Therapeutic compounds, formulations, and uses thereof

Abstract

Provided herein is a solid amorphous dispersion, composition, and solid oral dosage form that comprises the compound of formula (I).In certain examples, such compositions comprise polymer excipients and optionally crystallization-inhibiting polymers.In certain examples, such compositions are useful in treating fibrosis, cancer, and / or inflammatory diseases / disorders.

Description

[Technical field]

[0001] cross reference This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 268,723, filed March 1, 2022, which is incorporated by reference in its entirety herein. Summary of the Invention

[0002] Disclosed herein, in certain embodiments, are solid amorphous dispersions comprising a compound of formula (I) and a polymeric excipient, methods of making the dispersions, compositions comprising the dispersions, oral dosage forms comprising the compositions, and methods of treating a disease or disorder (e.g., cancer, fibrosis, inflammatory disease or disorder) comprising administering an oral dosage form comprising the composition.

[0003] In certain embodiments, a) Formula (I)

[0004] [ka] or a pharma- ceutically acceptable salt thereof; b) polymeric excipients; Disclosed herein is a solid amorphous dispersion comprising:

[0005] In certain embodiments, a solid amorphous dispersion comprising: a) adding a compound of formula (I) in an amount of about 40% w / w to about 60% w / w of the dispersion;

[0006] [ka] or a pharma- ceutically acceptable salt thereof; b) a polymeric excipient in an amount of about 40% w / w to about 60% w / w of the dispersion; Disclosed herein are solid amorphous dispersions.

[0007] In certain embodiments, a) at least 150 mg of formula (I)

[0008] [ka] or a pharma- ceutically acceptable salt thereof; b) polymeric excipients; Disclosed herein is a solid amorphous dispersion comprising:

[0009] In certain embodiments, a composition comprising: a) a solid amorphous dispersion, i) at least 150 mg of formula (I)

[0010] [ka] or a pharma- ceutically acceptable salt thereof, ii) comprising a polymer excipient in an amount of about 20-35% w / w of the composition; a solid amorphous dispersion; b) a crystallization inhibiting polymer in an amount of about 15-35% w / w of the composition; c) a diluent or filler in an amount of about 5-25% w / w of the composition; d) a disintegrant in an amount of about 1-8% w / w of the composition; e) a lubricant in an amount of about 0.1-3% w / w of the composition; A composition is disclosed herein.

[0011] In certain embodiments, a composition comprising: a) a solid amorphous dispersion, i) at least 150 mg of formula (I)

[0012] [ka] or a pharma- ceutically acceptable salt thereof, ii) comprising a polymeric excipient in an amount of about 15-25% w / w of the composition; a solid amorphous dispersion; b) a crystallization inhibiting polymer in an amount of about 15-25% w / w of the composition; c) a diluent or filler in an amount of about 20-35% w / w of the composition; d) a disintegrant in an amount of about 3-8% w / w of the composition; e) a lubricant in an amount of about 1-3% w / w of the composition; A composition is disclosed herein.

[0013] In certain embodiments, disclosed herein are solid oral dosage forms comprising a compound of formula (I).

[0014] Disclosed herein, in certain embodiments, are solid oral dosage forms comprising the compositions disclosed herein.

[0015] Disclosed herein in certain embodiments is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0016] Disclosed herein, in certain embodiments, is a method of treating fibrosis in an individual in need thereof, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0017] Disclosed herein in certain embodiments is a method of treating an inflammatory disease or disorder in an individual in need thereof, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0018] Disclosed herein, in certain embodiments, is a method of treating chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in an individual in need of treatment, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0019] Disclosed herein in certain embodiments is a method of treating cachexia in an individual in need thereof, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0020] Disclosed herein in certain embodiments is a method of treating anaplastic lymphoma in an individual in need thereof, the method comprising administering to the individual a solid oral dosage form disclosed herein.

[0021] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the kinetic solubility monitoring of TTI-101 compositions with 10%, 15%, or 25% CIP in FaSSIF (pH 6.5) over a 6 hour period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] As generally described herein, the disclosure provides, in part, solid amorphous dispersions comprising a compound of formula (I) and a polymeric excipient, methods of making the dispersions, compositions comprising the dispersions, oral dosage forms comprising the compositions, and methods of treating a disease or disorder (e.g., cancer, fibrosis, inflammatory disease or disorder) comprising administering an oral dosage form comprising the composition.

[0024] definition As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the term "comprising," the term "a" or "an" may mean one or more. As used herein, "another" may mean at least a second or more. Furthermore, the terms "having," "including," "containing," and "comprising" are interchangeable, and one of skill in the art will recognize that these terms are open-ended terms. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and / or methods of the invention. It is contemplated that any method, compound, or composition described herein may be implemented with respect to any other method, compound, or composition described herein.

[0025] "About" and "approximately" are generally intended to mean an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0026] As used herein, "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-type salts such as ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-type salts such as acetone, ethyl ester ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0027] The term "oral dosage form," as used herein, unless otherwise indicated, refers to a pharmaceutical composition that is formulated or otherwise prepared for oral administration, such as in a separate form.

[0028] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," "subject," and "individual" are used interchangeably herein. None of these terms require active supervision by a medical professional.

[0029] Disease, disorder, and illness are used interchangeably herein.

[0030] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or reverses or slows the progression of the disease, disorder, or condition (also for "therapeutic treatment").

[0031] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, an effective amount of a compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health, and condition of the subject. A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or illness (e.g., treating, preventing, and / or ameliorating cancer in a subject, or inhibiting protein-protein interactions mediated by SH2 domains in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment), or to delay or minimize one or more symptoms associated with a disease, disorder, or illness. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or illness. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or illness, or enhances the therapeutic effectiveness of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent. "Prophylactic treatment" contemplates actions that occur before a subject begins to suffer from a particular disease, disorder or condition.

[0032] Compositions, formulations, oral dosage forms The compound of formula (I) (also referred to as TTI-101) is highly insoluble ("brick dust"). The compound of formula (I) is insoluble in aqueous solutions and has relatively low solubility in most solvents. In addition, the compound of formula (I) has a crystal structure with high crystal lattice energy, contributing to the rapid precipitation or crystallization of the compound from solution. Its low solubility and high crystallinity contribute to various difficulties in preparing a formulation suitable for administration in human subjects. The current formulation is a liquid formulation delivered via capsule. For example, a formulation of the compound of formula (I) dissolved in 60:40 Labrasol® / PEG400 and encapsulated in a hard gelatin capsule (unit dose: 36 mg) shows promising results in three dose cohorts, but unacceptably high pill burden prevented progression to a fourth patient cohort (25.6 mg / kg / day, dosed at 12.8 mg / kg twice daily (BID)). For example, a 70 kg subject in cohort 4 would require 60 capsules per day divided into BID doses. Other oral dosage forms containing the compound of formula (I) (e.g., as a self-emulsifying drug dispersion containing, for example, Kolliphor® RH40 (PEG-40 hydrogenated castor oil), PEG600, polysorbate 20, Labrasol®, and citric acid) may reduce pill burdens compared to two-component systems (e.g., from 60 capsules per day for the two-component system to 22 capsules per day for the same cohort 4 containing a self-emulsifying drug dispersion). However, such formulations still have limited drug loading per single oral dosage form and may require, for example, refrigerated (e.g., 2-8°C) storage conditions.

