Oral pharmaceutical compositions and methods of treating inflammatory diseases

Abstract

The present disclosure describes pharmaceutical compositions including a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may include a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, to release the active agent at or above a specific pH. Methods of preparing such pharmaceutical compositions, and methods of treating an inflammatory disease using the same, are also provided. The pharmaceutical compositions of the present disclosure may be orally administered and may be used for the treatment of inflammatory diseases including gut-related inflammatory diseases, inflammatory neurological disorders, inflammatory respiratory diseases, rheumatological diseases, the like, and combinations thereof.

Description

Attorney Docket No. 143989.005502ORAL PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATING INFLAMMATORY DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 709,041 filed October 18, 2024, the entire contents of which are incorporated by reference.BACKGROUND

[0002] The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcription factors, is a cytosolic ligand-activated transcription factor that senses diverse endogenous and exogenous molecules mediating multiple biological activities. It is best known for mediating the toxic effects of environmental contaminants such as TCDD (dioxin) and a range of other xenobiotic substances. Recent evidence points to AhR as a highly-conserved pathway that can modulate inflammatory responses, thus the AhR pathway could be an important target for treating inflammatory diseases.

[0003] There is a wide expression of AhR in several cell types. Additionally, it has been shown that AhR plays a critical role as a regulator of both innate and adaptive immune responses by impacting the balance of Thl7 and Treg cells. Thl7-associated cytokines, including IL- 17, contribute to the immunopathogenesis of inflammatory diseases. Therefore, attention has recently been drawn to AhR as a target for the treatment or prevention of inflammatory diseases.

[0004] Compounds such as those described herein, that bind and activate the Aryl hydrocarbon Receptor (AhR), provide for a novel class of anti-inflammatory compounds with AhR-dependent cytokine modulation useful for the treatment of inflammatory disease states. Thus, the beneficial effects of AhR activation provide for new therapeutic interventions in the treatment of inflammatory disease states. The need exists for better treatment of inflammatory diseases including Crohn’s disease, colitis, irritable bowel syndrome, and the like. Suitably, a compound which binds and activates the Aryl hydrocarbon Receptor (AhR) in multiple cell types may provide a novel and useful treatment for inflammatory disease states. The present invention thus provides pharmaceutical compositions which include isoquinoline compounds or salts thereof, along with methods of making such compositions and methods of treating inflammatory diseases with the same.Attorney Docket No. 143989.005502SUMMARY

[0005] In some aspects, there is provided a pharmaceutical composition including: a therapeutically effective amount of a compound of Formula I:Formula I

[0006] or a pharmaceutically acceptable salt or cocrystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, and one or more pharmaceutically acceptable excipients.

[0007] In some aspects, the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0008] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a free base.

[0009] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a hydrochloride salt.

[0010] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a citrate salt.

[0011] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a cocrystal of citric acid.

[0012] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a tartrate salt.

[0013] In some aspects, the pharmaceutical composition includes the compound ofFormula I as a cocrystal of tartaric acid.Attorney Docket No. 143989.005502

[0014] In some aspects, the pharmaceutical composition includes the compound of Formula I as a maleate salt.

[0015] In some aspects, the pharmaceutical composition is in an oral dosage form.

[0016] In some aspects, the pharmaceutical composition is in the form of a tablet, a capsule, a powder, a pellet, a lozenge, a soft gelatin capsule, a spray dried dispersion, an extrudate, or a suspension.

[0017] In some aspects, the therapeutically effective amount is about 5 mg to about 2000 mg.

[0018] In some aspects, the therapeutically effective amount is about 5 mg to about 50 mg.

[0019] In some aspects, the therapeutically effective amount is about 250 mg to about 500 mg.

[0020] In some aspects, the therapeutically effective amount is about 500 mg to about 2000 mg.

[0021] In some aspects, the one or more pharmaceutically acceptable excipients include a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

[0022] In some aspects, the dispersion agent includes hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid- methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, ammonio methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion, or combinations thereof.

[0023] In some aspects, the pharmaceutical composition includes the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof and a dispersion agent in a solid dispersion.Attorney Docket No. 143989.005502

[0024] In some aspects, there is provided a method of making a pharmaceutical composition including: preparing a solid dispersion including a compound of Formula I:Formula I or a pharmaceutically acceptable salt or cocrystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, and one or more pharmaceutically acceptable excipients, and forming the solid dispersion into an oral dosage form.

[0025] In some aspects, the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0026] In some aspects, preparing the solid dispersion includes spray drying, hot melt extrusion, freeze drying, or combinations thereof.

[0027] In some aspects, the one or more pharmaceutically acceptable excipients include a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, or combinations thereof.

[0028] In some aspects, the dispersion agent includes hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid- methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, or combinations thereof.

[0029] In some aspects, the oral dosage form is in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, an extrudate, a spray dried dispersion, or a suspension.Attorney Docket No. 143989.005502

[0030] In some aspects, there is provided a method of treating an inflammatory disease in a patient in need thereof, the method including: orally administering to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt or cocrystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, thereby treating the inflammatory disease.

[0031] In some aspects, the inflammatory disease is Atopic dermatitis, Psoriasis, Seborrheic dermatitis, Rosacea, Acne vulgaris, Acne congloblata, Paular pustular acne, Nodulo-cystic acne, Lichen planus, Vitiligo, Cutaneous lupus, discoid lupus, subacute cutaneous lupus, Dermatomyositis, Graft versus host disease, Alopecia Areata, Alopecia Totalis, Alopecia universalis, Lichen nitidus, Granuloma annulare, Necrobiosis lipoidica diabeticorum, Sarcoid, bullous pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, Ulcerative colitis, Crohn’s disease, Eosinophilic esophagitis, Sjogren’s disease, steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema, emphysema, Blepharitis, Dry eye disease, Meibomian gland dysfunction, Uveitis, Age-related macular degeneration (AMD), Systemic Lupus Erythematosus (SLE), Dermatomyositis, Myositis, Rheumatoid Arthritis, Psoriatic Arthritis, Lupus erythematosus, Osteoarthritis, Synovitis, Ankylosing spondylitis, Multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, idiopathic pulmonary fibrosis, morphea, scleroderma, systemic sclerosis, or combinations thereof.Attorney Docket No. 143989.005502

[0032] In some aspects, the pharmaceutical composition is in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, an extrudate, a spray dried dispersion, or a suspension.

[0033] In some aspects, the therapeutically effective amount is about 5 mg to about 2000 mg.

[0034] In some aspects, the therapeutically effective amount is about 5 mg to about 50 mg.

[0035] In some aspects, the therapeutically effective amount is about 250 mg to about 500 mg.

