Therapeutic compounds, formulations, and uses thereof

Abstract

Provided herein are solid amorphous dispersions, compositions and solid oral dosage forms comprising a compound of Formula (I). In some embodiments, the composition comprises a polymeric excipient, and optionally a crystallization inhibiting polymer. In some embodiments, the compositions may be used to treat fibrosis, cancer, and / or inflammatory diseases / disorders.

Description

[0001] Cross-references

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 268,723, filed on March 1, 2022, the entire contents of which are incorporated herein by reference. Summary of the invention

[0003] In certain embodiments, disclosed herein are solid amorphous dispersions comprising a compound of Formula (I) and a polymer excipient, methods of making the dispersions, compositions comprising the dispersions, oral dosage forms comprising the compositions, and methods of treating a disease or disorder (e.g., cancer, fibrosis, inflammatory diseases or disorders) comprising administering an oral dosage form comprising the composition.

[0004] In certain embodiments, disclosed herein is a solid amorphous dispersion comprising:

[0005] a) Compounds of formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof; and

[0008] b) Polymeric excipients.

[0009] In certain embodiments, disclosed herein is a solid amorphous dispersion comprising:

[0010] a) Compounds of formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof in an amount of about 40% w / w to about 60% w / w of the dispersion; and

[0013] b) A polymer excipient in an amount of about 40% to about 60% w / w of the dispersion.

[0014] In certain embodiments, disclosed herein is a solid amorphous dispersion comprising:

[0015] a) at least 150 mg of a compound of formula (I):

[0016]

[0017] or a pharmaceutically acceptable salt thereof; and

[0018] b) Polymeric excipients.

[0019] In certain embodiments, disclosed herein are compositions comprising:

[0020] a) a solid amorphous dispersion comprising:

[0021] i) at least 150 mg of a compound of formula (I):

[0022]

[0023] or a pharmaceutically acceptable salt thereof; and

[0024] ii) a polymer excipient in an amount of about 20-35% w / w of the composition;

[0025] b) a crystallization inhibiting polymer in an amount of about 15-35% w / w of the composition;

[0026] c) a diluent or filler in an amount of about 5-25% of the composition;

[0027] d) a disintegrant in an amount of about 1-8% w / w of the composition; and

[0028] e) a lubricant in an amount of about 0.1-3% w / w of the composition.

[0029] In certain embodiments, disclosed herein are compositions comprising:

[0030] a) a solid amorphous dispersion comprising:

[0031] i) at least 150 mg of a compound of formula (I):

[0032]

[0033] or a pharmaceutically acceptable salt thereof; and

[0034] ii) a polymer excipient in an amount of about 15-25% w / w of the composition;

[0035] b) a crystallization inhibiting polymer in an amount of about 15-25% w / w of the composition;

[0036] c) a diluent or filler in an amount of about 20-35% of the composition;

[0037] d) a disintegrant in an amount of about 3-8% w / w of the composition; and

[0038] e) a lubricant in an amount of about 1-3% w / w of the composition.

[0039] In certain embodiments, disclosed herein are solid oral dosage forms comprising a compound of Formula (I).

[0040] Disclosed herein, in certain embodiments, are solid oral dosage forms comprising a composition disclosed herein.

[0041] In certain embodiments, disclosed herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0042] Disclosed herein, in certain embodiments, are methods of treating fibrosis in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0043]

[0013] Disclosed herein, in certain embodiments, are methods of treating an inflammatory disease or disorder in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0044] In certain embodiments, disclosed herein are methods of treating chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0045] Disclosed herein, in certain embodiments, are methods of treating cachexia in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0046]

[0013] Disclosed herein, in certain embodiments, are methods of treating anaphylaxis in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein.

[0047] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Shown are 6-hour monitored kinetic solubility of TTI-101 compositions with 10%, 15%, or 25% CIP in FaSSIF (pH 6.5). DETAILED DESCRIPTION

[0049] As generally described herein, the present disclosure provides, in part, solid amorphous dispersions comprising a compound of Formula (I) and a polymer excipient, methods of making the dispersions, compositions comprising the dispersions, oral dosage forms comprising the compositions, and methods of treating a disease or disorder (e.g., cancer, fibrosis, inflammatory diseases or disorders) comprising administering an oral dosage form comprising the composition.

[0050] definition

[0051] As used in this specification, "a" or "an" may mean one or more. As used herein, when used with the word "comprising", the word "a" or "an" may mean one or more than one. "Another" as used herein may mean at least a second or more. In addition, the terms "having", "including", "containing", and "comprising" are interchangeable and those skilled in the art know that these terms are open terms. Some embodiments of the present invention may consist of or consist essentially of one or more elements, method steps, and / or methods of the present invention. It is contemplated that any method, compound, or composition described herein may be implemented with respect to any other method, compound, or composition described herein.

[0052] "About" and "approximately" generally mean an acceptable degree of error in the measured amount, depending on the nature or precision of the measurement. An exemplary degree of error is within twenty percent (20%), typically within 10%, and more typically within 5% of a given value or range of values.

[0053] As used herein, "pharmaceutically acceptable salts" refer to salts that are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc. and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include derivatives of suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups 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, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art (such as ion exchange) to form salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, sulfate), malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N- + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts include (when appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0054] As used herein, the term "oral dosage form," unless otherwise indicated, refers to a pharmaceutical composition formulated or otherwise prepared for oral administration, such as in dispersed form.

[0055] As used herein, "subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, young children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" and "individual" are used interchangeably herein. None of these terms require active supervision by medical personnel.

[0056] Disease, disorder and condition are used interchangeably herein.

[0057] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to actions taken when a subject is suffering from a particular disease, disorder, or condition that may reduce the severity of, or reverse or slow the progression of, the disease, disorder, or condition (i.e., "therapeutic treatment").

[0058] In general, an "effective amount" of a compound refers to an amount sufficient to cause an expected biological response. As will be appreciated by those skilled in the art, the effective amount of the compounds of the invention may vary based on factors such as the expected biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject. A "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit (e.g., to treat, prevent and / or improve cancer in a subject, or to inhibit protein-protein interactions mediated by SH2 domains in a subject, at 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, when used alone or in combination with other therapies, can provide a therapeutic benefit for the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, alleviates or avoids symptoms or causes of a disease or condition, or enhances the 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 its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, when used 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 the overall prophylactic effect or enhances the prophylactic efficacy of another prophylactic agent. "Prophylactic treatment" refers to actions taken before a subject develops a particular disease, disorder, or condition.

