TW202341973A - Therapeutic compounds, formulations, and use thereof - Google Patents

Abstract

Provided herein are solid amorphous dispersions, compositions, and solid oral dosage forms comprising a compound of Formula (I). In specific instances, such compositions comprise a polymer excipient, and optionally a crystallization inhibiting polymer. In some instances, such compositions are useful for the treatment of fibrosis, cancer, and/or inflammatory disease/disorder.

Description

Therapeutic compounds, formulations, and uses thereof

without cross reference

This application claims the benefit and priority of U.S. Provisional Patent Application No. 63/268,723, filed on March 1, 2022, the entire content of which is incorporated herein by reference.

without

In certain embodiments, disclosed herein are solid amorphous dispersions comprising a compound of Formula (I) and a polymeric excipient, methods of making such dispersions, compositions comprising such dispersions, Oral dosage forms of such compositions, and methods of treating diseases or conditions (e.g., cancer, fibrosis, inflammatory diseases or conditions) comprising administering oral dosage forms containing such compositions.

In certain embodiments, disclosed herein are solid amorphous dispersions comprising: a) a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and b) polymeric excipient.

In certain embodiments, disclosed herein are solid amorphous dispersions comprising: a) a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof in an amount of about 40% w/w to about 60% w/w of the dispersion; and b) a polymeric excipient in an amount of about 60% w/w of the dispersion 40% to about 60% w/w.

In certain embodiments, disclosed herein are solid amorphous dispersions comprising: a) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and b) polymeric excipient.

In certain embodiments, disclosed herein are compositions comprising: a) a solid amorphous dispersion comprising: i) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and ii) polymeric excipients in an amount of about 20-35% w/w of the composition; b) crystallization-inhibiting polymers in an amount of the composition About 15-35% w/w of the composition; c) Diluent or filler, the amount is about 5-25% of the composition; d) Disintegrant, the amount is about 1-8% of the composition w/w; and e) lubricant in an amount of about 0.1-3% w/w of the composition.

In certain embodiments, disclosed herein are compositions comprising: a) a solid amorphous dispersion comprising: i) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and ii) polymeric excipients in an amount of about 15-25% w/w of the composition; b) crystallization-inhibiting polymers in an amount of the composition About 15-25% w/w of the composition; c) Diluent or filler, the amount is about 20-35% of the composition; d) Disintegrant, the amount is about 3-8% of the composition w/w; and e) lubricant in an amount of about 1-3% w/w of the composition.

In certain embodiments, disclosed herein are solid oral dosage forms comprising a compound of Formula (I).

In certain embodiments, those disclosed herein are solid oral dosage forms comprising the compositions disclosed herein.

In certain embodiments, disclosed herein are methods of treating cancer in a subject in need of treatment of cancer, the method comprising administering to the subject an oral dosage form disclosed herein.

In certain embodiments, disclosed herein are methods of treating fibrosis in a subject in need of treatment of fibrosis, the method comprising administering to the subject an oral dosage form disclosed herein.

In certain embodiments, disclosed herein are methods of treating an inflammatory disease or disorder in a subject in need of treatment thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

In certain embodiments, the disclosures herein provide for the treatment of chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in an individual in need of treatment of chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy. or familial amyloid polyneuropathy, the method comprising administering to the individual an oral dosage form disclosed herein.

In certain embodiments, disclosed herein are methods of treating cachexia in an individual in need of treatment of cachexia, the method comprising administering to the individual an oral dosage form disclosed herein.

In certain embodiments, disclosed herein are methods of treating severe allergy in an individual in need of treatment of severe allergy, the method comprising administering to the individual an oral dosage form disclosed herein.

Other objects and advantages will become apparent to those of ordinary skill in the art to which the invention belongs from consideration of the following embodiments , examples , and claims .

As generally described herein, the disclosure herein provides (in part) solid amorphous dispersions comprising compounds of formula (I) and polymeric excipients, methods of making such dispersions, including such dispersions. Compositions, oral dosage forms comprising the compositions, and methods of treating a disease or condition (e.g., cancer, fibrosis, inflammatory disease or condition) comprising administering an oral dosage form comprising the compositions. definition

As used in this specification, "a" or "an" may mean one or more. As used herein, the word "a" when used in conjunction with the word "comprises" may mean one or more than one. As used herein, "another" may mean at least a second or more. Furthermore, the terms "having," "includes," "containing," and "includes" are interchangeable and a person of ordinary skill in the art to which the invention pertains 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 considered possible that any method, compound, or composition described herein may be practiced in combination with any other method, compound, or composition described herein.

"About" and "approximately" shall generally mean an acceptable degree of error in the quantity measured given the nature or precision of the measurement. Illustrative error levels are within 20 percent (%) of a given value or range of values, typically within 10%, and more typically within 5%.

As used herein, "pharmaceutically acceptable salts" means salts suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc. and with reasonable Salt of proportionate benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art to which this invention belongs. For example, Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amines with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid). acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by other methods (such as ion exchange) used in the technical field to which the invention belongs. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate , camphorsulfonate, citric acid, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, grape enanthate, glycerophosphate, gluconic acid Salt, hemisulfate, enanthate, caproate, hydrogen iodide salt, 2-hydroxy-ethanesulfonate, lactosurate, lactate, laurate, lauryl sulfate, malate, cis Butenedioate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamateate, jellyate , peroxysulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, 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 ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and salts using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl amine cations formed by sulfonates, and arylsulfonates).

The term "oral dosage form" as used herein and unless otherwise indicated, refers to a pharmaceutical composition that has been formulated or otherwise prepared for oral administration (such as in discrete form).

As used herein, "individuals" to whom administration is considered possible include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric individuals (e.g., infants, toddlers, adolescents) or adult individuals ( (e.g. young, middle-aged, or old)) and/or non-human animals, such as mammals, such as primates (e.g., macaques, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats , and/or dogs. In some embodiments, the system is human. In some embodiments, the system is non-human animal. The terms "human," "patient," and "subject and individual" are used interchangeably herein. None of these terms require active supervision by a medical professional.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specifically stated, the terms "treat," "treating," and "treatment" are considered to be possible when an individual is suffering from the specified disease, disorder, or condition. , or an action that occurs during a disease, illness, or condition that reduces the severity of the disease, illness, or condition, or reverses or slows the progression of the disease, illness, or condition (also known as "therapeutic treatment").

Generally speaking, an "effective amount" of a compound is an amount sufficient to induce the desired biological response. As one of ordinary skill in the art will understand, the effective amount of a compound of the present invention may be based on factors such as the desired biological indicator, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age of the subject, Varies based on weight, health, and medical conditions. A "therapeutically effective amount" of a compound is sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition (e.g., treating, preventing, and/or alleviating cancer in an individual, or inhibiting a protein-protein mediated by the SH2 domain in an individual) interaction, a reasonable benefit/risk ratio applicable to any medical treatment) or an amount sufficient to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating a disease, disorder, or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. A "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent the recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. "Preventive treatment" considers actions that may occur before an individual suffers from a specified disease, disorder, or condition. Compositions, formulations, oral dosage forms

The compound of formula (I) (also known as TTI-101) is highly insoluble ("brick dust"). It is insoluble in aqueous solutions and has relatively low solubility in most solvents. In addition, the compound of formula (I) has a crystalline structure with high lattice energy, resulting in rapid precipitation or crystallization of the compound from solution. Its low solubility and high crystallinity have resulted in difficulties in preparing formulations suitable for administration in human subjects. Current formulations are liquid formulations delivered via capsules. For example, a formulation of a compound of formula (I) dissolved in 60:40 Labrasol®/PEG400 and encapsulated into hard gelatin capsules (single dose: 36 mg) and showing encouraging results in a 3-dose cohort could not be progressed to The fourth patient was assigned to the cohort (25.6 mg/kg/day in a 12.8 mg/kg twice daily (BID) dose) because of an intolerance to the high bolus burden. For example, a 70 kg individual in cohort 4 would require 60 capsules divided into BID doses daily. Other oral dosage forms containing compounds of formula (I) (e.g. in self-emulsifying pharmaceutical dispersions, e.g. containing Kolliphor® RH 40 (PEG-40 hydrogenated castor oil), PEG600, polysorbate 20, Labrasol®, and citric acid) The pill burden can be reduced compared to the two-component system (e.g. 60 capsules per day for the two-component system versus 22 capsules per day for the same cohort 4 using self-emulsifying drug dispersions); however, such a formulation Still have a limited drug load per single oral dosage form and may require, for example, refrigerated (e.g., 2-8 °C) storage conditions.