[0036] In some aspects, the therapeutically effective amount is about 500 mg to about 2000 mg.

[0037] In some aspects, the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

[0038] In some aspects, the compound of Formula I is in the form of a hydrochloride salt.

[0039] In some aspects, the compound of Formula I is in the form of a citrate salt.

[0040] In some aspects, the compound of Formula I is in the form of a cocrystal with citric acid.

[0041] In some aspects, the compound of Formula I in the form of as a tartrate salt.

[0042] In some aspects, the compound of Formula I in the form of as a cocrystal of tartaric acid.

[0043] In some aspects, the compound of Formula I is in the form of a maleate salt.

[0044] In some aspects, the pharmaceutical composition delivers the compound of Formula I to the patient’s small intestine, large intestine, or combinations thereof.

[0045] In some aspects, at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 5.5 or above.Attorney Docket No. 143989.005502

[0046] In some aspects, at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 7.0 or above.DRAWINGS

[0047] Aspects, features, benefits, and advantages of the embodiments described herein will be apparent with regard to the following description, appended claims, and accompanying drawings where:

[0048] FIG. 1 is a graph of mDSC thermograms of spray dried dispersions (SDD) containing the compound of Formula 1 (Comp. 1), according to embodiments of the present disclosure.

[0049] FIG. 2 is an overlay of XRPD diffractograms of amorphous spray dried dispersions(SDD) of the compound of Formula I compared to the crystalline compound, according to embodiments of the present disclosure.

[0050] FIGS. 3A, 3B, and 3C are SEM images of 40:60 Comp. 1 : IIPMCAS-II SDD.

[0051] FIGS. 4A, 4B, and 4C are SEM images of 40:60 Comp. 1 : HPMCAS-M SDD.

[0052] FIGS. 5A, 5B, and 5C are SEM images of 40:60 Comp. 1 : HPMCAS-L SDD.

[0053] FIGS. 6A, 6B, and 6C are SEM images of 60:40 Comp. 1 : HPMCAS-L SDD.

[0054] FIGS. 7A, 7B, and 7C are SEM images of 80:20 Comp. 1 : HPMCAS-L SDD.

[0055] FIGS. 8A, 8B, and 8C are SEM images of 60:40 Comp. 1 : Soluplus SDD.

[0056] FIGS. 9A, 9B, and 9C are SEM images of 40:60 Comp. 1 : Eudragit L100 SDD.

[0057] FIGS. 10A, 10B, and 10C are SEM images of 60:40 Comp. 1 : Eudragit LI 00 SDD.

[0058] FIGS. 11A, 11B, and 11C are SEM images of 100% Spray Dried Comp. 1.

[0059] FIG. 12 is a graph showing particle size distribution of the SDDs of the present disclosure.

[0060] FIG. 13 is a table of non-sink dissolution in biorelevant media for the SDDs of the present disclosure.

[0061] FIG. 14 shows dynamic vapor sorption (DVS) plots for the six lead SDDs.

[0062] FIG. 15 shows Tgas a function of relative humidity for the six lead SDDs.Attorney Docket No. 143989.005502

[0063] FIG. 16 shows an assay and impurities chromatogram overlap for the six lead SDDs.DETAILED DESCRIPTION

[0064] Before compounds, compositions and methods are described in detail, it is to be understood that this disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0065] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0066] As used in this document, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term “comprising” means “including, but not limited to.”

[0067] As used herein, the term “about” means plus or minus up to 10% of the numerical value of the number with which it is being used. For example, “about 50%” means in the range of 45-55% and also includes exactly 50%.

[0068] “Administering,” when used in conjunction with the compounds of the disclosure, means to administer a compound directly into or onto a target tissue or to administer a compound systemically or locally to a patient or other subject.Attorney Docket No. 143989.005502

[0069] The term “animal” as used herein includes, but is not limited to, humans and nonhuman vertebrates such as wild, experimental, domestic, and farm animals, and pets. As used herein, the terms “subject,” “individual,” and “patient,” are used interchangeably and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like.

[0070] The term “improves” is used to convey that the disclosure changes either the characteristics and / or the physical attributes of the tissue to which it is being provided, applied or administered. The term “improves” may also be used in conjunction with a disease state such that when a disease state is “improved” the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed, or averted.

[0071] The term “inhibiting” includes the blockade, aversion of a certain result or process, or the restoration of the converse result or process. In terms of treatment by administration of a compound of the disclosure, “inhibiting” includes protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, diminishing or eliminating a disease, condition, or disorder.

[0072] As used herein, the term “free base” refers to a non-salt or non-cocrystal form of a compound as described herein.

[0073] The term “salts” can include acid addition salts or addition salts of free bases. The salts as described herein may be pharmaceutically acceptable. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include but are not limited to salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, or phosphorus acids, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, hydrochloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and theAttorney Docket No. 143989.005502 like. Salts of amino acids are also contemplated, such as arginate, gluconate, galacturonate, and the like.

[0074] As used herein, the term “cocrystal” refers to a crystalline form that includes one or more compounds in the crystal lattice. Cocrystalline forms include crystalline molecular complexes of two or more compounds bonded together in a crystal lattice through non-ionic interactions, as would be commonly understood by one of ordinary skill in the art. As used herein, the term “a pharmaceutically acceptable cocrystal” of, for example, the compounds described herein, refers to the compounds of the present disclosure cocrystallized with a pharmaceutically acceptable compound. Pharmaceutically acceptable compounds will be familiar to those skilled in the art and may include, but are not limited to, non-toxic organic or inorganic acids, amino acids, the like, and combinations thereof.

[0075] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. For example, a complex with water is known as a “hydrate.” Solvates of the compounds of the present disclosure are within the scope of this disclosure. The salts of the compound of any of the formulae described herein may form solvates (e.g., hydrates) and the present disclosure includes all such solvates. The meaning of the word “solvates” is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well established in the art.

[0076] The compounds disclosed herein, including free bases, salts, solvates, hydrates, complexes, and the like, may be in a crystalline form, an amorphous form, or combinations thereof. The compounds disclosed herein may be in the form of cocrystals or co-amorphous systems. The amount of a crystalline or amorphous form in the compounds and compositions described herein is not particularly limited, unless otherwise stated. That is, unless otherwise stated, the compounds described herein may include any amount of either crystalline or amorphous forms.