[0059] Composition, preparation, oral dosage form

[0060] The compound of formula (I) (also known as TTI-101) is highly insoluble ("brick dust"). It is insoluble in aqueous solution and has relatively low solubility in most solvents. In addition, the compound of formula (I) has a crystalline structure with high lattice energy, which helps the compound to precipitate or crystallize quickly from solution. Its low solubility and high crystallinity pose difficulties in preparing formulations suitable for administration in human subjects. Current formulations are liquid formulations delivered via capsules. For example, the compound of formula (I) is dissolved in a 60:40 / PEG400 and encapsulated in hard gelatin capsules (unit dose: 36 mg), although showing encouraging results in 3 dose groups, could not be advanced to the fourth patient group (25.6 mg / kg / day, at a dose of 12.8 mg / kg twice daily (BID)) due to unacceptably high pill burden. For example, a 70 kg subject in group 4 would require 60 capsules per day, taken twice. Other oral dosage forms comprising a compound of formula (I) (e.g., self-emulsifying drug dispersions, e.g., containing RH 40 (PEG-40 hydrogenated castor oil), PEG600, polysorbate 20, and citric acid) can reduce the medication burden 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 group 4 using a self-emulsifying drug dispersion); however, the drug load per single oral dosage form of this formulation is still limited and storage conditions such as refrigeration (e.g., 2-8°C) may be required.

[0061] In certain embodiments, disclosed herein are solid oral dosage forms comprising a solid amorphous dispersion comprising a compound of formula (I):

[0062]

[0063] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which provides a high loading amount of the compound of formula (I), a good ability to provide high bioavailability of the compound of formula (I), good stability (e.g., chemical and / or physical stability), and / or reduces the medication burden of a subject receiving a therapy comprising administering a compound of formula (I).

[0064] The excipients or combinations of excipients disclosed herein provide improved solubility of the compound of formula (I), improved physical stability (e.g., low crystallinity, good solubility and / or dispersibility 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), lack of any liquid leakage (e.g., compared to banded capsules), long shelf life, favorable storage conditions (e.g., improved storage conditions of the compositions, formulations and oral dosage forms under ambient conditions, e.g., requiring less protection from oxidation and / or moisture), and / or desirable or therapeutic efficacy, while having a manageable medication burden (e.g., less than 10 pills per day (e.g., 8 pills per day or less) or other amounts described herein) and / or a reduced medication burden (e.g., relative to the two-component excipient systems described herein and the self-emulsifying drug dispersion systems described herein). In some embodiments, the excipient or combination of excipients is suitable for maintaining or stabilizing the compound of formula (I) in an amorphous state (e.g., as a stable amorphous dispersion). In some embodiments, the compositions disclosed herein can reduce or prevent crystallization of the compound of formula (I) when it is released in the gastrointestinal (GI) tract.

[0065] In some embodiments, the dispersions, compositions, and oral dosage forms described herein comprise a pharmaceutically acceptable salt, hydrate, or solvate of a compound of Formula (I).

[0066] In some embodiments, a composition disclosed herein is as set forth in Table 1 (eg, wherein the total wt. % in the composition does not exceed 100%).

[0067] Table 1: Exemplary solid amorphous dispersion compositions

[0068]

[0069] The solid amorphous dispersion described herein is prepared using a spray dried dispersion (SDD) technique. SDD produces a single-phase amorphous molecular dispersion (solid solution) of the API in a polymer matrix. Generally speaking, SDD is obtained by dissolving the API (e.g., TTI-101) and a polymer excipient in a solvent and then spray drying the solution. The key to this process is to determine the polymer excipient and process conditions, which allow the solvent to evaporate rapidly from the droplets of the spray solution of TTI-101 and the polymer excipient so that the TTI-101 or polymer excipient in the solution does not have enough time to phase separate or the TTI-101 in the solution does not have enough time to crystallize.

[0070] In some embodiments, the solid amorphous dispersion prepared using the spray-dried dispersion (SDD) technology described herein can reduce the burden of medication. In some embodiments, the preparation prepared using the SDD technology can reduce the burden of medication compared to the preparation prepared using the self-emulsifying drug dispersion (SEDD) technology. For example, compared with the preparation prepared using the SDD technology (such as Preparation 3), the preparation prepared using the SEDD technology (such as Preparation 2) requires three times the amount of drug. In certain embodiments, the number of drugs required for Preparation 3 is 15 or less. In certain embodiments, the number of drugs required for Preparation 3 is 10 or less. In certain embodiments, the number of drugs required for Preparation 3 is 8 or less. In certain embodiments, the number of drugs prepared by the method described herein is 6 or less. In certain embodiments, the number of drugs required for Preparation 3 is 4 or less. In certain embodiments, the number of drugs required for Preparation 3 is 3 or less. In certain embodiments, the number of drugs required for Preparation 3 is 2 or less.

[0071] In some embodiments, a formulation prepared using SDD technology (e.g., Formulation 3) reduces the medication burden required to achieve a therapeutic dose of TTI-101 compared to a formulation prepared using SEDD technology (e.g., Formulation 2) or Formulation 1. In certain embodiments, Formulation 3 delivers a 1.5-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. In certain embodiments, Formulation 3 delivers a 2.0-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. In certain embodiments, Formulation 3 delivers a 2.5-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. In certain embodiments, Formulation 3 delivers a 3.0-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. In certain embodiments, Formulation 3 delivers a 4-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. In certain embodiments, Formulation 3 delivers a 5-fold increase in TTI-101 compared to Formulation 1 or Formulation 2. For example, Formulation 3 may deliver 200 mg of TTI-101 per unit, compared to 80 mg of TTI-101 per unit when Formulation 2 is used and 30 mg of TTI-101 per unit when Formulation 1 is used.

[0072] In some embodiments, the solvent used to dissolve TTI-101 in the SDD technique is selected from the group consisting of dichloromethane, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, water, or mixtures thereof. In some embodiments, the solvent used to prepare the solid amorphous dispersion comprising TTI-101 and a polymer excipient in the SDD technique is a mixture of acetone:water.

[0073] In some embodiments, the polymer excipient is one or more cellulose or its derivatives (e.g., microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) or hypromellose, 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 TM (e.g. Methocel TM E3 (e.g. Methocel TM E3LV))), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and cellulose acetate phthalate), polyacrylates (e.g., polymethacrylates (e.g., copolymers containing methacrylic acid and methyl methacrylate, copolymers containing methacrylic acid and ethyl acrylate, copolymers containing N,N-dimethylaminoethyl methacrylate, methyl methacrylate and butyl methacrylate (e.g., (For example EPO, L30 D-55, L100, L100-55)))), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone vinyl acetate (PVPVA), other copolymers (e.g., copolymers containing polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., polyvinyl acetate phthalate (PVAP); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)) (e.g. ) or a copolymer comprising vinyl acetate and N-vinyl-2-pyrrolidone (e.g. Plasdone TM (e.g. Plasdone TM S630 (such as Plasdone TM S630Ultra)) or a mixture thereof.

[0074] In some embodiments, the polymer excipient is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), a copolymer comprising methacrylic acid, a copolymer comprising vinyl acetate and N-vinyl-2-pyrrolidone, and combinations thereof.

[0075] In some embodiments, the polymer excipient is hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the HPMC AS is HPMC AS L grade (HPMC AS-L).

[0076] In some embodiments, the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate. In some embodiments, the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate. In some embodiments, 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. In some embodiments, the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate at a ratio of about 1.2:1 to about 1:1.2. In some embodiments, the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate at a ratio of 1:1.