In certain embodiments, disclosed herein are solid oral dosage forms comprising a solid amorphous dispersion comprising a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which provides a high loading capacity of the compound of formula (I) and good bioavailability of the compound of formula (I). ability, good stability (e.g., chemical and/or physical stability), and/or reduced pill burden for individuals undergoing treatment involving administration of a compound of Formula (I).

An excipient or combination of excipients disclosed herein provides 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), no liquid leakage (e.g. compared to strip capsules), longer shelf life shelf life, favorable storage conditions (such as improved storage conditions under ambient conditions for such compositions, formulations, and oral dosage forms, such as requiring less protection against oxidation and/or moisture), and/or the Efficacy or therapeutic efficacy is desired while the pill burden is manageable (e.g., less than 10 pills per day (e.g., 8 pills per day or less) or other amounts described herein) and/or reduced (e.g., relative to those described herein The two-component excipient system and the self-emulsifying drug dispersion system described in this article). In some embodiments, the excipient or combination of excipients is suitable for maintaining or stabilizing a compound of Formula (I) in an amorphous state (eg, in a stable amorphous dispersion). In some embodiments, compositions disclosed herein reduce or prevent the crystallization of a compound of Formula (I) upon release in the gastrointestinal (GI) tract.

In some embodiments, the dispersions, compositions, and oral dosage forms described herein include compounds of Formula (I) in the form of a pharmaceutically acceptable salt, hydrate, or solvate.

In some embodiments, the compositions disclosed herein are as set forth in Table 1 (eg, wherein the total wt. % in the composition does not exceed 100%). Table 1 : Exemplary solid amorphous dispersion compositions Components Formulation 1 ( % w/w ) Formulation 2 ( % w/w ) Formulation 3 ( % w/w ) Concoction 4 ( %w/w ) Formulation 5 ( % w/w ) Polymeric excipients 10-40 20-30 30-70 40-60 50 crystallization inhibiting polymer 10-40 20-30 - - - API (TTI-101) 30-70 40-60 30-70 40-60 50

The solid amorphous dispersions described in this article were prepared using spray drying dispersion (SDD) technology. SDD produces a single-phase amorphous molecular dispersion (solid solution) of API in a polymer matrix. Generally, SDD is obtained by dissolving the API (eg TTI-101) and polymeric excipients in a solvent and then spray drying the solution. The key to this procedure is the identification of droplets of solvent that evaporate rapidly from the spray solution of TTI-101 and polymeric excipients without sufficient time for the TTI-101 or polymeric excipients in the solution to phase separate or dissolve. Polymer excipients and procedural conditions for TTI-101 crystallization.

In some embodiments, the solvent utilized in SDD technology to dissolve TTI-101 is selected from: methylene chloride, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, water, or mixtures thereof. In some embodiments, a solvent-based acetone:water mixture is utilized in SDD technology to prepare a solid amorphous dispersion containing TTI-101 and polymeric excipients.

In some embodiments, the polymeric excipient is one or more cellulose or derivatives thereof (such as microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose). Methylcellulose, hydroxypropylmethylcellulose 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. Methocel™ E3 (e.g. Methocel™ E3LV)), hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, and cellulose acetate phthalate esters), polyacrylates (such as polymethacrylates (such as copolymers containing methacrylic acid and methyl methacrylate, copolymers containing methacrylic acid and ethyl acrylate, N,N-dimethacrylate containing Copolymers of methylaminoethyl ester, methyl methacrylate, and butyl methacrylate (e.g. Eudragit®, (e.g. Eduragit® EPO, Eudragit® L30 D-55, Eudragit® L100, Eudragit® L100-55) ))), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA), other copolymers (such as polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate Copolymers of esters (e.g. polyvinyl acetate phthalate (PVAP); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) (e.g. Soluplus®), or containing vinyl acetate and copolymers of N-vinyl-2-pyrrolidone (such as Plasdone™ (such as Plasdone™ S630 (such as Plasdone™ S630 Ultra)), or mixtures thereof.

In some embodiments, the polymeric excipient is selected from: hydroxypropyl methylcellulose (HPMC), copolymers containing methacrylic acid, vinyl acetate and N-vinyl-2-pyrrolidone. Copolymers, and combinations thereof.

In some embodiments, the polymeric excipient is hydroxypropylmethylcellulose acetate succinate (HPMC AS). In some embodiments, the HPMC AS is HPMC AS Grade L (HPMC AS-L).

In some embodiments, the polymeric excipient is a copolymer comprising methacrylic acid and ethyl acrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethyl methacrylate. Copolymer of methylaminoethyl ester, methyl methacrylate, and butyl methacrylate. In some embodiments, the polymeric excipient is a copolymer of 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 1:1 copolymer of methacrylic acid and ethyl acrylate.

The polymeric excipient may also act as a crystallization inhibitor, which may help slow or inhibit the crystallization of TTI-101 as it is released from the formulation in the GI tract or mediate supersaturated stabilization (e.g., supersaturated solution stabilization change).

In some embodiments, the solid amorphous dispersion comprises from about 40% w/w to about 80% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises from about 40% w/w to about 70% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises from about 40% w/w to about 60% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises from about 45% w/w to about 55% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 40% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 45% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 50% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 55% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 60% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 65% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 70% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion contains about 75% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 80% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

In some embodiments, provided herein are compositions comprising an effective amount of a solid amorphous dispersion described herein and at least one additional component. In some embodiments, the composition includes about 5% w/w to about 50% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 5% w/w to about 40% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes from about 10% w/w to about 40% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes from about 15% w/w to about 40% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 20% w/w to about 40% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes from about 5% w/w to about 30% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 10% w/w to about 30% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes from about 20% w/w to about 35% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 25% w/w to about 35% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 15% w/w to about 30% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 15% w/w to about 25% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 20% w/w to about 25% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 25% w/w to about 30% w/w of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the composition includes about 5% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 10% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 15% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 20% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 25% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 30% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 35% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes about 40% w/w of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

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

In some embodiments, the composition comprises 1:1, on a w/w % basis, a compound of formula (I) or a pharmaceutically acceptable salt thereof versus the polymeric excipient. In some embodiments, the composition comprises 1:1.5 on a w/w % basis of a compound of formula (I) or a pharmaceutically acceptable salt thereof versus the polymeric excipient. In some embodiments, the composition comprises 1.5:1 on a w/w % basis of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the polymeric excipient. In some embodiments, the composition comprises 1:2 on a w/w % basis of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the polymeric excipient. In some embodiments, the composition comprises 2:1 on a w/w % basis of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the polymeric excipient.

In some embodiments, the composition includes a crystallization inhibiting polymer as the additional component. Generally speaking, the crystallization-inhibiting polymer helps slow or inhibit the crystallization of TTI-101 as it is released from the formulation in the GI tract, mediate supersaturated stabilization (eg, stabilize supersaturated solutions). Examples of crystallization inhibiting polymers include, but are not limited to, cellulose and its derivatives (such as microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, acetate Hydroxypropyl methylcellulose succinate (HPMCAS) or hypromellose acetate succinate (such as HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS-LF, HPMCAS-LMP), HPMC phthalate (HPMCP) (such as HPMCP-HP55, HPMCP-HP55S), Methocel™ (such as Methocel™ E3 (such as Methocel™ E3LV)), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and cellulose acetate Phthalates).

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 (eg, HPMCAS-LF, HPMCAS-LMP).

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

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

In some embodiments, when the selected crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 20% to about 60% w/w of the crystallization-inhibiting polymer. Material/polymer excipient. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 20% to about 50% w/w of the crystallization-inhibiting polymer/ Polymeric excipients. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 30% to about 60% w/w of the crystallization-inhibiting polymer/ Polymeric excipients. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 30% to about 50% w/w of the crystallization-inhibiting polymer/ Polymeric excipients. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 40% to about 60% w/w of the crystallization-inhibiting polymer/ Polymeric excipients. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 40% to about 50% w/w of the crystallization-inhibiting polymer/ Polymeric excipients.

