Pharmaceutical composition of PROTAC compound and application thereof

Abstract

The proteolytic targeting chimera (PROTAC) is a heterobifunctional degradation agent that specifically eliminates the targeted protein by hijacking the ubiquitin-proteasome system (UPS). Pharmaceutical compositions comprising PROTAC, a hydrophilic polymer, a surfactant, and optionally a mixture of an acid and an adsorbent are provided. Methods for making and using such pharmaceutical compositions are also described. In one aspect, disclosed herein is an amorphous solid dispersion comprising PROTAC.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of patent application No. PCT / CN2022 / 083105 filed on March 25, 2022 and patent application No. PCT / CN2023 / 079057 filed on March 1, 2023, the disclosures of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present invention belongs to the pharmaceutical field, and in particular relates to a pharmaceutical composition and a preparation method and use thereof. Background Art

[0004] Proteolysis targeting chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This approach has emerged as an orthogonal approach to knockdown classical targets and disease-associated proteins using small molecule inhibitors, which have been classified as "undruggable" so far. However, PROTACs often suffer from poor cellular permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA).

[0005] ARV-110, an androgen receptor (AR)-targeted Protein degrader. ARV-110 is being developed by Arvinas for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and those who have progressed on existing therapies. Its molecular weight is 812.29, and its calculated log P is about 4.18. It is poorly soluble in aqueous solutions, and it should reportedly be taken with food.

[0006] ARV-471, an estrogen receptor (ER)-targeted Protein degrader. ARV-471 is being developed by Arvinas for the treatment of women with locally advanced or metastatic estrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative (ER+ / HER2-) breast cancer. Its molecular weight is 723.92, and its calculated log P value is about 4-6. It is difficult to dissolve in aqueous solution, and it is reported that it should be taken with food in clinical studies.

[0007] Poor water solubility and very low oral absorbability are bottlenecks in the development of RPOTAC molecules for in vivo applications. In addition, the bioavailability of almost all PROTAC molecules is subject to food effects. PROTAC compositions with improved oral bioavailability, allowing for lower doses, reducing absorption differences caused by food intake, and reducing absorption differences between subjects in vivo are highly desirable.

[0008] Incorporated by Reference

[0009] All publications and patent applications mentioned in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Summary of the invention

[0010] Disclosed herein is a pharmaceutical composition, wherein the pharmaceutical composition comprises a) an amorphous solid dispersion (ASD) comprising: i) a proteolytic targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; ii) a surfactant; iii) a hydrophilic polymer; iv) an optional acid; and v) an optional adsorbent, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in an amorphous state in the ADS; and b) an optional pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 2 times the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of the ASD, the bioavailability being measured as the total area under the curve (AUC) or the maximum plasma concentration (C max In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 3-fold, 4-fold, or 5-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or maximum plasma concentration (C max). In some embodiments, the bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof exhibited by a pharmaceutical composition is at least 1.5 times the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of an ASD, and the bioavailability is measured by the total area under the curve (AUC) or the maximum plasma concentration (Cmax) after oral administration to a subject in a fed state. In some embodiments, the bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof exhibited by a pharmaceutical composition is at least 2 times, 2.5 times, or 3 times the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of an ASD, and the bioavailability is measured by the total area under the curve (AUC) or the maximum plasma concentration (Cmax) after oral administration to a subject in a fed state. In some embodiments, the bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof is at least 5 times the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of an ASD. In some embodiments, the bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof is at least 1.1 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof but not as part of an ASD. In some embodiments, the corresponding composition comprises a PROTAC compound or a pharmaceutically acceptable salt thereof in an amorphous state. In some embodiments, the corresponding composition comprises a PROTAC compound or a pharmaceutically acceptable salt thereof in a crystalline form. In some embodiments, when administered orally to a subject in a fed state, the pharmaceutical composition exhibits a bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof that changes by no more than 100%, 50%, or 25% compared to a fasted state, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max). In some embodiments, the bioavailability is measured in a dog model in a fasted state or in a fed state. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the PROTAC compound is represented by the structure of formula (I): ALB, wherein i) A is an E3 ubiquitin ligase binding portion; ii) L is a linker; and iii) B is a portion that binds to a target protein, wherein the target protein can be degraded by an E3 ubiquitin ligase. In some embodiments, B is an androgen receptor (AR) binding portion. In some embodiments, B is an estrogen receptor binding portion. In some embodiments, the PROTAC compound is an androgen receptor PROTAC degrader. In some embodiments, the androgen receptor PROTAC degrader is ARV-110 or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the androgen receptor PROTAC degrader is In some embodiments, the PROTAC compound is an estrogen receptor PROTAC degrader. In some embodiments, the estrogen receptor PROTAC degrader is ARV-471 or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the estrogen receptor PROTAC degrader is In some embodiments, the PROTAC compound has a log P of at least 2.0 in octanol-water. In some embodiments, the PROTAC compound has a log P of at least 2.0, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or at least 5 in octanol-water. In some embodiments, the PROTAC compound or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 10% to 30% by weight. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 25 mg to about 250 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 10% to 60% by weight. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 15% to 55% by weight. In some embodiments, the surfactant includes a nonionic surfactant, an anionic surfactant, a phospholipid, or any combination thereof. In some embodiments, the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), a block copolymer of polyethylene glycol and polypropylene glycol, polysorbate, lecithin, polyethylene glycol castor oil, hydrogenated castor oil, sorbitan oleate, sodium lauryl sulfate (SDS), a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof. In some embodiments, the surfactant comprises tocopherol polyethylene glycol succinate (TPGS) or lecithin or a combination thereof. In some embodiments, the hydrophilic polymer is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, the hydrophilic polymer is present in an amorphous solid dispersion in an amount of about 1% by weight to about 80% by weight. In some embodiments, the hydrophilic polymer is present in an amorphous solid dispersion in an amount of about 15% by weight to about 50% by weight. In some embodiments, the hydrophilic polymer is vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl acetate and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG), or a combination thereof. In some embodiments, the polymethacrylate comprises Eudragit.In some embodiments, the hydrophilic polymer is vinyl pyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), polyethylene caprolactam, polyvinyl acetate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the amorphous solid dispersion comprises an acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid. In some embodiments, the acid is tartaric acid, citric acid or succinic acid. In some embodiments, the weight ratio of the PROTAC compound or its pharmaceutically acceptable salt to the hydrophilic polymer is about 10: 1 to about 1: 10. In some embodiments, the ASD comprises an adsorbent. In some embodiments, the adsorbent is selected from the group consisting of silicon dioxide, activated carbon, magnesium aluminum silicate, diatomaceous earth, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sugars or sugar alcohols, such as sorbitol, mannitol, lactose, cyclodextrin and maltodextrin. In some embodiments, the adsorbent is silicon dioxide. In some embodiments, the adsorbent is present in the amorphous solid dispersion in an amount of about 10% by weight to about 35% by weight. In some embodiments, the D50 value of the particle size of the amorphous solid dispersion is 1 μm to 1000 μm. In some embodiments, the D50 value is about 1 μm to about 150 μm (for example, 10 μm to 15 μm). In some embodiments, the amorphous solid dispersion also includes an antioxidant (for example, vitamin E). In some embodiments, a pharmaceutically acceptable carrier or excipient does not contain an organic acid. In some embodiments, the pharmaceutically acceptable carrier or excipient comprises an external acid that is not present in the amorphous solid dispersion. In some embodiments, the pharmaceutical composition is storage stable at 5±3°C for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months, wherein the storage-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical composition is storage stable at 25±2°C for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months, wherein the storage-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period.In some embodiments, the pharmaceutical composition is storage stable at 40±2°C for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, wherein the storage stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical composition comprises a) an amorphous solid dispersion comprising: (i) ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP, KT-413 or a pharmaceutically acceptable salt thereof in an amount of about 5 wt % to about 50 wt % of the ASD; (ii) a surfactant in an amount of about 1 wt % to about 60 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap) or the like. -PEG) or a combination thereof; (iii) a hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof; and (iv) optionally an acid in an amount of about 1 wt % to about 50 wt % of the ASD; and b) an optional pharmaceutically acceptable carrier or excipient.In some embodiments, the pharmaceutical composition comprises a) an amorphous solid dispersion comprising: (i) an amorphous solid dispersion comprising: ARV-110, ARV-471, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to about 50% by weight of the ASD; (ii) a surfactant in an amount of about 1% to about 50% by weight of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof; (iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrole alkyl ketone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin or a combination thereof; and (iv) optionally an acid in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the acid comprises tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof; and b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the surfactant is about 1:0.5 to about 1:6, about 1:0.8 to about 1:5, or about 1:1 to about 1:3. In some embodiments, the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 1:0.5 to about 1:6, about 1:0.8 to about 1:5, or about 1:1 to about 1:3.In some embodiments, the ASD comprises ARV-110 or a pharmaceutically acceptable salt thereof in an amount of about 10 wt % to about 40 wt % of the ASD; a surfactant in an amount of about 5 wt % to about 60 wt % of the ASD, wherein the surfactant is TPGS or lecithin, or a combination thereof; a hydrophilic polymer in an amount of about 10 wt % to about 60 wt % of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or HPMCAS, or a combination thereof; and optionally an acid in an amount of about 5 wt % to about 40 wt % of the ASD, wherein the acid is tartaric acid or citric acid. In some embodiments, the ASD comprises ARV-110 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 35% by weight of the ASD; a surfactant in an amount of about 10% to about 50% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or HPMCAS; and optionally an acid in an amount of about 10% to about 35% by weight of the ASD, wherein the acid is tartaric acid or citric acid. In some embodiments, ARV-471, or a pharmaceutically acceptable salt thereof, is present in an amount of about 10% to about 40% by weight of the ASD; a surfactant is present in an amount of about 5% to about 60% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer is present in an amount of about 10% to about 60% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or HPMCAS; and optionally an acid is present in an amount of about 5% to about 40% by weight of the ASD, wherein the acid is tartaric acid or succinic acid.In some embodiments, the ASD comprises ARV-471 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 35% by weight of the ASD; a surfactant in an amount of about 10% to about 50% by weight of the ASD, wherein the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or HPMCAS; and an optional acid in an amount of about 10% to about 35% by weight of the ASD, wherein the acid is tartaric acid or succinic acid. In some embodiments, the pharmaceutical composition is formulated in a unit dosage form. In some embodiments, the unit dosage form comprises 30 mg to 300 mg of a PROTAC compound or a pharmaceutically acceptable salt thereof; 10 mg to 500 mg of a surfactant; 10 mg to 500 mg of a hydrophilic polymer; optionally an acid in an amount of 1 mg to 500 mg; and optionally an adsorbent in an amount of 1 mg to 500 mg; and optionally a pharmaceutically acceptable carrier or excipient.

