, compositions, capsules, or formulationsNOD-C-P3911PCT

[0134] comprising compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing NLRP3-modulating compounds are desired.

[0135] Definitions

[0136] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0137] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the invention intends to encompass operable embodiments having combinations of the options. The invention may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0138] It is to be understood that the compound of the present invention may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present invention. For example, when the compound of the present invention is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when the compound of the present invention is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound. In some embodiments, the amine of the compound of the present invention is protonated.

[0139] The terms “about” and “approximately” as used herein, are interchangeable, and should generally be understood to refer to a range of numbers around a given number, as well as to all numbers in a recited range of numbers (e.g., “about 5 to 15” means “about 5 to about 15” unless otherwise stated). Moreover, all numerical ranges herein should be understood to include each whole integer within the range. Unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.NOD-C-P3911PCT

[0140] When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ± 7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0141] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0142] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated those compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0143] As used herein, the term “pharmaceutical composition, capsule, or formulation” is a composition, capsule, or formulation containing the compound of the present invention in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition, capsule, or formulation is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a composition, capsule, or formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual,NOD-C-P3911PCT

[0144] intrapleural, intrathecal, intranasal, and the like. In one particular embodiment, the formulation will be delivered via the oral route. Dosage forms for the topical or transdermal administration of a composition, capsule, or formulation of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0145] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the exemplified ingredients in the exemplified amounts.

[0146] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0147] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0148] It is to be understood that a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.

[0149] It is to be understood that the present invention also provides compositions, capsules, or formulations comprising the compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.NOD-C-P3911PCT

[0150] As used herein, the composition, capsule, or fomulation comprising less than about 5% (e.g., less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, or less than about 0.5%) of a compound, reagent, or solvent is considered “substantially free.”

[0151] As used herein, the term “room temperature” can refer to a temperature of about 17 °C, about 18 °C, about 19°C, about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, or about 25 °C. In some embodiments, the room temperature is from about 20 °C to about 25 °C. In some embodiments, the room temperature is about 20 °C.

[0152] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Pharmaceutical compositions may be administered once or twice daily or every 2, 3 or 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0153] The pharmaceutical compositions, capsules, or formulations containing the active compound of the present invention may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes.

[0154] The active compound can be prepared with a pharmaceutically acceptable diluent, adjuvant, excipient, or carrier 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 will 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 infected cells with monoclonal antibodies to viral antigens) 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.

[0155] 4,522,811.NOD-C-P3911PCT

[0156] It may be advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0157] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0158] It is to be understood that, for the compound of the present invention being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed invention.

[0159] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compound of the present invention wherein the parent compound (e.g., Compound 1) is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0160] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathineNOD-C-P3911PCT

[0161] salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0162] The dosage regimen utilising the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.

[0163] Techniques for formulation and administration of the compound of the invention can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compound described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions, capsules, or formulations in amounts sufficient to provide the desired dosage amount in the range described herein.

[0164] A “therapeutically effective amount” or “effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” or “effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0165] It is to be understood that the compound of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCHNOD-C-P3911PCT

[0166] Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art.

[0167] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the composition, capsule, or formulation of the present invention to provide such treatment as is described herein, as well as use of the compound to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0168] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0169] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0170] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of the composition, capsule, or formulation of the present invention, to alleviate the symptoms orNOD-C-P3911PCT

[0171] complications of a disease, condition or disorder, orto eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0172] It is to be understood that the composition, capsule, or formulationof the present invention can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes.

[0173] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0174] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N. Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N. Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the invention.

[0175] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present invention are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present invention the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.

[0176] As used herein, the phrase “compound of the invention” or “compound of the present invention” refers to Compound 1 which is disclosed herein, both generically and specifically.

[0177] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of theNOD-C-P3911PCT

[0178] same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0179] Compositions

[0180] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0181] N O'

[0182] H

[0183]

[0184] (Compound 1),

[0185] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2- (((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1):

[0187] N

[0188] N O''

[0189] H

[0190]

[0191] (Compound 1).

[0192] It is understood that Compound 1 may be prepared as described in Example 101 in WO 2019 / 025467 (incorporated herein by reference).

[0193] It is also understood that Compound 1 may be prepared as described in WO 2024 / 074577 (incorporated herein by reference).

[0194] In some embodiments, Compound A is the active metabolite of Compound 1. Compound A has the following structure:NOD-C-P3911PCT

[0195]

[0196] In some embodiments, the present invention provides a composition comprising an NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), and one or more of a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0197] In some embodiments, the present invention provides a composition comprising an NLRP3 inhibitor (e.g., Compound 1), and one or more of a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0198] In some embodiments, the present invention provides a pharmaceutical composition comprising Compound 1.

[0199] In some embodiments, the present invention provides a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0200] In some embodiments, the present invention provides a pharmaceutical composition comprising Compound 1, and one or more of a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0201] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the present invention provides a composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1).

[0203] In some embodiments, the present invention provides a composition comprising:NOD-C-P3911PCT

[0204] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof; and

[0205] (ii) a non-ionic surfactant.

[0206] In some embodiments, the present invention provides a composition comprising:

[0207] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1); and

[0208] (ii) a non-ionic surfactant.

[0209] In some embodiments, the present invention provides a composition comprising:

[0210] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0211] (ii) a non-ionic surfactant; and

[0212] (iii) a co-surfactant and solubilizer.

[0213] In some embodiments, the present invention provides a composition comprising:

[0214] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0215] (ii) a non-ionic surfactant; and

[0216] (iii) a co-surfactant and solubilizer.

[0217] In some embodiments, the present invention provides a composition comprising:

[0218] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0219] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0220] (iii) a propylene glycol monolaurate; and

[0221] (iv) a hydroxypropyl methylcellulose (HPMC).

[0222] In some embodiments, the present invention provides a composition comprising:

[0223] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);NOD-C-P3911PCT

[0224] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0225] (iii) a propylene glycol monolaurate; and

[0226] (iv) a hydroxypropyl methylcellulose (HPMC).

[0227] In some embodiments, the present invention provides a composition comprising:

[0228] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0229] (ii) Gelucire 48 / 16;

[0230] (iii) Lauroglycol 90; and

[0231] (iv) Methocel K100 Premium.

[0232] In some embodiments, the present invention provides a composition comprising:

[0233] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0234] (ii) Gelucire 48 / 16;

[0235] (iii) Lauroglycol 90; and

[0236] (iv) Methocel K100 Premium.

[0237] In some embodiments, the present invention provides a composition comprising:

[0238] (i) an NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof;

[0239] (ii) a non-ionic surfactant;

[0240] (iii) a co-surfactant and solubilizer; and

[0241] (iv) a polymer.

[0242] In some embodiments, the present invention provides a composition comprising:

[0243] (i) an NLRP3 inhibitor;

[0244] (ii) a non-ionic surfactant;

[0245] (iii) a co-surfactant and solubilizer; and

[0246] (iv) a polymer.

[0247] In some embodiments, the present invention provides a composition comprising:NOD-C-P3911PCT

[0248] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0249] (ii) a non-ionic surfactant;

[0250] (iii) a co-surfactant and solubilizer; and

[0251] (iv) a polymer.

[0252] In some embodiments, the present invention provides a composition comprising:

[0253] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0254] (ii) a non-ionic surfactant;

[0255] (iii) a co-surfactant and solubilizer; and

[0256] (iv) a polymer.

[0257] In some embodiments, the present invention provides a composition comprising:

[0258] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0259] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0260] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0261] In some embodiments, the present invention provides a composition comprising:

[0262] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0263] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0264] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0265] In some embodiments, the present invention provides a composition comprising:

[0266] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0267] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;NOD-C-P3911PCT

[0268] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0269] In some embodiments, the present invention provides a composition comprising:

[0270] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0271] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0272] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0273] In some embodiments, the present invention provides a composition comprising:

[0274] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0275] (ii) about 37.1% w / w of a non-ionic surfactant;

[0276] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0277] (iv) about 5.8% w / w of a polymer.

[0278] In some embodiments, the present invention provides a composition comprising:

[0279] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0280] (ii) about 37.1% w / w of a non-ionic surfactant;

[0281] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0282] (iv) about 5.8% w / w of a polymer.

[0283] In some embodiments, the present invention provides a composition comprising:

[0284] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0285] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0286] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).NOD-C-P3911PCT

[0287] In some embodiments, the present invention provides a composition comprising:

[0288] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0289] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0290] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0291] In some embodiments, the present invention provides a composition comprising:

[0292] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0293] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0294] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0295] In some embodiments, the present invention provides a composition comprising:

[0296] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0297] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0298] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0299] In some embodiments, the present invention provides a composition comprising:

[0300] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0301] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0302] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0303] In some embodiments, the present invention provides a composition comprising:NOD-C-P3911PCT

[0304] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0305] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0306] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0307] In some embodiments, the present invention provides a composition comprising:

[0308] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0309] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0310] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0311] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0312] In some embodiments, the present invention provides a composition comprising:

[0313] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0314] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0315] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0316] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0317] In some embodiments, the present invention provides a composition comprising:

[0318] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0319] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0320] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0321] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0322] In some embodiments, the present invention provides a composition comprising:

[0323] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0324] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0325] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; andNOD-C-P3911PCT

[0326] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0327] In some embodiments, the present invention provides a composition comprising:

[0328] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0329] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0330] (iii) about 37.1% w / w of Lauroglycol 90; and

[0331] (iv) about 5.8% w / w of Methocel K100 Premium.

[0332] In some embodiments, the present invention provides a composition comprising:

[0333] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0334] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0335] (iii) about 37.1% w / w of Lauroglycol 90; and

[0336] (iv) about 5.8% w / w of Methocel K100 Premium.

[0337] In some embodiments, the present invention provides a suspension composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the present invention provides a suspension composition comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1).

[0339] In some embodiments, the present invention provides a suspension composition comprising:

[0340] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof; and

[0341] (ii) a non-ionic surfactant.

[0342] In some embodiments, the present invention provides a suspension composition comprising:

[0343] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1); andNOD-C-P3911PCT

[0344] (ii) a non-ionic surfactant.

[0345] In some embodiments, the present invention provides a suspension composition comprising:

[0346] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0347] (ii) a non-ionic surfactant; and

[0348] (iii) a co-surfactant and solubilizer.

[0349] In some embodiments, the present invention provides a suspension composition comprising:

[0350] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0351] (ii) a non-ionic surfactant; and

[0352] (iii) a co-surfactant and solubilizer.

[0353] In some embodiments, the present invention provides a suspension composition comprising:

[0354] (i) an NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof;

[0355] (ii) a non-ionic surfactant;

[0356] (iii) a co-surfactant and solubilizer; and

[0357] (iv) a polymer.