[0077] The polymer excipient may also act as a crystallization inhibitor, which helps slow or inhibit crystallization of TTI-101 when it is released from the formulation in the GI tract or mediates supersaturation stabilization (eg, supersaturated solution stabilization).

[0078] In some embodiments, the solid amorphous dispersion comprises 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 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 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 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 comprises about 40% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 45% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 50% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises about 55% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid amorphous dispersion comprises 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 comprises 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.

[0079] In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 80% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 70% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 40% w / w to about 60% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 45% w / w to about 55% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 40% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 45% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 50% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 55% w / w of polymer excipient. In some embodiments, the solid amorphous dispersion comprises about 60% w / w of a polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 65% w / w of a polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 70% w / w of a polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 75% w / w of a polymeric excipient. In some embodiments, the solid amorphous dispersion comprises about 80% w / w of a polymeric excipient.

[0080] In some embodiments, provided herein is a composition comprising an effective amount of a solid amorphous dispersion described herein and at least one additional component. In some embodiments, the composition comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises 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 comprises about 25% w / w to about 30% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the composition comprises about 5% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 10% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 15% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 20% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 25% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 30% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 35% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 40% w / w of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the composition comprises about 5% w / w to about 50% w / w of polymer excipients. In some embodiments, the composition comprises about 5% w / w to about 40% w / w of polymer excipients. In some embodiments, the composition comprises about 10% w / w to about 40% w / w of polymer excipients. In some embodiments, the composition comprises about 15% w / w to about 40% w / w of polymer excipients. In some embodiments, the composition comprises about 20% w / w to about 40% w / w of polymer excipients. In some embodiments, the composition comprises about 5% w / w to about 30% w / w of polymer excipients. In some embodiments, the composition comprises about 10% w / w to about 30% w / w of polymer excipients. In some embodiments, the composition comprises about 20% w / w to about 35% w / w of polymer excipients. In some embodiments, the composition comprises about 25% w / w to about 35% w / w of polymer excipients. In some embodiments, the composition comprises from about 15% w / w to about 30% w / w of a polymeric excipient. In some embodiments, the composition comprises from about 15% w / w to about 25% w / w of a polymeric excipient. In some embodiments, the composition comprises from about 20% w / w to about 25% w / w of a polymeric excipient. In some embodiments, the composition comprises from about 25% w / w to about 30% w / w of a polymeric excipient.

[0083] In some embodiments, the composition comprises about 5% w / w of a polymer excipient. In some embodiments, the composition comprises about 10% w / w of a polymer excipient. In some embodiments, the composition comprises about 15% w / w of a polymer excipient. In some embodiments, the composition comprises about 20% w / w of a polymer excipient. In some embodiments, the composition comprises about 25% w / w of a polymer excipient. In some embodiments, the composition comprises about 30% w / w of a polymer excipient. In some embodiments, the composition comprises about 35% w / w of a polymer excipient. In some embodiments, the composition comprises about 40% w / w of a polymer excipient.

[0084] In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof at 1:1 in w / w % relative to the polymer excipient. In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof at 1:1.5 in w / w % relative to the polymer excipient. In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof at 1.5:1 in w / w % relative to the polymer excipient. In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof at 1:2 in w / w % relative to the polymer excipient. In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof at 2:1 in w / w % relative to the polymer excipient.

[0085] In some embodiments, the composition comprises a crystallization inhibiting polymer as the additional component. Generally speaking, the crystallization inhibiting polymer helps to slow down or inhibit the crystallization of TTI-101, mediate supersaturation stabilization (e.g., stabilize supersaturated solutions) when TTI-101 is released from the formulation in the GI tract. Examples of crystallization inhibiting polymers include, but are not limited to, cellulose and its derivatives (e.g., microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS-LF, HPMCAS-LMP), HPMC phthalate (HPMCP) (e.g., HPMCP-HP55, HPMCP-HP55S), Methocel TM (e.g. Methocel TM E3 (e.g. Methocel TM E3LV)), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and cellulose acetate phthalate).

[0086] In some embodiments, the crystallization inhibiting polymer is methylcellulose or HPMC. In some embodiments, the crystallization inhibiting polymer is HPMC. In some embodiments, the crystallization inhibiting polymer is HPMCAS (e.g., HPMCAS-LF, HPMCAS-LMP).

[0087] In some embodiments, the composition comprises from about 1% w / w to about 40% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 5% w / w to about 40% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 10% w / w to about 40% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 5% w / w to about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 35% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 10% w / w to about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 40% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 20% w / w to about 40% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 5% w / w to about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 10% w / w to about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 15% w / w to about 25% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises from about 20% w / w to about 30% w / w of a crystallization inhibiting polymer.

[0088] In some embodiments, the composition comprises about 1% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 2% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 3% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 4% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 5% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 10% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 15% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 20% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 25% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 30% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 35% w / w of a crystallization inhibiting polymer. In some embodiments, the composition comprises about 40% w / w of a crystallization inhibiting polymer.

[0089] In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 20% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 20% to about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 30% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 30% to about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 40% to about 60% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 40% to about 50% w / w crystallization inhibiting polymer / polymeric excipient.

[0090] In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 20% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 30% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 40% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 50% w / w of the crystallization inhibiting polymer / polymeric excipient. In some embodiments, when the crystallization inhibiting polymer used in the composition is the same as the polymeric excipient, the composition comprises about 60% w / w of the crystallization inhibiting polymer / polymeric excipient.

[0091] In some embodiments, the composition further comprises an antioxidant.

[0092] 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.

[0093] In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.05 to about 5%, such as about 0.1 to about 3%, about 0.2 to about 1%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.05%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.1%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.2%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.3%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.4%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.5%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.6%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.7%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.8%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 0.9%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 1%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 2%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 3%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 4%. In some embodiments, the antioxidant is present in the composition at a %w / w of about 5%.

[0094] In some embodiments, the composition further comprises a surfactant.

[0095] In some embodiments, the surfactant is a copolymer comprising polyoxypropylene and polyoxyethylene, polyoxyl 40 hydrogenated castor oil, or a water-soluble derivative of natural vitamin E (e.g., D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS)). In some embodiments, the surfactant is poloxamer 188, poloxamer 407, RH40 or Vitamin E TPGS.

[0096] In some embodiments, the surfactant is present in the composition at a %w / w of about 0.01 to about 10%. In some embodiments, the surfactant is present in the composition at a %w / w of about 0.01 to about 5%. In some embodiments, the surfactant is present in the composition at a %w / w of about 0.1 to about 5%. In some embodiments, the surfactant is present in the composition at a %w / w of about 0.5 to about 5%. In some embodiments, the surfactant is present in the composition at a %w / w of about 1 to about 5%. In some embodiments, the surfactant is present in the composition at a %w / w of about 1%. In some embodiments, the surfactant is present in the composition at a %w / w of about 2%. In some embodiments, the surfactant is present in the composition at a %w / w of about 3%. In some embodiments, the surfactant is present in the composition at a %w / w of about 4%. In some embodiments, the surfactant is present in the composition at a %w / w of about 5%.