[0033] In certain embodiments, the compound of formula (I)

[0034] [ka] Disclosed herein is a solid oral dosage form comprising a solid amorphous dispersion comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, which provides high loading of the compound of formula (I), good ability to provide high bioavailability of the compound of formula (I), good stability (e.g., chemical and / or physical stability), and / or reduced pill burden for an individual undergoing treatment with administration of the compound of formula (I).

[0035] The excipients or combinations of excipients disclosed herein provide improved solubility of the compound of formula (I), improved physical stability (e.g., low crystallinity, good solubility and / or dispersion of the compound of formula (I)), improved chemical stability of the compound of formula (I), improved (e.g., oral) bioavailability of the compound of formula (I) and provide a desirable or therapeutic effect with improved shelf life, favorable storage conditions (e.g., improved storage conditions of the compositions, formulations, and oral dosage forms at ambient conditions, e.g., requiring less protection from oxygenation and / or humidity), and / or manageable (e.g., less than 10 tablets per day (e.g., 8 tablets or less per day), or other amounts described herein) and / or reduced pill loading (e.g., compared to the two-component excipient systems described herein and the self-emulsifying drug dispersion systems described herein). In some embodiments, the excipient or combination of excipients is suitable for maintaining or stabilizing the compound of formula (I) in an amorphous state (e.g., as a stable amorphous dispersion). In some embodiments, the compositions disclosed herein reduce or prevent crystallization of the compound of formula (I) when the compound is released in the gastrointestinal (GI) tract.

[0036] In some embodiments, the dispersions, compositions, and oral dosage forms described herein include a compound of formula (I) as a pharma- ceutically acceptable salt, hydrate, or solvate.

[0037] In some embodiments, the compositions disclosed herein are set forth in Table 1 (eg, the total weight percent of the composition does not exceed 100%).

[0038] [Table 1]

[0039] The solid amorphous dispersions described herein are prepared using spray-dried dispersion (SDD) technology. SDD produces a single-phase amorphous molecular dispersion (solid solution) of an API in a polymer matrix. In general, SDD is obtained by dissolving an API (e.g., TTI-101) and a polymer excipient in a solvent and then spray-drying the solution. The key to the process is to identify a polymer excipient and process conditions that allow the solvent to evaporate quickly from the droplets of the spray solution of TTI-101 and the polymer excipient, allowing insufficient time for phase separation of TTI-101 or the polymer excipient in the solution or crystallization of TTI-101 in the solution.

[0040] In some embodiments, the solid amorphous dispersions prepared using the spray-dried dispersion (SDD) technology described herein provide a reduced pill load. In some embodiments, the formulations described herein prepared using the SDD technology provide a reduced pill load compared to formulations prepared using the self-emulsifying drug dispersion (SEDD) technology. For example, three times as many pills are required for a formulation prepared using the SEDD technology (e.g., formulation 2) compared to a formulation prepared using the SDD technology (e.g., formulation 3). In some embodiments, the number of pills required for formulation 3 is 15 pills or less. In some embodiments, the number of pills required for formulation 3 is 10 pills or less. In some embodiments, the number of pills required for formulation 3 is 8 pills or less. In some embodiments, the number of pills prepared by the methods described herein is 6 pills or less. In some embodiments, the number of pills required for formulation 3 is 4 pills or less. In some embodiments, the number of pills required for formulation 3 is 3 pills or less. In some embodiments, the number of pills required for formulation 3 is 2 pills or less.

[0041] In some embodiments, formulations described herein prepared using SDD technology (e.g., formulation 3) reduce the pill load required to achieve a therapeutic dose of TTI-101 compared to formulations prepared using SEDD technology or formulation 1 (e.g., formulation 2). In some embodiments, 1.5-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. In some embodiments, 2-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. In some embodiments, 2.5-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. In some embodiments, 3-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. In some embodiments, 4-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. In some embodiments, 5-fold more TTI-101 is delivered from formulation 3 compared to formulation 1 or formulation 2. For example, formulation 3 can deliver 200 mg / unit of TTI-101, whereas when formulation 2 is used, 80 mg / unit of TTI-101 can be delivered, and when formulation 1 is used, 30 mg / unit of TTI-101 can be delivered.

[0042] In some embodiments, the solvent used in the SDD technique to dissolve TTI-101 is selected from dichloromethane, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, water, or mixtures thereof. In some embodiments, the solvent used in the SDD technique to prepare a solid amorphous dispersion comprising TTI-101 and a polymeric excipient is a mixture of acetone:water.

[0043] In some embodiments, the polymer excipient is one or more celluloses or derivatives thereof (e.g., microcrystalline cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hypromellose acetate succinate (e.g., HPMCAS-LG, HPMCAS-MG, HPMCAS-HG), HPMC phthalate (HPMCP) (e.g., HPMCP-HP55, HPMCP-HP55S), Methocel™ (e.g., E3 (e.g., (Methocel™ E3LV))), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and cellulose acetate phthalate), polyacrylates (e.g., polymethacrylates (e.g., copolymers comprising methacrylic acid and methyl methacrylic acid, copolymers comprising methacrylic acid and ethyl acrylate, N,N-dimethylaminoethyl meth ... acrylate, copolymers containing methyl methacrylate, and butyl methacrylate (e.g., Eudragit®, (e.g., Eduragit® EPO, Eudragit® L30D-55, Eudragit® L100, Eudragit® L100-55)), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA), other copolymers (e.g., copolymers containing polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate (e.g., copolymers containing polyvinyl acetate phthalate (PVAP)); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers) (e.g., Soluplus®), or copolymers containing vinyl acetate and N-vinyl-2-pyrrolidone (e.g., Plasdone®, (e.g., Plasdone® S630 (e.g., Plasdone® S630 Ultra)), or a mixture thereof.

[0044] In some embodiments, the polymer excipient is selected from hydroxypropylmethylcellulose (HPMC), copolymers comprising methacrylic acid, copolymers comprising vinyl acetate and N-vinyl-2-pyrrolidone, and combinations thereof.

[0045] In some embodiments, the polymer excipient is hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the HPMC AS is HPMC AS grade L (HPMC AS-L).