[0011] Disclosed herein is an amorphous solid dispersion, wherein the amorphous solid dispersion comprises: (i) a proteolytic targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; (ii) a surfactant; (iii) a hydrophilic polymer; (iv) an optional acid; and v. an optional adsorbent, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in an amorphous state in the ASD. In some embodiments, the PROTAC compound is ARV-110 or ARV-471.

[0012] Disclosed herein is a method for treating a disease or condition, comprising administering a pharmaceutical composition or amorphous solid dispersion as described herein to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered with or without food. In some embodiments, the subject is in a fasting state. In some embodiments, the subject is in a fed state. In some embodiments, the disease or condition is cancer. In some cases, the cancer is prostate cancer or breast cancer.

[0013] Disclosed herein is a method for ubiquitination or degradation of a target protein in a cell of a subject, comprising administering the pharmaceutical composition or amorphous solid dispersion described herein to the subject.

[0014] Disclosed herein is a method for preparing an amorphous solid dispersion comprising the steps of: a) combining: (i) a proteolysis targeting chimeric (PROTAC) compound or a pharmaceutically acceptable salt thereof, (ii) a surfactant, (iii) a hydrophilic polymer, (iv) optionally an additive, and (v) a solvent to produce a liquid mixture or solution, and b) removing the solvent from the mixture to produce an amorphous solid dispersion. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description of illustrative embodiments, in which the principles of the present invention are utilized, and in which:

[0016] Figure 1 Shown is an X-ray powder diffraction study of an amorphous solid dispersion (ASD) of ARV-110 formulation batch number P210803.

[0017] Figure 2 An X-ray powder diffraction study of particles of ARV-110 is shown.

[0018] Figure 3 Shown is a comparison of plasma concentrations of active pharmaceutical ingredient (API) (ARV-110) in a dog model when ARV-110 was delivered intravenously (iv) at a dose of 5 mg API or orally administered at a dose of 50 mg API, both under fasting conditions.

[0019] Figure 4 Shown is a comparison of plasma concentrations of the API (ARV-110) in a dog model when ARV-110 was orally administered as a dose of 45 mg API under fed and fasted conditions and not as part of an ASD formulation.

[0020] Figure 5 Shown is a comparison of plasma concentrations of API (ARV-110) in a dog model when the ASD composition of ARV-110 batch number P210803 was orally administered at a dose of 45 mg API under fed and fasted conditions.

[0021] Figure 6 Shown is a comparison of plasma concentrations of API (ARV-110) in a dog model when two ASD compositions of ARV-110 (lots P220622-1 and P220622-2) and the API alone were orally administered at a dose of 50 mg API under fed conditions.

[0022] Figure 7Shown is a comparison of plasma concentrations of API (ARV-110) in a dog model when the ASD composition of ARV-110 (lot P220802-1) was orally administered at doses of 50 mg API, 100 mg API, and 200 mg API under fed conditions (all performed under fed conditions).

[0023] Figure 8 Shown is an X-ray powder diffraction study of the ASD of ARV-471 composition batch number P220215-1.

[0024] Fig. 9 X-ray powder diffraction studies of particles of ARV-471 are shown.

[0025] Fig.10 Shown is a comparison of plasma concentrations of API ARV-471 in a dog model when ARV-471 was delivered intravenously (iv) at a dose of 6 mg API under fasting conditions or orally administered at a dose of 60 mg API under fasting and fed conditions.

[0026] Fig.11 Shown is a comparison of plasma concentrations of API (ARV-471) in a dog model when two ASD compositions of ARV-471 (lots P220215-1 and P220215-2) and the API alone were orally administered at a dose of 60 mg API under fed conditions.

[0027] Fig.12 Shown is a comparison of plasma concentrations of API (ARV-471) in a dog model when the ASD composition of ARV-471 (lot P220215-1) was orally administered at a dose of 60 mg API under fed conditions and under fasted conditions.

[0028] Fig.13 Shown is a comparison of plasma concentrations of API (ARV-471) in a dog model when the ASD composition of ARV-471 (lot number P220419-1) was orally administered at doses of 100 mg API, 150 mg API, and 200 mg API under fasting conditions.

[0029] Fig.14 Shown is a comparison of plasma concentrations of the API (ARV-471) in a dog model when only the API was orally administered at a high dose of 200 mg under fed and fasted conditions.

[0030] Fig.15Shown is a comparison of plasma concentrations of API (ARV-471) in a dog model when the ASD composition of ARV-471 (lot P220525-1) was orally administered at a high dose of 200 mg API under fed conditions and under fasted conditions. DETAILED DESCRIPTION

[0031] As further described herein, the present disclosure generally relates to compositions comprising a pharmaceutically active agent that can be used as a therapeutic agent for alleviating, reducing or eliminating one or more conditions in a subject in need thereof. Specifically, described herein are pharmaceutical compositions, methods for preparing the same and uses thereof, wherein the pharmaceutical compositions comprise a combined PROTAC, a hydrophilic polymer and a surfactant, such that the PROTAC has improved bioavailability compared to a single PROTAC. In some embodiments, PROTAC, a hydrophilic polymer, one or more surfactants and an optional acid are in an amorphous solid dispersion. Currently disclosed pharmaceutical compositions comprising an amorphous solid dispersion containing PROTAC and a suitable excipient or carrier provide better bioavailability and reduced food effect than crystalline forms or other conventional dosage forms of such PROTACs. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising PROTACs in a crystalline form. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising PROTACs in an amorphous state but not as part of an ASD. In some embodiments, conventional dosage forms comprise PROTACs in a crystalline form. In some embodiments, conventional dosage forms comprise PROTACs in an amorphous state. In some embodiments, conventional dosage forms comprise PROTAC compounds filled in capsules. In some embodiments, conventional dosage forms do not comprise ASD. In some embodiments, ASD comprises PROTAC, a surfactant (e.g., lecithin or TPGS), and a hydrophilic polymer.

[0032] definition

[0033] Unless otherwise stated, the general terms used above and below preferably have the following meanings in the context of the present disclosure:

[0034] Unless specifically stated or obvious from the context, as used herein, the term "about" means + / - 10% of the stated number or numbers, or 10% below the lower limit and 10% above the upper limit stated.

[0035] Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a surfactant" includes reference to one or more of the specific surfactants and reference to "an antioxidant" includes reference to one or more of such additives.

[0036] As used herein, the term "subject" refers to a mammal (eg, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, or baboon).