[0097] In some embodiments, the composition comprises 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 160 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 170 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 190 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 220 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 260 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 280 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, provided herein is a solid oral dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, a solid oral dosage form is provided herein, comprising a solid amorphous dispersion or composition described herein. In some embodiments, the oral dosage form is a tablet. In some embodiments, the oral dosage form comprises at least 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 110 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 130 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 160 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 170 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 190 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises at least 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the oral dosage form comprises about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 250 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 350 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises about 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the composition further comprises at least one additional component. The component may be an intragranular or extragranular component that improves the processability of tablet manufacturing (e.g., roller compaction, tablet compression, film coating). The additional component may also impart good powder flowability and compression characteristics to the material being compressed. The desirable properties of the additional component may include high compressibility to make strong tablets at low compression forces; good powder flowability to improve the powder flow of other excipients in the composition; and cohesiveness, such as preventing the tablet from crushing during processing, transportation, and handling. Other components that impart physical properties to the finished tablet are colorants and flavorings (e.g., in the case of chewable tablets). Examples of additional components are described, for example, in the Handbook of Pharmaceutical Excipients (5th Edition), edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0102] In some embodiments, the additional components include, but are not limited to, diluents, binders, fillers, disintegrants, surfactants, lubricants, flavoring agents, and pigments. The additional components may serve multiple functions. For example, a diluent may also serve as a filler. As another example, a surfactant may also serve as a lubricant.

[0103] In some embodiments, diluent or filler is added, for example, to increase the bulk weight of the blend, so as to reach a practical compression size. Available diluent or filler include one or more of the following: calcium salts, such as calcium hydrogen phosphate, and sugars, such as lactose, sucrose, dextrose (dextrose), microcrystalline cellulose, mannitol and maltodextrin. The examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include but are not limited to powdered sugar (confectioner'ssugar), compressible sugar, dextrate (dextrate), dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talcum. In some embodiments, diluent or filler is microcrystalline cellulose, which can be manufactured by the controlled hydrolysis of alpha-cellulose. In some embodiments, suitable microcrystalline cellulose has an average particle size of about 20nm to about 200nm. 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 SMCC 50 or SMCC HD 90. In some embodiments, the diluent or filler is lactose. In some embodiments, the diluent or filler is a mixture of two or more diluents or fillers. In some embodiments, the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose, or a mixture thereof.

[0104] In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 25% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 15% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 10% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 35% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 50% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 35% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% to about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% to about 30% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 5% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 10% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 15% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 20% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 25% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 30% w / w.In some embodiments, the amount of diluent or filler used in the composition is about 35% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 40% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 45% w / w. In some embodiments, the amount of diluent or filler used in the composition is about 50% w / w.

[0105] In some embodiments, the composition further includes a lubricant. Lubricants are usually added to prevent the tableting materials from agglomerating together and to prevent them from sticking to the tablet punch, reduce friction during tableting, and enable the compressed tablets to be removed from the mold. Such lubricants are included in the final tablet mixture in an amount that is usually less than 5 (by weight) of the composition per weight. Examples of lubricants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, talc, magnesium carbonate, stearic acid, magnesium oxide, glyceryl behaptate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, lauryl magnesium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. 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.

[0106] In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 5.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 4.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.05 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.01 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.05 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1 to about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 4.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 3.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 3.0 w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 2.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 3.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 2.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.5 to about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5 to 1.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.1% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.2% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.3% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.4% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.6% w / w.In some embodiments, the amount of lubricant used in the composition is about 0.7% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.8% w / w. In some embodiments, the amount of lubricant used in the composition is about 0.9% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.5% w / w. In some embodiments, the amount of lubricant used in the composition is about 1.8% w / w. In some embodiments, the amount of lubricant used in the composition is about 2.0% w / w. In some embodiments, the amount of lubricant used in the composition is about 2.5% w / w.

[0107] In some embodiments, a glidant is added to improve the flowability of the tablet powder, for example by reducing friction and cohesion between particles. Examples of glidants include magnesium stearate, magnesium carbonate, silica (e.g., colloidal silicon dioxide (such as different grades sold under the name Aerosil), starch, and talc. The glidant may be present in the composition in an amount of 0.01 to about 5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 4.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 3.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 2.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.05 to about 2.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.1 to about 2.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.01 to about 1.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.05 to about 1.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.1 to about 1.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.5 to 1.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.5 to 1.0% w / w. In some embodiments, the amount of glidant used in the composition is about 0.1% w / w. In some embodiments, the amount of glidant used in the composition is about 0.2% w / w. In some embodiments, the amount of glidant used in the composition is about 0.3% w / w. In some embodiments, the amount of glidant used in the composition is about 0.4% w / w. In some embodiments, the amount of glidant used in the composition is about 0.5% w / w. In some embodiments, the amount of glidant used in the composition is about 0.6% w / w. In some embodiments, the amount of glidant used in the composition is about 0.7% w / w. In some embodiments, the amount of glidant used in the composition is about 0.8% w / w. In some embodiments, the amount of glidant used in the composition is about 0.9% w / w. In some embodiments, the amount of glidant used in the composition is about 1.0% w / w. In some embodiments, the amount of glidant used in the composition is about 2.0% w / w.

[0108] In some embodiments, tablet disintegrants are present in the composition in an amount, for example, to accelerate dissolution (e.g., increase tablet disintegration rate). Disintegrants are excipients that resist the physical forces of particle bonds in the tablet when the dosage form is placed in an aqueous environment. Disintegrants include starch derivatives and carboxymethylcellulose salts. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, such as sodium starch glycolate, pregelatinized starch; clays; celluloses; alginates; gums; cross-linked polymers, such as cross-linked polyvinyl pyrrolidone (e.g., polyvinyl polypyrrolidone, PVPP, crospovidone, crospolividone), cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (cross-linked sodium carboxymethylcellulose) (sodium croscarmellose); and polysaccharides. In some embodiments, the disintegrant is a mixture of two or more disintegrants.

[0109] Typically, the amount of disintegrant can be 0.1 to about 25% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% to about 8% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% to about 15% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% to about 5% w / w of the composition. In some embodiments, the amount of disintegrant is about 1% w / w of the composition. In some embodiments, the amount of disintegrant is about 2% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% w / w of the composition. In some embodiments, the amount of disintegrant is about 4% w / w of the composition. In some embodiments, the amount of disintegrant is about 5% w / w 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.

[0110] 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%).

[0111] Table 2: Exemplary Formulations

[0112]

[0113] Table 3: Exemplary Formulations

[0114]

[0115]

[0116] Tablets can be plain tablets, film tablets, sugar coated tablets, bisected tablets, embossed tablets, layered tablets and / or sustained-release tablets. They can be made in a variety of sizes, shapes and colors. Tablets can be swallowed, chewed or dissolved in the mouth or under the tongue.