[0358] In some embodiments, the present invention provides a suspension composition comprising:

[0359] (i) an NLRP3 inhibitor;

[0360] (ii) a non-ionic surfactant;

[0361] (iii) a co-surfactant and solubilizer; and

[0362] (iv) a polymer.

[0363] In some embodiments, the present invention provides a suspension composition comprising:

[0364] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0365] (ii) a non-ionic surfactant;

[0366] (iii) a co-surfactant and solubilizer; and

[0367] (iv) a polymer.NOD-C-P3911PCT

[0368] In some embodiments, the present invention provides a suspension composition comprising:

[0369] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0370] (ii) a non-ionic surfactant;

[0371] (iii) a co-surfactant and solubilizer; and

[0372] (iv) a polymer.

[0373] In some embodiments, the present invention provides a suspension composition comprising:

[0374] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0375] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0376] (iii) a propylene glycol monolaurate; and

[0377] (iv) a hydroxypropyl methylcellulose (HPMC).

[0378] In some embodiments, the present invention provides a suspension composition comprising:

[0379] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0380] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0381] (iii) a propylene glycol monolaurate; and

[0382] (iv) a hydroxypropyl methylcellulose (HPMC).

[0383] In some embodiments, the present invention provides a suspension composition comprising:

[0384] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0385] (ii) Gelucire 48 / 16;

[0386] (iii) Lauroglycol 90; and

[0387] (iv) Methocel K100 Premium.

[0388] In some embodiments, the present invention provides a suspension composition comprising:

[0389] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);NOD-C-P3911PCT

[0390] (ii) Gelucire 48 / 16;

[0391] (iii) Lauroglycol 90; and

[0392] (iv) Methocel K100 Premium.

[0393] In some embodiments, the present invention provides a suspension composition comprising:

[0394] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0395] (ii) a non-ionic surfactant;

[0396] (iii) a co-surfactant and solubilizer; and

[0397] (iv) a polymer.

[0398] In some embodiments, the present invention provides a suspension composition comprising:

[0399] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0400] (ii) a non-ionic surfactant;

[0401] (iii) a co-surfactant and solubilizer; and

[0402] (iv) a polymer.

[0403] In some embodiments, the present invention provides a suspension composition comprising:

[0404] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0405] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0406] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0407] In some embodiments, the present invention provides a suspension composition comprising:

[0408] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0409] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0410] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.NOD-C-P3911PCT

[0411] In some embodiments, the present invention provides a suspension composition comprising:

[0412] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0413] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0414] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0415] In some embodiments, the present invention provides a suspension composition comprising:

[0416] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0417] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0418] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0419] In some embodiments, the present invention provides a suspension composition comprising:

[0420] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0421] (ii) about 37.1% w / w of a non-ionic surfactant;

[0422] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0423] (iv) about 5.8% w / w of a polymer.

[0424] In some embodiments, the present invention provides a suspension composition comprising:

[0425] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0426] (ii) about 37.1% w / w of a non-ionic surfactant;

[0427] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0428] (iv) about 5.8% w / w of a polymer.

[0429] In some embodiments, the present invention provides a suspension composition comprising:

[0430] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;NOD-C-P3911PCT

[0431] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0432] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0433] In some embodiments, the present invention provides a suspension composition comprising:

[0434] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0435] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0436] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0437] In some embodiments, the present invention provides a suspension composition comprising:

[0438] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0439] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0440] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0441] In some embodiments, the present invention provides a suspension composition comprising:

[0442] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0443] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0444] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0445] In some embodiments, the present invention provides a suspension composition comprising:

[0446] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;NOD-C-P3911PCT

[0447] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0448] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0449] In some embodiments, the present invention provides a suspension composition comprising:

[0450] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0451] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0452] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0453] In some embodiments, the present invention provides a suspension composition comprising:

[0454] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0455] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0456] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0457] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0458] In some embodiments, the present invention provides a suspension composition comprising:

[0459] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0460] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0461] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0462] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0463] In some embodiments, the present invention provides a suspension composition comprising:

[0464] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0465] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0466] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0467] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.NOD-C-P3911PCT

[0468] In some embodiments, the present invention provides a suspension composition comprising:

[0469] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0470] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0471] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0472] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0473] In some embodiments, the present invention provides a suspension composition comprising:

[0474] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0475] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0476] (iii) about 37.1% w / w of Lauroglycol 90; and

[0477] (iv) about 5.8% w / w of Methocel K100 Premium.

[0478] In some embodiments, the present invention provides a suspension composition comprising:

[0479] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0480] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0481] (iii) about 37.1% w / w of Lauroglycol 90; and

[0482] (iv) about 5.8% w / w of Methocel K100 Premium.

[0483] In some embodiments, the present invention provides a capsule comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the present invention provides a capsule comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1).

[0485] In some embodiments, the present invention provides a capsule comprising:

[0486] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof; andNOD-C-P3911PCT

[0487] (ii) a non-ionic surfactant.

[0488] In some embodiments, the present invention provides a capsule comprising:

[0489] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1); and

[0490] (ii) a non-ionic surfactant.

[0491] In some embodiments, the present invention provides a capsule comprising:

[0492] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0493] (ii) a non-ionic surfactant; and

[0494] (iii) a co-surfactant and solubilizer.

[0495] In some embodiments, the present invention provides a capsule comprising:

[0496] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0497] (ii) a non-ionic surfactant; and

[0498] (iii) a co-surfactant and solubilizer.

[0499] In some embodiments, the present invention provides a capsule comprising:

[0500] (i) an NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof;

[0501] (ii) a non-ionic surfactant;

[0502] (iii) a co-surfactant and solubilizer; and

[0503] (iv) a polymer.

[0504] In some embodiments, the present invention provides a capsule comprising:

[0505] (i) an NLRP3 inhibitor;

[0506] (ii) a non-ionic surfactant;

[0507] (iii) a co-surfactant and solubilizer; and

[0508] (iv) a polymer.

[0509] In some embodiments, the present invention provides a capsule comprising:NOD-C-P3911PCT

[0510] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0511] (ii) a non-ionic surfactant;

[0512] (iii) a co-surfactant and solubilizer; and

[0513] (iv) a polymer.

[0514] In some embodiments, the present invention provides a capsule comprising:

[0515] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0516] (ii) a non-ionic surfactant;

[0517] (iii) a co-surfactant and solubilizer; and

[0518] (iv) a polymer.

[0519] In some embodiments, the present invention provides a capsule comprising:

[0520] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0521] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0522] (iii) a propylene glycol monolaurate; and

[0523] (iv) a hydroxypropyl methylcellulose (HPMC).

[0524] In some embodiments, the present invention provides a capsule comprising:

[0525] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0526] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0527] (iii) a propylene glycol monolaurate; and

[0528] (iv) a hydroxypropyl methylcellulose (HPMC).

[0529] In some embodiments, the present invention provides a capsule comprising:

[0530] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0531] (ii) Gelucire 48 / 16;NOD-C-P3911PCT

[0532] (iii) Lauroglycol 90; and

[0533] (iv) Methocel K100 Premium.

[0534] In some embodiments, the present invention provides a capsule comprising:

[0535] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0536] (ii) Gelucire 48 / 16;

[0537] (iii) Lauroglycol 90; and

[0538] (iv) Methocel K100 Premium.

[0539] In some embodiments, the present invention provides a capsule comprising:

[0540] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0541] (ii) a non-ionic surfactant;

[0542] (iii) a co-surfactant and solubilizer; and

[0543] (iv) a polymer.

[0544] In some embodiments, the present invention provides a capsule comprising:

[0545] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0546] (ii) a non-ionic surfactant;

[0547] (iii) a co-surfactant and solubilizer; and

[0548] (iv) a polymer.

[0549] In some embodiments, the present invention provides a capsule comprising:

[0550] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0551] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0552] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0553] In some embodiments, the present invention provides a capsule comprising:NOD-C-P3911PCT

[0554] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0555] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0556] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0557] In some embodiments, the present invention provides a capsule comprising:

[0558] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0559] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0560] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0561] In some embodiments, the present invention provides a capsule comprising:

[0562] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0563] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0564] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0565] In some embodiments, the present invention provides a capsule comprising:

[0566] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0567] (ii) about 37.1% w / w of a non-ionic surfactant;

[0568] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0569] (iv) about 5.8% w / w of a polymer.

[0570] In some embodiments, the present invention provides a capsule comprising:

[0571] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0572] (ii) about 37.1% w / w of a non-ionic surfactant;

[0573] (iii) about 37.1% w / w of a co-surfactant and solubilizer; andNOD-C-P3911PCT

[0574] (iv) about 5.8% w / w of a polymer.

[0575] In some embodiments, the present invention provides a capsule comprising:

[0576] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0577] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0578] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0579] In some embodiments, the present invention provides a capsule comprising:

[0580] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0581] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0582] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0583] In some embodiments, the present invention provides a capsule comprising:

[0584] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0585] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0586] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0587] In some embodiments, the present invention provides a capsule comprising:

[0588] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0589] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0590] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; andNOD-C-P3911PCT

[0591] (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0592] In some embodiments, the present invention provides a capsule comprising:

[0593] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0594] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0595] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0596] In some embodiments, the present invention provides a capsule comprising:

[0597] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0598] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0599] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0600] In some embodiments, the present invention provides a capsule comprising:

[0601] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0602] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0603] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0604] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0605] In some embodiments, the present invention provides a capsule comprising:

[0606] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0607] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0608] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0609] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0610] In some embodiments, the present invention provides a capsule comprising:NOD-C-P3911PCT

[0611] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0612] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0613] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0614] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0615] In some embodiments, the present invention provides a capsule comprising:

[0616] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0617] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0618] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0619] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0620] In some embodiments, the present invention provides a capsule comprising:

[0621] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0622] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0623] (iii) about 37.1% w / w of Lauroglycol 90; and

[0624] (iv) about 5.8% w / w of Methocel K100 Premium.

[0625] In some embodiments, the present invention provides a capsule comprising:

[0626] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0627] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0628] (iii) about 37.1% w / w of Lauroglycol 90; and

[0629] (iv) about 5.8% w / w of Methocel K100 Premium.

[0630] In some embodiments, the capsule is liquid filled.

[0631] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C.NOD-C-P3911PCT

[0632] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C for about 1 day, 2 days, 3 days, or 4 days.

[0633] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C for about 3 days.

[0634] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C followed by cooling to a temperature from about 17 °C to about 25 °C.

[0635] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C followed by naturally cooling to a temperature from about 17 °C to about 25 °C in capsule without a cooling jacket.

[0636] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C followed by cooling to a temperature from about 20 °C to about 25 °C.

[0637] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C followed by naturally cooling to a temperature from about 20 °C to about 25 °C in capsule without a cooling jacket.

[0638] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C followed by cooling to about room temperature.