In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 20% w/w of the crystallization-inhibiting polymer/polymer excipient. agent. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 30% w/w of the crystallization-inhibiting polymer/polymer excipient. agent. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 40% w/w of the crystallization-inhibiting polymer/polymer excipient. agent. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 50% w/w of the crystallization-inhibiting polymer/polymer excipient. agent. In some embodiments, when the crystallization-inhibiting polymer used in the composition is the same as the polymeric excipient, the composition includes about 60% w/w of the crystallization-inhibiting polymer/polymer excipient. agent.

In some embodiments, the composition further includes an antioxidant.

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.

In some embodiments, the antioxidant is present in the composition at a % w/w of from about 0.05 to about 5% (eg, from about 0.1 to about 3%, from about 0.2 to about 1%). In some embodiments, the antioxidant is present in the composition at about 0.05% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.1% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.2% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.3% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.4% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.5% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.6% % w/w. In some embodiments, the antioxidant is present in the composition at about 0.7% % w/w. 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.

In some embodiments, the composition further includes a surfactant.

In some embodiments, the surfactant includes a copolymer of polyoxypropylene and polyoxyethylene, polyoxy40 hydrogenated castor oil, or a water-soluble derivative of natural vitamin E (such as D-α-tocopherol polyethylene glycol). alcohol succinate (vitamin E TPGS)). In some embodiments, the surfactant is Poloxamer 188, Poloxamer 407, Kolliphor® RH40, or Vitamin E TPGS.

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

In some embodiments, the composition includes 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 160 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 170 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes at least 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 190 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes at least 220 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes at least 260 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition includes at least 280 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains at least 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are solid oral dosage forms comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are solid oral dosage forms comprising a solid amorphous dispersion or composition described herein. In some embodiments, the oral dosage form is a lozenge. In some embodiments, the oral dosage form contains at least 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 110 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 130 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 160 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 170 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 190 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains at least 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral dosage form contains about 200 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 250 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 300 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 350 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 400 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 450 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form contains about 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof

In some embodiments, the composition further includes at least one additional component. The component may be an intragranular or extragranular component that improves processability in tablet manufacturing (eg, roll compaction, tableting, film coating processability). This additional component may also impart good powder flow and compression characteristics to the material being compressed. Desirable properties of the additional components may include high compressibility to allow for the manufacture of strong tablets at low compression forces; good powder flow properties that may improve powder flow for other excipients in the composition; and cohesion. , for example, to prevent tablets from shattering during processing, transportation, and handling. Other ingredients that impart physical properties to the finished tablet are coloring agents and flavoring agents (such as in the case of chewable tablets). Examples of additional components are found, for example, in the Handbook of Pharmaceutical Excipients (5th ed.), edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press narrated in.

In some embodiments, the additional components include, but are not limited to, diluents, binders, fillers, disintegrants, surfactants, lubricants, flavoring agents, and colors. This additional component can serve multiple functions. For example, diluents can also function as fillers. As another example, surfactants can also function as lubricants.

In some embodiments, diluents or fillers are added, for example, to increase the bulk weight of the blend, resulting in a practical size for compression. Diluents or fillers that may be used include one or more of: calcium salts, such as calcium hydrogen phosphate, and sugars, such as lactose, sucrose, dextrose, microcrystalline cellulose, mannitol, and malto paste. Refined. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include (but are not limited to) powdered sugar, compressible sugar, dextrate, 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 alpha-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 mixtures thereof.

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

In some embodiments, the composition further includes a lubricant. Lubricant is typically added to prevent the tableting material from clumping together and sticking to the tablet punch, to minimize friction during tableting, and to allow the pressed tablet to be removed from the mold. The lubricant is thus included in the final tablet mixture in an amount generally 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 behaptate, polyethylene glycol, ethylene oxide Alkane polymer, sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium lauryl stearate, and magnesium stearate and lauryl sulfate Sodium mixture. In some embodiments, the lubricant is sodium lauryl sulfate or sodium stearyl fumarate, or a mixture thereof. In some embodiments, the lubricant is a mixture of two or more lubricants.

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

In some embodiments, a glidant is added, for example, to improve the flowability of the tablet powder by reducing inter-particle friction and cohesion. Examples of glidants include magnesium stearate, magnesium carbonate, silica (eg, colloidal silica (such as grades sold under the name Aerosil)), starch, and talc. Glidants may be present in the composition in an amount from 0.01 to about 5% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.01 to about 4.0% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.01 to about 3.0% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.01 to about 2.0% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.05 to about 2.0% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.1 to about 2.0% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.01 to about 1.5% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.05 to about 1.5% w/w. In some embodiments, the amount of glidant utilized in the composition is from about 0.1 to about 1.5% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.5 to 1.5% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.5 to 1.0% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.1% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.2% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.3% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.4% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.5% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.6% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.7% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.8% w/w. In some embodiments, the amount of glidant utilized in the composition is about 0.9% w/w. In some embodiments, the amount of glidant utilized in the composition is about 1.0% w/w. In some embodiments, the amount of glidant utilized in the composition is about 2.0% w/w.

In some embodiments, a tablet disintegrant is present in the composition in an amount, such as to accelerate dissolution (eg, increase the rate of tablet disintegration). Disintegrants are excipients that resist the physical forces of particle bonding in the 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) starch, such as sodium starch glycolate, pregelatinized starch; clay; cellulose; alginate; gum; cross-linked polymers, such as cross-linked polymers; croscarmellose calcium and croscarmellose sodium ) sodium); and polysaccharides. In some embodiments, the disintegrant is a mixture of two or more disintegrants.

Generally, the amount of disintegrant may range from 0.1 to about 25% w/w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 15% w/w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 10% w/w of the composition. In some embodiments, the amount of disintegrant is from about 1% to about 8% w/w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 10% w/w of the composition. In some embodiments, the amount of disintegrant is from about 3% to about 10% w/w of the composition. In some embodiments, the amount of disintegrant is from about 3% to about 8% w/w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 10% w/w of the composition. In some embodiments, the amount of disintegrant is from about 5% to about 15% w/w of the composition. In some embodiments, the amount of disintegrant is from 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 of the composition. 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.

In some embodiments, the formulation is as set forth in Table 2 or Table 3 (eg, wherein the total wt. % in the composition does not exceed 100%). Table 2 : Exemplary formulations Components Formulation 6 (w/w) Formulation 7 (w/w) Concoction 8 (w/w) Spray Drying Dispersions - Solid Amorphous Dispersions TTI-101 10-30% 15-25% twenty two% Polymeric excipients 10-30% 15-25% twenty two% Intragranular blends Thinner/filler 5-20% 10-15% 12% disintegrant 0.5-5% 1-5% 3.2% Surfactant/lubricant 0.1-2% 0.5-1.0% 0.8% CIP 5-25% 10-20% 15% CIP 1-10% 5-10% 6% Extragranular blends Thinner/filler 5-25% 10-20% 15% disintegrant 0.5-10% 1-5% 3% Lubricant 0.1-2% 0.5-1.5% 1% Table 3 : Exemplary formulations Components Concoction 9 (w/w) Concoction 10 (w/w) Concoction 11 (w/w) TTI-101 10-30% 15-25% twenty two% Polymeric excipients 10-30% 15-25% twenty two% Thinner/filler 15-40% 20-35% 27% disintegrant 1-10% 3-8% 6% Surfactant/lubricant 0.1-2% 0.5-1.5% 1% CIP 10-30% 15-25% twenty one% Lubricant 0.1-2% 0.5-1.5% 1%

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

Tablets of the present invention may be coated or otherwise formulated to provide a dosage form that provides the following advantages: long-term action, protection of the tablet ingredients from deterioration, and easier swallowing of large or unpleasant-tasking tablets , or protection against acid conditions in the stomach. For example, a tablet or pill may contain an inner dosage component and an outer dosage component, the latter in the form of an outer film formed on the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact through the stomach into the duodenum or to be released with a delay. A wide variety of materials may be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

In certain embodiments, the tablet is polymer coated. In certain embodiments, the tablets are Opadry® EZ white coated.