[0117] The tablets of the present invention may be coated or otherwise compounded to provide a dosage form that provides advantages such as prolonged duration of action, protection of tablet ingredients from deterioration, easier swallowing of large or unpleasant-tasking tablets, or protection from acidic conditions in the stomach. For example, a tablet or pill may comprise an inner dosage and an outer dosage component, the latter being encapsulated over the former. The two components may be separated by an enteric layer that acts to prevent disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A wide variety of materials may be used for such enteric layers or coatings, including certain polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0118] In certain embodiments, the tablet is a polymer-coated tablet. In certain embodiments, the tablet is EZ white coated tablets.

[0119] In certain embodiments, the compositions described herein are administered in the form of a suspension in a pharmaceutically acceptable carrier (e.g., optionally, the composition or solid oral dosage form is first crushed into a fine powder for suspension). In certain embodiments, the suspension is administered orally. In certain embodiments, the suspension is administered through a feeding tube (e.g., a percutaneous endoscopic gastronomy (PEG) tube or G tube). PEG allows placement of a feeding tube through the abdominal wall into the stomach, thereby bypassing the mouth and esophagus to place the composition directly into the stomach.

[0120] Method for preparing solid amorphous dispersion

[0121] In certain embodiments, disclosed herein is a method for preparing a solid amorphous dispersion of a compound of Formula I, comprising:

[0122] i) the compound of formula (I)

[0123]

[0124] or a pharmaceutically acceptable salt thereof, and a polymer excipient are dissolved in a solvent to form a solution; and

[0125] ii) atomizing the solution of step (i) into a drying chamber in a spray drying dispersion device to prepare the solid amorphous dispersion.

[0126] In some embodiments, the method further comprises dissolving a crystallization inhibiting polymer in step (i).

[0127] How to use

[0128] In certain embodiments, methods of using a composition comprising a solid amorphous dispersion comprising a compound of formula (I) and a polymer excipient are also provided herein for treatment or other methods such as described herein. In some embodiments, the method comprises using (e.g., comprising administering) a compound of formula (I), wherein the compound of formula (I) is formulated as described herein (e.g., present in a composition described herein). In some embodiments, a compound of formula (I) (e.g., formulated as described herein, e.g., as an oral dosage form) is used in a method for treating a disease or disorder mediated by STAT3, or in a method for treating a disease or disorder treated with a STAT3 inhibitor. In specific embodiments, methods of treating cancer are provided herein. In other specific embodiments, methods of treating fibrosis are provided herein. In other specific embodiments, methods of treating inflammatory diseases / disorders are provided herein.

[0129] In certain embodiments, provided herein is a method of treating or preventing cancer, or reducing its risk or severity in a subject in need thereof, the method comprising administering to the subject any composition or oral agent described herein. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, stomach cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myeloid leukemia. In some embodiments, the cancer treated according to the methods provided herein is liver cancer, lung cancer, liver cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor positive breast cancer. In some embodiments, the cancer treated according to the methods provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer. In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0130] In certain embodiments, provided herein is a method for treating or preventing inflammatory diseases / disorders, or reducing their risk or severity in a subject in need thereof, the method comprising administering any composition or oral agent described herein to the subject. In some embodiments, the inflammatory diseases / disorders treated herein are inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, asthma, allergic reactions, cancer cachexia, chronic kidney disease cachexia, non-alcoholic fatty liver disease (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, allergic reactions, cancer cachexia, chronic kidney disease cachexia, or non-alcoholic fatty liver disease (NASH). In some embodiments, allergic reactions include anaphylactic shock.

[0131] In certain embodiments, provided herein is a method of treating or preventing a fibrotic disease / disorder in a subject in need thereof, or reducing the risk or severity thereof, the method comprising administering to the subject any composition or oral agent described herein. In certain embodiments, the fibrotic disease / disorder is skin fibrosis or dermalfibrosis, cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneum, kidney fibrosis, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or limited systemic sclerosis), myocardial endometrial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis. In certain embodiments, fibrosis is skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneum, myelofibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis. In certain embodiments, fibrosis is skin fibrosis (scleroderma), cardiac fibrosis, liver cirrhosis, or pulmonary fibrosis.

[0132] In certain embodiments, the fibrotic disease / disorder is fibrosis following exposure to certain drugs (such as chemotherapy), fibrosis following exposure to environmental or other toxins or allergens, fibrosis occurring after ischemia / reperfusion injury (such as myocardial infarction or hypotension), fibrosis occurring after radiation, fibrosis following hepatitis induced by alcohol, toxins, drugs, or infection, primary biliary cirrhosis, fibrosis following viral infection involving the heart, liver, or lungs, and / or idiopathic retroperitoneal fibrosis.

[0133] In certain embodiments, provided herein is a method for treating or preventing muscle wasting disease / disorder, muscle weakness disease / disorder or cachexia in a subject in need thereof or reducing the risk or severity thereof, the method comprising administering to the subject any composition or oral agent described herein. Muscle weakness and / or muscle wasting and / or cachexia may have unknown etiology, or it may be associated with an underlying condition. The underlying condition may be a metabolic condition. In some embodiments, the underlying condition associated with cachexia is least renal disease or failure, cancer, AIDS, HIV infection, chronic obstructive pulmonary disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormone deficiency, metabolic acidosis, infectious disease, chronic pancreatitis, autoimmune disease, 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 transplantation, atypical pneumonia, brucellosis, endocarditis, hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome, syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, polymyositis, dematomyositis, rheumatic diseases, autoimmune diseases, collagen vascular diseases, visceral leishmaniasis, prolonged bed rest, and / or drug addiction (such as amphetamines, opioids, or barbiturates).

[0134] In certain embodiments, provided herein are methods for treating or preventing an allergic reaction or reducing its risk or severity in a subject in need thereof, the method comprising administering to the subject any composition or oral dose described herein. In some embodiments, the allergic reaction is induced after exposure to an allergen. In some embodiments, the allergen is a food allergen (such as milk, beans, shellfish, tree nuts, eggs, fish, soy, and wheat), an environmental allergen or a seasonal allergen (such as pollen or mold), a venom allergen (such as from a wasp, bee, ant, hornet, yellow jacket, or asp), a drug allergen (such as an anesthetic, beta-lactam antibiotic, aspirin, nonsteroidal anti-inflammatory drugs, chemotherapy, a vaccine, protamine, or a herbal preparation) or latex. In some embodiments, the allergic reaction is anaphylaxis, anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenoptera allergy, bronchoconstriction, asthma, or eczema.

[0135] STAT3 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, provided herein is a method for treating or preventing viral infection or reducing its risk or severity in a subject in need thereof, the method comprising administering to the subject any composition or oral agent described herein. In some embodiments, the viral infection is a chronic viral infection. In some embodiments, the chronic viral infection is AIDS, HIV infection, hepatitis B infection, hepatitis C virus infection, or Epstein-Barr virus infection.

[0136] Certain embodiments herein provide methods of treating, preventing, or reducing the risk or severity of graft-versus-host disease, pulmonary lymphangioleiomyomatosis, Chagasic cardiomyopathy, age-related macular degeneration, amyloid degeneration, astrogliosis in Alzheimer's disease or other neurodegenerative diseases, or familial amyloid polyneuropathy.