[0639] In some embodiments, the capsule is liquid filled and solidified after heating at about 50 °C for about 3 days followed by naturally cooling to about room temperature in capsule without a cooling jacket.

[0640] In some embodiments, the present invention provides a pharmaceutical formulation comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof.

[0641] In some embodiments, the present invention provides a pharmaceutical formulation comprising isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1).NOD-C-P3911PCT

[0642] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0643] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof; and

[0644] (ii) a non-ionic surfactant.

[0645] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0646] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1); and

[0647] (ii) a non-ionic surfactant.

[0648] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0649] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0650] (ii) a non-ionic surfactant; and

[0651] (iii) a co-surfactant and solubilizer.

[0652] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0653] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0654] (ii) a non-ionic surfactant; and

[0655] (iii) a co-surfactant and solubilizer.

[0656] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0657] (i) an NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof;

[0658] (ii) a non-ionic surfactant;

[0659] (iii) a co-surfactant and solubilizer; and

[0660] (iv) a polymer.

[0661] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0662] (i) an NLRP3 inhibitor;

[0663] (ii) a non-ionic surfactant;NOD-C-P3911PCT

[0664] (iii) a co-surfactant and solubilizer; and

[0665] (iv) a polymer.

[0666] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0667] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0668] (ii) a non-ionic surfactant;

[0669] (iii) a co-surfactant and solubilizer; and

[0670] (iv) a polymer.

[0671] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0672] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0673] (ii) a non-ionic surfactant;

[0674] (iii) a co-surfactant and solubilizer; and

[0675] (iv) a polymer.

[0676] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0677] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0678] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0679] (iii) a propylene glycol monolaurate; and

[0680] (iv) a hydroxypropyl methylcellulose (HPMC).

[0681] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0682] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0683] (ii) a glycerol or polyethylene glycol ester of fatty acids;

[0684] (iii) a propylene glycol monolaurate; and

[0685] (iv) a hydroxypropyl methylcellulose (HPMC).

[0686] In some embodiments, the present invention provides a pharmaceutical formulation comprising:NOD-C-P3911PCT

[0687] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0688] (ii) Gelucire 48 / 16;

[0689] (iii) Lauroglycol 90; and

[0690] (iv) Methocel K100 Premium.

[0691] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0692] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0693] (ii) Gelucire 48 / 16;

[0694] (iii) Lauroglycol 90; and

[0695] (iv) Methocel K100 Premium.

[0696] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0697] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0698] (ii) a non-ionic surfactant;

[0699] (iii) a co-surfactant and solubilizer; and

[0700] (iv) a polymer.

[0701] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0702] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0703] (ii) a non-ionic surfactant;

[0704] (iii) a co-surfactant and solubilizer; and

[0705] (iv) a polymer.

[0706] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0707] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0708] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;NOD-C-P3911PCT

[0709] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0710] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0711] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0712] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0713] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0714] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0715] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0716] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0717] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0718] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0719] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0720] (ii) about 35% w / w to about 40% w / w of a non-ionic surfactant;

[0721] (iii) about 35% w / w to about 40% w / w of a co-surfactant and solubilizer; and (iv) about 2% w / w to about 10% w / w of a polymer.

[0722] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0723] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0724] (ii) about 37.1% w / w of a non-ionic surfactant;

[0725] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0726] (iv) about 5.8% w / w of a polymer.

[0727] In some embodiments, the present invention provides a pharmaceutical formulation comprising:NOD-C-P3911PCT

[0728] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0729] (ii) about 37.1% w / w of a non-ionic surfactant;

[0730] (iii) about 37.1% w / w of a co-surfactant and solubilizer; and

[0731] (iv) about 5.8% w / w of a polymer.

[0732] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0733] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0734] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0735] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0736] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0737] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0738] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0739] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0740] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0741] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0742] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0743] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0744] In some embodiments, the present invention provides a pharmaceutical formulation comprising:NOD-C-P3911PCT

[0745] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0746] (ii) about 35% w / w to about 40% w / w of a glycerol or polyethylene glycol ester of fatty acids;

[0747] (iii) about 35% w / w to about 40% w / w of a propylene glycol monolaurate; and (iv) about 2% w / w to about 10% w / w of a hydroxypropyl methylcellulose (HPMC).

[0748] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0749] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0750] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0751] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0752] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0753] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0754] (ii) about 37.1% w / w of a glycerol or polyethylene glycol ester of fatty acids; (iii) about 37.1% w / w of a propylene glycol monolaurate; and

[0755] (iv) about 5.8% w / w of a hydroxypropyl methylcellulose (HPMC).

[0756] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0757] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0758] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0759] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0760] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0761] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0762] (i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1);

[0763] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;NOD-C-P3911PCT

[0764] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0765] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0766] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0767] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0768] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0769] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0770] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0771] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0772] (i) about 15% w / w to about 25% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0773] (ii) about 35% w / w to about 40% w / w of Gelucire 48 / 16;

[0774] (iii) about 35% w / w to about 40% w / w of Lauroglycol 90; and

[0775] (iv) about 2% w / w to about 10% w / w of Methocel K100 Premium.

[0776] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0777] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;

[0778] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0779] (iii) about 37.1% w / w of Lauroglycol 90; and

[0780] (iv) about 5.8% w / w of Methocel K100 Premium.

[0781] In some embodiments, the present invention provides a pharmaceutical formulation comprising:

[0782] (i) about 20% w / w isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoate (Compound 1);

[0783] (ii) about 37.1% w / w of Gelucire 48 / 16;

[0784] (iii) about 37.1% w / w of Lauroglycol 90; and

[0785] (iv) about 5.8% w / w of Methocel K100 Premium.

[0786] In some embodiments, the composition, capsule, or formulation comprises a surfactant.NOD-C-P3911PCT

[0787] In some embodiments, the co-surfactant is a non-ionic surfactant.

[0788] Non-ionic surfactants include, but are not limited to, surfactants that have polar head groups that are not electrically charged. Exemplary non-ionic surfactants include alkylphenyl ethers of poly(ethylene glycol), alkylethers of poly(ethylene glycol), alkylethers of poly(propylene glycol), alkylethers of glycerol, ethanolamine derivatives, and the like. In some embodiments, the non-ionic surfactants include lauroyl macrogol-32 glyceride (Gelucire® 44 / 14), PEG-32 mono- and diesters of stearic and palmitic acids (Gelucire® 48 / 16), and stearoyl macrogol glyceride (Gelucire® 50 / 13).

[0789] In some embodiments, the non-ionic surfactant is a glycerol or polyethylene glycol ester of fatty acids.

[0790] In some embodiments, the non-ionic surfactant is Gelucire® 48 / 16.

[0791] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 3:1, about 2:1, about 1:1, about 1:2, or about 1:3.

[0792] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 3:1.

[0793] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 2:1.

[0794] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.

[0795] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.1. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.2. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.3. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.4. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.5. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.6. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.7. In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.9.NOD-C-P3911PCT

[0796] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1.8.

[0797] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:2.

[0798] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:3.

[0799] In some embodiments, the compound to the non-ionic surfactant weight ratio is about 1:1 or about 1:2.

[0800] In some embodiments, the non-ionic surfactant is present in an amount from about 15% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 20% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 25% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 30% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 35% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 40% w / w to about 50% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 45% w / w to about 50% w / w.

[0801] In some embodiments, the non-ionic surfactant is present in an amount from about 15% w / w to about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 20% w / w to about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 25% w / w to about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 30% w / w to about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 35% w / w to about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 40% w / w to about 45% w / w.

[0802] In some embodiments, the non-ionic surfactant is present in an amount from about 15% w / w to about 40% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 20% w / w to about 40% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 25% w / w to about 40% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 30% w / w to about 40% w / w. In some embodiments, the non-ionic surfactant is present in an amount from about 35% w / w to about 40% w / w.NOD-C-P3911PCT

[0803] In some embodiments, the non-ionic surfactant is present in an amount of about 15% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 20% w / w.

[0804] In some embodiments, the non-ionic surfactant is present in an amount of about 25% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 30% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 35% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 40% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 45% w / w. In some embodiments, the non-ionic surfactant is present in an amount of about 50% w / w.

[0805] In some embodiments, the non-ionic surfactant is present in an amount of about 37.1% w / w.

[0806] In some embodiments, the composition, capsule, or formulation comprises a co-surfactant.

[0807] In some embodiments, the composition, capsule, or formulation comprises a solubilizer.

[0808] In some embodiments, the composition, capsule, or formulation comprises a co-surfactant and solubilizer.

[0809] In some embodiments, the co-surfactant and solubilizer are the same reagent.

[0810] In some embodiments, the cosurfactant Is selected from Capryol 90 (propylene glycol monocaprylate). Lauroglycol™ 90 (propylene glycol monolaurate), CAPTEX™ 200 (propylene glycol dicaprylate / dicaprate), Miglyol™ 840 (propylene glycol dicaprylate / dicaprate), Labrafac™ lipophile WL 1349 (medium-chain triglycerides of caprylic (C₈) and capric (C₁₀) acids), and Span™ 80 (sorbitan monooleate).

[0811] In some embodiments, the composition, capsule, or formulation comprises a solubilizer.

[0812] In some embodiments, the solubilizer is selected from oleic acid, Kolliphor® EL (polyoxyl castor oil or Cremophor EL), Vitamin E TPGS (D-α-tocopherol polyethylene glycol-1000 succinate), Savie (a polysarcosine-derived emulsifying agent). Maisine® CC (glyceryl monolinoleate), Gelucire® 44 / 14 (lauroyl polyoxyl-32 glycerides), Miglyol® 812 (esters ofNOD-C-P3911PCT

[0813] saturated coconut and palm kernel oil-derived caprylic fatty acids and glycerin), Plurol® Oleique (Polyglyceryl~6 Dioleate), Lauroglycol™ 90 (propylene glycol monolaurate (type II), Labrasol® (Caprylocaproyl polyoxyl-8 glycerides), Captisol® (SBE-beta-cyclodextrin), Encapsin™ HPB (hydroxypropylbeta-cyclodextrin), Peceol™ (glycerol / glyceryl monooleate (type 40)), sodium deoxycholate, deoxycholic acid, Labrafil® M2125CS (linoleoyl Polyoxyl-6 glycerides) and medium-chain mono- and diglycerides.

[0814] In some embodiments, the co-surfactant and solubilizer is a propylene glycol monolaurate.

[0815] In some embodiments, the co-surfactant and solubilizer is Lauroglycol™ 90.

[0816] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 3:1, about 2:1, about 1:1, about 1:2, or about 1:3.

[0817] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 3:1. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 2:1.

[0818] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.

[0819] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.1. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.2. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.3. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.4. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.5. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.6. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.7. In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.9.

[0820] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1.8.

[0821] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:2.