[0077] As used herein, unless specifically indicated, the term “active ingredient” refers to a compound of any of the formulae as described herein. The terms “active ingredient” and “active pharmaceutical ingredient (API)” may be used interchangeably.Attorney Docket No. 143989.005502

[0078] The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are generally regarded as safe and nontoxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other ingredients, and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a subject. In some embodiments, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The phrase “pharmaceutically acceptable salt(s)”, as used herein, includes those salts of compounds of the disclosure that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the disclosure or in compounds identified pursuant to the methods of the disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodidc, nitrate, sulfate, bisulfatc, phosphate, acid phosphate, isonicotinatc, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1 ’-methylene -bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0079] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, protect against, or improve an unwanted condition or disease of a subject.

[0080] A “therapeutically effective amount” or “effective amount” of a compound or composition of the disclosure is a predetermined amount which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect or physician observes a change). The effectAttorney Docket No. 143989.005502 contemplated herein includes medical therapeutic treatment, as appropriate. The specific dose of a compound administered according to this disclosure to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment. The effective amount administered will be determined by the physician in the light of the foregoing relevant circumstances and the exercise of sound medical judgment. A therapeutically effective amount of a compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0081] The terms “treat”, “treated”, or “treating” as used herein refers to therapeutic treatment measures, wherein the object is to protect against (partially or wholly) or slow down (e.g, lessen or postpone the onset of) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results such as partial or total restoration or inhibition in decline of a parameter, value, function or result that had or would become abnormal. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent or vigor or rate of development of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether or not it translates to immediate lessening of actual clinical symptoms, or enhancement or improvement of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0082] In some embodiments, there is provided a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Attorney Docket No. 143989.005502Formula I or a pharmaceutically acceptable salt or cocrystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, and one or more pharmaceutically acceptable excipients.

[0083] In some embodiments, the pharmaceutical composition includes the compound of Formula I in the form of a free base or a salt of cocrystal of sulfuric acid, tartaric acid, citric acid, maleic acid, hydrochloric acid, or combinations thereof. For example, in some embodiments, the pharmaceutical composition includes the compound of Formula I as a free base. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a hydrochloride salt. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a citrate salt. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a cocrystal with citric acid. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a maleate salt. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a tartrate salt. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a cocrystal with tartaric acid. In some embodiments, the pharmaceutical composition includes the compound of Formula I as a sulfate salt.

[0084] In some embodiments, the pharmaceutical composition is in an oral dosage form. For example, the pharmaceutical composition may be in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, a spray dried dispersion, an extrudate, a suspension, or other oral dosage form known to those skilled in the art. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is in the form of a solid dispersion which may further include one or more pharmaceutically acceptable excipients.

[0085] In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof is in tablet form. In someAttorney Docket No. 143989.005502 embodiments, the compound of Formula I or pharmaceutically acceptable salt or cocrystal thereof is in an amorphous form. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt or cocrystal thereof is in a crystalline form.

[0086] In some embodiments, the pharmaceutical composition delivers the compound of Formula I to the patient’s small intestine, large intestine, or combinations thereof, such that the compound of Formula I is released and absorbed within the gut of a patient taking the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a pH-dependent release agent which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater. In some embodiments, at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 5.0 or above. In some embodiments, at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 7.0 or above, For example, in some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, and so forth, or any value contained within a range formed by any of the preceding values. The components of the pharmaceutical composition, including but not limited to enteric coatings, modified release agents, and other excipients can aid in the release of the compound of Formula I or a pharmaceutically acceptable salt thereof at or above a specific pH.

[0087] The pharmaceutical compositions of the present disclosure may, in some embodiments, be designed to maximize local availability in the gut of the patient. Without wishing to be bound by theory, the pharmaceutical compositions of the present disclosure may be capable of site specific delivery to the gut, such as the small intestine and / or large intestine. It will be understood by those skilled in the art that the various regions of gastrointestinal tract have different pH levels, and a pharmaceutical composition which is designed to dissolve and release an active agent at a particular pH may be advantageous in achieving targeted delivery to a specific region of the gut. The pharmaceutical compositions of the present disclosure may, without wishing to be bound by theory, allow targeted delivery of the active agent to a specific region of the patient’s gut without relying on high dosages to achieve the desired result.

[0088] In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 5 mg to about 1000 mg, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35Attorney Docket No. 143989.005502 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000, or any range or value contained within the preceding values. In some embodiments, the therapeutically effective amount of the compound of Formula I refers to the free base equivalent, in embodiments wherein the compound of Formula I is in the form of a salt or cocrystal as described herein.

[0089] The pharmaceutical composition of the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may include, in addition to the carrier, any suitable binder(s), disintegrant(s), lubricant(s), modified release agent(s), suspending agent(s), coating agent(s), surfactant(s) and / or solubilizing agent(s).

[0090] There may be different composition / formulation requirements depending on the different delivery systems. It is to be understood that not all of the compounds need to be administered by the same route. Likewise, if the composition includes more than one active component, then those components may be administered by different routes. By way of example, the pharmaceutical composition of the disclosure may be formulated to be delivered using a mini pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by multiple routes.Attorney Docket No. 143989.005502

[0091] Where appropriate, the pharmaceutical compositions can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions, or suspensions containing flavoring or coloring agents. For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0092] The pharmaceutical compositions of the present disclosure can be prepared and administered in the form of tablets, capsules, troches, ovules, elixirs, solutions, or suspensions, for immediate-, delayed-, modified-, sustained-, pulsed-, or controlled-release applications. The pharmaceutical compositions of the present disclosure may also be prepared and presented in the form of solutions, gels, syrups, or suspensions, or a dry powder for reconstitution with water or other suitable vehicle before use. Solid compositions such as tablets, capsules, lozenges, troches, pastilles, pills, boluses, powder, pastes, granules, pellets, bullets, or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well-known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

[0093] Oral preparations may optionally include various standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, glidants, dyes, disintegrants, odorants, sweeteners, surfactants, modified release agents, antiadhesive agents, and coatings. Some excipients may have multiple roles in the compositions, that is, act as both binders and disintegrants.

[0094] In some embodiments, the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof. Other excipients, particularly those used in gut-specific oral formulations, are also contemplated. In some embodiments, the pharmaceutical composition includes a modified release agent (such as a pH-dependent release agent or an enzymatic- dependent release agent) to target delivery of the compound of Formula I to the small intestine and / or colon. The modified release agent may include an enteric coating that dissolves at pH values at or above pH 5.0, and / or a coating that is digested by bacterial enzymes. Without wishing to be bound by theory, such a modifiedAttorney Docket No. 143989.005502 release agent may allow targeted release of the compound of Formula I or a pharmaceutically acceptable salt thereof to a target region of the gut.