[0137] In certain embodiments herein, a method for treating or preventing a neurodegenerative disease or reducing its risk or severity is provided. In some embodiments, the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemo-brain. In certain embodiments herein, a method for treating or preventing pain or reducing its risk or severity in a subject in need is provided, the method comprising administering to the subject any composition or oral dosage form described herein. In some embodiments, the pain is neuropathic pain.

[0138] In certain embodiments herein, a method for treating or preventing insulin resistance in a subject in need thereof or reducing its risk or severity is provided, the method comprising administering any composition or oral agent described herein to the subject. In some embodiments, insulin resistance is the result of an underlying condition. In some embodiments, insulin resistance is associated with the muscle of the subject being treated. In some embodiments, insulin resistance is caused by any cause of the subject (such as elevated free fatty acids in the blood, obesity, overweight, visceral obesity, high fructose intake, inflammation, inactivity, intestinal flora imbalance, and / or genetic predisposition). In certain embodiments, any method provided herein is a method for treating a medical condition or reducing its risk or severity that is associated with insulin resistance or is at least in part a complication of insulin resistance, such as severe hyperglycemia; severe hypoglycemia; heart disease; stroke; kidney disease (including chronic, such as chronic kidney disease (CKD)); eye disease; cancer; non-alcoholic fatty liver disease (NAFLD); polycystic ovary syndrome (PCOS); metabolic syndrome; diabetes; or Alzheimer's disease. In certain embodiments, insulin resistance is a feature of metabolic syndrome and type 2 diabetes. Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Its symptoms include high blood triglycerides, high blood pressure, abdominal obesity and high blood sugar, and low high-density lipoprotein (HDL) (good) cholesterol levels.

[0139] In some embodiments, the medication burden discussed herein is related to any suitable therapeutic (e.g., daily) dose of a compound of Formula (I) and / or the loading amount of a compound of Formula (I) in an oral dosage form (such as any dose or amount recited herein).

[0140] In certain embodiments, the method comprises administering to the subject 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).

[0141] In some embodiments, the use of the SDD formulation reduces the number of adverse events compared to the SEDD formulation. In some embodiments, the use of the SDD formulation reduces the severity of adverse events compared to the SEDD formulation. In some embodiments, the use of the SDD formulation reduces the number of subjects experiencing adverse events compared to the SEDD formulation. In some embodiments, the adverse event is diarrhea.

[0142] Example

[0143] Example 1. Screening of polymers and surfactants for TTI-101 solid amorphous dispersion

[0144] Liquid-liquid phase separation (LLPS) was used to identify polymers capable of preventing crystallization and precipitation of supersaturated solutions of TTI-101 in simulated fasting intestinal fluid (FaSSIF). The polymers screened in this study included: HPMC AS-MPP, HPMC AS-HG, HPMC AS-LG, HPMC-3, PVPVA64, and Eudragit L100. HPMC-based polymers showed good performance, maintaining supersaturated concentrations of TTI-101 throughout the experiment (240 minutes). Eudragit L100 showed similar performance in the first 50 minutes.

[0145] 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. The surfactants used in this study included: 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 resulted in a slight improvement in LLPS performance.

[0146] Example 2. TTI-101 Spray Dried Dispersion (SDD)

[0147] The particle size of TTI-101 was reduced by micronization and nano-milling, and the bioavailability was lower (e.g., the bioavailability was 10-20 times lower than that of TTI-101 solution). Hot melt extrusion (HME) was used, and the resulting dispersions were evaluated by DSC miscibility, DSC extrudability, and rheological studies. The polymer systems attempted included: Soluplus; Soluplus+Kolliphor RH40; Soluplus+Vitamin E TPGS; and PVPVA64+Kolliphor RH40. Dispersions of TTI-101 made using HME showed high TTI-101 degradation and performance in in-vitro biorelevant super-saturated kinetic dissolution.

[0148] To prevent TTI-101 from degrading, SDD technology was used to produce compositions containing TTI-101. Exemplary SDD compositions were prepared with the polymer systems and concentrations of TTI-101 shown in Table 4.

[0149] Table 4: Exemplary SDD compositions

[0150]

[0151]

[0152] Compositions 1-5 showed weak performance in supersaturated kinetic dissolution (SSKD). Characterization of compositions 1-5 showed that they were not completely amorphous. On the other hand, compositions 6-10 were completely amorphous. Addition of a crystallization inhibiting polymer (CIP) such as HPMC AS-LG to the compositions improved the peak concentration and supersaturation of TTI-101. Compositions 11 and 12 showed good stability while composition 13 showed two glass transition temperatures (Tg), indicating phase separation in the SDD, and TTI-101 crystallization also occurred during the stability evaluation. Composition 14 showed a change in Tg during the stability evaluation, and compositions 15 and 16 showed two Tgs, indicating phase separation in the SDD.

[0153] Other CIPs used included: MC-A4M, HPMC-E4M, and HPMC-K4M. The composition with MC-A4M performed similarly to the composition with HPMC AS-LG as the CIP.

[0154] Example 3. Antioxidant Screening of SDD-Based Compositions of TTI-101

[0155] Antioxidants such as citric acid, ascorbic acid or ascorbyl palmitate (1% w / w each) were added to SDD compositions of TTI-101 with HPMC AS-LG or Eudragit L100-55. The resulting compositions showed a shift in Tg during stability evaluation and slightly improved the chemical stability of the SDD-based compositions.

[0156] Example 4. CIP Screening of SDD-Based Compositions of TTI-101

[0157] CIP was added to SDD compositions of TTI-101 with HPMC AS-LG or Eudragit L100-55. The CIPs screened included: HPMC AS-LG, MC-A4M, HPMC-E4M, and HPMC-K4M. The compositions with MC-A4M performed similarly to the compositions with HPMCAS-LG as the CIP. The HPMC AS-LG concentrations were: 10% w / w, 15% w / w, and 25% w / w (ratio of HPMCAS-LG (CIP) to SDD). The composition with 25% w / w HPMC AS-LG to SDD showed the highest TTI-101 concentration throughout the test period (6 hours), and the concentration of TTI-101 steadily increased without a drop ( Figure 1 ).

[0158] Example 5. Tablet Formulation

[0159] An exemplary tablet formulation (Table 5) was prepared with methacrylic acid and ethyl acrylate copolymer as polymer excipients and TTI-101 as SDD. The formulation was mixed, roller compacted (RC), milled, blended, compressed, and film-coated to form an exemplary tablet. Intragranular and extragranular components were added to improve the processing of roller compaction, tableting, and film coating.

[0160] Table 5: Example 200 mg TTI-101 tablet formulation

[0161]

[0162]

[0163] Example 6. Pharmacokinetic and bioavailability studies of SDD-based formulations of TTI-101

[0164] In this study, the pharmacokinetics and oral bioavailability of SDD-based formulations in rats were evaluated. Formulations AD were prepared according to Tables 6-7. Formulation E was prepared according to the method described in WO2021150912.

[0165] Table 6: Exemplary Formulations AB

[0166]

[0167] Table 7: Exemplary Formulations CD

[0168]

[0169]

[0170] Table 8 shows exemplary doses of TTI-101 administered to rats and the % TTI-101 in each formulation.