In certain embodiments, the compositions described herein are administered as a suspension in a pharmaceutically acceptable carrier (e.g., such compositions or solid oral dosage forms may be crushed, if necessary, for suspension After using fine powder). In certain embodiments, the suspension is administered orally. In certain embodiments, the suspension is administered through a feeding tube (eg, through a percutaneous endoscopic gastroenterology (PEG) tube or G-tube). PEG allows placement of a feeding tube through the abdominal wall and into the stomach, allowing the composition to be placed directly into the stomach, avoiding the mouth and esophagus. Method for preparing solid amorphous dispersions

In certain embodiments, disclosed herein are methods for preparing solid amorphous dispersions of compounds of formula I, comprising: i) adding a compound of formula (I) or a pharmaceutically acceptable salt thereof, and polymer excipients are dissolved in a solvent to form a solution; and ii) the solution of step (I) is atomized into a drying chamber in a spray drying dispersion device to prepare the solid non- Crystalline dispersion.

In some embodiments, the method further comprises dissolving the crystallization inhibiting polymer in step (I). Instructions

In certain embodiments, also provided herein are methods of using compositions comprising a solid amorphous dispersion comprising a compound of formula (I) and a polymeric excipient, such as treatments or other methods described in this article. In some embodiments, the methods include using (e.g., comprising administering) a compound of Formula (I), wherein the compound of Formula (I) is formulated in a manner described herein (e.g., is present in a composition described herein) . In some embodiments, a compound of Formula (I) (e.g., as formulated herein, e.g., in an oral dosage form) is a method for treating a disease or disorder mediated by STAT3 or a disease or disorder that is otherwise treatable with a STAT3 inhibitor. utilized. In certain embodiments, provided herein are methods of treating cancer. In other specific embodiments, provided herein are methods of treating fibrosis. In yet other specific embodiments, provided herein are methods of treating inflammatory diseases/disorders.

In certain embodiments provided herein are methods of treating or preventing cancer or reducing the risk or severity of cancer in an individual in need of treatment or prevention or reducing the risk or severity thereof, the method comprising administering to the individual any of the methods described herein Described compositions or oral dosage forms. 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, gastric cancer, skin cancer, metastasis 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 lymphoma Proliferative disease, restenosis, myelodysplasia syndrome, leukemia, lymphoma, or acute myelogenous leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver epithelial cell carcinoma, hepatocellular epithelial cell 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 myelogenous leukemia. In some embodiments, the gastric cancer is gastric adenocarcinoma.

Certain embodiments herein provide methods for treating or preventing, or reducing the risk or severity of, an inflammatory disease/disorder in an individual in need of treatment or prevention, or reducing the risk or severity thereof, the method comprising The individual is administered any of the compositions or oral agents described herein. In some embodiments, the inflammatory disease/disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, severe allergies, cancer cachexia, chronic kidney disease cachexia, Nonalcoholic 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, severe allergies, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic Steatohepatitis (NASH). In some embodiments, the severe allergy includes severe anaphylactic shock.

Certain embodiments herein provide methods for treating or preventing, or reducing the risk or severity of, a fibrotic disease/disorder in an individual in need of treatment or prevention, or reducing the risk or severity thereof, the method comprising The individual is administered any of the compositions or oral agents 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 Visceral fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal cavity, renal fibrosis, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or restrictive systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloids, arthrofibrosis, adhesive Bursitis, or cystic fibrosis. In certain embodiments, the fibrosis is cutaneous fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint Fibrosis, hepatic fibrosis, retroperitoneal cavity, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, the fibrosis is cutaneous fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, or pulmonary fibrosis.

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

Certain embodiments herein provide for the treatment or prevention of muscle wasting diseases/disorders, muscle weakness diseases/disorders, or cachexia in individuals in need of treatment or prevention of, or reduction of the risk or severity of, muscle wasting diseases/disorders, muscle wasting diseases/disorders, muscle weakness diseases/disorders, or cachexia. A method of reducing the risk or severity of a debilitating disease/condition, or cachexia, comprising administering to the subject any of the compositions or oral agents described herein. The muscle weakness and/or muscle wasting and/or cachexia may have an unknown cause or it may be related to an underlying condition. The underlying condition may be a catabolic condition. In some embodiments, the underlying medical condition associated with cachexia is renal disease or failure, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure , tuberculosis, familial amyloid polyneuropathy, crotalgia, hormone deficiencies, metabolic acidosis, infectious diseases, chronic pancreatitis, autoimmune disorders, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever, long bone fractures, hyperthyroidism, long-term steroid therapy, surgery, bone marrow transplant, SARS, brucellosis, endocarditis, hepatitis B, lungs Abscesses, obesocytosis, neoplastic syndromes, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dermatomyositis, rheumatological diseases, autoimmune diseases, Collagen vasculopathy, visceral leishmaniasis, prolonged bed rest, and/or addiction to drugs (such as amphetamines, opioids, or barbiturates).

Certain embodiments herein provide for a method of treating or preventing an allergic reaction or reducing the risk or severity of an allergic reaction in an individual in need of treatment or prevention of an allergic reaction, the method comprising administering to the individual the method herein Any composition, or oral dosage, described in. In some embodiments, the allergic reaction is induced upon exposure to an allergen. In some embodiments, the allergen is a food allergen (such as milk, soy, shellfish, tree nuts, eggs, fish, soy, and wheat), an environmental allergen, or a seasonal allergen (such as pollen or mold) , venom allergens (such as from wasps, bees, ants, hornets, yellow jackets, or hornets), drug allergens (such as anesthetics, beta-lactam antibiotics, acetylcholine) acids, non-steroidal anti-inflammatory drugs, chemotherapy, vaccines, protamine, or herbal preparations), or latex. In some embodiments, the allergic reaction is severe allergy, severe anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenopteran allergy, bronchoconstriction, asthma, or eczema.

STAT3 also plays an important role in viral infection and pathogenicity (Chang Z, et al. STAT3 roles in viral infection: antiviral or proviral?). Future Virol. 2018;13 (8):557-574). In certain embodiments herein, the provider is a method of treating or preventing a viral infection or reducing the risk or severity of a viral infection in an individual in need of it, the method comprising administering to the individual any The compositions or oral dosage forms 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 Einstein-Barr virus infection,

Certain embodiments herein provide methods of treating or preventing, or reducing the risk or severity of, graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chogeustic cardiomyopathy, age-related macular degeneration, amyloidosis, stellate cell hyperplasia in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

Certain embodiments herein provide methods of treating or preventing neurodegenerative diseases or reducing the risk or severity thereof. In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemotherapy brain. Certain embodiments herein provide for a method of treating or preventing pain or reducing the risk or severity of pain in an individual in need of treatment or prevention of pain or reducing the risk or severity thereof, the method comprising administering to the individual any of the methods described herein Described compositions or oral dosage forms. In some embodiments, the pain is neuropathic pain.

Certain embodiments herein provide a method of treating or preventing insulin resistance or reducing the risk or severity of insulin resistance in an individual in need thereof, the method comprising administering to the individual Administer any of the compositions or oral dosage forms described herein. In some embodiments, the insulin resistance is the result of an underlying condition. In some embodiments, the insulin resistance is associated with muscle in the individual being treated. In some embodiments, the insulin resistance is caused by any reason for the individual (such as having elevated free fatty acids in the blood, being obese, being overweight, having visceral obesity, having high fructose intake, having inflammation, being inactive, having an inactive gut microbiome) phase imbalance, and/or genetic predisposition). In certain embodiments, any of the methods provided herein are methods of treating or reducing the risk or severity of a medical condition associated with, or at least in part a complication of, insulin resistance, such as, for example: severe high Blood sugar; severe hypoglycemia; heart attack; stroke; kidney disease (including chronic, such as chronic kidney disease (CKD)); eye problems; cancer; non-alcoholic fatty liver disease (NAFLD); polycystic ovary syndrome (PCOS) ; metabolic syndrome; diabetes; or Alzheimer's disease. In certain embodiments, the 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. Symptoms include high blood triglycerides, blood pressure, abdominal obesity, blood sugar, and low HDL (good) cholesterol levels.