[0095] In some embodiments, the diluent is selected from microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous calcium phosphate, anhydrous lactose, calcium carbonate, calcium lactate, calcium sulfate dihydrate, com starch, fructose, kaolin, lactose monohydrate, magnesium hydroxide, maltitol, maltose monohydrate, mannitol, sorbitol, sucrose, tribasic calcium phosphate, sodium citrate, glycine, croscarmellose sodium, ethanol, propylene glycol, glycerin, polyvinylpyrrolidone, cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, or any combination thereof.

[0096] In some embodiments, the disintegrant is selected from starch glycolate sodium, com starch, potato starch, tapioca starch, croscarmellose sodium, pre-gelatinized starch, sodium carboxymethylcellulose, alginates, resins, aqueous aluminum silicates, cross-linked polyvinylpyrrolidone, or any combination thereof.

[0097] In some embodiments, the surfactant is selected from poloxamer microprilled, sodium lauryl sulfate, polysorbates, or any combination thereof.

[0098] In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, glyceryl behenate, talc, carnauba wax, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, D,L leucine, sodium oleate, sodium stearyl fumarate, colloidal silicon dioxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylate-methacrylate copolymers, or any combination thereof.

[0099] In some embodiments, the color coating is selected from riboflavin, anthocyanin, paprika oleoresin, beet root, curcumin, indigo carmine, tartrazine, allura red, quinoline yellow, titanium dioxide, iron oxide, mica, betacarotene, or any combination thereof.

[0100] In some embodiments, the dispersion agent includes hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid-methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, ammonio methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion, or combinations thereof.Attorney Docket No. 143989.005502

[0101] In some embodiments, the binder includes a polyethylene glycol-polyvinyl alcohol graft copolymer. In some embodiments, the pharmaceutical composition does not include hydroxypropyl methylcellulose or derivatives thereof.

[0102] In some embodiments, the pharmaceutical composition includes the compound of Formula I and a dispersion agent in a solid dispersion. The solid dispersion may have an average particle size of about 1 pm to about 100 pm, such as about 1 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 30 pm, about 40 pm, about 50 pm, about 60 pm, about 70 pm, about 80 pm, about 90 pm, about 100 pm, or any range or value contained therein.

[0103] In some embodiments, the solid dispersion contains less than about 5% total impurities as measured by assay and related substances testing. For example, the solid dispersion may contain less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or any range or value contained therein, of total impurities. Without wishing to be bound by theory, the dispersion agent which is used in the solid dispersion may contribute to one or more decomposition pathways of the compound of Formula I. One of ordinary skill in the art may, accordingly, select a dispersion agent which minimizes the degradation of the compound of Formula I and thus allows a solid dispersion with fewer impurities to be obtained. It is desirable to minimize the impurities in the solid dispersion, so as to similarly minimize the impurities in the pharmaceutical composition.

[0104] In some embodiments, the solid dispersion is stable for at least three months at 25 °C / 60%RH in open packaging, and 40 °C / 75%RH in open and closed packaging. Stability may be evaluated by comparing an initial characterization of the solid dispersion to characterization after one, two, or three months. Characterization may include but is not limited to differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), assay and related substances testing, or any other characterization method known to those skilled in the art. In some embodiments, the amount of total impurities in the solid dispersion after three months does not increase by more than five percentage points, relative to the initial amount of total impurities. For example, in embodiments wherein the initial total impurities are 1%, the total impurities after three months are, in some embodiments, no more than 6%.

[0105] The pharmaceutical composition or unit dosage form of the disclosure may be administered according to a dosage and administration regimen defined by routine testing in the light of the guidelines given above in order to obtain optimal activity while minimizingAttorney Docket No. 143989.005502 toxicity or side effects for a particular subject. The dosing regimen of the pharmaceutical composition of the disclosure is not particularly limited and may be determined by one of skill in the art.

[0106] The dosage of the compounds of the disclosure may vary according to a variety of factors such as underlying disease conditions, the individual's condition, weight, sex and age, and the mode of administration. An effective amount for treating a disorder can easily be determined by empirical methods known to those of ordinary skill in the art, for example by establishing a matrix of dosages and frequencies of administration and comparing a group of experimental units or subjects at each point in the matrix. The exact amount to be administered to a subject will vary depending on the state and severity of the disorder and the physical condition of the subject. A measurable amelioration of any symptom or parameter can be determined by a person skilled in the art or reported by the subject to the physician. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of urinary tract disorders is within the scope of the disclosure. Clinically significant attenuation or amelioration means perceptible to the subject and / or to the physician. It will be understood that the pharmaceutical formulations of the disclosure need not necessarily contain the entire amount of the compound that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of divided doses of such pharmaceutical formulations.

[0107] There is provided a method of making a pharmaceutical composition including preparing a solid dispersion including a compound of Formula I:Formula I or a pharmaceutically acceptable salt or a co-crystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater,Attorney Docket No. 143989.005502 and one or more pharmaceutically acceptable excipients, and forming the solid dispersion into an oral dosage form.

[0108] In some embodiments, the compound of Formula I is in the form of a free base or a salt or cocrystal of sulfuric acid, tartaric acid, citric acid, maleic acid, hydrochloric acid, or combinations thereof.

[0109] In some embodiments, the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof. In some embodiments, the dispersion agent comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid-methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, ammonio methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion, or combinations thereof.

[0110] In some embodiments, the oral dosage form is in the form of a tablet, a capsule, a powder, a pellet, or a lozenge. The oral dosage form may include a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof, such as about 5 mg to about 500 mg. For example, the oral dosage form may include about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or any range or value contained therein, of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, preparing the solid dispersion includes combining the compound of Formula I with a dispersion agent. The dispersion agent may be any dispersionAttorney Docket No. 143989.005502 agent described herein, including but not limited to hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid- methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, ammonio methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer dispersion, or combinations thereof. In some embodiments, the dispersion agent may include Soluplus, HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMCP-HP55, Eudragit L100, Eudragit S100, PVP-K30, the like, or combinations thereof.

[0112] The ratio of the compound of Formula 1 to the dispersion agent is not particularly limited. For example, the ratio of the compound of Formula 1 : dispersion agent may be about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30, about 80:20, about 90:10, or any range or value contained therein. In some embodiments, the solid dispersion does not include a dispersion agent, and includes only the compound of Formula 1. In some embodiments, the solid dispersion does not include a dispersion agent and includes the compound of Formula 1 and one or more pharmaceutically acceptable excipients, such as excipients other than dispersion agents.

[0113] In some embodiments, preparing the solid dispersion includes spray drying, hot melt extrusion, freeze drying, or combinations thereof. In some embodiments, the compound of Formula 1 and the one or more pharmaceutically acceptable excipients are spray dried to form a solid dispersion. Spray drying may utilize a solvent, such as for example acetone, water, methanol, the like, or combinations thereof.