[0171] Table 8: Administration of TTI-101 formulations in rats

[0172] Formulation / 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

[0173] Formulation F (IV) was prepared in 5 / 2 / 43 / 50% v / v DMSO / EtOH / PEG400 / saline (TTI-10 15 mg / mL). For oral formulations, the absolute oral bioavailability of Formulations AE relative to Formulation F was 0.183, 0.156, 0.229, 0.139, and 0.173, respectively. Cmax was: 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 AUCs were preparation F (188000 h*ng / mL), preparation C (41800 h*ng / mL), preparation E (31400 h*ng / mL), preparation A (30700 h*ng / mL), preparation B (28600 h*ng / mL) and preparation D (25800 h*ng / mL), respectively.

[0174] The above results show that the formulation containing Composition 7 of Example 2 with a CIP such as HPMC AS LF shows higher bioavailability than the capsule formulation of TTI-101 (Formulation E), while the formulation containing Composition 7 of Example 2 with a CIP such as HPMC AS LG shows similar bioavailability 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). 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.

[0175] Example 7. Use of the oral STAT3 inhibitor TTI-101 in patients with advanced cancer and healthy volunteers

[0176] In one Phase I trial, TTI-001 is being evaluated in patients with advanced cancer. In another trial, TTI-001 is being evaluated in healthy volunteers.

[0177] In short, the method for preparing formulations 1-3 is the same as the previous example. Two trials were conducted. The first trial is similar to the trial summarized in Table 9 below (for advanced cancer patients), consisting of a first group of subjects receiving formulation 1, a second group of subjects receiving formulation 2, and a third group of subjects receiving formulation 3. The second trial is similar to the trial summarized in Table 10 (for healthy volunteers), consisting of a group of subjects receiving formulation 3.

[0178] Table 9. Trial Information of TTI-101 in Patients with Advanced Cancer

[0179]

[0180]

[0181] Table 10. Trial information of TTI-101 in healthy volunteers

[0182]

[0183] The most common treatment-related adverse event observed with the SEDD formulation (Formulation 2) was diarrhea, which was reported in 44.7% of the 47 patients treated with TTI-101 SEDD (Table 11). A total of 48 patients were treated with the SDD formulation (Formulation 3) of TTI-101 in both studies, and as shown in the table below, fewer patients reported diarrhea (6.3%) compared with the SEDD formulation, and there were no Grade 2 or 3 diarrhea events. Patients treated with Formulation 3 also had a lower proportion of diarrhea events compared with those treated with the Labrasol / PEG formulation (Formulation 1).

[0184] Table 11. Treatment-related adverse events observed with formulations 1-3

[0185]

[0186]

[0187] In addition, pharmacokinetic data from the healthy volunteer study (dosing with Formulation 3) showed comparable mean exposures compared to the Phase 1 study (dosing with Formulation 2). Furthermore, patient exposures exceeded the IC90 for STAT3-dependent growth at every time point in the curve (data not shown).

[0188] In summary, Formulation 3 (prepared by SDD technology) reduces the medication burden required to achieve therapeutic doses of TTI-101. For example, Formulation 3 provides 200 mg of TTI-101 per unit, compared to 80 mg of TTI-101 per unit using Formulation 2 and 30 mg of TTI-101 per unit using Formulation 1. Formulation 3 reduces the incidence and severity of treatment-emergent adverse events and provides exposures similar to those of Formulation 2.

Claims

1. A solid amorphous dispersion comprising: a) Compounds of formula (I): or a pharmaceutically acceptable salt thereof; and b) Polymeric excipients.

2. The solid amorphous dispersion of claim 1, comprising from about 40% w / w to about 80% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

3. The solid amorphous dispersion of claim 1, comprising from about 40% w / w to about 70% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

4. The solid amorphous dispersion of claim 1, comprising from about 40% w / w to about 60% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

5. The solid amorphous dispersion of claim 1, comprising from about 45% w / w to about 55% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

6. The solid amorphous dispersion of claim 1, comprising about 50% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

7. The solid amorphous dispersion of claim 1, comprising about 60% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

8. The solid amorphous dispersion of claim 1, comprising about 70% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

9. The solid amorphous dispersion of any one of claims 1 to 8, wherein the polymer excipient is hydroxypropylmethylcellulose (HPMC), a copolymer comprising methacrylic acid, a copolymer comprising vinyl acetate and N-vinyl-2-pyrrolidone.

10. The solid amorphous dispersion of any one of claims 1 to 9, wherein the polymer excipient is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

11. The solid amorphous dispersion of claim 10, wherein the HPMC AS is HPMC AS grade L (HPMC AS-L).

12. 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, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate.

13. The solid amorphous dispersion of claim 12, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate.

14. The solid amorphous dispersion of claim 13, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.4:1 to about 1:1.

4.

15. The solid amorphous dispersion of claim 13, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.2:1 to about 1:1.

2.

16. The solid amorphous dispersion of claim 13, wherein the polymer excipient is a 1:1 copolymer of methacrylic acid and ethyl acrylate.

17. The solid amorphous dispersion of any one of claims 1 to 16, further comprising a crystallization inhibiting polymer.

18. The solid amorphous dispersion of claim 17, wherein the crystallization inhibiting polymer (CIP) is methylcellulose or HPMC.

19. The solid amorphous dispersion of claim 18, wherein the crystallization inhibiting polymer is HPMC.

20. The solid amorphous dispersion of claim 19, wherein the crystallization inhibiting polymer is HPMC AS.

21. The solid amorphous dispersion of claim 20, wherein the HPMC AS is HPMC AS-LF or HPMC AS-LMP, or a mixture thereof.

22. 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.

23. 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.

24. The solid amorphous dispersion of any one of claims 17-22, comprising from about 20% w / w to about 30% w / w of the crystallization inhibiting polymer in the dispersion.

25. The solid amorphous dispersion of any one of claims 17-22, comprising about 25% w / w of the crystallization inhibiting polymer in the dispersion.

26. A solid amorphous dispersion comprising: a) Compounds of formula (I): or a pharmaceutically acceptable salt thereof in an amount of about 40% w / w to about 60% w / w of said dispersion; and b) a polymer excipient in an amount of about 40% w / w to about 60% w / w of the dispersion.

27. The solid amorphous dispersion of claim 26, comprising from about 45% w / w to about 55% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

28. The solid amorphous dispersion of claim 26, comprising about 50% w / w of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the dispersion.

29. The solid amorphous dispersion of any one of claims 26-28, wherein the polymer excipient is hydroxypropylmethylcellulose (HPMC), a copolymer comprising methacrylic acid, a copolymer comprising vinyl acetate and N-vinyl-2-pyrrolidone.

30. The solid amorphous dispersion of any one of claims 26-29, wherein the polymer excipient is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

31. The solid amorphous dispersion of claim 30, wherein the HPMC AS is HPMC AS grade L (HPMC AS-L).

32. The solid amorphous dispersion of any one of claims 26-29, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate, a copolymer comprising methacrylic acid and methyl methacrylate, or a copolymer comprising N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate.