[0037] As used herein, "AUC" or "AUC inf " refers to the area under the plasma drug concentration-time curve extrapolated from time zero to infinity. As used herein, "AUC last " refers to the area under the curve from the time of administration to the last measurable concentration time. As used herein, "C max " refers to the maximum drug concentration observed in plasma after extravascular administration. As used herein, "T max ” refers to the time to reach maximum plasma concentration after administration of a drug. In some cases, AUC, AUC inf or C max Can be used to measure the bioavailability of an API described herein (e.g., PROTAC). In some cases, AUC, AUC inf or C max To evaluate the improvement or difference in the bioavailability of the API in various oral compositions (e.g., the ASD compositions described herein). In some cases, the bioavailability of the API is evaluated in a subject under fed conditions or fasting conditions. In some cases, the absolute bioavailability of the API is measured by the plasma concentration of the API obtained by iv injection.

[0038] "D10", "D50" and "D90" are used herein to describe particle size distributions. "D10" as used herein refers to the diameter at which ten percent of the total mass of particles are smaller and ninety percent are larger. "D50" as used herein refers to the median diameter at which fifty percent of the total mass of particles are larger and 50% are smaller. "D90" defines the diameter at which ninety percent of the mass distribution has a smaller particle size and ten percent has a larger particle size.

[0039] In some embodiments, error bands are included. The term "total error band" is used herein to specify all sources, including sampling and sample preparation calculated at a 95% confidence level. Examples are: D50 100 μm, where the total error band for size is + / -5%. Other statistics are sometimes used to describe particle size distribution. The most common calculations are standard deviation and variance. Standard Deviation (St Dev.). The standard deviation specification defines the diameter that approximately 68.27% of the total population is within + / -1St Dev, and 95.45% is within + / -2St Dev.

[0040] "Effective amount" and "sufficient amount" are used interchangeably and refer to an amount of a substance sufficient to achieve the intended purpose or objective.

[0041] When used in conjunction with the pharmaceutical compositions described herein, a "therapeutically effective amount" is an amount of one or more pharmaceutically active agents sufficient to produce a therapeutic effect in a subject in need thereof.

[0042] When used in conjunction with the pharmaceutical compositions described herein, a "therapeutic equivalent" refers to the amount of a pharmaceutically acceptable salt or ester of a pharmaceutically active agent that is equivalent to a therapeutically effective amount of the free base or alcohol of the pharmaceutically active agent.

[0043] The prefix "lower" denotes a group having up to and including 7 carbon atoms, especially up to and including 4 carbon atoms, which group is linear or branched with singly or multiple branches.

[0044] "Amino" refers to the -NH2 group.

[0045] "Cyano" refers to a -CN group.

[0046] "Nitro" refers to a -NO2 group.

[0047] "Methoxy" refers to the radical -O-Me.

[0048] "Oxa" refers to an -O- group.

[0049] "Oxo" refers to a =0 group.

[0050] "Thio" refers to a =S group.

[0051] "Imino" refers to a =NH group.

[0052] "Oximo" refers to a =N-OH group.

[0053] "Hydrazino" refers to the =N-NH2 radical.

[0054] "Hydroxy" or "hydroxyl" refers to an -OH group.

[0055] "Hydroxyamino" refers to a -NH-OH group.

[0056] "Acyl" refers to substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless otherwise specifically stated in the specification, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, amide or ester groups are optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0057] "Acyl-sulfonamide" refers to a monovalent group in which the carbon atom of the carbonyl group is bound to a sulfonamide group. Exemplary acyl-sulfonamides include -C(O)NR a S(O)2R a 、-C(O)NR a S(O)2N(R a )2.-NR a S(O)2C(O)R a 、-NR a S(O)2C(O)N(R a )2. -C(O)NR a S(O)2C(O)N(R a )2.-NR a S(O)2NR a C(O)N(R a )2. -C(O)NR a S(O)2NR a C(O)N(R a )2 and -C(O)S(O)2N(R a )2, where each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0058] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical. The alkyl group can have one to about twenty carbon atoms, one to about ten carbon atoms, or one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also includes the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C1-C6 alkyl. 10 In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2 or -C≡CH. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0059] "Alkenyl" refers to an optionally substituted straight chain or optionally substituted branched hydrocarbon monogroup having one or more carbon-carbon double bonds. In some embodiments, the alkenyl group has two to about ten carbon atoms or two to about six carbon atoms. The group can be a cis or trans configuration of the double bond, and should be understood to include two isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also covers the occurrence of the term "alkenyl" without specifying a numerical range. In some embodiments, the alkenyl group is C2-C6.10 Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl or C2 alkenyl.Unless otherwise specifically stated in the specification, alkenyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2.In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe.In some embodiments, alkenyl is optionally substituted by halogen.

[0060] "Alkynyl" refers to an optionally substituted straight chain or optionally substituted branched hydrocarbon monoradical having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl group has two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever a numerical range such as "C2-C6 alkynyl" appears in this document, it means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. In some embodiments, the alkynyl group is C2-C6. 10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl or C2 alkynyl.Unless otherwise specifically stated in the specification, alkynyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkynyl is optionally substituted by halogen.

[0061] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen. In some embodiments, alkylene is -CH2-, -CH2CH2- or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2-.

[0062] "Alkylamino" refers to a group of the formula -N(R a )2, wherein R a is an alkyl group as defined above, or two R a Together with the nitrogen atom, it can form a substituted or unsubstituted C2-C7 heterocycloalkyl ring, such as: Unless otherwise specifically stated in the specification, alkylamino can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylamino is optionally substituted by oxo, halogen, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, alkylamino is optionally substituted by oxo, halogen, -CN, -CF , -OH or -OMe. In some embodiments, alkylamino is optionally substituted by halogen.

[0063] "Alkoxy" refers to a group of the formula -OR a A group in which R a It is an alkyl group as defined. Unless specifically stated otherwise in the specification, alkoxy can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0064] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0065] "Aryl" refers to a group derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, the aryl group contains hydrogen and 6 to 30 carbon atoms. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, aryl groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, The aryl of the hydrocarbon ring system of fluoranthene, fluorene, indane, indene, naphthalene, phenanthrene, phenanthrene, pyrene and triphenylene. In some embodiments, aryl is phenyl. Unless otherwise specifically stated in the specification, aryl can be optionally substituted by, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S (O) 2NH-C1-C6 alkyl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S (O) 2NH2, -S (O) 2NHCH 3、 -S(O)2NHCH2CH3, -S(O)2NHCH ( In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen. In some embodiments, aryl is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0066] "Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyl groups include, but are not limited to, groups having three to fifteen carbon atoms (C3-C 15 Cycloalkyl), three to ten carbon atoms (C3-C 10In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane, and 7,7-dimethylbicyclo[2.2.1]heptane. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0067] As used herein, the term "carbocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring, wherein each atom of the ring is a carbon atom.Carbocycles include 3-10-membered monocycles, 6-12-membered bicyclic rings and 6-12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring and an aromatic ring. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused with a saturated ring or an unsaturated ring (e.g., cyclohexane, cyclopentane or cyclohexene). As long as valence permits, bicyclic carbocycles include any combination of saturated bicyclic rings, unsaturated bicyclic rings and aromatic bicyclic rings. Bicyclic carbocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl and naphthyl. The term "unsaturated carbocycle" refers to a carbocycle having at least one degree of unsaturation, and does not include aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. As used herein, the term "saturated cycloalkyl" refers to a saturated carbocycle. Exemplary saturated cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. The carbocycle may optionally be substituted with one or more substituents, such as those described herein.

[0068] When the plural form is used for compounds, salts, etc., this also means a single compound, salt, etc.

[0069] Any asymmetric carbon atom may be present in (R)-configuration, (S)-configuration or (R,S)-configuration, preferably in (R)-configuration or (S)-configuration. Thus, the compound may exist as a mixture of isomers or as a pure isomer, preferably as an enantiomerically pure diastereomer.

[0070] The present disclosure also relates to possible tautomers of the compounds of formula (I).