[0822] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:3.NOD-C-P3911PCT

[0823] In some embodiments, the compound to co-surfactant and solubilizer weight ratio is about 1:1 or about 1:2.

[0824] In some embodiments, the co-surfactant and solubilizer is present in an amount from about 15% w / w to about 50% w / w.

[0825] In some embodiments, the co-surfactant and solubilizer is present in an amount from about 20% w / w to about 50% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 25% w / w to about 50% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 30% w / w to about 50% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 35% w / w to about 50% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 40% w / w to about 50% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 45% w / w to about 50% w / w.

[0826] In some embodiments, the co-surfactant and solubilizer is present in an amount from about 15% w / w to about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 20% w / w to about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 25% w / w to about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 30% w / w to about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 35% w / w to about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 40% w / w to about 45% w / w.

[0827] In some embodiments, the co-surfactant and solubilizer is present in an amount from about 15% w / w to about 40% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 20% w / w to about 40% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 25% w / w to about 40% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 30% w / w to about 40% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount from about 35% w / w to about 40% w / w.

[0828] In some embodiments, the co-surfactant and solubilizer is present in an amount of about 15% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of aboutNOD-C-P3911PCT

[0829] 20% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 25% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 30% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 35% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 40% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 45% w / w. In some embodiments, the co-surfactant and solubilizer is present in an amount of about 50% w / w.

[0830] In some embodiments, the co-surfactant and solubilizer is present in an amount of about 37.1 % w / w

[0831] In some embodiments, the composition, capsule, or formulation comprises a polymer.

[0832] In some embodiments, the composition, capsule, or formulation comprises a polymer selected from the group comprising, but not limited to, hydroxypropyl methylcellulose (BENECEL™ K4M PH DC), hydroxypropyl methylcellulose (METHOCEL™ K100 Premium), a polyethylene oxide polymer, a carbomer, and sodium alginate, or mixtures thereof.

[0833] In some embodiments, the polymer is a hydroxypropyl methylcellulose (HPMC).

[0834] In some embodiments, HPMC is utilised for its rheology (e.g., viscosity) control properties.

[0835] In some embodiments, the polymer is Methocel™ K100 Premium.

[0836] In some embodiments, the compound to polymer weight ratio is about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, or about 1:7.

[0837] In some embodiments, the compound to polymer weight ratio is about 3:1. In some embodiments, the compound to polymer weight ratio is about 2:1. In some embodiments, the compound to polymer weight ratio is about 1:1. In some embodiments, the compound to polymer weight ratio is about 1:2. In some embodiments, the compound to polymer weight ratio is about 1:3. In some embodiments, the compound to polymer weight ratio is about 1:4. In some embodiments, the compound to polymer weight ratio is about 1:5. In some embodiments, the compound to polymerNOD-C-P3911PCT

[0838] weight ratio is about 1:6. In some embodiments, the compound to polymer weight ratio is about 1:7.

[0839] In some embodiments, the compound to polymer weight ratio is about 1:3.1. In some embodiments, the compound to polymer weight ratio is about 1:3.2. In some embodiments, the compound to polymer weight ratio is about 1:3.3. In some embodiments, the compound to polymer weight ratio is about 1:3.5. In some embodiments, the compound to polymer weight ratio is about 1:3.6. In some embodiments, the compound to polymer weight ratio is about 1:3.7. In some embodiments, the compound to polymer weight ratio is about 1:3.8. In some embodiments, the compound to polymer weight ratio is about 1:3.9.

[0840] In some embodiments, the compound to polymer weight ratio is about 1:3.4.

[0841] In some embodiments, the compound to polymer weight ratio is about 1:3 or about 1:4.

[0842] In some embodiments, the polymer is present in an amount from about 1% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 1% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 1% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 1% w / w to about 10% w / w.

[0843] In some embodiments, the polymer is present in an amount from about 1.5% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 1.5% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 1.5% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 1.5% w / w to about 10% w / w.

[0844] In some embodiments, the polymer is present in an amount from about 2% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 2% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 2% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 2% w / w to about 10% w / w.NOD-C-P3911PCT

[0845] In some embodiments, the polymer is present in an amount from about 3% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 3% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 3% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 3% w / w to about 10% w / w.

[0846] In some embodiments, the polymer is present in an amount from about 4% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 4% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 4% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 4% w / w to about 10% w / w.

[0847] In some embodiments, the polymer is present in an amount from about 5% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 5% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 5% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 5% w / w to about 10% w / w.

[0848] In some embodiments, the polymer is present in an amount from about 6% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 6% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 6% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 6% w / w to about 10% w / w.

[0849] In some embodiments, the polymer is present in an amount from about 7% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 7% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 7% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 7% w / w to about 10% w / w.

[0850] In some embodiments, the polymer is present in an amount from about 8% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 8% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 8% w / w toNOD-C-P3911PCT

[0851] about 15% w / w. In some embodiments, the polymer is present in an amount from about 8% w / w to about 10% w / w.

[0852] In some embodiments, the polymer is present in an amount from about 9% w / w to about 25% w / w. In some embodiments, the polymer is present in an amount from about 9% w / w to about 20% w / w. In some embodiments, the polymer is present in an amount from about 9% w / w to about 15% w / w. In some embodiments, the polymer is present in an amount from about 9% w / w to about 10% w / w.

[0853] In some embodiments, the polymer is present in an amount of about 1% w / w. In some embodiments, the polymer is present in an amount of about 1.5% w / w. In some embodiments, the polymer is present in an amount of about 2% w / w. In some embodiments, the polymer is present in an amount of about 2.5% w / w. In some embodiments, the polymer is present in an amount of about 3% w / w. In some embodiments, the polymer is present in an amount of about 3.5% w / w. In some embodiments, the polymer is present in an amount of about 4% w / w. In some embodiments, the polymer is present in an amount of about 4.5% w / w. In some embodiments, the polymer is present in an amount of about 5% w / w. In some embodiments, the polymer is present in an amount of about 5.5% w / w. In some embodiments, the polymer is present in an amount of about 6% w / w. In some embodiments, the polymer is present in an amount of about 6.5% w / w. In some embodiments, the polymer is present in an amount of about 7% w / w. In some embodiments, the polymer is present in an amount of about 7.5% w / w. In some embodiments, the polymer is present in an amount of about 8% w / w. In some embodiments, the polymer is present in an amount of about 8.5% w / w. In some embodiments, the polymer is present in an amount of about 9% w / w. In some embodiments, the polymer is present in an amount of about 9.5% w / w. In some embodiments, the polymer is present in an amount of about 10% w / w.

[0854] In some embodiments, the polymer is present in an amount of about 5.8% w / w.

[0855] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 40% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 40% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 15% w / w to about 40% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 20% w / w to about 40% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 25% w / w to about 40% w / w. In some embodiments, the NLRP3NOD-C-P3911PCT

[0856] inhibitor is present in an amount from about 30% w / w to about 40% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 35% w / w to about 40% w / w.

[0857] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 35% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 35% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 15% w / w to about 35% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 20% w / w to about 35% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 25% w / w to about 35% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 30% w / w to about 35% w / w.

[0858] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 30% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 30% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 15% w / w to about 30% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 20% w / w to about 30% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 25% w / w to about 30% w / w.

[0859] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 25% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 25% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 15% w / w to about 25% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 20% w / w to about 25% w / w.

[0860] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 20% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 20% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 15% w / w to about 20% w / w.

[0861] In some embodiments, the NLRP3 inhibitor is present in an amount from about 5% w / w to about 15% w / w. In some embodiments, the NLRP3 inhibitor is present in an amount from about 10% w / w to about 15% w / w.

[0862] In some embodiments, the NLRP3 inhibitor is present in an amount of about 5% w / w.NOD-C-P3911PCT

[0863] In some embodiments, the NLRP3 inhibitor is present in an amount of about 10% w / w.

[0864] In some embodiments, the NLRP3 inhibitor is present in an amount of about 15% w / w.

[0865] In some embodiments, the NLRP3 inhibitor is present in an amount of about 16% w / w.

[0866] In some embodiments, the NLRP3 inhibitor is present in an amount of about 17% w / w.

[0867] In some embodiments, the NLRP3 inhibitor is present in an amount of about 18% w / w.

[0868] In some embodiments, the NLRP3 inhibitor is present in an amount of about 19% w / w.

[0869] In some embodiments, the NLRP3 inhibitor is present in an amount of about 20% w / w.

[0870] In some embodiments, the NLRP3 inhibitor is present in an amount of about 21 % w / w.

[0871] In some embodiments, the NLRP3 inhibitor is present in an amount of about 22% w / w.

[0872] In some embodiments, the NLRP3 inhibitor is present in an amount of about 23% w / w.

[0873] In some embodiments, the NLRP3 inhibitor is present in an amount of about 24% w / w.

[0874] In some embodiments, the NLRP3 inhibitor is present in an amount of about 25% w / w.

[0875] In some embodiments, the NLRP3 inhibitor is present in an amount of about 30% w / w.

[0876] In some embodiments, the NLRP3 inhibitor is present in an amount of about 35% w / w.

[0877] In some embodiments, the NLRP3 inhibitor is present in an amount of about 40% w / w.

[0878] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 15% w / w toNOD-C-P3911PCT

[0879] about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 20% w / w to about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 25% w / w to about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 30% w / w to about 40% w / w. In some embodiments, Compound 1 is present in an amount from about 35% w / w to about 40% w / w.

[0880] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 35% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 35% w / w. In some embodiments, Compound 1 is present in an amount from about 15% w / w to about 35% w / w. In some embodiments, Compound 1 is present in an amount from about 20% w / w to about 35% w / w. In some embodiments, Compound 1 is present in an amount from about 25% w / w to about 35% w / w. In some embodiments, Compound 1 is present in an amount from about 30% w / w to about 35% w / w.

[0881] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 30% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 30% w / w. In some embodiments, Compound 1 is present in an amount from about 15% w / w to about 30% w / w. In some embodiments, Compound 1 is present in an amount from about 20% w / w to about 30% w / w. In some embodiments, Compound 1 is present in an amount from about 25% w / w to about 30% w / w.

[0882] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 25% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 25% w / w. In some embodiments, Compound 1 is present in an amount from about 15% w / w to about 25% w / w. In some embodiments, Compound 1 is present in an amount from about 20% w / w to about 25% w / w.

[0883] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 20% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 20% w / w. In some embodiments, Compound 1 is present in an amount from about 15% w / w to about 20% w / w.NOD-C-P3911PCT

[0884] In some embodiments, Compound 1 is present in an amount from about 5% w / w to about 15% w / w. In some embodiments, Compound 1 is present in an amount from about 10% w / w to about 15% w / w.

[0885] In some embodiments, Compound 1 is present in an amount of about 5% w / w.