[0114] In some embodiments, forming the oral dosage form includes compression, encapsulation, extrusion, suspension, dissolving, grinding and / or milling, the like, combinations thereof, or any other method for forming an oral dosage form known to those skilled in the art. In some embodiments, forming the oral dosage form includes transferring the solid dispersion into a sachet, a stick pack, or other container, such that the solid dispersion is administered to the patient in a powder form.

[0115] In some embodiments, the pharmaceutical composition of the present disclosure is in the form of a soft gel capsule. A soft gel capsule may contain a solution of the compound of Formula I or a pharmaceutically acceptable salt thereof, along with any of the excipients or other components as described herein. In such an embodiment, the method of making theAttorney Docket No. 143989.005502 pharmaceutical composition may omit the step of forming a solid dispersion and may instead include a step of preparing a solution of the compound of Formula I or a pharmaceutically acceptable salt thereof and forming the solution into an oral dosage form such as a soft gel capsule.

[0116] There is provided a method of treating an inflammatory disease in a patient in need thereof, the method including orally administering to the patient a pharmaceutical composition including a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt or cocrystal thereof and a pH-dependent release agent, a enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, thereby treating the inflammatory disease.

[0117] In some embodiments, the inflammatory disease is Crohn’s disease, colitis, irritable bowel syndrome (IBS), or combinations thereof. In some embodiments, the inflammatory disease is an inflammatory dermatologic condition including but not limited to atopic dermatitis, psoriasis, lichen planus, vitiligo, lupus, dermatomyositis, hidradenitis suppurativa, the like, or combinations thereof. In some embodiments, the inflammatory disease is an inflammatory neurologic disorder including but not limited to neuromyelitis optica, antimyelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, the like, and combinations thereof. In some embodiments, the inflammatory disease is an inflammatory respiratory disease, including but not limited to asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, the like, and combinations thereof. In some embodiments, the inflammatory disease is a rheumatologic disease, including but not limited to osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Sjogren’s syndrome, gout,Attorney Docket No. 143989.005502 scleroderma, infectious arthritis, juvenile idiopathic arthritis, polymyalgia rheumatica, the like, and combinations thereof.

[0118] In some embodiments, the inflammatory disease includes diseases wherein activation of AhR leads to suppression of inflammation, barrier repair, and reduced oxidative stress including atopic dermatitis and psoriasis. In some embodiments, the inflammatory disease includes diseases wherein activation of AhR leads to suppression of inflammation, barrier repair, and reduced oxidative stress including vitiligo, lichen planus, and cutaneous lupus and dermatomyositis. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to suppression of inflammation, barrier repair, and reduced oxidative stress including granuloma annulare, necrobiosis lipoidica diabeticorum, and sarcoid. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to suppression of inflammation, barrier repair, and reduced oxidative stress including bullous pemphigoid, epidermolysis bullosa acquisita, and herpes gestationis. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to barrier repair, suppression of inflammation and suppression of oxidative stress including, but not limited to, ulcerative colitis, Crohn’s disease and eosinophilic esophagitis. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to barrier repair, suppression of inflammation (including, but not limited to TH1, Th2, Thl7 and neutrophilic inflammation) and suppression of oxidative stress including, but not limited to, steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to barrier repair, suppression of inflammation and suppression of oxidative stress including, but not limited to, blepharitis, dry eye disease and uveitis. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to suppression of inflammation and suppression of oxidative stress including, but not limited to, systemic lupus erythematosus, psoriatic arthritis, and rheumatoid arthritis. In some embodiments, the inflammatory disease includes diseases wherein AhR activation leads to suppression of inflammation and suppression of oxidative stress including, but not limited to, Multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. In some embodiments, the inflammatory disease includes diseases wherein AhR activation can suppress inflammation and reduce oxidative stress that contribute to disease pathophysiology and where Nrf2 activation can lead to improvement and remodeling of extracellular matrix including, but not limited to, fibrotic disease of the lung such as idiopathic pulmonary fibrosis, fibrotic diseaseAttorney Docket No. 143989.005502 of the skin including, but not limited to, morphea, scleroderma, and systemic fibrotic diseases including systemic sclerosis.

[0119] In some embodiments, the inflammatory disease includes Atopic dermatitis, Psoriasis, Seborrheic dermatitis, Rosacea, Acne (such as Acne vulgaris, Acne congloblata, Paular pustular acne, Nodulo-cystic acne, or combinations thereof), Lichen planus, Vitiligo, Cutaneous lupus, discoid lupus, subacute cutaneous lupus, Dermatomyositis, Graft versus host disease, Alopecia Areata, Alopecia Totalis, Alopecia universalis, Lichen nitidus, Granuloma annulare, Necrobiosis lipoidica diabeticorum, Sarcoid, bullous pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, Ulcerative colitis, Crohn’s disease, Eosinophilic esophagitis, Sjogren’s disease, steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema, emphysema, Blepharitis, Dry eye disease, Meibomian gland dysfunction, Uveitis, Age-related macular degeneration (AMD), Systemic Lupus Erythematosus (SLE), Dermatomyositis, Myositis, Rheumatoid Arthritis, Psoriatic Arthritis, Lupus erythematosus, Osteoarthritis, Synovitis, Ankylosing spondylitis, Multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, idiopathic pulmonary fibrosis, morphea, scleroderma, systemic sclerosis, or combinations thereof.

[0120] In some embodiments, administering the pharmaceutical composition as described herein delivers the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof to the patient’s small intestine, large intestine, or combinations thereof.

[0121] In some embodiments, the pharmaceutical composition orally administered to the patient is in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, a spray dried dispersion, an extrudate, or a suspension. In some embodiments, the pharmaceutical composition orally administered to the patient includes the compound of Formula I in the form of a free base or a salt or cocrystal of sulfuric acid, tartaric acid, citric acid, maleic acid, hydrochloric acid, or combinations thereof.

[0122] In some embodiments, the therapeutically effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof is about 5 mg to about 1 ,000 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof is about 5 mg, about 10 mg, about 15 mg, about 20Attorney Docket No. 143989.005502 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or any range or value contained therein.

[0123] The pharmaceutical composition for orally administering to the patient in need thereof may include one or more pharmaceutically acceptable excipients as described herein, including a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, , an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

[0124] The methods and compositions of the present disclosure may be employed in the disclosed embodiments, which may be combined as appropriate to form new embodiments.EXAMPLES

[0125] The following examples were carried out according to embodiments of the present disclosure.