[0046] In some embodiments, the polymeric excipient is a copolymer comprising methacrylic acid and ethyl acrylate, a copolymer comprising methacrylic acid and methyl methacrylic acid, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methyl methacrylic acid, and butyl methacrylate. In some embodiments, the polymeric excipient is a copolymer comprising methacrylic acid and ethyl acrylate. In some embodiments, the polymeric excipient is a copolymer of about 1.4:1 to about 1:1.4 methacrylic acid and ethyl acrylate. In some embodiments, the polymeric excipient is a copolymer of about 1.2:1 to about 1:1.2 methacrylic acid and ethyl acrylate. In some embodiments, the polymeric excipient is a copolymer of 1:1 methacrylic acid and ethyl acrylate.

[0047] The polymer excipient may also act as a crystallization inhibitor, which helps to delay or inhibit crystallization of TTI-101 as it is released from the formulation in the GI tract, or mediate supersaturated stabilization (e.g., stabilization of a supersaturated solution).

[0048] In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 80% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 70% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 60% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 45% w / w to about 55% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 40% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 45% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 50% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 55% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 60% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 65% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 70% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 75% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 80% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, the solid amorphous dispersion comprises from about 40% w / w to about 80% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 40% w / w to about 70% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 40% w / w to about 60% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 45% w / w to about 55% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 40% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 45% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 50% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises from about 55% w / w of the polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 60% w / w polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 65% w / w polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 70% w / w polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 75% w / w polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 80% w / w polymeric excipient.

[0050] In some embodiments, provided herein is a composition comprising an effective amount of a solid amorphous dispersion described herein and at least one additional ingredient. In some embodiments, the composition comprises about 5% w / w to about 50% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 5% w / w to about 40% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 10% w / w to about 40% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 15% w / w to about 40% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 20% w / w to about 40% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 5% w / w to about 30% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 10% w / w to about 30% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 20% w / w to about 35% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 25% w / w to about 35% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 15% w / w to about 30% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 15% w / w to about 25% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 20% w / w to about 25% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 25% w / w to about 30% w / w of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0051] In some embodiments, the composition comprises about 5% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 10% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 15% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 20% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 25% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 30% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 35% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 40% w / w of the compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the composition comprises from about 5% w / w to about 50% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 5% w / w to about 40% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 10% w / w to about 40% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 15% w / w to about 40% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 20% w / w to about 40% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 5% w / w to about 30% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 10% w / w to about 30% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 20% w / w to about 35% w / w of the polymeric excipient. In some embodiments, the composition comprises from about 25% w / w to about 35% w / w of the polymeric excipient. In some embodiments, the composition comprises about 15% w / w to about 30% w / w of the polymeric excipient. In some embodiments, the composition comprises about 15% w / w to about 25% w / w of the polymeric excipient. In some embodiments, the composition comprises about 20% w / w to about 25% w / w of the polymeric excipient. In some embodiments, the composition comprises about 25% w / w to about 30% w / w of the polymeric excipient.

[0053] In some embodiments, the composition comprises about 5% w / w of the polymeric excipient. In some embodiments, the composition comprises about 10% w / w of the polymeric excipient. In some embodiments, the composition comprises about 15% w / w of the polymeric excipient. In some embodiments, the composition comprises about 20% w / w of the polymeric excipient. In some embodiments, the composition comprises about 25% w / w of the polymeric excipient. In some embodiments, the composition comprises about 30% w / w of the polymeric excipient. In some embodiments, the composition comprises about 35% w / w of the polymeric excipient. In some embodiments, the composition comprises about 40% w / w of the polymeric excipient.

[0054] In some embodiments, the composition comprises 1:1 (w / w%) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the polymeric excipient. In some embodiments, the composition comprises 1:1.5 w / w% of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the polymeric excipient. In some embodiments, the composition comprises 1.5:1 w / w% of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the polymeric excipient. In some embodiments, the composition comprises 1:2 (w / w%) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the polymeric excipient. In some embodiments, the composition comprises 2:1 (w / w%) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the polymeric excipient.

[0055] In some embodiments, the composition includes a crystallization-inhibiting polymer as an additional component. In general, the crystallization-inhibiting polymer helps to delay or inhibit the crystallization of TTI-101 when released from the formulation in the GI tract and mediates supersaturation stabilization (e.g., stabilization of a supersaturated solution). Examples of crystallization-inhibiting polymers include, but are not limited to, cellulose and its derivatives (e.g., microcrystalline cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hypromellose acetate succinate (e.g., HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS-LF, HPMCAS-LMP), HPMC phthalate (HPMCP) (e.g., HPMCP-HP55, HPMCP-HP55S), Methocel™ (e.g., Methocel™ E3 (e.g., Methocel™ E3LV)), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and cellulose acetate phthalate).

[0056] In some embodiments, the crystallization inhibiting polymer is methylcellulose or HPMC. In some embodiments, the crystallization inhibiting polymer is HPMC. In some embodiments, the crystallization inhibiting polymer is HPMCAS (e.g., HPMCAS-LF, HPMCAS-LMP).

[0057] In some embodiments, the composition comprises from about 1% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 5% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 10% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises from about 20% w / w to about 40% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w to about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w to about 30% w / w of the crystallization inhibiting polymer.

[0058] In some embodiments, the composition comprises about 1% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 2% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 3% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 4% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 25% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 30% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 35% w / w of the crystallization inhibiting polymer. In some embodiments, the composition comprises about 40% w / w of the crystallization inhibiting polymer.

[0059] In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 20% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 20% to about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 30% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 30% to about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 40% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for a composition is the same as the polymer excipient, the composition comprises about 40% to about 50% w / w crystallization inhibiting polymer / polymer excipient.

[0060] In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 20% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 30% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 40% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer for the composition is the same as the polymeric excipient, the composition comprises about 60% w / w of the crystallization inhibiting polymer / polymeric excipient.

[0061] In some embodiments, the composition further comprises an antioxidant.

[0062] In some embodiments, the antioxidant is vitamin E. In some embodiments, the antioxidant is ascorbyl palmitate. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, the antioxidant is triethyl citrate. In some embodiments, the antioxidant is citric acid. In some embodiments, the antioxidant is ascorbic acid.

[0063] In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.05 to about 5% (e.g., about 0.1 to about 3%, about 0.2 to about 1%). In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.05%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.1%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.2%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.3%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.4%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.5%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.6%. In some embodiments, the antioxidant is present in the composition at a % w / w of about 0.7%. In some embodiments, the antioxidant is present in the composition at about 0.8% % w / w. In some embodiments, the antioxidant is present in the composition at about 0.9% % w / w. In some embodiments, the antioxidant is present in the composition at about 1% % w / w. In some embodiments, the antioxidant is present in the composition at about 2% % w / w. In some embodiments, the antioxidant is present in the composition at about 3% % w / w. In some embodiments, the antioxidant is present in the composition at about 4% % w / w. In some embodiments, the antioxidant is present in the composition at about 5% % w / w.

[0064] In some embodiments, the composition further comprises a surfactant.