In some embodiments, the bolus burden discussed herein is consistent with any suitable therapeutic (e.g., daily) dose of a compound of Formula (I) and/or loading of a compound of Formula (I) in the oral dosage form (such as herein any dose or amount described in).

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 subject at least 10 mg/kg/day of a compound of Formula (I). In certain embodiments, the method comprises administering to the subject at least 20 mg/kg/day of a compound of Formula (I). In certain embodiments, the method comprises administering to the subject at least 25 mg/kg/day of a compound of Formula (I).

In some embodiments, some adverse events are reduced with SDD formulations compared to SEDD formulations. In some embodiments, the severity of adverse events is reduced using SDD formulations compared to SEDD formulations. In some embodiments, some individuals experience reduced adverse events using the SDD formulation compared to the SEDD formulation. In some embodiments, the adverse event is diarrhea. EXAMPLES 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 intestinal fluid simulating the fasting state (FaSSIF). The polymers screened in this study included: HPMC AS-MPP, HPMC AS-HG, HPMC AS-LG, HPMC-3, PPVVA64, and Eudragit L100. The HPMC-based polymer showed good performance, maintaining the supersaturation concentration of TTI-101 throughout the experiment (240 minutes). Eudragit L100 showed similar performance during the first 50 minutes.

In addition, a mixture of HPMC AS-LG/HPMC-E3 +/- 5% w/w surfactant and HPMAC AS-LG +/- 5% w/w surfactant was prepared and evaluated by LLPS. Surfactants used in this study include: Poloxamer 188, Poloxamer 407, Kolliphor RH40, and Vitamin E TPGS. For the HPMC AS-LG / HPMC-E3 mixture, the addition of Poloxamer 407, Kolliphor RH40, and Vitamin E TPGS provided a slight improvement in LLPS performance. Example 2. TTI-101 spray-dried dispersion ( SDD )

Particle size reduction of TTI-101 by micronization and nanomilling provides poor bioavailability (eg, 10-20 times lower bioavailability than solutions of TTI-101). The resulting dispersions were evaluated using hot melt extrusion (HME) and using DSC miscibility, DSC extrudability, and rheology studies. Polymer systems tried include: Soluplus; Soluplus + Kolliphor RH40; Soluplus + Vitamin E TPGS; and PPVVA64 + Kolliphor RH40. The dispersion of TTI-101 produced using HME showed high TTI-101 degradation and performance in supersaturated dynamic dissolution in biorelevant test tubes.

To prevent degradation of TTI-101, SDD technology is used to create compositions containing TTI-101. Exemplary SDD compositions were prepared with the polymer systems and concentrations of TTI-101 shown in Table 4 . Table 4 : Exemplary SDD compositions Composition % w/w TTI-101 in polymer systems polymer systems SDD solvent 1 50 HPMC-E3 DCM:MeOH (80:20) 2 50 HPMC AS-LG DCM:MeOH (80:20) 3 50 HPMC AS-LG + 5% Poloxamer 407 DCM:MeOH (80:20) 4 50 HPMC AS-GD + 5% Vitamin E TPGS DCM:MeOH (80:20) 5 67 HPMC AS-LG DCM:MeOH (80:20) 6 20 Eudragit EPO Acetone or acetone:water (90:10) 7 50 Eudragit L100-55 Acetone or acetone:water (90:10) 8 50 Plasdone S630 Ultra Acetone or acetone:water (90:10) 9 50 HPMC AS-LG Acetone or acetone:water (90:10) 10 50 HPMC AS-LG + 5% Vitamin ETPGS Acetone or acetone:water (90:10) 11 60 Eudragit L100-55 Acetone or acetone:water (90:10) 12 70 Eudragit L100-55 Acetone or acetone:water (90:10) 13 80 Eudragit L100-55 Acetone or acetone:water (90:10) 14 60 HPMC AS-LG Acetone or acetone:water (90:10) 15 70 HPMC AS-LG Acetone or acetone:water (90:10) 16 80 HPMC AS-LG Acetone or acetone:water (90:10)

Compositions 1-5 exhibit slight performance in supersaturated dynamic dissolution (SSKD). Characterization of compositions 1-5 shows that they are not completely amorphous. On the other hand, compositions 6-10 are completely amorphous. The addition of a crystallization inhibiting polymer (CIP), such as HPMC AS-LG, to these compositions improves the peak concentration and supersaturation of TTI-101. Compositions 11 and 12 exhibited good stability while composition 13 exhibited two glass transition temperatures (Tg), showed phase separation in the SDD and also showed crystallization of TTI-101 during stability evaluation. Composition 14 showed a change in Tg during stability evaluation and compositions 15 and 16 exhibited two Tgs, indicating phase separation in SDD.

Other CIPs used include: MC-A4M, HPMC-E4M, and HPMC-K4M. The composition with MC-A4M behaved similarly to the composition with HPMC AS-LG as CIP. Example 3. Antioxidant screening of SDD - based compositions for TTI-101

Antioxidants such as citric acid, ascorbic acid, or ascorbyl palmitate (1% w/w each) were added to the SDD composition of TTI-101 with HPMC AS-LG or Eudragit L100-55. The resulting composition exhibited a change in Tg during stability evaluation and provided a slight improvement in the chemical stability of the SDD-based composition. Example 4. CIP screening of SDD - based compositions for TTI-101

CIP was added to the SDD composition of TTI-101 with HPMC AS-LG or Eudragit L100-55. The screened CIPs include: HPMC AS-LG, MC-A4M, HPMC-E4M, and HPMC-K4M. The composition with MC-A4M behaved similarly to the composition with HPMC AS-LG as CIP. HPMC AS-LG concentration system: 10%, 15%, and 25% w/w (HPMC AS-LG (CIP) vs. SDD ratio. The composition with 25% w/w HPMC AS-LG vs. SDD was used throughout the trial The period (6 hours) showed the highest TTI-101 concentration and a steady increase in TTI-101 without a drop in concentration ( Figure 1 ). Example 5. Tablet Formulation

Exemplary tablet formulations ( Table 5 ) were prepared using SDD of TTI-101 and copolymer of methacrylic acid and ethyl acrylate as polymeric excipients. The formulation is mixed, roller compacted (RC), milled, blended, compressed, and film-coated to form exemplary tablets. Intra-granular and extra-granular components are added to improve the processability of roller compaction, tableting, and film coating. Table 5 : Example 200 mg TTI-101 Tablet Formulation Components Function %w/w Amount per unit Spray dried dispersions TTI-101 active ingredients 22.28% 200 mg Methacrylic acid and ethyl acrylate copolymer Polymeric excipients 22.28% 200 mg Intragranular blends Silicated microcrystalline cellulose Thinner/filler 12.15% 109.1 mg Croscarmellose Sodium disintegrant 3.24% 29.1 mg sodium lauryl sulfate Surfactant/lubricant 0.81% 7.3 mg Hypromellose acetate succinate LMP crystallization inhibitor 14.58% 130.9 mg Hypromellose acetate succinate LF crystallization inhibitor 5.67% 50.9 mg Total: 81.00% 727.3 mg Extragranular blends Silicated microcrystalline cellulose Thinner/filler 15.00% 134.7 mg Croscarmellose Sodium disintegrant 3.00% 26.9 mg Sodium stearyl fumarate Lubricant 1.00% 9.0 mg Total: 100.00% 897.9 mg Coating Opadry EZ white film coating 3.0% of core 26.9 mg Example 6. Pharmacokinetics and bioavailability studies of SDD - based formulations of TTI-101