[0126] Example 1 - Solid Dispersion Formulation Screening

[0127] Nine solid dispersion formulations with the compound of Formula I were manufactured for feasibility screening. These formulations were spray dried from neat acetone or a 95:5 acetone and water blend, then secondary dried in a tray dryer to remove residual solvent remaining after spray drying. In this operation, the “wet” spray-dried dispersion (SDD) was held at 40°C in a convection tray oven for approximately 24 hours. GC-HS was used to measure the residual solvent in the compound of Formula I SDDs. Some of the SDD formulations had acceptable levels of residual solvent, as set forth by the International Conference on Harmonization (ICH) but some were also found to still be solvent wet. The “wet” SDD formulations were dried for an additional 24 hours at 50 °C and, despite still beingAttorney Docket No. 143989.005502 above the ICH limit of 5000 ppm for acetone, were subsequently characterized. A summary of spray drying parameters, yields, residual solvent, and appearance are shown in TABLE 1. The compound of Formula I is represented by “Comp. 1” in the following tables and examples.

[0128] TABLE 1

[0129] The spray-dried dispersions in TABLE 1 were characterized by Appearance, gas chromatography (GC), X-ray diffraction (XRD), modulated differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), particle size distribution (PSD), and non-sink dissolution in biorelevant media. The formulations were characterized by Karl Fischer titration (KF), dynamic vapor sorption (DVS), and assay and related substances.Attorney Docket No. 143989.005502

[0130] The appearance of all nine SDDs were off-white powders with a slightly yellow tinge.

[0131] SDD residual solvent content was tested following tray drying and prior to any additional analytical testing. After the initial drying step, the 80:20 Comp. 1 :HPMCAS-L, 40:60 Comp. l :Eudragit L100, 60:40 Comp. l :Eudragit L100, and 100% Spray Dried Comp. 1 were still solvent ‘wet’ with acetone above the ICH limit (5000 ppm). This indicated that the compound of Formula I does not dry easily, without wishing to be bound by theory. Eudragit LI 00 also retains solvent, so the combination of the two likely contributed to the SDDs remaining solvent ‘wet’. After the additional drying, these four SDDs retained acetone levels higher than the ICH limit of 5000 ppm, but were characterized with the known manufacturing risk.

[0132] TABLE 2

[0133] Thermal analysis by mDSC showed all dispersions had a single Tgindicating a homogeneous amorphous solid dispersion. The 80:20 Comp. 1 :HPMCAS-L SDD had a crystallization event at the end of the scan, as did the 60:40 Comp. l:Eudragit LI 00. The 100% Spray Dried Comp. 1 experienced both a crystallization event and a melt. This indicates potential for physical instability in the higher loaded SDD formulations, as well as formulations containing Eudragit LI 00. However, this is only a noted risk. To ensure long-term physical stability, an SDD should be stored at least 10 °C below the Tgat a given condition so that mobility of the drug in the dispersion is low. Based on the observed thermal data and risks associated, SDDs should still be physically stable if stored at room temperature. The mDSC data is summarized in TABLE 3 and FIG. 1.Attorney Docket No. 143989.005502

[0134] TABLE 3

[0135] XRPD indicated that the SDDs were amorphous dispersions with no crystalline peaks observed. The diffractograms are shown in FIG. 2.

[0136] Surface morphology of the SDD particles was characterized using scanning electron microscopy. The SEM micrographs in FIGS. 3A-3C, FIGS. 4A-4C, FIGS. 5A-5C, FIGS. 6A-6C, FIGS. 7A-7C, FIGS. 8A-9C, FIGS. 9A-9C, FIGS. 10A-10C, and FIGS. 11A- 11C show the SDDs captured at 500, 1500, and 5000x magnification. Typical SDD morphology was observed including collapsed and uncollapsed spheres with smooth surfaces. No crystalline material was observed in any sample.

[0137] Particle sizes for the different SDDs are generally uniform and in the same size class. Some plots and measurements are broad, likely due to agglomeration. Particle size data is shown in FIG. 12 and TABLE 4.

[0138] TABLE 4Attorney Docket No. 143989.005502

[0139] The dissolution performance of the feasibility SDDs and bulk Comp. 1 was tested in a non-sink dissolution in biorelevant media experiment. The design of this experiment is meant to rank-order formulations. Samples were tested at multiple timepoints for both total drug by microcentrifuge, which may include micelles and colloidal species, and freely dissolved drug by ultracentrifuge. Significant enhancement over the crystalline API was observed in total drug measurements. The Eudragit LI 00 formulations provided the most solubility enhancement. Soluplus and HPMCAS H had noticeably poorer performance relative to all other formulations, while all HPMCAS-L formulations, the HPMCAS-M SDD, and the 100% Spray Dried Comp. 1 performed similarly, but not quite at the level of the Eudragit LI 00 SDDs. Overall levels of freely dissolving drug were similar for all SDDs except for the Soluplus formulation. For Soluplus, the dissolved drug appeared to be so efficiently sequestered into colloids and micelles that measured freely solubilized drug was lower than concentrations represented by crystalline API. Free drug solubility was most significantly enhanced for the 60:40 Comp. 1 :HPMCAS-L and both loadings of Eudragit LI 00 formulations. The following SDD formulations were further evaluated:

[0140] 40:60 Comp. 1:HPMCAS-M

[0141] 40:60 Comp. 1 :HPMCAS-L

[0142] 60:40 Comp. l :Soluplus

[0143] 40:60 Comp. l :Eudragit LI 00Attorney Docket No. 143989.005502

[0144] 60:40 Comp. l :Eudragit LI 00

[0145] 100% Spray Dried Comp. 1

[0146] The formulations were selected for further testing based on the drug dissolution rate, since free drug levels were mostly similar across different formulations. Soluplus was included due to the high propensity to form drug species, and the potential for resupply of free drug from species in vivo. Dissolution results are shown in FIG. 13.

[0147] The six SDDs selected for further evaluation were also characterized by KF, DVS, Tgvs. RH, and assay and related substances.

[0148] Initial water content was low and was similar for 100% spray dried Comp. 1 and dispersions of Comp. 1 with HPMCAS, Eudragit LI 00 and Soluplus. Water content data is shown in TABLE 5.

[0149] TABLE 5

[0150] The DVS of the lead Comp. 1 SDD formulations show that 100% Spray Dried Comp. 1 and the Soluplus formulations have the lowest tendencies to uptake water, whereas the HPMCAS formulations have the highest tendency to uptake water. The Eudragit LI 00 formulation at higher loading takes on less water than the lower loading SDD. Generally, all formulations lose the majority of the water content in the desorption process, but about lwt% of additional water is retained. These results are displayed in TABLE 6 and FIG. 14.