[0065] In some embodiments, the surfactant is a copolymer comprising polyoxypropylene and polyoxyethylene, polyoxyl 40 hydrogenated castor oil, or a water-soluble derivative of natural vitamin E (e.g., D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS)). In some embodiments, the surfactant is poloxamer 188, poloxamer 407, Kolliphor® RH40, or vitamin E TPGS.

[0066] In some embodiments, the surfactant is present in the composition at a % w / w of about 0.01 to about 10%. In some embodiments, the surfactant is present in the composition at a % w / w of about 0.01 to about 5%. In some embodiments, the surfactant is present in the composition at a % w / w of about 0.1 to about 5%. In some embodiments, the surfactant is present in the composition at a % w / w of about 0.5 to about 5%. In some embodiments, the surfactant is present in the composition at a % w / w of about 1 to about 5%. In some embodiments, the surfactant is present in the composition at a % w / w of about 1%. In some embodiments, the surfactant is present in the composition at a % w / w of about 2%. In some embodiments, the surfactant is present in the composition at a % w / w of about 3%. In some embodiments, the surfactant is present in the composition at a % w / w of about 4%. In some embodiments, the surfactant is present in the composition at a % w / w of about 5%.

[0067] In some embodiments, the composition comprises 150 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 160 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 170 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 180 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 190 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 200 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 220 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 240 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 260 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 280 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises at least 300 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0068] In some embodiments, provided herein is a solid oral dosage form comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0069] In some embodiments, provided herein is a solid oral dosage form comprising a solid amorphous dispersion or composition described herein. In some embodiments, the oral dosage form is a tablet. In some embodiments, the oral dosage form comprises at least 100 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 110 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 120 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 130 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 140 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 150 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 160 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 170 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 180 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 190 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 200 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 300 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 400 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 500 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, the oral dosage form comprises about 200 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 250 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 300 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 350 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 400 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 450 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 500 mg of the compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, the composition further comprises at least one additional ingredient. The ingredient can be an intragranular or extragranular ingredient that improves the processability of tablet manufacture (e.g., roller compaction, tablet compression, and film coating processability). The additional ingredient can also impart good powder flow and compression properties to the compressed material. Desirable properties of the additional component can include high compressibility so that strong tablets can be produced at low compression forces, good powder flow properties that can improve the powder flow of other excipients in the composition, and cohesiveness, for example, to prevent the tablet from crumbling during processing, shipping, and handling. Other ingredients that impart physical properties to the finished tablet are colorants and flavoring agents (e.g., in the case of chewable tablets). Examples of additional ingredients are described, for example, in Handbook of Pharmaceutical Excipients (5th eds.), published by the Pharmaceutical Press, Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen. th It is described in the edition.

[0072] In some embodiments, the additional components include, but are not limited to, diluents, binders, fillers, disintegrants, surfactants, lubricants, flavorings, and colorings. Additional components can perform multiple functions. For example, a diluent can also function as a filler. As another example, a surfactant can also function as a lubricant.

[0073] In some embodiments, the diluent or filler is added to, for example, increase the bulk weight of the blend and provide a practical size for compression. Diluents or fillers that can be used include one or more of calcium salts, such as calcium phosphate, and sugars, such as lactose, sucrose, dextrose, microcrystalline cellulose, mannitol, and maltodextrin. Examples of pharma-ceutically acceptable fillers and pharma-ceutically acceptable diluents include, but are not limited to, confectionery sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. In some embodiments, the diluent or filler is microcrystalline cellulose, which can be produced by controlled hydrolysis of α-cellulose. In some embodiments, suitable microcrystalline cellulose has an average particle size of about 20 nm to about 200 nm. Suitable microcrystalline celluloses include Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200. In some embodiments, the diluent or filler is silicified microcrystalline cellulose, such as ProSolv® SMCC 50 or ProSolv® SMCC HD 90. In some embodiments, the diluent or filler is lactose. In some embodiments, the diluent or filler is a mixture of two or more diluents or fillers. In some embodiments, the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose, or a mixture thereof.

[0074] In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 25% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 15% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 10% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 35% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 35% w / w, In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 20% w / w.In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 25% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 35% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 45% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 50% w / w.

[0075] In some embodiments, the composition further comprises a lubricant. Lubricants are typically added to prevent tablet material from clumping and adhering to tablet punches, minimize friction during tablet compression, and remove compressed tablets from dies. Such lubricants are typically included in the final tablet mix in amounts of less than 5% by weight per weight of the composition. Examples of lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, magnesium carbonate, stearic acid, magnesium oxide, glyceryl beheptate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium lauryl stearate, and mixtures of magnesium stearate and sodium lauryl sulfate. In some embodiments, the lubricant is sodium stearyl fumarate or sodium stearyl or mixtures thereof. In some embodiments, the lubricant is a mixture of two or more lubricants.

[0076] In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 5.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 4.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.05 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.05 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 4.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 3.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 3.0 w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 2.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 2.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.5 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to 1.0% w / w.In some embodiments, the amount of lubricant used in the composition is about 0.1% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.2% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.3% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.4% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.6% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.7% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.8% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.9% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.8% w / w. In some embodiments, the amount of lubricant used in the composition is about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 2.5% w / w.

[0077] In some embodiments, glidants are added to improve the flow of tablet powders, for example, by reducing interparticle friction and cohesion. Examples of glidants include magnesium stearate, magnesium carbonate, silica (e.g., colloidal silicon dioxide (such as the grade sold as Aerosil)), starch, and talc. The glidant may be present in the composition in an amount of 0.01 to about 5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 4.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 3.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 2.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.05 to about 2.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.1 to about 2.0% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.01 to about 1.5% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.05 to about 1.5% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.1 to about 1.5% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.5 to 1.5% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.5 to 1.0% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.1% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.2% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.3% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.4% w / w. In some embodiments, the amount of the flow enhancer used in the composition is about 0.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.6% w / w. In some embodiments, the amount of glidant used in the composition is about 0.7% w / w.In some embodiments, the amount of the glidant used in the composition is about 0.8% w / w. In some embodiments, the amount of the glidant used in the composition is about 0.9% w / w. In some embodiments, the amount of the glidant used in the composition is about 1.0% w / w. In some embodiments, the amount of the glidant used in the composition is about 2.0% w / w.

[0078] In some embodiments, tablet disintegrants are present in the composition, for example in an amount that promotes dissolution (e.g., increases tablet disintegration rate). Disintegrants are excipients that can counter the physical force of particle binding in a tablet when the dosage form is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethylcellulose. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, such as sodium starch glycolate, pregelatinized starch; clays; cellulose; alginates; gums; cross-linked polymers, such as cross-linked polyvinylpyrrolidone (e.g., polyvinylpolypyrrolidone, PVPP, crospovidone, crospolyvidone), cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (sodium croscarmellose); and polysaccharides. In some embodiments, the disintegrant is a mixture of two or more disintegrants.