In this study, the pharmacokinetics and oral bioavailability of SDD-based formulations were evaluated in rats. Formulation AD was prepared according to Tables 6-7 . Formulation E was prepared according to the method described in WO2021150912. Table 6 : Exemplary Formulation AB Components Amount (% w/w) Weight(mg) Components Amount (% w/w) Weight(mg) Formulation A - Intragranular Blend/RC Blend Formulation B - Intragranular Blend/RC Blend TTI-101: Eudragit L100-55: (50:50) 55.00 825 TTI-101: Eudragit L100-55: (50:50) 65.00 975 HPMC AS LF 25.00 375 HPMC AS LF 15.00 225 Prosolve HD 90 15.00 225 Prosolve HD 90 15.00 225 Croscarmellose sodium 4.00 60 Croscarmellose sodium (Ac-Di-Sol) 4.00 60 SLS (sodium lauryl sulfate) 1.00 15 SLS 1.00 15 total 100.00 1500 total 100.00 1500 Table 7 : Exemplary Formulation CD Components Amount (% w/w) Weight(mg) Components Amount (% w/w) Weight(mg) Formulation C Formulation D Intragranular (IG) blends Intragranular (IG) blends TTI-101: Eudragit L100-55: (50:50) 55.00 825 TTI-101: Eudragit L100-55: (50:50) 55.00 825 HPMC AS LF 25.00 375 HPMC AS LG 25.00 375 Prosolve HD 90 15.00 225 Prosolve HD 90 15.00 225 Croscarmellose sodium 4.00 60 Croscarmellose sodium (Ac-Di-Sol) 4.00 60 SLS 1.00 15 SLS 1.00 15 total 100.00 1500 total 100.00 1500 Extragranular blends Extragranular blends IG particles 81.00 1215 IG particles 81.00 1215 Prosolve HD 90 15.00 225 Prosolve HD 90 15.00 225 Croscarmellose sodium 3.00 45 Croscarmellose sodium (Ac-Di-Sol) 3.00 45 SSF (sodium stearyl fumarate) 1.00 15 SSF (sodium stearyl fumarate) 1.00 15 total 100.00 1500.00 total 100.00 1500.00

Table 8 shows exemplary doses of TTI-101 administered to rats and the % TTI-101 in each formulation. Table 8 : Administration of TTI-101 formulations in rats Preparation/Route of Administration Dosage (mg/kg) % TTI-101 in formulation (w/w) A(PO) 25 27.5 B（PO） 25 32.5 C（PO） 25 22.3 D(PO) 25 22.3 E(PO) 25 7.2 F(IV) 25 N/A

Formulation F(IV) was prepared in 5/2/43/50 % v/v DMSO/EtOH/PEG400/saline (TTI-101 5 mg/mL). For oral formulations, the absolute oral bioavailability of Formulations A-E relative to Formulation F were 0.183, 0.156, 0.229, 0.139, and 0.173, respectively. C max series: 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 final AUC is 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).

The above results show that the formulation containing Composition 7 of Example 2 with CIP such as HPMC AS LF showed higher bioavailability compared to the capsule formulation of TTI-101 (Formulation E) and with CIP such as HPMC AS The formulation of LG's CIP containing Composition 7 of Example 2 compared to Formulation E of TTI-101 (Kolliphor RH40: PEG600: Polysorbate 20: Labrasol: Citric Acid: TTI-101 - about 27.1:38.8 :10.8:13.5:0.5:9.2) showed similar bioavailability. 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. Example 7. Oral STAT3 inhibitor TTI-101 in patients with advanced cancer

In this Phase I study, TTI-001 was evaluated in patients with advanced cancer and healthy patients.

Briefly, Formulations 1-3 were prepared as in the previous examples. Patients in the first cohort (n=15) received Formulation 1, patients in the second cohort (n=47) received Formulation 2, and patients in the third cohort (n=48) received Formulation 3. For patients with advanced cancer, the trial was conducted similar to that outlined in Table 9 below. Table 9. Trial information for TTI-101 in patients with advanced cancer result Main outcome measures ˙Maximum tolerated dose of TTI-101 [Period: 28 days] To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and dose-limiting toxicities of TTI-101 administered orally to patients with advanced breast cancer and other solid tumors tolerance. Dose-limiting toxicity was defined as a grade 3 or higher adverse event (using CTCAE v5.0) within the first treatment cycle (day 28). ˙ Pharmacokinetics - Cmax (Cmax) [Period: 18 months] Cmax (observed) will be determined by direct examination of plasma drug concentration versus time data point values. ˙ Pharmacokinetics - Tmax [Period: 18 months] Tmax (observed) will also be determined by direct examination of plasma drug concentration versus time data point values. ˙ Pharmacokinetics - AUC(0-t) [Period: 18 months] AUC(0-t) (where t = the time point for the last sample for the pharmacokinetic profile at which quantifiable drug was detected) Estimates will be calculated using linear or linear/log trapezoidal calculations. secondary outcome measures ˙ Pharmacodynamics of TTI-101 in patients [Period: 18 months] The levels of pY-STAT3 will be measured before and before and after receiving TTI-101. ˙ Complete response (CR) - target lesions [Period: 18 months] Complete response (CR): disappearance of all target lesions. Any pathologic lymph node (whether targeted or nontarget) must be reduced to <10 mm in the short axis. ˙ Partial response (PR) - Target lesions [Period: 18 months] Partial response (PR): The sum of the diameters of the target lesions is reduced by at least 30%, using the baseline sum diameter as a reference. ˙ Progressive disease (PD) - Target lesions [Period: 18 months] Progressive disease (PD): The sum of the diameters of target lesions increases by at least 20% to the smallest sum within the study (if the baseline sum is the within-study sum) The minimum value includes the baseline sum) as a reference. In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). ˙ Stable disease (SD) - Target lesion [Period: 18 months] Stable disease (SD): Not shrinking enough to be called PR and not growing enough to be called PD, based on the smallest sum diameter within the study refer to. ˙ Complete response (CR) - non-target lesions [Period: 18 months] Complete response (CR): disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm short axis). ˙ Non-CR/Non-PD - Non-target lesions [Period: 6 months] Non-CR/Non-PD: Persistence of one or more non-target lesions and/or maintenance of tumor marker levels above normal limits. ˙ Progressive disease (PD) - non-target lesions [Period: 18 months] Progressive disease (PD): Definite progression of existing non-target lesions. (Note: The appearance of one or more new lesions is also considered progression). ˙Best overall response [Period: 18 months] Best overall response is the best response recorded from the beginning of study treatment until the end of treatment, taking into account any need for confirmation. Attribution of a patient's best overall response will depend on findings of both target and non-target disease and will also take into account the emergence of new lesions. Other prespecified outcome measures ˙ Association between biomarkers and anti-tumor efficacy and survival outcomes in uHCC patients based on RECIST 1.1 study. [Period: 18 months] To assess the association between STAT3 inhibition, fibrosis (if applicable), anti-tumor activity, and survival outcomes after receipt of TTI-101. Tissue and blood immune surveillance will be based on 2 biological examinations. Correlations between biomarkers (including pY-STAT3, PD1, and PD-L1 protein expression by IHC), gene expression profiles, and anti-tumor efficacy and survival outcomes based on RECIST 1.1 for TTI-101. ˙ Assess the impact of food on bioavailability of TTI-101 [Period: 18 months] Assess the impact of food on bioavailability of TTI-101 during the dose expansion period ˙ Assess the impact of food on bioavailability of TTI-101 between different formulations Rate [Period: 18 months] To assess the bioavailability of TTI-101 among different formulations during the dose expansion period Research information Research Type intervening research period Issue 1 research design Allocation: Nonrandomized Intervention Mode: Single Arm Allocation Masking: None (Open Label) Primary Objective: Treatment condition ˙ Breast cancer ˙ Head and neck squamous cell carcinoma ˙ Non-small cell lung cancer ˙ Hepatocellular carcinoma ˙ Colorectal cancer ˙ Gastric adenocarcinoma ˙ Melanoma ˙ Advanced cancer InterventionICMJE _ ˙Drug: TTI-101 Oral Capsule˙Drug: TTI-101 Oral Tablet Research arm ICMJE ˙ Experimental: Dose Escalation Study Participants will receive up to 4 dose levels of TTI-101 to measure RP2D Intervention: Drug: TTI-101 ˙ Experimental: Dose Expansion Study Enrollment in dose expansion can begin with approval of the Safety Review Board. Participants will be recruited and treated with TTI-101's RP2D therapeutic intervention: Drug: TTI-101 ˙ Experiment: Food Effect Study Participants will be treated with TTI-101 of RP2D under food and fasting conditions to evaluate the effects of TTI-101 Bioavailability and intervention to determine optimal conditions for uptake of study drug: Drug: TTI-101 ˙ Experiment: Dose expansion, crossover study participants will be administered different formulations of TTI-101 to compare bioavailability Rate. Intervention: . Drug: TTI-101. Drug: TTI-101 Eligibility criteria Inclusion criteria: Owners must meet the following inclusion criteria to be eligible: 1. Age ≥18 years; 2. For patients with solid tumors (non-unresectable HCC): patients with histologically confirmed locally advanced, unresectable Patients with surgically treated, metastatic, and/or treatment-resistant solid tumors for whom there are no available treatments that would confer clinical benefit; 3. For patients with unresectable HCC: Histologically confirmed diagnosis of localized Patients with advanced, inoperable, unresectable HCC who have failed the first and second lines of treatment and have a Child-Pugh of A or who have exceeded the second line and have a Child-Pugh of A if their performance status is maintained. 4. Eastern Cooperative Oncology Group performance status 0-1; 5. Hemoglobin ≥9.0 g/dL, neutrophil count ≥1.0 x 109/l, platelets ≥75 x 109/L ; 6. Adequate renal function level, as calculated by creatinine clearance >40 ml/min using the Cockroft-Gault formula; 7. Adequate liver function, defined as total bilirubin <1.5 x ULN, and asparagine Acid aminotransferase (AST)/alanine aminotransferase (ALT) <3 x ULN. For individuals with liver invasion, AST/ALT <5 x ULN; For individuals with liver invasion, AST/ALT <5 x ULN; 8. Use clinically appropriate criteria for the type of malignancy (for solid tumors RECIST v 1.1) Measurable disease; 9. Non-pregnancy test at the screening visit in women of childbearing potential, defined as post-pubertal female individuals (unless they have been menopausal for at least two years) who are surgically contraceptive or who are not Sexual life and will remain so during the trial; 10. Willingness to avoid pregnancy and breastfeeding starting two weeks before the first dose of TTI-101 and ending three months after the final trial treatment. During the administration of investigational treatment and for 3 months after the last dose of the study, male subjects and female subjects of childbearing potential who have female partners of childbearing potential must use an appropriate method of contraception at the discretion of the program administrator, such as Two-barrier method or one-barrier method, use of spermicide or intrauterine contraceptive device; and 11. Ability to read and understand informed consent forms and give informed consent and demonstrate understanding of the trial before undergoing any trial activities willingness and ability. Exclusion Criteria Individuals are not eligible for recruitment in this trial if they meet any of the following exclusion criteria: 1. Have been previously treated with: a. Standard therapy, including chemotherapy, immunotherapy, biological therapy, or any other antibiotic. Cancer treatment, within 28 days (or five exclusion half-lives for non-cytotoxic drugs, whichever is shorter) from the first day of trial drug treatment (6 weeks for nitrosourea or mitomycin); b . For any investigational drug, within 28 days of the first day of treatment with the investigational drug or 5 half-lives for small molecule/targeted therapies; 2. For extensive prior radiation therapy of more than 30% of bone marrow reserve, or within 28 days before enrollment Previous bone marrow/stem cell transplant within 5 years; ongoing toxicities (other than alopecia) due to prior therapy unless return to baseline or grade 1 or less; 3. Days since the first dose of TTI-101 Major surgical intervention or participation in therapeutic clinical trials within 1 to 28 days; 4. Significantly impaired cardiac function, such as unstable angina, New York Heart Association (NYHA) class III or IV congestive heart failure , Myocardial infarction within the last 12 months before trial entry; signs of pericardial effusion, severe arrhythmia (including QTc prolongation >470 ms and/or pacemaker), or congenital long-term abnormalities previously diagnosed on screening cardiac ultrasound QT syndrome or left ventricular ejection fraction <50%; 5. History of cerebrovascular accident or stroke within the previous 2 years; 6. Uncontrolled hypertension (>160/100mm Hg); 7. Caused by TTI- 101 History of grade 3 or 4 allergic reactions to chemically or biologically similar compounds (hydroxy-naphthalenesulfonamide); 8. Known transfer of activity in the central nervous system (unless brain imaging studies show stability for at least 1 month (without evidence of cerebral edema and without the need for corticosteroids or antispasmodics); 9. History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or condition that may interfere with compliance and/or absorption of the product under investigation; 10. Known human immunodeficiency virus (HIV); 11. Individuals with chronic hepatitis B virus (HBV) infection, unless screening viral load is <100 IU/mL after stable administration of antiviral therapy. Note: Individuals with chronic HCV infection are allowed to be recruited into the study but do not have a defined maximum viral load required for entry into the study; 12. Legally incapacitated or legally restricted; 13. Pregnant or breastfeeding women; 14. Any other condition that, in the opinion of the project sponsor, may compromise the individual's tolerance of the trial treatment, the safety of the individual subject, or the outcome of the trial; 15. Previous treatment of the current malignancy with a STAT inhibitor. Sex（ Sex ／ Gender ） Gender eligible for study: All age 18 to 65 years old (adults, senior citizens)