[0071] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0072] "Heteroaryl" refers to a ring system group comprising carbon atoms and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepanyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxenyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl or benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, oxazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxazepinene, oxazolyl, oxiranyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (thienyl). Unless otherwise specifically stated in the specification, heteroaryl is optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0073] "Heterocyclyl", "heterocycle" or "heterocyclic" refers to a stable 3- to 18-membered saturated, unsaturated or aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, the heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused, bridged or spirocyclic system. The heteroatoms in the heterocyclyl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclyl group can be partially or completely saturated. The heterocyclyl group is connected to the rest of the molecule through any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is meant to include heterocyclyl groups as defined above, which are optionally substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -CN, -R b -OR e -C(O)N(R a )2. -R b -N(R a )C(O)ORa , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R e is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0074] Active Pharmaceutical Ingredients (API)

[0075] The present disclosure relates to pharmaceutical compositions and methods of administration and use thereof, the compositions comprising an amorphous solid dispersion comprising an API, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, the API is a PROTAC. Proteolytic targeting chimeras (PROTACs) generally have poor water solubility and low oral absorbability, even if the PROTAC compound is in an amorphous form. Due to these characteristics, it is difficult to develop a PROTAC composition with good oral bioavailability at lower doses and reduced absorbability changes caused by food intake. Compared with conventional dosage forms, the pharmaceutical compositions described herein show significantly improved PROTAC oral bioavailability. In some embodiments, the pharmaceutical composition for PROTAC is an amorphous solid dispersion (ASD). In some embodiments, the ASD comprises a surfactant. In some embodiments, the surfactant comprises a phospholipid. In some embodiments, the surfactant comprises lecithin. In some embodiments, PROTAC is one of those listed in Table 1. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, PROTAC is ARV-471. In some embodiments, conventional dosage forms of PROTAC include dosage forms comprising PROTAC in crystalline form. In some embodiments, conventional dosage forms of PROTAC include dosage forms comprising PROTAC in an amorphous state but not as part of an ASD. In some embodiments, conventional dosage forms do not include an ASD. In some embodiments, an ASD comprises a PROTAC, a surfactant (e.g., lecithin or TPGS), and a hydrophilic polymer.

[0076] In some embodiments, the solid dispersion is a solid solution in which the API (or API salt) and the hydrophilic polymer serve as the solute and solvent, respectively. Depending on the composition and the sample processing history, the solid dispersion can form a variety of structures. When the API loading is lower than the equilibrium solubility of the API in the hydrophilic polymer, the drug is dispersed in the polymer matrix in molecular form and forms a thermodynamically stable uniform solution. A uniform solution can usually be obtained only at very low API loadings and / or high temperatures. For higher loadings, the mixture becomes a supersaturated solution, and the drug precipitates out. This can result in the dispersion of crystalline API particles in a hydrophilic polymer matrix, wherein the drug concentration corresponds to its equilibrium solubility at that temperature. Alternatively, since API crystallization may be a slow process, an intermediate metastable structure can be formed in which amorphous API aggregates are dispersed in a hydrophilic polymer matrix containing an API in a non-crystalline amorphous state. Compared with crystalline API, such amorphous solid dispersions can provide excellent dissolution characteristics.

[0077] Amorphous solid dispersions described herein may include API, hydrophilic polymers and surfactants. In some embodiments, amorphous solid dispersions described herein additionally include one or more adsorbents. In some embodiments, amorphous solid dispersions described herein additionally include one or more other additives. In some embodiments, other additives include organic acids and inorganic acids. In some embodiments, other additives include antioxidants. In some embodiments, amorphous solid dispersions described herein are uniform amorphous solid dispersions. In some embodiments, the components of the amorphous dispersion are mixed and heated in a solvent, and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the solvent is water. In some embodiments, the solvent is a polar organic solvent. In some embodiments, the solvent is a non-polar organic solvent. In some embodiments, the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, methyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide, dichloromethane (DCM), acetone, tetrahydrofuran (THF) and any combination thereof. In some embodiments, the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid and any combination thereof. In some embodiments, the solvent is selected from water, methanol, ethanol and isopropanol. In some embodiments, the solvent is selected from dichloromethane, methanol, THF and acetone. In some embodiments, the solvent is selected from a mixture of these solvents.

[0078] The amorphous solid dispersion described herein may comprise an API, a hydrophilic polymer, a surfactant, and an optional adsorbent. In some embodiments, the components of the amorphous dispersion (such as the API, the hydrophilic polymer, and the surfactant) are mixed and dissolved in a solvent with or without heating to form a solution. In some embodiments, the adsorbent is further added to the solution to form a uniform suspension and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the solution is sprayed onto the adsorbent and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the adsorbent is selected from silicon dioxide (also known as silica), magnesium aluminum silicate (Neusilin), microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, sugars, and sugar alcohols. In some embodiments, sugars and sugar alcohols include sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0079] PROTAC Compounds

[0080] Various embodiments described herein relate to compositions comprising an effective amount of an active pharmaceutical agent (API). "Active pharmaceutical agent," "API," "drug," "pharmaceutically active agent," "biologically active agent," "therapeutic agent," and "active agent" are used interchangeably and refer to substances, such as chemical compounds, complexes, or PROTACs, that have a measurable beneficial physiological effect on the body when administered in an effective amount, such as a therapeutic effect in the treatment of a disease or disorder. In addition, when these terms are used, or when a particular active agent is specifically identified by name or class, it should be understood that such description is intended to include the active agent itself, as well as its pharmaceutically acceptable pharmacologically active derivatives, or compounds significantly related thereto, including but not limited to salts, pharmaceutically acceptable salts, N-oxides, prodrugs, active metabolites, isomers, fragments, analogs, solvates hydrates, radioactive isotopes, and the like.

[0081] The partition coefficient (P) referred to herein is the ratio of the concentration of a compound between two immiscible solvent phases at equilibrium. Most commonly, one solvent is water and the other is hydrophobic, usually 1-octanol. The logarithm of this ratio is log P, as shown below, (usually the lipophilic phase is the numerator and the hydrophilic phase is the denominator.)

[0082]

[0083] log P is a measure of lipophilicity or hydrophobicity. Hydrophobicity affects drug absorption, bioavailability, hydrophobic drug-receptor interactions, molecular metabolism, and toxicity. Hydrophilic compounds are soluble in water ("hydrophilic") and polar solvents. Lipophilic compounds are less soluble in water ("water-fearing" or hydrophobic) and polar solvents, but more soluble in organic solvents. Therefore:

[0084] Low hydrophilicity = high lipophilicity = high log P = poor water solubility = poor absorption.

[0085] High hydrophilicity = low lipophilicity = low log P = good water solubility = good absorption.

[0086] The partition coefficient can be measured experimentally or estimated computationally. Various methods for calculating (or predicting) log P have been developed, typically by fitting the calculated log P values ​​to experimentally measured log P values ​​for a training set of thousands of molecules, most of which are drug-like. Log P calculations are considered to be very reliable and can accurately handle many organic molecules. For example, more than 50% of the molecular log Ps have a prediction error of less than 0.25, and more than 80% have a prediction error of less than 0.5. Less than 3.5% of the structures have a prediction error greater than 1.0. To distinguish it from the measured log P, calculated log P is sometimes written as clog P. Unless otherwise specified, "log P" as used herein refers to the experimental log P value.

[0087] In some embodiments, the API is lipophilic. An API is considered lipophilic if its log P value or calculated log P value is 2.0 or greater. A log P of 2.0 or greater indicates that the solubility of the API in a lipophilic solvent is 100 times or greater than in water. In some embodiments, the API is insoluble in polar solvents. In some embodiments, the API is insoluble in aqueous media. In some embodiments, the API is insoluble in water.

[0088] In some embodiments, the PROTAC has a log P of at least 2.0, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0.

[0089] In some embodiments, PROTACs described herein have low solubility. In some embodiments, PROTAC has a solubility of less than 10 mg / mL in water at about 25°C. In some embodiments, PROTAC has a solubility of up to 1 mg / mL in water at about 25°C. In some embodiments, PROTAC has a solubility of less than 1 mg / mL in water at about 25°C. In some embodiments, PROTAC has a solubility of less than 0.5 mg / mL in water at about 25°C. In some embodiments, PROTAC has a solubility of less than 0.1 mg / mL in water at about 25°C. In some embodiments, PROTAC has a solubility of less than 0.01 mg / mL in water at about 25°C.

[0090] In some embodiments, the API described herein is a heterobifunctional small molecule. In some embodiments, the heterobifunctional small molecule is a PROTAC. In some embodiments, the PROTAC comprises a first active domain. In some embodiments, the heterobifunctional small molecule comprises a second active domain. The heterobifunctional small molecule comprises a linker. In some embodiments, the linker binds the first active domain and the second active domain. In some embodiments, the first active domain and the second active domain are covalently linked. In some embodiments, the first active domain engages an E3 ubiquitin ligase. In some embodiments, the second active domain binds a target protein. In some embodiments, the target protein is meant for degradation.

[0091] In some embodiments, PROTAC works by inducing selective intracellular proteolysis. In some embodiments, PROTAC binds the target protein and the E3 ligase together. In some embodiments, PROTAC recruits E3 ligases and target proteins. In some embodiments, such recruitment of PROTAC leads to ubiquitination of the target protein and subsequent degradation of the target protein by the proteasome. In some embodiments, PROTAC achieves degradation of the target protein by "hijacking" the ubiquitin-proteasome system (UPS) of the cell. In some embodiments, E1 ligase activates ubiquitin and conjugates it with E2 ligase. In some embodiments, the E2 ligase then forms a complex with the E3 ligase. In some embodiments, the E3 ligase targets the protein of interest by covalently linking ubiquitin to the protein of interest. In some embodiments, after forming a ubiquitin chain, the protein of interest is recognized and degraded by the 26S proteasome. In some embodiments, PROTAC utilizes the UPS cell system by placing the target protein near the E3 ligase that catalyzes the degradation of the target protein. In some embodiments, PROTAC has a catalytic mechanism that allows PROTAC itself to be recycled after degradation of the target protein. As used herein, the terms "PROTAC" and "PROTAC compound" are used interchangeably.