[0079] Generally, the amount of disintegrant may be 0.1 to about 25% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 5% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% w / w of the composition. In some embodiments, the amount of disintegrant is about 2% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% w / w of the composition. In some embodiments, the amount of disintegrant is about 4% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% w / w. In some embodiments, the amount of disintegrant is about 6% w / w of the composition. In some embodiments, the amount of disintegrant is about 7% w / w of the composition. In some embodiments, the amount of disintegrant is about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 9% w / w of the composition. In some embodiments, the amount of disintegrant is about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 15% w / w of the composition.

[0080] In some embodiments, the formulation is described in Table 2 or Table 3 (eg, the total weight percent of the composition does not exceed 100%).

[0081] [Table 2]

[0082] [Table 3]

[0083] Tablets can be plain, film, sugar-coated, bisected, embossed, layered, and / or sustained release. They can be made in a variety of sizes, shapes, and colors. Tablets can be swallowed, chewed, or dissolved in the mouth or under the tongue.

[0084] The tablets of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action, to protect the tablet components from deterioration, to facilitate swallowing of large or uncomfortable tasking tablets, or to protect against the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being in the form of an envelope that covers the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0085] In certain embodiments, the tablets are polymer coated. In certain embodiments, the tablets are coated with Opadry® EZ White.

[0086] In certain embodiments, the compositions described herein are administered as a suspension in a pharma- ceutically acceptable carrier (e.g., optionally after grinding the composition or solid oral dosage form into a fine powder for suspension). In certain embodiments, the suspension is administered orally. In certain embodiments, the suspension is administered via a feeding tube (e.g., via a percutaneous endoscopic gastrectomy (PEG) tube or G-tube). The PEG allows the feeding tube to be placed through the abdominal wall into the stomach, allowing the composition to bypass the mouth and esophagus and directly into the stomach.

[0087] Method for preparing solid amorphous dispersions In certain embodiments, disclosed herein is a method for preparing a solid amorphous dispersion of a compound of formula I, the method comprising: i) Formula (I)

[0088] [ka] or a pharma- ceutically acceptable salt thereof, and a polymer excipient in a solvent to form a solution; ii) spraying the solution of step (i) into a drying chamber in a spray dryer disperser to prepare a solid amorphous dispersion.

[0089] In some embodiments, the method further comprises dissolving the crystallization-inhibiting polymer in step (i).

[0090] How to use In certain embodiments, further provided herein is a method of using a composition comprising a solid amorphous dispersion comprising a compound of formula (I) and a polymer excipient, for example in the treatment methods or other methods described herein. In some embodiments, the method involves the use of (e.g., includes administration of) a compound of formula (I), which is formulated in the manner described herein (e.g., present in a composition described herein). In some embodiments, a compound of formula (I) (e.g., as formulated herein, e.g., as an oral dosage form) is utilized in a method for treating a disease or disorder mediated by STAT3 or a disease or disorder that is otherwise treatable with a STAT3 inhibitor. In a specific embodiment, a method of treating cancer is provided herein. In another specific embodiment, a method of treating fibrosis is provided herein. In yet another specific embodiment, a method of treating an inflammatory disease / disorder is provided herein.

[0091] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of cancer in an individual in need of cancer treatment, comprising administering to the individual any of the compositions or oral doses described herein.In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia.In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor positive breast cancer. In some embodiments, the cancer treated according to the methods provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer. In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0092] In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of an inflammatory disease / disorder in an individual in need thereof, the methods comprising administering to the individual any of the compositions or oral dosages described herein. In some embodiments, the inflammatory disease / disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaemia, cancer cachexia, chronic kidney disease cachexia, non-alcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis, multiple sclerosis, or pancreatitis. In some embodiments, the inflammation treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, anaemia, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic steatohepatitis (NASH). In some embodiments, the anaemia comprises anaemia shock.

[0093] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of a fibrotic disease / disorder in an individual in need thereof, comprising administering to the individual any of the compositions or oral dosages described herein.In certain embodiments, the fibrotic disease / disorder is skin fibrosis (or dermal fibrosis), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal, renal fibrosis, bone marrow fibrosis, non-alcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or localized systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis. In certain embodiments, the fibrosis is skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal, bone marrow fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.In certain embodiments, the fibrosis is skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, or pulmonary fibrosis.

[0094] In certain embodiments, the fibrotic disease / disorder is fibrosis following exposure to certain drugs such as chemotherapy, fibrosis following exposure to environmental or other toxins or allergens, fibrosis occurring after ischemia / reperfusion injury such as myocardial infarction or hypotension, fibrosis occurring after radiation, fibrosis following hepatitis induced by alcohol, toxins, drugs or infection, primary biliary cirrhosis, fibrosis following viral infection involving the heart, liver, liver or lungs, and / or idiopathic retroperitoneal fibrosis.

[0095] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of muscle wasting disease / disorder, muscle weakness disease / disorder, or cachexia in an individual in need of such treatment, prevention, or reducing the risk or severity of such muscle wasting disease / disorder, muscle weakness disease / disorder, or cachexia, comprising administering to the individual any composition or oral dosage described herein.Muscle weakness and / or muscle wasting and / or cachexia may have unknown causes or may be associated with an underlying disease.The underlying condition may be a catabolic condition. In some embodiments, the underlying medical condition associated with cachexia is minimal renal disease or failure, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormone deficiency, metabolic acidosis, infection, chronic pancreatitis, autoimmune disorders, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease, sepsis, tumor, trauma, fever, long bone fracture, hyperthyroidism, long term steroid therapy, surgery, bone marrow transplant, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, paraneoplastic syndromes, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dermatomyofibrillosis, rheumatoid disease, autoimmune disease, collagen vascular disease, visceral leishmaniasis, prolonged bed rest. and / or addiction to drugs such as amphetamines, opiates, or barbiturates.

[0096] In certain embodiments, a method is provided for treating, preventing, or reducing the risk or severity of allergic reactions in an individual who needs such treatment, prevention, or reducing the risk or severity of allergic reactions, comprising administering to the individual any of the compositions or oral doses described herein.In some embodiments, the allergic reaction is induced after exposure to an allergen.In some embodiments, the allergen is a food allergen (such as milk, legumes, shellfish, nuts, eggs, fish, soybean, and wheat), an environmental allergen or seasonal allergen (such as pollen or mold), a venom allergen (such as from ash, honeybee, anise, hornet, yellow jacket, or ash), a drug allergen (such as anesthetics, P-lactam antibiotics, aspirin, nonsteroidal anti-inflammatory drugs, chemotherapy, vaccines, protamine, or herbal preparations), or latex. In some embodiments, the allergic reaction is anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, diptera allergy, bronchoconstriction, asthma, or eczema.