[0886] In some embodiments, Compound 1 is present in an amount of about 10% w / w.

[0887] In some embodiments, Compound 1 is present in an amount of about 15% w / w.

[0888] In some embodiments, Compound 1 is present in an amount of about 16% w / w.

[0889] In some embodiments, Compound 1 is present in an amount of about 17% w / w.

[0890] In some embodiments, Compound 1 is present in an amount of about 18% w / w.

[0891] In some embodiments, Compound 1 is present in an amount of about 19% w / w.

[0892] In some embodiments, Compound 1 is present in an amount of about 20% w / w.

[0893] In some embodiments, Compound 1 is present in an amount of about 21% w / w.

[0894] In some embodiments, Compound 1 is present in an amount of about 22% w / w.

[0895] In some embodiments, Compound 1 is present in an amount of about 23% w / w.

[0896] In some embodiments, Compound 1 is present in an amount of about 24% w / w.

[0897] In some embodiments, Compound 1 is present in an amount of about 25% w / w.

[0898] In some embodiments, Compound 1 is present in an amount of about 30% w / w.

[0899] In some embodiments, Compound 1 is present in an amount of about 35% w / w.NOD-C-P3911PCT

[0900] In some embodiments, Compound 1 is present in an amount of about 40% w / w.

[0901] In some embodiments, the formulation is a suspension formulation.

[0902] In some embodiments, the formulation is a suspension capsule formulation.

[0903] In some embodiments, the suspension capsule formulation delivers to the subject a higher unit dose of Compound 1, or a pharmaceutically acceptable salt thereof than a standard solution filled capsule.

[0904] In some embodiments, the suspension capsule formulation delivers to the subject a higher unit dose of Compound 1 than a standard solution filled capsule.

[0905] In some embodiments, the suspension capsule formulation results in enhancement of stability (e.g., evaluated through assay and related substances analysis after storing at specific conditions for a certain amount of time) of Compound 1, or a pharmaceutically acceptable salt thereof, compared to stability of Compound 1, or a pharmaceutically acceptable salt thereof, when dissolved in solution.

[0906] In some embodiments, the suspension capsule formulation results in enhancement of stability (e.g., evaluated through assay and related substances analysis after storing at specific conditions for a certain amount of time) of Compound 1 compared to stability of Compound 1 when dissolved in solution.

[0907] In some emobdiments, the enhancement of stability of the suspension capsule formulation results in improved shelf-life.

[0908] In some emobdiments, the enhancement of stability of the suspension capsule formulation results in improved formulation integrity. In some emobdiments, the enhancement of stability of the suspension capsule formulation results in improved formulation integrity (e.g., stability, consistency, and effectiveness of the formulation throughout its shelf life).

[0909] In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 45 °C and about 65 °C. In some embodiments, the composition, capsule, orNOD-C-P3911PCT

[0910] formulation is prepared at a temperature between about 45 °C and about 60 °C. In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 45 °C and about 55 °C. In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 45 °C and about 50 °C.

[0911] In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 50 °C and about 65 °C. In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 50 °C and about 60 °C. In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 50 °C and about 55 °C.

[0912] In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 55 °C and about 65 °C. In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 55 °C and about 60 °C.

[0913] In some embodiments, the composition, capsule, or formulation is prepared at a temperature between about 60 °C and about 65 °C.

[0914] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 45 °C.

[0915] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 50 °C.

[0916] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 51 °C.

[0917] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 52 °C.

[0918] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 53 °C.NOD-C-P3911PCT

[0919] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 54 °C.

[0920] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 55 °C.

[0921] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 56 °C.

[0922] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 57 °C.

[0923] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 58 °C.

[0924] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 59 °C.

[0925] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 60 °C.

[0926] In some embodiments, the composition, capsule, or formulation is prepared at a temperature of about 65 °C.

[0927] In some embodiments, the composition of the suspension formulation is described in Table 1.

[0928] In some embodiments, the composition of the capsule is described in Table 1.

[0929] In some embodiments, the formulation is described in Table 1.

[0930] Table 1. Composition and Preparation Temperature for Compound 1 Drug ProductNOD-C-P3911PCT

[0931] Material Unit Target Unit Range of Target Preparation Target Formulation Formulation Required Required Temperature Preparation Range (%w / w) Quantity Quantity Range Temperature (%w / w) (g) (g)

[0932] Compound 1 19.99 - 219.90 - 20.00 220.00

[0933] 20.10 221.10

[0934] Gelucire 36.89 - 405.84 - 37.08 407.88

[0935] 48 / 16 37.27 409.92

[0936] Lauroglycol 36.89 – 405.84 – 37.08 407.88 55°C 50°C – 60°C 90 37.27 409.92

[0937] Methocel

[0938] 63.92 - K100 5.81 - 5.87 5.84 64.24

[0939] 64.56

[0940] Premium

[0941] Total 100.0 1100.00

[0942]

[0943] In some embodiments, the composition, capsule, or formulation is substantially free from TPGS Vitamin E.

[0944] In some embodiments, the composition, capsule, orformulation is substantially free from Absolute Ethanol.

[0945] In some embodiments, the composition, capsule, orformulation is substantially free from TPGS Vitamin E and Absolute Ethanol.

[0946] Methods of Use

[0947] In some embodiments, the present invention provides a method of treating an NLRP3 related disease or disorder in a subject, comprising administering a composition, capsule, or formulation as described herein.

[0948] In some embodiments, the present invention provides a composition, capsule, orformulation as described herein for use in treating an NLRP3 related disease or disorder in a subject.

[0949] In some embodiments, the present invention provides a composition, capsule, orformulation as described herein for treating an NLRP3 related disease or disorder in a subject.NOD-C-P3911PCT

[0950] In some embodiments, the present invention provides use of a composition, capsule, or formulation as described herein, in the manufacture of a medicament for the treatment of an NLRP3 related disease or disorder in a subject.

[0951] In some embodiments, the present invention provides a method of treating an inflammatory disorder, an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject, comprising administering a composition, capsule, or formulation as described herein.

[0952] In some embodiments, the NLRP3 related disease or disorder is an inflammatory disorder, an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer.

[0953] In some embodiments, the subject is human.

[0954] In some embodiments, the subject is administered the composition, capsule, or formulation once or twice daily.

[0955] In some embodiments, the subject is administered the composition, capsule, or formulation once daily.

[0956] In some embodiments, the subject is administered the composition, capsule, or formulation twice daily.

[0957] In some embodiments, the subject is administered the composition, capsule, or formulation three times daily.

[0958] In some embodiments, the subject is administered the composition, capsule, or formulation four times daily.

[0959] In some embodiments, the composition, capsule, or formulation described herein is administered orally.

[0960] In some embodiments, the composition, capsule, or formulation described herein is administered orally once or twice daily.NOD-C-P3911PCT

[0961] In some embodiments, the composition, capsule, or formulation described herein is administered orally once daily.

[0962] In some embodiments, the composition, capsule, or formulation described herein is administered orally twice daily.

[0963] In some embodiments, the composition, capsule, or formulation described herein is administered orally three times daily.

[0964] In some embodiments, the composition, capsule, or formulation described herein is administered orally four times daily.

[0965] In some embodiments, the present invention provides a method of inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo), comprising contacting a cell with an amount of the composition, capsule, or formulation of the present invention.

[0966] In some embodiments, the present invention provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0967] In some embodiments, the present invention provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0968] In some embodiments, the disease or disorder is associated with an implicated inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[0969] In some embodiments, the disease or disorder is an inflammatory disorder, autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0970] In some embodiments, the disease or disorder is an inflammatory disorder, autoinflammatory disorder and / or an autoimmune disorder.NOD-C-P3911PCT

[0971] In some embodiments, the disease or disorder is selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), atherosclerosis, gout, heart failure, rheumatoid arthritis, osteoarthritis, Irritable Bowel Disease (IBD), Crohn’s disease, ulcerative colitis (UC), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease (e.g. acne), clonal hematopoiesis of indeterminate potential (CHIP), epilepsy, age-related macular degeneration, and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease). E

[0972] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0973] In some embodiments, the neurodegenerative disease is Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

[0974] In some embodiments, the disease or disorder is Parkinson’s disease or Alzheimer’s disease.

[0975] In some embodiments, the disease or disorder is a dermatological disease.

[0976] In some embodiments, the dermatological disease is acne.

[0977] In some embodiments, the disease or disorder is cancer.

[0978] In some embodiments, the cancer is metastasising cancer, gastrointestinal cancer, skin cancer, non-small-cell lung carcinoma, brain cancer (e.g., glioblastoma) or colorectal adenocarcinoma.

[0979] In some embodiments, the present invention provides a method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.NOD-C-P3911PCT

[0980] In some embodiments, the present invention provides a method of treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0981] In some embodiments, the present invention provides a method of treating or preventing an inflammatory disorder, autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease (e.g., acne), and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0982] In some embodiments, the present invention provides a method of treating an inflammatory disorder, autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease (e.g., acne), and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof, comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0983] In some embodiments, the present invention provides a method of treating or preventing a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof, said methodNOD-C-P3911PCT

[0984] comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0985] In some embodiments, the present invention provides a method of treating a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof, said method comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0986] In some embodiments, the present invention provides a method of treating or preventing cancer in a subject in need thereof, said method comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0987] In some embodiments, the present invention provides a method of treating cancer in a subject in need thereof, said method comprising administering to the subject a composition, capsule, or formulation of the present invention.

[0988] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0989] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating or preventing a disease or disorder disclosed herein.

[0990] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating a disease or disorder disclosed herein.

[0991] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.

[0992] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.NOD-C-P3911PCT

[0993] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof.

[0994] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating an inflammatory disorder, an autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof.

[0995] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating or preventing a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof.

[0996] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof.NOD-C-P3911PCT

[0997] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating or preventing cancer in a subject in need thereof.

[0998] In some embodiments, the present invention provides the composition, capsule, or formulation of the present invention for use in treating cancer in a subject in need thereof.

[0999] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[1000] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[1001] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[1002] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.

[1003] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.

[1004] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystemNOD-C-P3911PCT

[1005] inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disorders (e.g., acne), and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof.

[1006] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder and / or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disorders (e.g., acne), and neuroinflammation occurring in protein misfolding disease (e.g., Prion disease) in a subject in need thereof.

[1007] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating or preventing a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof.

[1008] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating a neurodegenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease) in a subject in need thereof.

[1009] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.NOD-C-P3911PCT

[1010] In some embodiments, the present invention provides use of the composition, capsule, or formulation of the present invention in the manufacture of a medicament for treating cancer in a subject in need thereof.

[1011] The present invention provides a composition, capsule, or formulation of the present invention that functions as inhibitors of inflammasome activity. The present invention therefore provides a method of inhibiting inflammasome activity in vitro or in vivo, said method comprising contacting a cell with a composition, capsule, or formulation, as defined herein.