[0092] Exemplary PROTACs include, but are not limited to, those listed in Table 1. In some embodiments, the API is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the API is ARV-110. In some embodiments, the API is a pharmaceutically acceptable salt of ARV-110. In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0093] Table 1

[0094]

[0095]

[0096] 1Heimbach, T. et al.; Physiologically Based Pharmacokinetic ModelingtoSupplement ARV-110Pharmacokinetics and ConfirmDose Selection in PediatricPatients; Journal of Pharmaceutical Sciences 108(2019)2191-2198

[0097] 2 Calculation source - calculated by XLogP3 3.0 (PubChem release 2021.05.07) listed on www.pubchem.ncbi.nlm.nih.gov

[0098] The acid dissociation constant Ka (or acidity constant) is a measure of the strength of an acid or base in a solution (usually water). It is the equilibrium constant for the chemical decomposition of acids and bases. In aqueous solution, the equilibrium for acid dissociation is written as:

[0099]

[0100] HA is a kind of - (the conjugate base of the acid) and the hydrogen ion (which combines with a water molecule to form a hydronium ion, H3O + ) acid. The dissociation constant can also be written without H2O:

[0101]

[0102]

[0103] The dissociation equilibrium of the conjugate acid of a base is written as:

[0104]

[0105] Among them, BH + (the conjugate acid of the base) dissociates into B (the free base) and a hydrogen ion, and the hydrogen ion combines with a water molecule to form a hydronium ion, i.e., H3O + .

[0106] The dissociation constant can also be written without H2O:

[0107]

[0108]

[0109] pK a (K aThe logarithm of a base is more commonly used to express the strength of an acid or the conjugate acid of a base:

[0110] pK a =-log 10 (K a )

[0111] pK a The larger the value, the less dissociated and the weaker the acid. In general, for acids:

[0112] pK a = -2 to 12 → weak acid (little or only partially dissociated in water)

[0113] pKa < -2 → strong acid (completely or mostly dissociates in water)

[0114] And for the base:

[0115] pK a <12 → weak base (little or only partially dissociated in water)

[0116] pKa ≥ 12 → strong base (completely or mostly dissociated in water)

[0117] In some embodiments, the API is a weak base.

[0118] In some embodiments, the API comprises a weak base functional group.

[0119] In some embodiments, the API has a pKa equal to or greater than 3.0. In some embodiments, the API has a pKa equal to or greater than 3.5. In some embodiments, the API has a pKa equal to or greater than 4.0. In some embodiments, the API has a pKa equal to or greater than 4.5. In some embodiments, the API has a pKa equal to or greater than 5.0.

[0120] In some embodiments, the API is present in the form of a free base. In some embodiments, the API is present in the form of a pharmaceutically acceptable salt. As used herein, pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, etc.; inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; and amino acid salts such as arginine salts, aspartates, glutamates, etc. In some embodiments, the API is a PROTAC. In some embodiments, the API is a PROTAC listed in Table 1. In some embodiments, the API is ARV-110 or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the API is ARV-110. In some embodiments, the API is a pharmaceutically acceptable salt of ARV-110. In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is a PROTAC. In some embodiments, the PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC, a hydrophilic polymer, and a surfactant are formulated into an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants.

[0121] Exemplary PROTAC compounds including ARV-110 and ARV-471 and their analogs

[0122] A pharmaceutical composition is described herein, comprising an amorphous solid dispersion comprising an API. In some embodiments, the API is a PROTAC. In some embodiments, the API is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the API is ARV-110. In some embodiments, the API is ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, the API is ARV-471.

[0123] In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is a compound of formula (I),

[0124] ALB

[0125] Formula (I)

[0126] in

[0127] (i) A is the E3 ubiquitin ligase binding part;

[0128] (ii) L is a linker; and

[0129] (iii) B is the part that binds to the target protein, where the target protein can be degraded by E3 ubiquitin ligase.

[0130] In some embodiments, A is an E3 ubiquitin ligase binding moiety. In some embodiments, the E3 ubiquitin ligase binding moiety is a small molecule. In some embodiments, the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase. In some embodiments, the E3 ubiquitin ligase is selected from Von Hippel-Lindau (VLM), cereblon (CLM), mouse double minute homolog 2 (MLM) and IAP (ILM). In some embodiments, the E3 ubiquitin ligase is VLM. In some embodiments, the E3 ubiquitin ligase is CLM. In some embodiments, the E3 ubiquitin ligase is MLM. In some embodiments, the E3 ubiquitin ligase is ILM. In some embodiments, CLM is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, its analogs, its isosteres or derivatives thereof.

[0131] In some embodiments, the CLM has a chemical structure represented by formula (A):

[0132]

[0133] in:

[0134] W is selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0135] Each X is independently selected from the group consisting of: O, S and H2;

[0136] Z is selected from the group consisting of: O, S and H2;

[0137] G is independently selected from the group consisting of H, C1-C6 alkyl (straight chain, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH, C1-C6 heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0138] Q1, Q2, Q3 and Q4 are independentlyn The carbon or nitrogen atom to which it is attached;

[0139] A is selected from the group consisting of H, C1-C6 alkyl (linear, branched, optionally substituted), cycloalkyl, Cl and F;

[0140] R includes -CONR'R", -OR', -NR'R", -SR', -SO,R', -SO,NR'R", -CR'R"-, -CR'NR'R"-, (-CR'OO), R", C1-C6 aryl, -C1-C6 heteroaryl, C1-C6 alkyl (linear, branched, optionally substituted), C1-C6 cycloalkyl, C1-C6 heterocyclyl, -P(O)(OR")R", -P(O)R'R", -OP(O)(OR")R", -OP(O)R'R", -Cl, -F, -Br, - I, -CF;, -CN, -NR'SO,NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -N R'C(=C-NO)NR'R", -SO,NR'COR", -NO2, -COR', -C(C=N-OR")R", -CR'=CR'R", -CCR', -S(C=O)(C=NR")R", -SF5 and -OCF3;

[0141] R' and R" are independently selected from the group consisting of a bond, H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 aryl, C1-C6 heteroaryl, halogen, -C(=O)R, and C1-C6 heterocyclyl;

[0142] represents a stereospecific ((R) or (S)) or non-stereospecific bond; and

[0143] R n contains a functional group, a bond or an atom, wherein n is an integer from 4 to 10, and wherein one R n is a bond that covalently connects one of Q1, Q2, Q3 or Q4 to the linker (L), and any other Rn is optionally selected from the group consisting of H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 aryl, C1-C6 heteroaryl, halogen and C1-C6 heterocyclyl.

[0144] In some embodiments, the CLM has a chemical structure represented by formula (A), wherein W is selected from the group consisting of: CH2, C=O, and NH;

[0145] Each X is independently selected from the group consisting of: O and S;

[0146] Z is selected from the group consisting of: O and S;

[0147] G is independently selected from the group consisting of: H, C1-C3 alkyl (linear, branched, optionally substituted), OH;

[0148] Q1, Q2, Q3 and Q4 are independently n The carbon atom to which it is attached;

[0149] A is selected from the group consisting of H, C1-C3 alkyl (straight or branched), Cl and F;

[0150] represents a stereospecific ((R) or (S)) or non-stereospecific bond; and

[0151] R n contains a functional group, a bond or an atom, wherein n is an integer from 4 to 10, and wherein one R n is a bond that covalently connects one of Q1, Q2, Q3, or Q4 to the Linker (L), and any other R n Optionally selected from the group consisting of H, C1-C3 alkyl and halogen.

[0152] In some embodiments, the CLM has a chemical structure represented by formula (A), wherein W is selected from the group consisting of: CH2 and C=O;

[0153] Every X is O;

[0154] Z is O;

[0155] G is H;

[0156] Q1, Q2, Q3 and Q4 are independently n The carbon atom to which it is attached;

[0157] A is H;

[0158] represents a stereospecific ((R) or (S)) or non-stereospecific bond; and

[0159] R n contains a functional group, bond, or atom, wherein n is 4, and each R n Connect to one of Q1, Q2, Q3 or Q4, where one R n is the bond that covalently links Q2 or Q3 to the Linker (L), and any other R n Optionally selected from the group consisting of: H and F.