[0097] STAT3 also plays an important role in viral infection and pathogenesis (Chang Z et al., STAT3 roles in viral infection: antiviral or proviral?. Future Virol. 2018;13(8):557-574). In certain embodiments, a method of treating, preventing, or reducing the risk or severity of a viral infection in an individual in need thereof is provided, the method comprising administering to the individual any of the compositions or oral dosages described herein. In some embodiments, the viral infection is a chronic viral infection. In some embodiments, the chronic viral infection is AIDS, HIV infection, Hepatitis B infection, Hepatitis C virus infection, or Epstein-Barr virus infection.

[0098] In certain embodiments, provided herein are methods of treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagas' cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

[0099] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of neurodegenerative disease.In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemical brain.In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of pain in an individual in need thereof, comprising administering to the individual any composition or oral dosage described herein.In some embodiments, the pain is neuropathic pain.

[0100] In certain embodiments, provided herein is a method for treating, preventing, or reducing the risk or severity of insulin resistance in an individual in need of such treatment, prevention, or reducing the risk or severity thereof, comprising administering to the individual any composition or oral dosage described herein.In some embodiments, insulin resistance is the result of an underlying disease.In some embodiments, insulin resistance is associated with the muscle of the individual being treated.In some embodiments, insulin resistance is caused by any reason related to the individual, such as elevated free fatty acids in blood, obesity, overweight, having visceral fat, high fructose intake, having inflammation, inactivity, dysbiosis of gut microbiota, and / or genetic predisposition. In certain embodiments, any method provided herein is a method of treating or reducing the risk or severity of a medical condition that is related to insulin resistance or is at least partially a complication of insulin resistance, such as, for example, severe hypoglycemia; heart attack; stroke; kidney disease (including chronic, e.g., chronic kidney disease (CKD)); eye problems; cancer; nonalcoholic fatty liver disease (NAFLD); polycystic ovarian syndrome (PCOS); metabolic syndrome; diabetes; or Alzheimer's disease. In certain embodiments, insulin resistance is a characteristic of metabolic syndrome and type 2 diabetes. Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Its symptoms include high blood triglycerides, blood pressure, abdominal fat, and blood sugar, as well as low HDL (good) cholesterol levels.

[0101] In some embodiments, the pill burden discussed herein relates to any suitable therapeutic (e.g., daily) dose of a compound of Formula (I) and / or loading of a compound of Formula (I) in an oral dosage form, e.g., any dose or amount described herein.

[0102] In certain embodiments, the method comprises administering to the individual at least 1 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the individual at least 10 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the individual at least 20 mg / kg / day of a compound of formula (I). In certain embodiments, the method comprises administering to the individual at least 25 mg / kg / day of a compound of formula (I).

[0103] In some embodiments, the number of adverse events is reduced with the SDD formulation compared to the SEDD formulation. In some embodiments, the severity of adverse events is reduced with the SDD formulation compared to the SEDD formulation. In some embodiments, the number of individuals experiencing adverse events is reduced with the SDD formulation compared to the SEDD formulation. In some embodiments, the adverse event is diarrhea. EXAMPLES

[0104] Example 1. Polymer and surfactant screening for solid amorphous dispersions of TTI-101 Liquid-liquid phase separation (LLPS) was used to identify polymers that prevent crystallization and precipitation of supersaturated solutions of TTI-101 in fasted-state simulated intestinal fluid (FaSSIF). Polymers screened in this study include HPMC AS-MPP, HPMC AS-HG, HPMC AS-LG, HPMC-3, PVPVA64, and Eudragit L100. HPMC-based polymers performed well, maintaining supersaturated concentrations of TTI-101 throughout the entire experiment (240 min). Eudragit L100 performed similarly in the first 50 min.

[0105] Additionally, mixtures of HPMC AS-LG / HPMC-E3 + / - 5% w / w surfactant and HPMAC AS-LG + / - 5% w / w surfactant were prepared and evaluated using LLPS. The surfactants used in this study included poloxamer 188, poloxamer 407, Kolliphor RH40, and vitamin E TPGS. The addition of poloxamer 407, Kolliphor RH40, and vitamin E TPGS slightly improved the LLPS performance of the HPMC AS-LG / HPMC-E3 mixture.

[0106] Example 2. TTI-101 Spray Dried Dispersion (SDD) Reduction of TTI-101 particle size by micronization and nano-milling resulted in poor bioavailability (e.g., 10-20 times lower bioavailability than solutions of TTI-101). Hot melt extrusion (HME) was used and the resulting dispersions were evaluated using DSC miscibility, DSC extrudability, and rheology tests. Polymer systems tried included Soluplus; Soluplus + Kolliphor RH40; Soluplus + Vitamin E TPGS; and PPVVA64 + Kolliphor RH40. Dispersions of TTI-101 made using HME demonstrated high TTI-101 degradation and biorelevant in vitro super-saturated kinetic dissolution performance.

[0107] To prevent TTI-101 degradation, SDD technology was used to generate compositions containing TTI-101. Exemplary SDD compositions were prepared with the polymer systems and TTI-101 concentrations shown in Table 4.

[0108] [Table 4]

[0109] Compositions 1-5 showed marginal performance in supersaturated kinetic dissolution (SSKD). Characterization of compositions 1-5 showed that they were not completely amorphous. On the other hand, compositions 6-10 were completely amorphous. The addition of a crystallization inhibiting polymer (CIP) such as HPMC AS-LG to the compositions improved the peak concentration and supersaturation of TTI-101. Compositions 11 and 12 showed good stability, but composition 13 showed two glass transition temperatures (Tg) indicative of phase separation in SDD and also showed TTI-101 crystallization during stability evaluation. Composition 14 showed a change in Tg during stability evaluation, and compositions 15 and 16 showed two Tg indicative of phase separation in SDD.

[0110] Other CIPs used included MC-A4M, HPMC-E4M, and HPMC-K4M. The composition with MC-A4M performed similarly to the composition with HPMC AS-LG as the CIP.

[0111] Example 3. Antioxidant screening of TTI-101 SDD-based compositions Antioxidants such as citric acid, ascorbic acid, or ascorbyl palmitate (1% w / w each) were added to SDD compositions of TTI-101 along with HPMC AS-LG or Eudragit L100-55. The resulting compositions showed a shift in Tg during stability evaluation, providing a slight improvement in the chemical stability of the SDD-based compositions.

[0112] Example 4. CIP screening of TTI-101 SDD-based compositions CIPs were added to the SDD compositions of TTI-101 along with HPMC AS-LG or Eudragit L100-55. The CIPs screened included HPMC AS-LG, MC-A4M, HPMC-E4M, and HPMC-K4M. The compositions with MC-A4M performed similarly to the compositions with HPMC AS-LG as the CIP. The HPMC AS-LG concentrations were as follows: 10%, 15% and 25% w / w (HPMC AS-LG (CIP) to SDD ratio). The composition with 25% w / w HPMC AS-LG to SDD showed the highest TTI-101 concentration and a steady rise in TTI-101 with no drop in concentration throughout the run (6 hours) (Figure 1).