[1012] Effectiveness of the compound of the invention can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[1013] The present invention also provides a method of treating a disease or disorder in which inflammasome activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a composition, capsule, or formulation of the present invention.

[1014] On a general level, the composition, capsule, or formulation of the present invention, which inhibit the maturation of cytokines of the IL-1 family, are effective in all therapeutic indications that are mediated or associated with elevated levels of active forms of cytokines belonging to IL-1 family of cytokines (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010).

[1015] Exemplary diseases and the corresponding references will be given in the following: inflammatory, autoinflammatory and autoimmune diseases like CAPS (Dinarello CA. Immunity. 2004 Mar;20(3):243-4; Hoffman HM. al. Reumatologla 2005; 21(3)), gout, rheumatoid arthritis (Gabay C et al. Arthritis Research & Therapy 2009, 11:230; Schett G. et al. Nat Rev Rheumatol. 2016 Jan; 12(1): 14-24.), Crohn’s disease (Jung Mogg Kim Korean J Gastroenterol Vol. 58 No. 6, 300-310), COPD (Mortaz E. et al. Tanaffos. 2011; 10(2): 9–14.), fibrosis (Gasse P. et al. Am J Respir Crit Care Med. 2009 May 15; 179(10):903-13), obesity, type 2 diabetes ((Dinarello CA. et al. Curr Opin Endocrinol Diabetes Obes. 2010 Aug;17(4):314-21)) multiple sclerosis (see EAE-model in Coll RC. et al. Nat Med. 2015 Mar;21(3):248-55) and many others (Martinon F. et al. Immunol.

[1016] 2009. 27:229-65) like Parkinson’s disease or Alzheimer’s disease (Michael T. et al. Nature 493, 674–678 (31 January 2013); Halle A. et al., Nat Immunol. 2008 Aug;9(8):857-65; Saresella M. et al. Mol Neurodegener. 2016 Mar 3;11:23) and some oncological disorders.NOD-C-P3911PCT

[1017] Suitably, the composition, capsule, or formulation according to the present invention can be used for the treatment of a disease selected from the group consisting of an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a neurodegenerative disease and cancer. Said inflammatory, autoinflammatory and autoimmune disease is suitably selected from the group consisting of a cryopyrin-associated autoinflammatory syndrome (CAPS, such as for example familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn’s disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease (e.g., acne), and neuroinflammation occurring in protein misfolding disease, such as Prion disease. Said neurodegenerative disease includes, but is not limited to Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.

[1018] Accordingly, the composition, capsule, or formulation of the present invention can be used for the treatment of a disease selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS, such as for example familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), atherosclerosis, gout, heart failure, rheumatoid arthritis, osteoarthritis, Irritable Bowel Disease (IBD), Crohn’s disease, ulcerative colitis (UC), COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological disease (e.g., acne), clonal hematopoiesis of indeterminate potential (CHIP), epilepsy, age-related macular degeneration, neuroinflammation occurring in protein misfolding disease, such as Prion disease, neurogenerative disease (e.g., Parkinson’s disease, Alzheimer’s disease), and oncological disorders.

[1019] Treatment in Cancer; links with inflammasome

[1020] Chronic inflammation responses have long been observed to be associated with various types of cancer. During malignant transformation or cancer therapy inflammasomes may becomeNOD-C-P3911PCT

[1021] activated in response to danger signals and this activation may be both beneficial and detrimental in cancer.

[1022] IL-1 p expression is elevated in a variety of cancers (including breast, prostate, colon, lung, head and neck cancers and melanomas) and patients with IL-1 p producing tumours generally have a worse prognosis (Lewis, Anne M., et al. " Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment." Journal of translational medicine 4.1 (2006): 48).

[1023] Cancers derived from epithelial cells (carcinoma) or epithelium in glands (adenocarcinoma) are heterogeneous; consisting of many different cell types. This may include fibroblasts, immune cells, adipocytes, endothelial cells and pericytes amongst others, all of which may be cytokine / chemokine secreting (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. " Immunity, inflammation, and cancer." Cell 140.6 (2010): 883-899). This can lead to cancer-associated inflammation through the immune cell infiltration. The presence of leukocytes in tumours is known but it has only recently become evident that an inflammatory microenvironment is an essential component of all tumours. Most tumours (>90%) are the result of somatic mutations or environmental factors rather than germline mutations and many environmental causes of cancer are associated with chronic inflammation (20% of cancers are related to chronic infection, 30% to smoking / inhaled pollutants and 35% to dietary factors (20% of all cancers are linked to obesity) (Aggarwal, Bharat B., R. V. Vijayalekshmi, and Bokyung Sung. " Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe." Clinical Cancer Research 15.2 (2009): 425-430).

[1024] Gl cancer

[1025] Cancers of the gastrointestinal (Gl) tract are frequently associated with chronic inflammation. For example, H. pylori infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. " Pathobiology of Helicobacter pylori-lnduced Gastric Cancer." Gastroenterology 150.1 (2016): 64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N., et al. " Cancer risk in patients with inflammatory bowel disease." Cancer 91.4 (2001): 854-862). Chronic inflammation in stomach leads to the upregulation of IL-1 and other cytokines (Basso D, et al., (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207–210) and polymorphisms in IL-1 [3 gene can increase risk of gastric cancer (Wang P, et al., (2007)NOD-C-P3911PCT

[1026] Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120:552–562).

[1027] In 19% of gastric cancer cases, caspase-1 expression is decreased which correlates with stage, lymph node metastasis and survival (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer its activation of the NLRP3 inflammasome may be associated with its promotion of gastric cancer metastasis (Xu et al., 2013).

[1028] Skin cancers

[1029] Ultraviolet radiation is the greatest environmental risk for skin cancer which is promoted by causing DNA damage, immunosuppression and inflammation. The most malignant skin cancer, melanoma, is characterised by the upregulation of inflammatory cytokines, all of which can be regulated by IL-1 [3 (Lazar-Molnar, Eszter, et al. " Autocrine and paracrine regulation by cytokines and growth factors in melanoma." Cytokine 12.6 (2000): 547-554). Systemic inflammation induces an enhancement of melanoma cell metastasis and growth by IL-1-dependent mechanisms in vivo. Using thymoquinone inhibition of metastasis in a B16F10 mouse melanoma model was shown to be dependent on inhibition of the NLRP3 inflammasome (Ahmad, Israr, et al. " Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome." Toxicology and applied pharmacology 270.1 (2013): 70-76).

[1030] Glioblastoma

[1031] NLRP3 contributes to radiotherapy resistance in glioma. Ionising radiation can induce NLRP3 expression whereas NLRP3 inhibition reduced tumour growth and prolonged mouse survival following radiation therapy. NLRP3 inflammasome inhibition can therefore provide a therapeutic strategy for radiation-resistant glioma (Li, Lianling, and Yuguang Liu. " Aging-related gene signature regulated by Nlrp3 predicts glioma progression." American journal of cancer research 5.1 (2015): 442).

[1032] Metastasis

[1033] More widely, NLRP3 is considered by the applicant to be involved in the promotion of metastasis and consequently modulation of NLRP3 should plausibly block this. IL-1 is involved in tumour genesis, tumour invasiveness, metastasis, tumour host interactions (Apte, Ron N., et al. " The involvement of IL-1 in tumorigenesis, tumour invasiveness, metastasis and tumour-host interactions." Cancer and Metastasis Reviews 25.3 (2006): 387-408) and angiogenesis (Voronov,NOD-C-P3911PCT

[1034] Elena, et al. " IL-1 is required for tumor invasiveness and angiogenesis." Proceedings of the National Academy of Sciences 100.5 (2003): 2645-2650).

[1035] The IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. For example, IL-1mRNA was highly expressed in more than half of all tested metastatic human tumour specimens including specifically non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumour samples (Elaraj, Dina M., et al. " The role of interleukin 1 in growth and metastasis of human cancer xenografts." Clinical Cancer Research 12.4 (2006): 1088-1096) and IL-1RA inhibits xenograft growth in IL-1 producing tumours but without antiproliferative effects in vitro.

[1036] Further, IL-1 signalling is a biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models IL-1 p and its receptor are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. In a mouse model the IL-1 receptor antagonist anakinra reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1 p and TNF alpha (Holen, Ingunn, et al. " IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016).

[1037] IL-18 induced the production of MMP-9 in the human leukaemia cell line HL-60, thus favouring degradation of the extracellular matrix and the migration and invasiveness of cancer cells (Zhang, Bin, et al. " IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression." Leukemia research 28.1 (2004): 91-95). Additionally, IL-18 can support the development of tumour metastasis in the liver by inducing expression of VCAM-1 on hepatic sinusoidal endothelium (Carrascal, Maria Teresa, et al. " Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium." Cancer Research 63.2 (2003): 491-497).

[1038] CD36

[1039] The fatty acid scavenger receptor CD36 serves a dual role in priming gene transcription of pro-IL-1 p and inducing assembly of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognise oxLDL, which initiates a signalling pathway leading to transcriptional upregulation of NLRP3 and pro-IL-1 p (signal 1). CD36 also mediates the internalisation of oxLDL into the lysosomal compartment, where crystals are formed that induce lysosomal rupture andNOD-C-P3911PCT

[1040] activation of the NLRP3 inflammasome (signal 2) (Kagan, J. and Horng T., " NLRP3 inflammasome activation: CD36 serves double duty." Nature immunology 14.8 (2013): 772-774).

[1041] A subpopulation of human oral carcinoma cells express high levels of the fatty acid scavenger receptor CD36 and are unique in their ability to initiate metastasis. Palmitic acid or a high fat diet boosted the metastatic potential of the CD36+ cells. Neutralising anti-CD36 antibodies blocked metastasis in orthotopic mouse models of human oral cancer. The presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas. It is suggested that dietary lipids may promote metastasis (Pasqual, G, Avgustinova, A., Mejetta, S, Martin, M, Castellanos, A, Attolini, CS-O, Berenguer, A., Prats, N, Toll, A, Hueto, JA, Bescos, C, Di Croce, L, and Benitah, SA. 2017 “Targeting metastasis-initiating cells through the fatty acid receptor CD36” Nature 541:41-45).

[1042] In hepatocellular carcinoma exogenous palmitic acid activated an epithelial-mesenchymal transition (EMT)-like program and induced migration that was decreased by the CD36 inhibitor, sulfo-N-succinimidyl oleate (Nath, Aritro, et al. " Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma." Scientific reports 5 (2015). Body mass index was not associated with the degree of EMT highlighting that it is actually CD36 and free fatty acids that are important.