33. The solid amorphous dispersion of claim 32, wherein the polymer excipient is a copolymer comprising methacrylic acid and ethyl acrylate.

34. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.4:1 to about 1:1.

4.

35. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1.2:1 to about 1:1.

2.

36. The solid amorphous dispersion of claim 33, wherein the polymer excipient is a 1:1 copolymer of methacrylic acid and ethyl acrylate.

37. The solid amorphous dispersion of any one of claims 26-36, comprising about 50% w / w of the polymer excipient in the dispersion.

38. The solid amorphous dispersion of any one of claims 26-37, further comprising a crystallization inhibiting polymer.

39. The solid amorphous dispersion of claim 38, wherein the crystallization inhibiting polymer is HPMC.

40. The solid amorphous dispersion of claim 39, wherein the HPMC is HPMC AS.

41. The solid amorphous dispersion of any one of claims 37-40, wherein the HPMC AS is HPMCAS-LF or HPMC AS-LMP, or a mixture thereof.

42. The solid amorphous dispersion of any one of claims 1-41, further comprising an antioxidant.

43. A composition comprising a solid amorphous dispersion, the solid amorphous dispersion comprising: a) at least 150 mg of a compound of formula (I): or a pharmaceutically acceptable salt thereof; and b) Polymeric excipients.

44. The composition of claim 43, further comprising a diluent or filler.

45. The composition of claim 44, wherein the diluent or filler is a mixture of two or more diluents or fillers.

46. ​​The composition of claim 45, wherein the amount of the diluent or filler is about 20-35% w / w of the composition.

47. The composition of claim 45 or 46, wherein the amount of the diluent or filler is about 15-40% w / w of the composition.

48. The composition of any one of claims 44-47, wherein the diluent or filler is microcrystalline cellulose, silicified microcrystalline cellulose, or powdered cellulose.

49. The composition of any one of claims 43-48, further comprising a disintegrant.

50. The composition of claim 49, wherein the disintegrant is a mixture of two or more diluents.

51. The composition of claim 50, wherein the amount of disintegrant is about 3-8% w / w of the composition.

52. The composition of claim 50, wherein the amount of disintegrant is about 1-10% w / w of the composition.

53. The composition of any one of claims 49-52, wherein the disintegrant is croscarmellose sodium.

54. The composition of any one of claims 43-53, further comprising a lubricant.

55. The composition of claim 54, wherein the lubricant is a mixture of two or more lubricants.

56. The composition of claim 55, wherein the lubricant is present in an amount of about 0.5-4% w / w of the composition.

57. The composition of claim 55, wherein the lubricant is present in an amount of about 1-3% w / w of the composition.

58. The composition of any one of claims 54-57, wherein the lubricant is sodium lauryl sulfate, magnesium stearate, or sodium stearyl fumarate.

59. The composition of any one of claims 43-58, further comprising a crystallization inhibiting polymer.

60. The composition of claim 59, wherein the amount of the crystallization inhibiting polymer is about 10-30% w / w of the composition.

61. The composition of claim 59, wherein the amount of the crystallization inhibiting polymer is about 15-25% w / w of the composition.

62. A composition comprising: a) a solid amorphous dispersion comprising: i) at least 150 mg of a compound of formula (I): or a pharmaceutically acceptable salt thereof; and ii) a polymer excipient in an amount of about 20-35% w / w of the composition; b) a crystallization inhibiting polymer in an amount of about 15-35% w / w of the composition; c) a diluent or filler in an amount of about 5-25% of the composition; d) a disintegrant in an amount of about 1-8% w / w of the composition; and e) a lubricant in an amount of about 0.1-3% w / w of the composition.

63. A composition comprising: a) a solid amorphous dispersion comprising i) at least 150 mg of a compound of formula (I): or a pharmaceutically acceptable salt thereof; and ii) a polymer excipient in an amount of about 15-25% w / w of the composition; b) a crystallization inhibiting polymer in an amount of about 15-25% w / w of the composition; c) a diluent or filler in an amount of about 20-35% of the composition; d) a disintegrant in an amount of about 3-8% w / w of the composition; and e) a lubricant in an amount of about 1-3% w / w of the composition.

64. A solid oral dosage form comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

65. A solid oral dosage form comprising the solid amorphous dispersion of any one of claims 1-43 or the composition of any one of claims 44-63.

66. The oral dosage form of claim 64 or 65, wherein the oral dosage form is a tablet.

67. The oral dosage form of claim 66, further comprising a coating.

68. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the oral dosage form of any one of claims 64-67.

69. The method of 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, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, or lymphoma.

70. 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, myelodysplastic syndrome, leukemia, lymphoma, neuroblastoma, kidney cancer, skin cancer, or metastatic melanoma.

71. 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.

72. A method of treating fibrosis in a subject in need thereof, the method comprising administering to the subject the oral dosage form of any one of claims 64-67.

73. The method of claim 72, wherein the fibrosis is pulmonary fibrosis, bone marrow fibrosis, intestinal fibrosis, pancreatic fibrosis, arthrofibrosis, liver fibrosis, retroperitoneal fibrosis, kidney fibrosis, myelofibrosis, skin fibrosis, nonalcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.

74. A method of treating an inflammatory disease or disorder in a subject in need thereof, the method comprising administering to the subject the oral dosage form of any one of claims 64-67.

75. The method of claim 74, wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, psoriasis, uveitis, scleritis, multiple sclerosis, pancreatitis, or asthma.

76. The method of claim 74, wherein the inflammatory disease or disorder is inflammatory bowel disease, ulcerative colitis, asthma, or psoriasis.

77. A method of treating chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or familial amyloid polyneuropathy in a subject in need thereof, the method comprising administering to the subject an oral dosage form of any one of claims 64-67.

78. A method of treating cachexia in a subject in need thereof, the method comprising administering to the subject the oral dosage form of any one of claims 64-67.

79. A method of treating an allergic reaction in a subject in need thereof, the method comprising administering to the subject the oral dosage form of any one of claims 64-67.

80. The method of any one of claims 68-79, comprising administering to the subject at least 1 mg / kg / day of a compound of Formula (I).

81. 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).

82. The method of any one of claims 68-79, comprising administering to the subject at least 20 mg / kg / day of a compound of Formula (I).

83. The method of any one of claims 68-79, comprising administering to the subject at least 25 mg / kg / day of a compound of Formula (I).

84. A method for preparing a solid amorphous dispersion, the solid amorphous dispersion comprising a) Compounds of formula (I): or a pharmaceutically acceptable salt thereof, and b) a polymer excipient, the method comprising: i) dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer excipient in a solvent to form a solution; and ii) atomizing the solution of step (i) into a drying chamber in a spray drying dispersion device to prepare the solid amorphous dispersion.

85. The method of claim 84, further comprising dissolving a crystallization inhibiting polymer in step (i).

86. A composition prepared according to the method of claim 84 or 85.

87. An oral dosage form comprising an effective amount of the composition of claim 86.

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