[0113] Example 5. Tablet Formulation An exemplary tablet formulation was prepared using SDD of TTI-101 and methacrylic acid and ethyl acrylate copolymer as polymer excipients (Table 5). The formulation was mixed, roller compacted (RC), milled, blended, compressed, and film coated to form an exemplary tablet. Intragranular and extragranular ingredients were added to improve the processability of roller compaction, tablet compression, and film coating.

[0114] [Table 5]

[0115] Example 6. Pharmacokinetic and bioavailability studies of TTI-101 SDD-based formulations In this study, the pharmacokinetics and oral bioavailability of SDD-based formulations were evaluated in rats. Formulations A-D were prepared according to Tables 6-7. Formulation E was prepared according to the method described in WO2021150912.

[0116] [Table 6]

[0117] [Table 7]

[0118] Table 8 shows exemplary doses of TTI-101 administered to rats and the % TTI-101 in each formulation.

[0119] [Table 8]

[0120] Formulation F (IV) was prepared at 5 / 2 / 43 / 50% v / v (TTI-101 5 mg / mL) in DMSO / EtOH / PEG400 / saline. Absolute oral bioavailability compared to formulation F for oral formulations was 0.183, 0.156, 0.229, 0.139, and 0.173 for formulations A-E, respectively. Cmax were as follows: formulation F (77000 ng / mL), formulation E (10300 ng / mL), formulation C (5500 ng / mL), formulation D (4490 ng / mL), formulation A (4060 ng / mL), and formulation B (3500 ng / mL). The AUClast was: Formulation F (188000 h*ng / mL), Formulation C (41800 h*ng / mL), Formulation E (31400 h*ng / mL), Formulation A (30700 h*ng / mL), Formulation B (28600 h*ng / mL), and Formulation D (25800 h*ng / mL).

[0121] The above results show that the formulation comprising composition 7 of Example 2 with a CIP such as HPMC AS LF exhibited higher bioavailability than the capsule formulation of TTI-101 (formulation E), and the formulation comprising composition 7 of Example 2 with a CIP such as HPMC AS LG exhibited similar bioavailability to formulation E of TTI-101 (Kolliphor RH40:PEG600:Polysorbate 20:Labrasol:Citric acid:TTI-101 at about 27.1:38.8:10.8:13.5:0.5:9.2). Formulation E is a capsule formulation containing 80 mg of TTI-101, while the exemplary tablet formulation described herein contains 200 mg of TTI-101.

[0122] Example 7. Oral STAT3 inhibitor TTI-101 in patients with advanced cancer and healthy volunteers One Phase I study evaluated TTI-101 in patients with advanced cancer. Another study evaluated TTI-101 in healthy volunteers.

[0123] Briefly, formulations 1-3 were prepared as in the previous examples. Two studies were conducted. The first study was conducted similarly to the study outlined in Table 9 below (for patients with advanced cancer) and consisted of a first cohort of subjects receiving formulation 1, a second cohort of subjects receiving formulation 2, and a third cohort of subjects receiving formulation 3. The second study was similar to the study outlined in Table 10 below (for healthy volunteers) and consisted of a cohort of subjects receiving formulation 3.

[0124] [Table 9-1]

[0125] [Table 9-2]

[0126] [Table 9-3]

[0127] [Table 10-1]

[0128] [Table 10-2]

[0129] The most common treatment-related adverse event observed with the SEDD formulation (Formulation 2) was diarrhea, which was reported in 44.7% of the 47 patients treated with TTI-101 SEDD (Table 11). A total of 48 patients were treated with the SDD formulation of TTI-101 (Formulation 3) across both studies, and fewer patients (6.3%) reported diarrhea compared to the SEDD formulation, with no grade 2 or grade 3 diarrhea events, as shown in the table below. Patients treated with Formulation 3 also had fewer diarrhea events than patients receiving the Labrasol / PEG formulation (Formulation 1).

[0130] [Table 11]

[0131] Additionally, pharmacokinetic data from healthy volunteer studies (administered formulation 3) demonstrate comparable mean exposure compared to the Phase 1 study (administered formulation 2). Furthermore, patient exposure at each time point on the curve exceeded the IC90 for STAT3-dependent proliferation (data not shown).

[0132] In summary, formulation 3 (prepared by SDD technology) reduces the pill load required to achieve a therapeutic dose of TTI-101. For example, formulation 3 can deliver 200 mg of TTI-101 per unit, compared to 80 mg of TTI-101 per unit when formulation 2 is used and 30 mg of TTI-101 per unit when formulation 1 is used. Formulation 3 has a reduced rate and severity of treatment-emergent adverse events and similar exposure to formulation 2.

Claims

1. a) about 40% w / w to about 80% w / w of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; b) a polymeric excipient selected from the group consisting of cellulose or its derivatives, polyacrylates, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate, polyethylene glycol, polyvinylcaprolactam, and copolymers comprising polyvinyl acetate, and copolymers comprising vinyl acetate and N-vinyl-2-pyrrolidone; 1. A solid amorphous dispersion comprising:

2. i) about 40% w / w to about 70% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion; ii) about 40% w / w to about 60% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion; iii) about 45% w / w to about 55% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion. iv) about 50% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion; v) about 60% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion; or vi) about 70% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion.

3. The solid amorphous dispersion of claim 1, wherein the polymer excipient is i) a copolymer comprising hydroxypropyl methylcellulose (HPMC), methacrylic acid, or a copolymer comprising vinyl acetate and N-vinyl-2-pyrrolidone, ii) hydroxypropyl methylcellulose acetate succinate (HPMC AS), or iii) a copolymer comprising methacrylic acid and ethyl acrylate, a copolymer comprising methacrylic acid and methyl methacrylic acid, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methyl methacrylic acid, and butyl methacrylate.

4. The solid amorphous dispersion of claim 3, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate.

5. The solid amorphous dispersion of claim 4, wherein the polymeric excipient is i) a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.4:1 to about 1:1.4, ii) a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.2:1 to about 1:1.2, or iii) a copolymer of methacrylic acid and ethyl acrylate in a ratio of 1:

1.

6. The solid amorphous dispersion of claim 1, further comprising a crystallization-inhibiting polymer.

7. The solid amorphous dispersion of claim 6, wherein the crystallization inhibiting polymer (CIP) is methylcellulose or HPMC.

8. The solid amorphous dispersion of claim 6, comprising: i) about 5% w / w to about 30% w / w of the crystallization-inhibiting polymer in the solid amorphous dispersion; ii) about 10% w / w to about 30% w / w of the crystallization-inhibiting polymer in the solid amorphous dispersion; iii) about 20% w / w to about 30% w / w of the crystallization-inhibiting polymer in the solid amorphous dispersion; or iv) about 25% w / w of the crystallization-inhibiting polymer in the solid amorphous dispersion.