[0160] In some embodiments, CLM has a chemical structure represented by Formula (A), wherein W is C=O; each X is O; Z is O; G is H; Q1, Q2, Q3 and Q4 are independently n The carbon atom to which it is attached; A is H;

[0161] represents a stereospecific ((R) or (S)) or non-stereospecific bond; and

[0162] R n contains a functional group, bond, or atom, wherein n is 4, and each R n connected to one of Q1, Q2, Q3 or Q4, and one of the R n is the bond that covalently links Q3 to the linker (L), an R n is connected to F of Q2, and any other R n It's H.

[0163] In some embodiments, CLM has a chemical structure represented by Formula (A), wherein W is CH2, each X is O; Z is O; G is H; Q1, Q2, Q3 and Q4 are independently n The carbon atom to which it is attached; A is H;

[0164] represents a stereospecific ((R) or (S)) or non-stereospecific bond; and

[0165] R n contains a functional group, bond, or atom, wherein n is 4, and each R n connected to one of Q1, Q2, Q3 or Q4, and one of the R n is the bond that covalently links Q2 to the Linker (L), and any other R n It's H.

[0166] In some embodiments, the CLM has a chemical structure represented by the following formula:

[0167]

[0168] In some embodiments, the CLM has a chemical structure represented by the following formula:

[0169]

[0170] In some embodiments, L is a linker. In some embodiments, a linker is a bond. In some embodiments, a linker is a chemical linking moiety connecting A and B.

[0171] In some embodiments, L is selected from:

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] Where m = 1 or 2, n = 0, 1;

[0178] in Indicates the connection point to A or B.

[0179] In some embodiments, L is selected from:

[0180]

[0181] Where m = 1 or 2, n = 0, 1;

[0182] in Indicates the connection point to A or B.

[0183] In some embodiments, L is selected from: in Indicates the connection point to A or B.

[0184] In some embodiments, L is: in Indicates the connection point to A or B.

[0185] In some embodiments, L is Where L is The groups A and B in formula (I) are connected in the order of

[0186] In some embodiments, B is an androgen receptor (AR) binding portion. In some embodiments, PROTAC is an AR PROTAC degrader. In some embodiments, B is an estrogen receptor (ER) binding portion. In some embodiments, PROTAC is an ER PROTAC degrader.

[0187] In some embodiments, the AR binding moiety is represented by the structure of Formula (B1):

[0188]

[0189] in

[0190] Y 3 , Y 4 , Y 5are each independently a bond, O, C=O, NR, CR', CHR', heteroaryl or aryl;

[0191] Indicates the point of attachment to the linker group L;

[0192] R' is each independently H or C 1-6 Alkyl (straight chain, branched, optionally with 1

[0193] or more halo, C 1-6 Alkoxy, C 1-6 Ring or C 1-6 Heterocyclic substitution);

[0194] R Q3 H, halide, hydroxyl, nitro, CN, C=CH, C 1-6 Alkyl (straight chain, branched, optionally substituted with 1 or more halogens, C 1-6 Alkoxy substituted), C 1-6 Alkoxy (straight chain, branched, optionally substituted by one or more halo groups), C 1-6 Alkenyl, C 1-6 Alkynyl or CF3;

[0195] R Q2 H, halogen, C 1-6 Alkyl (straight chain, branched, optionally substituted by one or more halo or C4 alkoxy groups), or R Q2 and R Q3 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms; and

[0196] Each X 1 , X 2 , X 3 and X 4 are independently N or CR'.

[0197] In some embodiments, the AR binding moiety is represented by the structure of Formula (B1):

[0198] in

[0199] R Q3 H, halogen, hydroxyl, nitro, CN, C=CH, C 1-3 Alkyl, C 1-3 Alkenyl, C 1-3 Alkynyl or CF3;

[0200] Y 3 , Y 4 , Y 5 Each independently represents O, C═O, NR′;

[0201] Indicates the point of attachment to the linker group L;

[0202] R' is each independently H or C 1-3 Alkyl (straight chain, branched, optionally with 1

[0203] or more halogens, C 1-3 Alkoxy, C 1-6 Ring or C 1-6 Heterocyclic substitution);

[0204] R Q2 is H or a halogen, and

[0205] Each X is independently N or CH.

[0206] In some embodiments, the AR binding moiety is represented by the structure of Formula (B1):

[0207] in

[0208] R Q3 is H, halogen, CN or CF3;

[0209] Y 3 , Y 4 , Y 5 are each independently O, C=O, NH;

[0210] Indicates the point of attachment to the linker group L;

[0211] R Q2 It is a halogen;

[0212] X 1 and X 2 is N; and

[0213] X 1 and X 2 It is CH.

[0214] In some embodiments, the AR binding moiety is represented by the structure of Formula (B1):

[0215] in

[0216] R Q3 It is CN;

[0217] Y 3 It is O;

[0218] Y 4 It is NH;

[0219] Y 5 is C=O;

[0220] Indicates the point of attachment to the linker group L; R Q2 is Cl;X 1 and X 2 Yes N; X 1 and X 2 It is CH.

[0221] In some embodiments, the AR binding portion is represented by the following structure:

[0222] in The point of attachment to the linker group L is indicated.

[0223] In some embodiments, the AR binding portion is represented by the following structure:

[0224] in represents the point of connection to the linker group L, where L is

[0225] In some embodiments, the ER binding moiety is represented by the structure of Formula (B2):

[0226]

[0227] Formula (B2)

[0228] in

[0229] Each X is independently CH or N;

[0230] Indicates the point of attachment to the linker group L;

[0231] Each R1 is independently H, OH, halogen, alkoxy, methoxy, ethoxy, O(CO)R', wherein the substitution may be mono-, di- or tri-substituted, and R' is an alkyl or cycloalkyl or aryl having 1 to 6 carbons;

[0232] Each R2 is independently H, halogen, CN, CF, straight or branched chain alkyl, alkoxy, methoxy, ethoxy, wherein the substitution may be mono- or di-substituted;

[0233] Each R3 is independently H, halogen, wherein the substitution may be mono- or di-.

[0234] In some embodiments, the ER binding moiety is represented by the structure of Formula (B2):

[0235] in

[0236] Each X is independently CH;

[0237] Indicates the point of attachment to the linker group L;

[0238] Each R1 is independently H, OH or halogen;

[0239] Each R2 is independently H, halogen, CN or CF;

[0240] Each R3 is independently H or halogen.

[0241] In some embodiments, the ER binding moiety is represented by the structure of Formula (B2):

[0242] in

[0243] Each X is independently CH;

[0244] Indicates the point of attachment to the linker group L;

[0245] Each R1 is independently H or OH;

[0246] Each R2 is H;

[0247] Each R3 is H.

[0248] In some embodiments, the ER binding moiety is represented by the structure of Formula (B2):

[0249] in

[0250] Each X is independently CH;

[0251] Indicates the point of attachment to the linker group L;

[0252] each R1 is independently H or OH, wherein one R1 is OH;

[0253] Each R2 is independently H;

[0254] Each R3 is independently H.

[0255] In some embodiments, the ER binding portion is represented by the structure: in The point of attachment to the linker group L is indicated.

[0256] In some embodiments, the ER binding portion is represented by the structure: in indicates the point of attachment to the linker group L, where L is

[0257] In some embodiments, a salt of a compound of formula (I) is formed by a compound of formula I (e.g., a pharmaceutically acceptable salt) having a basic nitrogen atom, such as an acid addition salt (e.g., with an organic acid or an inorganic acid). Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids, or aminosulfonic acids, acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids (such as glutamic acid or aspartic acid), maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid , mandelic acid, cinnamic acid, methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylaminosulfonic acid, N-methyl-aminosulfonic acid, N-ethyl-aminosulfonic acid or N-propyl-aminosulfonic acid or other organic protic acid, such as ascorbic acid.

[0258] In the presence of negatively charged groups such as carboxyl or sulfonyl groups, salts may also be formed with bases, for example metal or ammonium salts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tris(2-hydroxyethyl)amine, or heterocyclic bases, for example ammonium salts of N-ethyl-piperidine or N,N′-dimethylpiperazine.

[0259] When a basic group and an acidic group are present in the same molecule, the compounds of formula I may also form internal salts.

[0260] For isolation or purification purposes, pharmaceutically unacceptable salts, for example picrates or perchlorates, may also be used. For therapeutic use, only pharmaceutically acceptable salts or, if applicable in the form of pharmaceutical preparations, free compounds are employed, and these are therefore preferred.