The most common treatment-related adverse event observed with the SEDD formulation (Formulation 2) was diarrhea, which was reported in 44.7% of 47 patients treated with TTI-101 SEDD ( Table 10 ). Forty-eight patients were treated with the SDD formulation of TTI-101 (Formulation 3), and as shown in the table below, fewer patients reported diarrhea (6.3%) and no Grade 2 or Grade 3 diarrhea events. Note that patients treated with Formulation 3 also had fewer diarrheal events than those administered the Labrasol/PEG formulation (Formulation 1). Table 10. Treatment-Related Adverse Events Observed with Formulations 1-3 Better term/level Concoction 1 Concoction 2 Concoction 3 N=15 N=47 N=48 Diarrhea 6 ( 40.0% ) 21 ( 44.7% ) 3 ( 6.3% ) Level 1: Mild 1(6.7%) 13 (27.7) 3(6.3%) Level 2: Moderate 2(13.3%) 3(6.4%) Level 3: Severe 3(20.0%) 5 (10.6%)

Additionally, pharmacokinetic data from the study in healthy volunteers (dose with Formulation 3) compared to the Phase 1 study (dose with Formulation 2) showed that the average exposure was equivalent. Further, for STAT3-dependent growth, patient exposure exceeded the IC90 at every time point in the curve (data not shown).

Overall, Formulation 3 had a significantly lower billing burden, a reduced rate and severity of treatment-attributable adverse events, and similar exposures to Formulation 2 compared to Formulation 2.

without

[ Figure 1] shows the dynamic solubility of TTI-101 compositions with 10%, 15%, or 25% CIP in FaSSIF (pH 6.5) monitored for 6 hours.

without

Claims (87)