9. The solid amorphous dispersion of claim 8, wherein the solid amorphous dispersion is a dispersion of a compound represented by the formula (I) in an amount of about 40% w / w to about 60% w / w. 【Chemistry 2】 or a pharmaceutically acceptable salt thereof; b) a polymeric excipient in an amount of about 40% w / w to about 60% w / w of said solid amorphous dispersion; 2. The solid amorphous dispersion of claim 1, comprising:

10. The solid amorphous dispersion of claim 9, comprising about 45% w / w to about 55% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion, or about 50% w / w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the solid amorphous dispersion.

11. The solid amorphous dispersion of claim 9, comprising about 45% w / w to about 55% w / w of said polymeric excipient in said solid amorphous dispersion, or about 50% w / w of said polymeric excipient in said solid amorphous dispersion. Claim 12: a) at least 150 mg of formula (I) 【Transformation 3】 or a pharmaceutically acceptable salt thereof; b) a polymeric excipient selected from the group consisting of cellulose or its derivatives, polyacrylates, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate, polyethylene glycol, polyvinylcaprolactam, and copolymers comprising polyvinyl acetate, and copolymers comprising vinyl acetate and N-vinyl-2-pyrrolidone, or mixtures thereof; 1. A pharmaceutical composition comprising a solid amorphous dispersion comprising:

13. The pharmaceutical composition of claim 12, further comprising: i) a diluent or filler; ii) a disintegrant; iii) a lubricant; and / or iv) a crystallization-inhibiting polymer.

14. The pharmaceutical composition of claim 13, wherein i) the diluent or filler is a mixture of two or more diluents or fillers, ii) the disintegrant is a mixture of two or more diluents, and / or iii) the lubricant is a mixture of two or more lubricants.

15. The pharmaceutical composition of claim 13, wherein i) the diluent or filler is present in an amount of about 15-40% w / w of the pharmaceutical composition or about 20-35% w / w of the pharmaceutical composition; ii) the disintegrant is present in an amount of about 1-10% w / w of the pharmaceutical composition or about 3-8% w / w of the pharmaceutical composition; iii) the lubricant is present in an amount of about 0.5-4% w / w of the pharmaceutical composition or about 1-3% w / w of the pharmaceutical composition; and / or iv) the crystallization-inhibiting polymer is present in an amount of about 10-30% w / w of the pharmaceutical composition or about 15-25% w / w of the pharmaceutical composition.

16. The pharmaceutical composition of claim 13, wherein i) the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose, or a mixture thereof; ii) the disintegrant is croscarmellose sodium; iii) the lubricant is sodium lauryl sulfate, or sodium stearyl fumarate, or a mixture thereof; and / or iv) the crystallization-inhibiting polymer is HPMC or HPMC AS.

17. A pharmaceutical composition comprising: a) a solid amorphous dispersion, i) at least 150 mg of formula (I) 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, and ii) a polymeric excipient in an amount of about 15-25% w / w of said pharmaceutical composition, said polymeric excipient being selected from the group consisting of cellulose or derivatives thereof, polyacrylates, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate, polyethylene glycol, polyvinylcaprolactam, and copolymers comprising polyvinyl acetate, and copolymers comprising vinyl acetate and N-vinyl-2-pyrrolidone; a solid amorphous dispersion; and b) a crystallization-inhibiting polymer in an amount of about 15-25% w / w of said pharmaceutical composition; c) a diluent or filler in an amount of about 20-35% w / w of said pharmaceutical composition; d) a disintegrant in an amount of about 3-8% w / w of said pharmaceutical composition; e) a lubricant in an amount of about 1-3% w / w of said pharmaceutical composition; Pharmaceutical compositions.

18. The pharmaceutical composition of claim 17, wherein i) the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate, ii) the crystallization-inhibiting polymer is hydroxypropyl methylcellulose acetate succinate, iii) the diluent or filler is silicified microcrystalline cellulose, iv) the disintegrant is croscarmellose sodium, and / or v) the lubricant is sodium lauryl sulfate, or sodium stearyl fumarate, or a mixture thereof.

19. The pharmaceutical composition of claim 17, comprising about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

20. A solid oral dosage form comprising the pharmaceutical composition of claim 12.

21. The solid oral dosage form of claim 20, comprising about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

22. The solid oral dosage form of claim 20, which is a tablet.

23. The solid oral dosage form of claim 22, further comprising a coating film.

24. Use of a pharmaceutical composition according to any one of claims 12 to 18 or a solid oral dosage form according to any one of claims 20 to 23 in the manufacture of a medicament for treating cancer in an individual in need thereof.

25. The use of claim 24, wherein the cancer is i) head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain tumor, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disorder, restenosis, myelodysplastic syndrome, leukemia, or lymphoma; ii) head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain tumor, pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, skin cancer, or metastatic melanoma; or iii) head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer.

26. Use of a pharmaceutical composition according to any one of claims 12 to 18 or a solid oral dosage form according to any one of claims 20 to 23 in the manufacture of a medicament for treating fibrosis in an individual in need thereof.

27. The use of claim 26, wherein the fibrosis is pulmonary fibrosis, myelofibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, hepatic fibrosis, retroperitoneal, renal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

28. Use of a pharmaceutical composition according to any one of claims 12 to 18 or a solid oral dosage form according to any one of claims 20 to 23 in the manufacture of a medicament for treating an inflammatory disease or disorder in an individual in need thereof.

29. The use of claim 28, wherein the inflammatory disease or disorder is i) inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis, or asthma, or ii) inflammatory bowel disease, ulcerative colitis, asthma, or psoriasis.

30. Use of a pharmaceutical composition according to any one of claims 12 to 18 or a solid oral dosage form according to any one of claims 20 to 23 in the manufacture of a medicament for: i) treating chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in an individual in need thereof; ii) treating cachexia in an individual in need thereof; or iii) treating anaphylaxis in an individual in need thereof.

31. The use of claim 24, comprising administering to the individual i) at least 1 mg / kg / day of the compound of formula (I), ii) at least 10 mg / kg / day of the compound of formula (I), iii) at least 20 mg / kg / day of the compound of formula (I), or iv) at least 25 mg / kg / day of the compound of formula (I).

32. a) Formula (I) 【Transformation 5】 or a pharmaceutically acceptable salt thereof; b) a polymer excipient; 1. A method for preparing a solid amorphous dispersion comprising: i) dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer excipient in a solvent to form a solution; ii) atomizing the solution of step (i) into a drying chamber of a spray-drying disperser to prepare the solid amorphous dispersion; method.

33. The method of claim 32, further comprising dissolving the crystallization-inhibiting polymer in step (i).

34. The method of claim 32, wherein the solvent is dichloromethane, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, water, or a mixture thereof.

35. A solid amorphous dispersion prepared according to the method of any one of claims 32 to 34.

36. An oral dosage form comprising an effective amount of the solid amorphous dispersion of claim 35.

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