[0261] In some embodiments, PROTAC is an AR PROTAC degrader. In some embodiments, PROTAC has a B group as an AR binding portion. In some embodiments, the AR PROTAC degrader is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-110. In some embodiments, the ARV-110 compound is N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoindolyl-S-yl)piperazine-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide. In some embodiments, the ARV-110 compound is represented by the following structure:

[0262] In some embodiments, PROTAC is an ER PROTAC degrader. In some embodiments, PROTAC has a B group as an ER binding portion. In some embodiments, the ER PROTAC degrader is ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471. In some embodiments, the ARV-471 compound is (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetrahydronaphthalene-1-yl]phenyl]-4-piperidinyl]methyl]piperazine-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione. In some embodiments, the ARV-471 compound is represented by the following structure:

[0263]

[0264] In some embodiments, the API is a pharmaceutically acceptable salt of a PROTAC compound described herein. Pharmaceutically acceptable salts include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, pentafluoropropionate, hydrobromide, mucinate, oleate, dihydrogen phosphate, dihydrogen phosphate, acetate trihydrate, bis(heptafluorobutyrate), bis(pentafluoropropionate), bis(pyridinecarboxylate), bis(trifluoroacetate), chlorohydrate, and sulfuric acid pentahydrate. Other representative pharmaceutically acceptable salts include, for example, water-soluble and water-insoluble salts such as acetate, sulfamate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, fumarate, glucoheptonate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hydrazine ... The invention relates to pharmaceutically acceptable salts of the present invention. The pharmaceutically acceptable salts of the present invention include hydroxylamine, hydroxynaphthoate, hydroxylamine ...

[0265] In some embodiments, the API has a low solubility at a pH of about 6-8. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 10 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 1.0 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.5 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.1 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.05 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.04 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.03 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.02 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.01 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-8 is less than 0.001 mg / ml. In some embodiments, the API has a low solubility at a pH of about 4-8. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 10 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 1.0 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.5 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.1 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.05 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.04 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.03 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.02 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.01 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 4-8 is less than 0.001 mg / ml. In some embodiments, the API has a low solubility at a pH of about 6-10. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 10 mg / ml.In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 1.0 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.5 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.1 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.05 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.04 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.03 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.02 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.01 mg / ml. In some embodiments, the solubility of the API in a solution with a pH between about 6-10 is less than 0.001 mg / ml.

[0266] In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0267] In some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions described herein do not contain an organic acid. In some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions do not contain any acid.

[0268] In some embodiments, a pharmaceutical composition comprising an ASD comprising a PROTAC described herein (e.g., ARV-110 or ARV-471) has acceptable storage stability. In some embodiments, the pharmaceutical composition is storage stable for at least 6 months at 40°C / 75% RH, wherein the storage-stable pharmaceutical composition has less than 0.5% of any impurity at the end of the storage period. In some embodiments, the pharmaceutical composition is storage stable for at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months at 25°C / 60% RH, wherein the storage-stable pharmaceutical composition has less than 0.5% of any impurity at the end of the storage period.

[0269] In some embodiments, the pharmaceutical compositions described herein comprise PROTAC or a salt thereof, such as ARV-110 or ARV-471 or a pharmaceutically acceptable salt thereof), a surfactant and a nonionic or ionic hydrophilic polymer. In some embodiments, PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of about 20 mg to about 200 mg. In some embodiments, PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of about 25 mg, about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of about 20 mg to about 200 mg. In some embodiments, the hydrophilic polymer is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, the hydrophilic polymer is present in the pharmaceutical composition in an amount of about 20 mg to about 200 mg. In some embodiments, the hydrophilic polymer is a nonionic polymer. In some embodiments, the hydrophilic polymer is an ionic polymer, such as sulfobutyl ether-β-cyclodextrin. In some embodiments, the hydrophilic polymer is copolyvidone (VA64). In some embodiments, the hydrophilic polymer is an enteric polymer. In some embodiments, the enteric polymer is polymethacrylate (e.g., sold under the trade name Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCAS, cellulose phthalate hydroxypropyl methyl ether, hydroxypropyl methylcellulose benzene-1,2-dicarboxylate, 2-hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, Mantrocel HP-55, methyl hydroxypropyl cellulose phthalate or Soluplus. In some embodiments, the hydrophilic polymer comprises PEG, polymethacrylate (e.g., sold under the trade name Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., sold under the trade name Soluplus). In some embodiments, the hydrophilic polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0270] In some embodiments, the weight ratio of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 1:1 to about 1:10. In some embodiments, the weight ratio of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10:1 to about 8:1, about 10:1 to about 6:1, about 10:1 to about 4:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about 1:2, about 10:1 to about 1:4, about 10:1 to about 1:6, about 10:1 to about 1:8, about 10:1 to about 1:10, about 8:1 to about 6:1, about 8:1 to about 4:1, about 8:1 to about 2:1, about 8:1 to about 1:1, about 8:1 to about 1:2, about 8:1 to about 1:4, about 8:1 to about 1:6, about 8:1 to about 1:8, about 8:1 to about 1:10, about 6:1 to about 4:1, about 6:1 to about 2:1, about 6:1 to about 1:1, about 6:1 to about 1:2, about 6:1 to about 1:4, about 6:1 to about 1:6, about 8:1 to about 1:8, about 8:1 to about 1:10, about 6:1 to about 4:1, about 6:1 to about 2:1, about 6:1 to about 1:1, about 6:1 to about 1:2, about 6:1 to about 1:4, about 6:1 to about 1:6, about 6:1 to about 1:8, about 6:1 to about 1:10, about 4:1 to about 2:1, about 4:1 to about 1:1, about 4:1 to about 1:2, about 4:1 to about 1:4, about 4:1 to about 1:6, about 4:1 to about 1:8, about 4:1 to about 1:10, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:4, about 2:1 to about 1:6, about 2:1 to about 1:8, about 2:1 to about 1:1 In some embodiments, the weight ratio of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1, about 1:2, about 1:4, about 1:6, about 1:8, about 1:2 to 1:10, about 1:4 to 1:6, about 1:4 to 1:8, about 1:4 to 1:10, about 1:6 to 1:8, about 1:6 to 1:10, or about 1:8 to 1:10. In some embodiments, the weight ratio of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is at least about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1, about 1:2, about 1:4, about 1:6, or about 1:8.In some embodiments, the weight ratio of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is at most about 8:1, about 6:1, about 4:1, about 2:1, about 1:1, about 1:2, about 1:4, about 1:6, about 1:8, or about 1:10. In some embodiments, PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0271] In some embodiments, when measured by AUC, AUC inf or AUC last When measured, the pharmaceutical compositions described herein have superior bioavailability than a corresponding reference composition comprising a crystalline form of a PROTAC (e.g., ARV-110 or ARV-471) or an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising a crystalline form of a PROTAC (e.g., ARV-110 or ARV-471) or an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD when measured by AUC after oral administration. In some embodiments, when measured by AUC after oral administration, the bioavailability of the pharmaceutical composition is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising a crystalline form of a PROTAC (e.g., ARV-110 or ARV-471) or an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD. maxWhen measured, the pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising a crystalline form of a PROTAC (e.g., ARV-110 or ARV-471) or an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD capsule comprising the amorphous PROTAC (e.g., ARV-110 or ARV-471). In some embodiments, when measured by AUC after oral administration, the bioavailability of the amorphous PROTAC (e.g., ARV-110 or ARV-471) is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD capsule comprising the amorphous PROTAC (e.g., ARV-110 or ARV-471). maxWhen measured, the pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD capsule comprising the amorphous PROTAC (e.g., ARV-110 or ARV-471). In some embodiments, the pharmaceutical composition exhibits a bioavailability that is about 1.1-fold to about 10-fold greater than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is about 1.1-fold to about 2-fold, about 1.1-fold to about 3-fold, about 1.1-fold to about 4-fold, about 1.1-fold to about 5-fold, about 1.1-fold to about 6-fold, about 1.1-fold to about 7-fold, about 1.1-fold to about 8-fold, about 1.1-fold to about 10-fold, about 1.5-fold to about 2-fold, about 1.5-fold to about 3-fold, about 1.5-fold to about 4-fold, about 1.5-fold to about 5-fold, about 1.5-fold to about 6-fold, about 1.5-fold to about 7-fold, about 1.5-fold to about 8-fold, about 1.5-fold to about 10-fold, about 1.5-fold to about 2-fold, about 1.5-fold to about 3-fold, about 1.5-fold to about 4-fold, about 1.5-fold to about 5-fold, about 1.5-fold to about 6-fold, about 1.5-fold to about 7-fold, about 1.5-fold to about 8-fold, about 1.5-fold to about In some embodiments, the PROTAC is one of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0272] In some embodiments, when measured by AUC or C maxWhen measured, the pharmaceutical compositions described herein exhibit a bioavailability that is at least about 1.1 times, about 1.3 times, about 1.5 times, about 1.8 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, or about 8 times higher than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in an ASD described herein. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 2 times higher than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 4 times higher than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is up to about 1.3 times, about 1.5 times, about 1.8 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, or about 10 times higher than the bioavailability of an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not present in the ASD. In some embodiments, the bioavailability is measured in a dog model in the fasted state. In some embodiments, the bioavailability is measured in a dog model in the fed state. In some embodiments, when measured by AUC after oral administration, the bioavailability of the pharmaceutical composition when administered orally in the fed state changes by no more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15% or 10% compared to administration in the fasted state. In some embodiments, when measured by AUC after oral administration, the bioavailability of the pharmaceutical composition when administered orally in the fed state changes by no more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15% or 10%. maxWhen measured, the bioavailability of the pharmaceutical composition does not change by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15% or 10% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 100% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 90% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 80% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 70% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 50% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition changes by no more than 50% when orally administered in a fed state compared to administration in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition changes by no more than 40% when orally administered in a fed state compared to administration in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition changes by no more than 20% when orally administered in a fed state compared to administration in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition changes by no more than 10% when orally administered in a fed state compared to administration in a fasted state. In some embodiments, bioavailability is measured in a dog model. In some embodiments, the dog model is a beagle. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0273] In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 1.2, 1.5, 2, 3, 4, 5, or 10 times greater than the bioavailability of a corresponding composition comprising the PROTAC or a pharmaceutically acceptable salt thereof, wherein the PROTAC is in crystalline form. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 1.2, 1.5, 2, 3, 4, 5, or 10 times greater than the bioavailability of a corresponding composition comprising the PROTAC or a pharmaceutically acceptable salt thereof in a dosage form, wherein the PROTAC is in amorphous form but not as part of an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC compound (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 2 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a PROTAC in crystalline form, or a PROTAC in amorphous form but not as part of an ASD). In some embodiments, the bioavailability of the PROTAC compound (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is at least 2 times greater than the bioavailability of a corresponding composition comprising the ... max ) is measured by bioavailability. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising the PROTAC or a pharmaceutically acceptable salt thereof in amorphous form in a conventional dosage form (e.g., not part of an ASD). In some embodiments, the AUC or maximum plasma concentration (C max) measure bioavailability. In some embodiments, conventional dosage forms of PROTAC include dosage forms comprising PROTAC in crystalline form. In some embodiments, conventional dosage forms of PROTAC include dosage forms comprising PROTAC in an amorphous state but not as part of ASD. In some embodiments, conventional dosage forms do not contain ASD. In some embodiments, conventional dosage forms comprise PROTAC compounds filled in capsules. In some embodiments, the bioavailability of PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof exhibited by a pharmaceutical composition is at least 1.2 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, or 10 times the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof (such as a PROTAC in crystalline form, or a PROTAC in amorphous form but not as part of ASD) in a conventional dosage form. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 6 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a PROTAC in crystalline form, or a PROTAC in amorphous form but not as part of an ASD). In some embodiments, the maximum plasma concentration (C max ) to measure bioavailability. In some embodiments, the subject comprises a dog. In some embodiments, the subject comprises six beagles. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0274] In some embodiments, when measured by AUC after oral administration last or C maxWhen measured, the pharmaceutical compositions described herein exhibit a bioavailability that is about 100% to about 1500%, 120% to about 1000%, 125% to about 500%, about 130% to about 450%, 140% to about 400%, or about 150% to about 300% of the bioavailability of a corresponding reference composition (such as a crystalline form or a PROTAC in amorphous form but not as part of an ASD) comprising a PROTAC (e.g., ARV-110 or ARV-471), wherein the corresponding reference pharmaceutical composition does not comprise an amorphous solid dispersion. In some embodiments, the reference composition is at least about 1.1 times the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the dose of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an ASD, which comprises a PROTAC or a pharmaceutically acceptable salt thereof. In some embodiments, the reference composition comprises a PROTAC (e.g., ARV-110 or ARV-471) free base or a pharmaceutically acceptable salt thereof, wherein the reference composition does not comprise an ASD. In some embodiments, the reference composition comprises a PROTAC (e.g., ARV-110 or ARV-471) in an amorphous form but not as part of an ASD. In some embodiments, bioavailability is measured under fasting conditions. In some embodiments, bioavailability is measured under fed conditions. In some embodiments, PROTAC is one of the ones listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0275] In some embodiments, a salt of a PROTAC compound (e.g., ARV-110 or ARV-471) is formed by an ARV-110 compound (e.g., a pharmaceutically acceptable salt) having a basic nitrogen atom, for example, an acid addition salt (e.g., with an organic acid or an inorganic acid). Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids, or aminosulfonic acids, acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids (such as glutamic acid or aspartic acid), maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid , mandelic acid, cinnamic acid, methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylaminosulfonic acid, N-methyl-aminosulfonic acid, N-ethyl-aminosulfonic acid or N-propyl-aminosulfonic acid or other organic protic acid, such as ascorbic acid.