[1043] Cancer stems cells (CSCs) use CD36 to promote their maintenance. Oxidised phospholipids, ligands of CD36, were present in glioblastoma and the proliferation of CSCs but not non-CSCs increased with exposure to oxidised LDL. CD36 also correlated with patient prognosis.

[1044] Chemotherapy resistance

[1045] In addition to direct cytotoxic effects, chemotherapeutic agents harness the host immune system which contributes to anti-tumour activity. However, gemcitabine and 5-FU were shown to activate NLRP3 in myeloid-derived suppressor cells leading to production of IL-1 p which curtails antitumour efficacy. Mechanistically these agents destabilised the lysosome to release cathepsin B to activate NLRP3. IL-1 [3 drove the production of IL-17 from CD4+ T cells which in turn blunted the efficacy of the chemotherapy. Higher anti-tumoral effects for both gemcitabine and 5-FU were observed when tumours were established in NLRP3- / - or Capsl- / - mice, or WT mice treated with IL-1RA. Myeloid-derived suppressor cell NLRP3 activation therefore limits the anti-tumour efficacy of gemcitabine and 5-FU (Bruchard, Melanie, et al. " Chemotherapy-triggered cathepsinNOD-C-P3911PCT

[1046] B release in myeloid-derived suppressor cells activates the NLRP3 inflammasome and promotes tumour growth." Nature medicine 19.1 (2013): 57-64.). The composition, capsule, or formulation of the present invention may therefore be useful in chemotherapy to treat a range of cancers.

[1047] The composition, capsule, or formulation of the present invention may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[1048] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant ( / .e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the composition, capsule, or formulation of the present invention with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[1049] In the instances where the composition, capsule, or formulation of the present invention is administered in combination with other therapeutic agents, the composition, capsule, or formulation of the invention need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the composition, capsule, or formulation of the invention may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[1050] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the invention there is provided a combination for use in the treatment of a disease in which inflammasome activity is implicated comprising the composition, capsule, or formulation of the present invention, and another suitable agent.NOD-C-P3911PCT

[1051] According to a further embodiment of the invention there is provided a a composition, capsule, or formulation of the present invention, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.

[1052] In addition to its use in therapeutic medicine, the composition, capsule, or formulation of the present invention are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of inflammasome in laboratory animals such as dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

[1053] In any of the above-mentioned composition, capsule, formulation, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of macromolecules of the present invention described herein also apply.

[1054] Methods of Preparation

[1055] In some embodiments, the composition, capsule, or formulation described herein is prepared in bulk.

[1056] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1057] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1058] (ii) adding a polymer to the mixture of step (i); and

[1059] (iii) adding Compound 1 to the mixture of step (ii).

[1060] In some embodiments, the mixture of the non-ionic surfactant and co-surfactant and solubilizer is prepared by:

[1061] (i-a) melting the non-ionic surfactant; and

[1062] (i-b) melting the co-surfactant and solubilizer,

[1063] wherein (i-a) and (i-b) are melted separately prior to mixing.

[1064] In some embodiments, the non-ionic surfactant is melted at a temperature between about 50 °C and about 60 °C. In some embodiments, the non-ionic surfactant is melted at a temperature between about 50 °C and about 55 °C. In some embodiments, the non-ionic surfactant is melted at a temperature between about 55 °C and about 60 °C.NOD-C-P3911PCT

[1065] In some embodiments, the co-surfactant and solubilizer is melted at a temperature between about 50 °C and about 60 °C. In some embodiments, the co-surfactant and solubilizer is melted at a temperature between about 50 °C and about 55 °C. In some embodiments, the co-surfactant and solubilizer is melted at a temperature between about 55 °C and about 60 °C.

[1066] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1067] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1068] (ii) adding a polymer to the mixture of step (i);

[1069] (iii) adding Compound 1 to the mixture of step (ii) to form a second mixture;

[1070] (iv) mixing the second mixture;

[1071] (v) degassing the second mixture; and

[1072] (vi) storing the second mixture with stirring.

[1073] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1074] (i-a) melting the non-ionic surfactant;

[1075] (i-b) melting the co-surfactant and solubilizer;

[1076] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer of steps (i-a) and (i-b);

[1077] (ii) adding a polymer to the mixture of step (i);

[1078] (iii) adding Compound 1 to the mixture of step (ii) to form a second mixture;

[1079] (iv) mixing the second mixture;

[1080] (v) degassing the second mixture; and

[1081] (vi) storing the second mixture with stirring.

[1082] In some embodiments, the second mixture is degassed at a pressure of < 30 °Hg, < 25 °Hg, or < 20 °Hg.

[1083] In some embodiments, the second mixture is stored at a temperature between about 50 °C and about 60 °C. In some embodiments, the second mixture is stored at a temperature between about 50 °C and about 55 °C. In some embodiments, the second mixture is stored at a temperature between about 55 °C and about 60 °C.NOD-C-P3911PCT

[1084] In some embodiments, mixing the second mixture is performed under N2flush.

[1085] In some embodiments, degassing the second mixture is performed under N2flush.

[1086] In some embodiments, storing the second mixture with stirring is performed under N2flush.

[1087] In some embodiments, mixing the second mixture, degassing the second mixture, and storing the second mixture with stirring is performed under N2flush.

[1088] In some embodiments, the present invention provides a method of preparing a capsule described herein by:

[1089] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1090] (ii) adding a polymer to the mixture of step (i);

[1091] (iii) adding Compound 1 to the mixture of step (ii) to form a second mixture;

[1092] (iv) filling the second mixture into capsules; and

[1093] (v) adding a banding solution.

[1094] In some embodiments, after adding the banding solution, capsule bands are dried.

[1095] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1096] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1097] (ii) adding a polymer to the mixture of step (i); and

[1098] (iii) adding Compound 1 to the mixture of step (ii) to form a bulk mixture (or bulk mix).

[1099] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1100] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1101] (ii) adding a polymer to the mixture of step (i);

[1102] (iii) adding Compound 1 to the mixture of step (ii) to form a bulk mixture;

[1103] (iv) mixing the bulk mixture;

[1104] (v) degassing the bulk mixture; and

[1105] (vi) storing the bulk mixture with stirring.NOD-C-P3911PCT

[1106] In some embodiments, the present invention provides a method of preparing a composition, capsule, or formulation described herein by:

[1107] (i-a) melting the non-ionic surfactant;

[1108] (i-b) melting the co-surfactant and solubilizer;

[1109] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer of steps (i-a) and (i-b);

[1110] (ii) adding a polymer to the mixture of step (i);

[1111] (iii) adding Compound 1 to the mixture of step (ii) to form a bulk mixture;

[1112] (iv) mixing the bulk mixture;

[1113] (v) degassing the bulk mixture; and

[1114] (vi) storing the bulk mixture with stirring.

[1115] In some embodiments, the bulk mixture is degassed at a pressure of < 30 °Hg, < 25 °Hg, or < 20 °Hg.

[1116] In some embodiments, the bulk mixture is stored at a temperature between about 50 °C and about 60 °C. In some embodiments, the bulk mixture is stored at a temperature between about 50 °C and about 55 °C. In some embodiments, the bulk mixture is stored at a temperature between about 55 °C and about 60 °C.

[1117] In some embodiments, mixing the bulk mixture is performed under N2flush.

[1118] In some embodiments, degassing the bulk mixture is performed under N2flush.

[1119] In some embodiments, storing the bulk mixture with stirring is performed under N2flush.

[1120] In some embodiments, mixing the bulk mixture, degassing the bulk mixture, and storing the bulk mixture with stirring is performed under N2flush.

[1121] In some embodiments, the present invention provides a method of preparing a capsule described herein by:

[1122] (i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer;

[1123] (ii) adding a polymer to the mixture of step (i);NOD-C-P3911PCT

[1124] (iii) adding Compound 1 to the mixture of step (ii) to form a bulk mixture;

[1125] (iv) filling the bulk mixture into capsules; and

[1126] (v) adding a banding solution.

[1127] In some embodiments, the mixture of step (iii) is filled into capsules.

[1128] In some embodiments, the capsules are HPMC LiCaps Size 0 Swedish Orange capsules.

[1129] In some embodiments, the target fill weight of the capsule is 375 mg.

[1130] In some embodiments, the target fill weight of the capsule is 125 mg.

[1131] In some embodiments, the composition, capsule, or formulation described herein is prepared as depicted in Figure 1.

[1132] In some embodiments, Gelucire 48 / 16 is melted ata temperature of about 55 ± 5 °C in a stainless steel mixing vessel. In a separate container, Lauroglycol 90 is melted at a temperature of about 55 ± 5 °C and then added to the melted Gelucire 48 / 16. Next, Methocel K100 Premium LV is added and hand stirring is applied. Afterwards, Compound 1 is added while applying high shear mixing and the resulting bulk mix is degassed at about < 25 °Hg. Homogenous bulk mix and full degassing are visually confirmed. Finally, the bulk mix is stored at about 55 ± 5 °C with stirring until capsules are manufactured. The high shear mixinig, bulk mixing desassing, and bulk mix storage are all performed under N2 flush.

[1133] In some embodiments, the capsule described herein is prepared as depicted in Figure 2.

[1134] In some embodiments, after confirming stability of hopper and pump block at about 55 ± 5 °C and setting stirrer speed, the bulk mix is manually transferred to the filling machine hoppers. The filling machine is set to fill to about 375 mg. The fill is set through displacement pump adjustments with weigh checks. Separately, the bulk mix is prepared and capsules are provided. Next, the bulk mix is filled into the capsules. The composite weights (set of 12) are checked every about 10 minutes and individual weights (set of 24) are also checked. Next, filled capsules are manually transferred by banding machine hopper. Banding solution is prepared using standard prodecure. Filled capsules are banded and collected on trays to dry. The capsules are inspected for bandNOD-C-P3911PCT

[1135] application and banding discs are adjusted as required. The speed is adjusted to match filling machine. Next, capsule bands are dried for at least about 8 hours. Afterwards, the capsules are in-process packed while capsules weight are sorted and metal is checked. Finally, Acceptable Quality Level (AQL) analysis is conducted followed by capsules final packing.

[1136] EXAMPLES

[1137] The invention having been described, the following examples are offered by way of illustration and not limitation. It is understood that all values presented in the examples are approximate, and are subject to instrumental and / or experimental variations.

[1138] Example 1 - Suspension Formulation (F1)

[1139] Suspension Formulation Preparation

[1140] A suspension formulation F1 of Compound 1 was prepared with the composition as provided in Table A.