[0151] TABLE 6Attorney Docket No. 143989.005502

[0152] The physical stability of the lead SDDs was evaluated by equilibrating SDD to selected relative humidities: 32.8%, 50%, and 75.3% RH, then measuring the Tgby mDSC. Results are reported in TABLE 7 and FIG. 15. All lead SDD formulations except for the Eudragit LI 00 SDDs have a Tgthat is low at high humidity conditions and is predicted to require protective packaging (i.e., desiccant, foil-foil seal, etc.) to achieve sufficient long-term physical stability of the SDDs. SDD should be stored at least 10 °C below the Tgto ensure long-term physical stability.

[0153] TABLE 7Attorney Docket No. 143989.005502

[0154] Assay and related substances testing was performed on the six selected formulations in preparation for stability initiation. Assay values were on target for the six selected formulations. Impurity levels were lowest in the Soluplus and 100% Spray Dried Comp. 1 formulations, which may be due to the lack of acidic polymers, without wishing to be bound by theory. Impurities at RRT 1.35 and 1.44 showed a slight increase in the presence of HPMCAS and Eudragit LI 00 polymers, and was monitored on stability for additional growth. Results are shown in TABLE 8 and FIG. 16.

[0155] TABLE 8Attorney Docket No. 143989.005502

[0156] Example 2 - Spray Dried Dispersion Stability

[0157] The following SDD formulations were aged for 3 months at 25 °C / 60%RH in open packaging, and 40 °C / 75%RH in open and closed packaging per stability protocol RD-ST-22- 963 to rapidly assess the physical and chemical stability.

[0158] 40:60 Comp. 1:HPMCAS-M

[0159] 40:60 Comp. 1:HPMCAS-L

[0160] 60:40 Comp. LSoluplus

[0161] 40:60 Comp. l :Eudragit LI 00

[0162] 60:40 Comp. l :Eudragit LI 00

[0163] 100% Spray Dried Comp. 1

[0164] The aged SDDs were evaluated by appearance, water content by KF, and assay and impurities at 1 and 2 months, then by appearance, water content by KF, amorphous character by XRPD, thermal properties by mDSC, and assay and impurities by HPLC at 3 months.

[0165] The SDDs were stored in an open container, wherein the powder was placed directly in an open HOPE bottle without a cap, with cotton batting in the neck of the bottle, and a closed container, wherein the powder was placed in amber scintillation vial and inserted into a foil- foil pouch and heat induction sealed. 0.5 g silica desiccant gel added in between vial and foil bag. Approximately 0.5 g of SDD was placed in each container and the containers stored upright.

[0166] Appearance testing showed slight changes in physical appearance after a short period on stability. After 3 months, significant changes were noted for samples held at 40 °C and 75%RH open. Sample consistency did not seem to change, but the samples were muchAttorney Docket No. 143989.005502 darker after exposure to harsh conditions for 3 months. Appearance is summarized in TABLE 9.

[0167] TABLE 9Attorney Docket No. 143989.005502Attorney Docket No. 143989.005502

[0168] Water content of the SDDs decreases at 25 °C / 60%RH open, but gradually increases over time, likely as a result of equilibration over 3 months. At 40 °C / 75%RH closed, the same phenomenon occurs, with less drying and additional water uptake, likely due to the presence of desiccant and increased temperature. Increased temperature and humidity at 40 °C / 75%RH open greatly increase the water uptake for all formulations. Water content over 3 months is shown in TABLE 10.

[0169] TABLE 10Attorney Docket No. 143989.005502Attorney Docket No. 143989.005502

[0170] XRPD analysis of the aged SDD samples showed all formulations remain amorphous with no detectable crystalline material after 3 months. Diffractograms are shown in Figure 27, Figure 28, Figure 29, Figure 30, Figure 31, and Figure 32.

[0171] Stability mDSC data was collected at 3 months. After 3 months at stability conditions, samples had no significant change in thermal properties. Data are presented in TABLE 11, TABLE 12, TABLE 13, TABLE 14, TABLE 15, and TABLE 16.

[0172] TABLE 11

[0173] TABLE 12Attorney Docket No. 143989.005502

[0174] TABLE 13

[0175] TABLE 14Attorney Docket No. 143989.005502

[0176] TABLE 15

[0177] TABLE 16

[0178] Assay and impurities analysis of the aged SDD samples showed significant increases in impurities over time in the presence of humidity and high temperatures. Individual impurities were not reliably integrated between RRT 1.12 and 1.37 due to coelution ofmultiple growing impurity peaks, but total impurity levels can be used to track impurity growth. The impurities noted at initial analysis at RRT 1.34-1.36 are also not reliably integrated, but the RRT 1.44 impurity shows clear growth in increased humidity and temperatures for all formulations. Samples experience limited impurity growth at 25 °C and 60%RH open, and a significant increase at 40 °C and 75%RH open. More significant impurity growth occurs in the presence of acidic polymers but is not dependent on the polymer loading in the SDD formulations. This is shown by the similar growth levels observed between 40:60 Comp. l :Eudragit L100 and 60:40 Comp. LEudragit L100 SDDs. However, between HPMCAS and Eudragit LI 00, the Eudragit LI 00 formulations experience more significant impurity growth.Attorney Docket No. 143989.005502The 60:40 Comp. ESoluplus SDD experiences the lowest levels of impurity growth. This indicates that the formulation with the lowest overall risk for chemical stability is likely the 60:40 Comp. 1 :Soluplus SDD. However, the low levels of impurity growth in all formulations at 25 °C and 60%RH open indicate that storing samples at room temperature with protection from humidity will likely protect the SDDs from any impurity growth moving forward.

[0179] The assay and impurities results for 40:60 Comp. 1 : HPMCAS-M SDDs are shown in TABLE 17.

[0180] TABLE 17Attorney Docket No. 143989.005502

[0181] The assay and impurities results for 40:60 Comp. 1 : HPMCAS-L SDDs are shown in TABLE 18.

[0182] TABLE 18Attorney Docket No. 143989.005502

[0183] The assay and impurities results for 60:40 Comp. 1 : Soluplus SDDs are shown inTABLE 19.

[0184] TABLE 19Attorney Docket No. 143989.005502

[0185] The assay and impurities results for 40:60 Comp. 1: Eudragit LI 00 SDDs are shown in TABLE 20.

[0186] TABLE 20Attorney Docket No. 143989.005502

[0187] The assay and impurities results for 60:40 Comp. 1: Eudragit LI 00 SDDs are shown in TABLE 21.

[0188] TABLE 21Attorney Docket No. 143989.005502

[0189] The assay and impurities results for 100% Spray Dried Comp. 1 SDDs are shown in TABLE 22.

[0190] TABLE 22Attorney Docket No. 143989.005502

[0191] This disclosure is not limited to the particular systems, devices and methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope.