A solid amorphous dispersion comprising: a) a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and b) polymeric excipient. The solid amorphous dispersion of claim 1, which contains about 40% w/w to about 80% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 40% w/w to about 70% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 40% w/w to about 60% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 45% w/w to about 55% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 50% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 60% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 1, which contains about 70% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of any one of claims 1-8, wherein the polymer excipient is hydroxypropyl methylcellulose (HPMC), a copolymer containing methacrylic acid, vinyl acetate and N -Copolymer of vinyl-2-pyrrolidone. The solid amorphous dispersion of any one of claims 1-9, wherein the polymer excipient is hydroxypropyl methylcellulose acetate succinate (HPMC AS). Such as the solid amorphous dispersion of claim 10, wherein HPMC AS is HPMC AS L grade (HPMC AS-L). The solid amorphous dispersion of any one of claims 1 to 8, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate, or a copolymer comprising methacrylic acid and methyl methacrylate. , or a copolymer containing N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate. The solid amorphous dispersion of claim 12, wherein the polymer excipient comprises a copolymer of methacrylic acid and ethyl acrylate. The solid amorphous dispersion of claim 13, wherein the polymeric excipient is a copolymer of methacrylic acid and ethyl acrylate at about 1.4:1 to about 1:1.4. The solid amorphous dispersion of claim 13, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate in a range of about 1.2:1 to about 1:1.2. The solid amorphous dispersion of claim 13, wherein the polymer excipient is a 1:1 copolymer of methacrylic acid and ethyl acrylate. The solid amorphous dispersion of any one of claims 1 to 16, further comprising a crystallization inhibiting polymer. The solid amorphous dispersion of claim 17, wherein the crystallization inhibiting polymer (CIP) is methylcellulose or HPMC. The solid amorphous dispersion of claim 18, wherein the crystallization inhibiting polymer is HPMC. The solid amorphous dispersion of claim 19, wherein the crystallization inhibiting polymer is HPMC AS. The solid amorphous dispersion of claim 20, wherein HPMC AS is HPMC AS-LF or HPMC AS-LMP, or a mixture thereof. The solid amorphous dispersion of any one of claims 17-21, comprising from about 5% w/w to about 30% w/w of the crystallization-inhibiting polymer in the dispersion. The solid amorphous dispersion of any one of claims 17-22, comprising from about 10% w/w to about 30% w/w of the crystallization-inhibiting polymer in the dispersion. The solid amorphous dispersion of any one of claims 17-22, comprising about 20% w/w to about 30% w/w of the crystallization-inhibiting polymer in the dispersion. The solid amorphous dispersion of any one of claims 17-22, comprising about 25% w/w of the crystallization-inhibiting polymer in the dispersion. A solid amorphous dispersion comprising: a) a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof in an amount of about 40% w/w to about 60% w/w of the dispersion; and b) a polymeric excipient in an amount of about 60% w/w of the dispersion 40% to about 60% w/w. The solid amorphous dispersion of claim 26, which contains about 45% w/w to about 55% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of claim 26, which contains about 50% w/w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion. The solid amorphous dispersion of any one of claims 26-28, wherein the polymer excipient is hydroxypropyl methylcellulose (HPMC), a copolymer containing methacrylic acid, vinyl acetate and N -Copolymer of vinyl-2-pyrrolidone. The solid amorphous dispersion of any one of claims 26-29, wherein the polymer excipient is hydroxypropyl methylcellulose acetate succinate (HPMC AS). Such as the solid amorphous dispersion of claim 30, wherein HPMC AS is HPMC AS L grade (HPMC AS-L). The solid amorphous dispersion of any one of claims 26-29, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate, or a copolymer comprising methacrylic acid and methyl methacrylate. , or a copolymer containing N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate. The solid amorphous dispersion of claim 32, wherein the polymer excipient comprises a copolymer of methacrylic acid and ethyl acrylate. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate at a ratio of about 1.4:1 to about 1:1.4. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a copolymer of about 1.2:1 to about 1:1.2 methacrylic acid and ethyl acrylate. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a 1:1 copolymer of methacrylic acid and ethyl acrylate. The solid amorphous dispersion of any one of claims 26-36, comprising about 50% w/w of the polymeric excipient in the dispersion. The solid amorphous dispersion of any one of claims 26-37, further comprising a crystallization inhibiting polymer. The solid amorphous dispersion of claim 38, wherein the crystallization inhibiting polymer is HPMC. The solid amorphous dispersion of claim 39, wherein HPMC is HPMC AS. The solid amorphous dispersion of any one of claims 37-40, wherein the HPMC AS is HPMC AS-LF or HPMC AS-LMP, or a mixture thereof. The solid amorphous dispersion of any one of claims 1-41, further comprising an antioxidant. A composition comprising a solid amorphous dispersion comprising: a) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and b) polymeric excipient. The composition of claim 43, further comprising a diluent or filler. The composition of claim 44, wherein the diluent or filler is a mixture of two or more diluents or fillers. The composition of claim 45, wherein the amount of the diluent or filler is about 20-35% w/w of the composition. The composition of claim 45 or 46, wherein the amount of the diluent or filler is about 15-40% w/w of the composition. The composition of any one of claims 44-47, wherein the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose. The composition of any one of claims 43-48, further comprising a disintegrant. The composition of claim 49, wherein the disintegrant is a mixture of two or more diluents. The composition of claim 50, wherein the amount of the disintegrant is about 3-8% w/w of the composition. The composition of claim 50, wherein the amount of the disintegrant is about 1-10% w/w of the composition. The composition of any one of claims 49-52, wherein the disintegrant is croscarmellose sodium. The composition of any one of claims 43-53, further comprising a lubricant. The composition of claim 54, wherein the lubricant is a mixture of two or more lubricants. The composition of claim 55, wherein the amount of lubricant is about 0.5-4% w/w of the composition. The composition of claim 55, wherein the amount of lubricant is about 1-3% w/w of the composition. The composition of any one of claims 54-57, wherein the lubricant is sodium lauryl sulfate, magnesium stearate, or sodium stearyl fumarate. The composition of any one of claims 43-58, further comprising a crystallization inhibiting polymer. The composition of claim 59, wherein the amount of the crystallization inhibiting polymer is about 10-30% w/w of the composition. The composition of claim 59, wherein the amount of the crystallization inhibiting polymer is about 15-25% w/w of the composition. A composition comprising: a) a solid amorphous dispersion comprising: i) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and ii) polymeric excipients in an amount of about 20-35% w/w of the composition; b) crystallization-inhibiting polymers in an amount of the composition About 15-35% w/w of the composition; c) Diluent or filler, the amount is about 5-25% of the composition; d) Disintegrant, the amount is about 1-8% of the composition w/w; and e) lubricant in an amount of about 0.1-3% w/w of the composition. A composition comprising: a) a solid amorphous dispersion comprising i) at least 150 mg of a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof; and ii) polymeric excipients in an amount of about 15-25% w/w of the composition; b) crystallization-inhibiting polymers in an amount of the composition About 15-25% w/w of the composition; c) Diluent or filler, the amount is about 20-35% of the composition; d) Disintegrant, the amount is about 3-8% of the composition w/w; and e) lubricant in an amount of about 1-3% w/w of the composition. A solid oral dosage form comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A solid oral dosage form comprising the solid amorphous dispersion according to any one of claims 1-43 or the composition according to any one of claims 44-63. The oral dosage form of claim 64 or 65, wherein the oral dosage form is a tablet. The oral dosage form of claim 66, further comprising a film coating. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual an oral dosage form of any one of claims 64-67. Such as claim 68, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, skin cancer, metastatic melanoma, prostate cancer Cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer (stomach cancer), anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, Stenosis, myelodysplasia syndrome, leukemia, or lymphoma. Such as the method of claim 68, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, cervical cancer, brain cancer, pancreatic cancer, myeloid metaplasia syndrome , leukemia, lymphoma, neuroblastoma, kidney cancer, skin cancer, or metastatic melanoma. The method of claim 68, wherein the cancer is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia or pancreatic cancer. A method of treating fibrosis in an individual in need thereof, the method comprising administering to the individual an oral dosage form of any one of claims 64-67. Such as the method of claim 72, wherein the fibrosis is pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal cavity, renal fibrosis, Myelofibrosis, cutaneous fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. A method of treating an inflammatory disease or condition in an individual in need thereof, the method comprising administering to the individual an oral dosage form of any one of claims 64-67. The method of claim 74, wherein the inflammatory disease or condition is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis, or asthma. The method of claim 74, wherein the inflammatory disease or condition is inflammatory bowel disease, ulcerative colitis, asthma, or psoriasis. A method of treating chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in an individual in need thereof, the method comprising administering to the individual a compound as claimed in any one of claims 64-67 Oral dosage form. A method of treating cachexia in an individual in need thereof, the method comprising administering to the individual an oral dosage form of any one of claims 64-67. A method of treating severe allergy in an individual in need thereof, the method comprising administering to the individual an oral dosage form of any one of claims 64-67. The method of any one of claims 68-79, comprising administering to the individual at least 1 mg/kg/day of a compound of formula (I). The method of any one of claims 68-79, comprising administering to the subject at least 10 mg/kg/day of a compound of formula (I). The method of any one of claims 68-79, comprising administering to the individual at least 20 mg/kg/day of a compound of formula (I). The method of any one of claims 68-79, comprising administering to the individual at least 25 mg/kg/day of a compound of formula (I). A method for preparing a solid amorphous dispersion, the solid amorphous dispersion comprising a) a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, and b) a polymer excipient, the method includes: i) dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer excipient in into a solvent to form a solution; and ii) atomizing the solution of step (i) into a drying chamber in a spray drying dispersion device to prepare the solid amorphous dispersion. The method of claim 84, further comprising dissolving the crystallization inhibiting polymer in step (i). A composition prepared according to the method of claim 84 or 85. An oral dosage form comprising an effective amount of the composition of claim 86.