[1141] Table A. Composition and Preparation Temperature for Suspension Formulation of Compound 1 (F1)

[1142] Material in Unit Target Unit Range of Target Preparation Target Suspension Formulation Formulation Required Required Temperature Preparation Formulation Range (%w / w) Quantity Quantity Range Temperature F1 (%w / w) (g) (g)

[1143] Compound 1 19.99 - 219.90 - 20.00 220.00

[1144] 20.10 221.10

[1145] Gelucire 48 / 16 36.89 - 405.84 - 37.08 407.88

[1146] 37.27 409.92

[1147] Lauroglycol 90 36.89 - 405.84 - 37.08 407.88 55°C 50°C - 60°C 37.27 409.92

[1148] Methocel

[1149] 63.92 - K100 5.81 - 5.87 5.84 64.24

[1150] 64.56

[1151] Premium

[1152] Total 100.0 1100.00

[1153]

[1154] The components of the formulation were provided as follows: Gelucire 48 / 15 is a non-ionic surfactant, Lauroglycol 90 is a co-surfactant and a solubiliser, Methocel K100 Premimum is aNOD-C-P3911PCT

[1155] polymer, and hydroxypropyl methylcellulose (HPMC) is utilised for its rheology (e.g., viscosity) conontrol properties.

[1156] Suspension Formulation F1 was dosed in clinical trials and the exposures and PK obtained were studied.

[1157] The composition (e.g., 20% w / w of Compound 1) in Table A was used in a Drug Product of both 75 mg and 25 mg dose of Compound 1, which have target fill weights of 375 mg and 125 mg, respectively, into HPMC LiCaps Size 0 Swedish Orange Capsules.

[1158] Figures 1 and 2 depict the manufacturing processes for F1.

[1159] Suspension Formulation Properties

[1160] F1 was studied at 0, 4, and 8 weeks storage at 40 °C / 75% RH.

[1161] F1 delivers a high Compound 1 unit dose with enhanced stability (e.g., longer term stability) relative to a solution formulation.

[1162] The enhanced stability of Compound 1 in F1 is attributed to the suspension of the majority of Compound 1, rather than being in solutions ( / .e., being dissolved). Drugs in solution tend to be less stable due to an increase in chemical interactions and an increase in degradation pathways such as hydrolysis.

[1163] F1 supports once a day dosing by providing improved release PK profile relative to a solution formulation.

[1164] Example 2 - Assessment of Suspension Formulation

[1165] Suspension formulation F2 was prepared as shown in Table B and assay and related substances analysis at T=0, 4, and 8 weeks storage at 40 °C / 75% RH were studied (Table C).

[1166] Table B. Preparation Temperature, Composition and Dispense Weight of Suspension Formulation F2NOD-C-P3911PCT

[1167] Percentage

[1168] Suspension Preparation Dispense weight Material composition

[1169] Formulation Temperature active mix (g)

[1170] (%)

[1171] Compound 1 18.0 20.73 Lauroglycol 90 38.5 44.273F2 50 -60 °C Gelucire 48 / 16 38.5 44.27

[1172] Methocel K100

[1173] 5.0 5.75

[1174] Premium

[1175]

[1176] Table C. Results of Assay and Related Substances Analysis at T=0, 4, and 8 Weeks Storage at 40 °C / 75% RH

[1177] Absolute Capsule Shell T=0 T=4 weeks T=8 weeks Change type & (Over 8 weeks) Formulation Assay Total RS Assay Total RS Assay Total RS Assay Total RS (%) (% Area) (%) (% Area) (%) (% Area) (%) (% Area) Gelatin F2 98.5 0.7 97.9 1.2 96.2 3.1 -2.3 +2.4 HPMC F2 99.7 0.6 98.4 0.8 98.4 1.3 -1.3 +0.7

[1178]

[1179] The suspension formulation (F2) was developed and selected for further assessments, including capsule shell computability. The capsule shell compatibility study (Table C) demonstrated that over the full 8 weeks at 40°C / 75 % RH, smaller assay decreases and related substances (RS) increases were observed for Formulation F2 in both the gelatin and the HPMC capsules, indicating potential greater formulation stability for this formulation (Figure 3 and Figure 4).

[1180] Formulation F2 demonstrated the most optimum results in HPMC shells. For example, optimum results were a mix of achieving more prolonged exposures than the initial solution formulation and appropriate factors such as viscosity which allow said formulation to be commercially viable.

[1181] Formulation F2 was manufactured at small scale in HPMC capsules and the stability of these capsules was tested.

[1182] Formulation F2 was selected as the lead based upon having prolonged exposures ( / .e., higher blood concentration of Compound 1 in the same amount of time after dosing). Formulation F1NOD-C-P3911PCT

[1183] has a decrease in viscosity of the formulation as compared to Formulation F2. Decreased viscosity may allow a higher volume of suspension formulation to be manufactured.

[1184] Example 3 - Preparation of the Bulk Mix

[1185] The bulk mix of the composition, capsule, or formulation comprising Compound 1 was prepared as depicted in Figure 1.

[1186] Gelucire 48 / 16 was melted at a temperature of 55 ± 5 °C in a stainless steel mixing vessel. In a separate container, Lauroglycol 90 was melted at a temperature of 55 ± 5 °C and then added to the melted Gelucire 48 / 16. Next, Methocel K100 Premium LV was added and hand stirring was applied. Afterwards, Compound 1 was added while applying high shear mixing and the resulting bulk mix was degassed at about < 25 °Hg. Homogenous bulk mix and full degassing were visually confirmed. Finally, the bulk mix was stored at 55 ± 5 °C with stirring until capsules were manufactured. The high shear mixinig, bulk mixing desassing, and bulk mix storage were all performed under N2flush.

[1187] Example 4 - Preparation of the Capsule

[1188] The capsule described herein was prepared as depicted in Figure 2.

[1189] The bulk mix was transferred to the filling machine hoppers. The bulk mix was filled into the capsules. Next, filled capsules were manually transferred by banding machine hopper. Filled capsules were banded and collected on trays to dry. The capsules were inspected for band application and banding discs were adjusted as required. Capsule bands were dried for at least about 8 hours. Afterwards, the capsules were in-process packed while capsules weight were sorted and checked.

Claims

NOD-C-P3911PCTCLAIMS1. A composition comprising:(i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;(ii) a non-ionic surfactant;(iii) a co-surfactant and solubilizer; and(iv) a polymer.

2. A suspension composition comprising:(i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;(ii) a non-ionic surfactant;(iii) a co-surfactant and solubilizer; and(iv) a polymer.

3. A capsule comprising:(i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;(ii) a non-ionic surfactant;(iii) a co-surfactant and solubilizer; and(iv) a polymer.

4. A pharmaceutical formulation comprising:(i) isopropyl (R)-2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3- (pyrimidin-2-yl)propanoate (Compound 1), or a pharmaceutically acceptable salt thereof;(ii) a non-ionic surfactant;(iii) a co-surfactant and solubilizer; and(iv) a polymer.NOD-C-P3911PCT5. The composition, capsule, or formulation of any one of the preceding claims, wherein the non-ionic surfactant is a glycerol or polyethylene glycol ester of fatty acids.

6. The composition, capsule, or formulation of any one of the preceding claims, wherein the non-ionic surfactant is Gelucire 48 / 16.

7. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to non-ionic surfactant weight ratio is about 1:1 or about 1:2.

8. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to non-ionic surfactant weight ratio is about 1:1.8.

9. The composition, capsule, or formulation of any one of the preceding claims, wherein the non-ionic surfactant is present in an amount from about 35% w / w to about 40% w / w.

10. The composition, capsule, or formulation of any one of the preceding claims, wherein the non-ionic surfactant is present in an amount from 37.1% w / w.

11. The composition, capsule, or formulation of any one of the preceding claims, wherein the co-surfactant and solubilizer is a propylene glycol monolaurate.

12. The composition, capsule, or formulation of any one of the preceding claims, wherein the co-surfactant and solubilizer is Lauroglycol 90.

13. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to co-surfactant and solubilizer weight ratio is about 1:1 or about 1:2.

14. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to co-surfactant and solubilizer weight ratio is about 1:1.8.

15. The composition, capsule, or formulation of any one of the preceding claims, wherein the co-surfactant and solubilizer is present in an amount from about 35% w / w to about 40% w / w.NOD-C-P3911PCT16. The composition, capsule, or formulation of any one of the preceding claims, wherein the co-surfactant and solubilizer is present in an amount from 37.1% w / w.

17. The composition, capsule, or formulation of any one of the preceding claims, wherein the polymer is a hydroxypropyl methylcellulose (HPMC).

18. The composition, capsule, or formulation of any one of the preceding claims, wherein the polymer is Methocel K100 Premium.

19. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to polymer weight ratio is about 1:3 or about 1:4.

20. The composition, capsule, or formulation of any one of the preceding claims, wherein the compound to polymer weight ratio is about 1:3.4.

21. The composition, capsule, or formulation of any one of the preceding claims, wherein the polymer is present in an amount from about 2% w / w to about 10% w / w.

22. The composition, capsule, or formulation of any one of the preceding claims, wherein the polymer is present in an amount from 5.8% w / w.

23. The composition, capsule, or formulation of any one of the preceding claims, wherein Compound 1 is present in an amount from about 15% w / w to about 25% w / w.

24. The composition, capsule, or formulation of any one of the preceding claims, wherein Compound 1 is present in an amount from 20% w / w.

25. The composition, capsule, or formulation of any one of the preceding claims, wherein the composition, capsule, or formulation is prepared between about 45 °C and about 65 °C.

26. The composition, capsule, or formulation of any one of the preceding claims, wherein the composition, capsule, or formulation is prepared between about 50 °C and about 60 °C.NOD-C-P3911PCT27. The composition, capsule, or formulation of any one of the preceding claims, wherein the composition, capsule, or formulation is prepared at about 55 °C.

28. The composition, capsule, or formulation of any one of the preceding claims, being substantially free from TPGS Vitamin E and Absolute Ethanol.

29. The composition, capsule, or formulation of any one of the preceding claims, being administered orally.

30. The capsule of claim 3, wherein the capsule is liquid filled, wherein the capsule is filled with a liquid that is then solidified after heating at about 50 °C followed by cooling to about room temperature.

31. A method of treating an NLRP3 related disease or disorder in a subject, comprising administering a composition, capsule, or formulation of any one of the preceding claims.

32. A method of treating an inflammatory disorder, an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject, comprising administering a composition, capsule, or formulation of any one of the preceding claims.

33. The method of claim 31 or claim 32, wherein the subject is human.

34. The method of any one of claims 31-32, wherein the subject is administered the composition, capsule, or formulation once or twice daily.

35. The composition, capsule, or formulation of any one of claims 1 -30 prepared in bulk.

36. A method of preparing a composition, capsule, or formulation of any one of claims 1 -30 by:(i) preparing a mixture of the non-ionic surfactant and co-surfactant and solubilizer; (ii) adding a polymer to the mixture of step (i); and(iii) adding Compound 1 to the mixture of step (ii).

37. The method of claim 36, wherein the mixture of step (iii) is filled into capsules.

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