[0192] In the above detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0193] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0194] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity.

[0195] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” theAttorney Docket No. 143989.005502 term “includes” should be interpreted as “includes but is not limited to,” et cetera). While various compositions, methods, and devices are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and devices can also “consist essentially of’ or “consist of’ the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups. It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present.

[0196] For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (for example, “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations.

[0197] In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, et cetera). In those instances where a convention analogous to “at least one of A, B, or C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, et cetera). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplateAttorney Docket No. 143989.005502 the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0198] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0199] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 compounds refers to groups having 1, 2, or 3 compounds. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 compounds, and so forth.

[0200] Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments.

Claims

Attorney Docket No. 143989.005502CLAIMSWhat is claimed is:

1. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt or cocrystal thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

3. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a free base.

4. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a hydrochloride salt.

5. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a citrate salt.

6. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a cocrystal with citric acid.Attorney Docket No. 143989.0055027. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a maleate salt.

8. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a tartrate salt.

9. The pharmaceutical composition of claim 1, comprising the compound of Formula I as a cocrystal with tartaric acid.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in an oral dosage form.

11. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, an extrudate, a spray dried dispersion, or a suspension.

12. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount is about 5 mg to about 1,000 mg.

13. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount is about 5 mg to about 250 mg.

14. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount is about 250 mg to about 500 mg.

15. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount is about 500 mg to about 1000 mg.

16. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, a pH-adjusting agent, or combinations thereof.

17. The pharmaceutical composition of claim 16, wherein the dispersion agent comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid-methyl methacrylate copolymer, polymethylmethacrylic acid-ethylAttorney Docket No. 143989.005502 acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, or combinations thereof.

18. The pharmaceutical composition of claim 1, comprising the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof and a dispersion agent in a solid dispersion.

19. A method of making a pharmaceutical composition, comprising: preparing a solid dispersion comprising a compound of Formula I:or a pharmaceutically acceptable salt thereof, a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, and one or more pharmaceutically acceptable excipients, and forming the solid dispersion into an oral dosage form.

20. The method of claim 19, wherein the compound of Formula 1 is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

21. The method of claim 19, wherein the one or more pharmaceutically acceptable excipients comprise a diluent, a binder, a filler, a buffer, a lubricant, a glidant, a dye, a disintegrant, a solubilizer, an odorant, a sweetener, a surfactant, a modified release agent, an antiadhesive agent, a coating, a dispersion agent, or combinations thereof.

22. The method of claim 21, wherein the dispersion agent comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalateAttorney Docket No. 143989.005502(HPMCP), polymethylmethacrylate, polyethylene glycol, polyvinylpyrrolidone, polymethacrylic acid-methyl methacrylate copolymer, polymethylmethacrylic acid-ethyl acrylate copolymer, polyethylene glycol 6000 / vinylcaprolactam / vinyl acetate, or combinations thereof.

23. The method of claim 19, wherein the oral dosage form is in the form of a tablet, a capsule, a powder, pellets, a lozenge, a soft gelatin capsule, an extrudate, a spray dried dispersion, or a suspension.

24. A method of treating an inflammatory disease in a patient in need thereof, the method comprising: orally administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:Formula I or a pharmaceutically acceptable salt or cocrystal thereof and a pH-dependent release agent, an enzymatic-dependent release agent, or a combination thereof, which releases the compound of Formula I or a pharmaceutically acceptable salt or cocrystal thereof at a pH of 5.0 or greater, thereby treating the inflammatory disease.

25. The method of claim 24, wherein the inflammatory disease is Atopic dermatitis, Psoriasis, Seborrheic dermatitis, Rosacea, Acne vulgaris, Acne congloblata, Paular pustular acne, Nodulo-cystic acne, Lichen planus, Vitiligo, Cutaneous lupus, discoid lupus, subacute cutaneous lupus, Dermatomyositis, Graft versus host disease, Alopecia Areata, Alopecia Totalis, Alopecia universalis, Lichen nitidus, Granuloma annulare, Necrobiosis lipoidica diabeticorum, Sarcoid, bullous pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, Ulcerative colitis, Crohn’s disease, Eosinophilic esophagitis, Sjogren’s disease,Attorney Docket No. 143989.005502 steroid responsive asthma, steroid unresponsive asthma, chronic obstructive pulmonary disease, hereditary emphysema, emphysema, Blepharitis, Dry eye disease, Meibomian gland dysfunction, Uveitis, Age-related macular degeneration (AMD), Systemic Lupus Erythematosus (SLE), Dermatomyositis, Myositis, Rheumatoid Arthritis, Psoriatic Arthritis, Lupus erythematosus, Osteoarthritis, Synovitis, Ankylosing spondylitis, Multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein antibody disorder, autoimmune encephalitis, acute disseminated encephalomyelitis, transverse myelitis, neurosarcoidosis, idiopathic pulmonary fibrosis, morphea, scleroderma, systemic sclerosis, or combinations thereof.

26. The method of claim 24, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a powder, a pellet, a lozenge, a soft gelatin capsule, an extrudate, a spray dried dispersion, or a suspension.

27. The method of claim 24, wherein the therapeutically effective amount is about 5 mg to about 1,000 mg.

28. The method of claim 24, wherein the therapeutically effective amount is about 5 mg to about 250 mg.

29. The method of claim 24, wherein the therapeutically effective amount is about 250 mg to about 500 mg.

30. The method of claim 24, wherein the therapeutically effective amount is about 500 mg to about 1000 mg.

31. The method of claim 24, wherein the compound of Formula I is in the form of a free base or a salt or cocrystal of hydrochloric acid, citric acid, maleic acid, tartaric acid, sulfuric acid, or combinations thereof.

32. The method of claim 24, wherein the compound of Formula I is in the form of a hydrochloride salt.

33. The method of claim 24, wherein the compound of Formula I is in the form of a citrate salt.

34. The method of claim 24, wherein the compound of Formula I is in the form of a cocrystal with citric acid.Attorney Docket No. 143989.00550235. The method of claim 24, wherein the compound of Formula I is in the form of a maleate salt.

36. The method of claim 24, wherein the compound of Formula I is in the form of a tartrate salt.

37. The method of claim 24, wherein the compound of Formula I is in the form of a cocrystal with tartaric acid.

38. The method of claim 24, wherein the pharmaceutical composition delivers the compound of Formula I to the patient’s small intestine, large intestine, or combinations thereof.

39. The method of claim 24, wherein at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 5.0 or above.

40. The method of claim 24, wherein at least about 90% of the compound of Formula I or a pharmaceutically acceptable salt thereof is released at a pH of about 7.0 or above.

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