[0276] In the presence of negatively charged groups such as carboxyl or sulfonyl groups, salts may also be formed with bases, for example metal or ammonium salts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tris(2-hydroxyethyl)amine, or heterocyclic bases, for example ammonium salts of N-ethyl-piperidine or N,N′-dimethylpiperazine.

[0277] PROTAC compounds can also form internal salts when basic and acidic groups are present in the same molecule.

[0278] For isolation or purification purposes, pharmaceutically unacceptable salts, for example picrates or perchlorates, may also be used. For therapeutic use, only pharmaceutically acceptable salts or, if applicable in the form of pharmaceutical preparations, free compounds are employed, and these are therefore preferred.

[0279] Amorphous solid dispersion

[0280] The present disclosure relates to pharmaceutical compositions comprising amorphous solid dispersions, methods for preparing the pharmaceutical compositions thereof, and methods for treating diseases or conditions by administering the pharmaceutical compositions thereof. In some embodiments, the pharmaceutical compositions comprising amorphous solid dispersions further comprise PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the pharmaceutical compositions optionally comprise an adsorbent, an acid, or both.

[0281] In one aspect, disclosed herein is an amorphous solid dispersion, wherein the amorphous solid dispersion comprises: a) a PROTAC or a pharmaceutically acceptable salt thereof, wherein the PROTAC has a log P in octanol-water of equal to or greater than 2.0; b) a surfactant, wherein the surfactant is selected from a polymeric surfactant and a phospholipid; c) a hydrophilic polymer; d) optionally an adsorbent; and optionally an acid.

[0282] In some embodiments, PROTAC or a pharmaceutically acceptable salt thereof is a PROTAC. In some embodiments, PROTAC is represented by the structure of formula (I):

[0283] ALB

[0284] Formula (I)

[0285] in

[0286] -A is the E3 ubiquitin ligase binding part;

[0287] -L is a linker; and

[0288] -B is the moiety that binds to a target protein, wherein the target protein can be degraded by an E3 ubiquitin ligase.

[0289] In some embodiments, B is an AR binding moiety. In some embodiments, B is an ER binding moiety. In some embodiments, the PROTAC compound is an AR PROTAC degrader. In some embodiments, the AR PROTAC degrader is ARV-110, wherein the compound is represented by the following structure: or a pharmaceutically acceptable salt or enantiomer thereof.

[0290] In some embodiments, the PROTAC compound is an ER PROTAC degrader. In some embodiments, the estrogen receptor PROTAC degrader is ARV-471, wherein the compound is represented by the following structure:

[0291]

[0292] In some embodiments, PROTAC is selected from ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413, its corresponding free base and its pharmaceutically acceptable salt. In some embodiments, PROTAC is selected from Table 1 or its pharmaceutically acceptable salt. In some embodiments, PROTAC or its pharmaceutically acceptable salt is present in an amorphous solid dispersion in an amount of about 5% to about 70% by weight based on solids. In some embodiments, the surfactant comprises one or more surfactants. In some embodiments, the surfactant is selected from phospholipids, lecithin, polysorbate, TPGS, Kolliphor series (RH40), sorbitan oleate, SDS, Solutol and Soluplus or a combination thereof. In some embodiments, the surfactant comprises one or more phospholipids. In some embodiments, the surfactant comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin and phosphatidic acid. In some embodiments, the surfactant comprises lecithin. In some embodiments, the surfactant is present in the amorphous solid dispersion in an amount of about 5% by weight to about 70% by weight.

[0293] In some embodiments, PROTAC is present in the amorphous solid dispersion at about 5% to about 60% by weight. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 15% to about 50% by weight. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 15% to about 30% by weight. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 15% to about 25% by weight. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 20% to about 30% by weight.In some embodiments, PROTACs are present in an amount of about 5 wt % to about 10 wt %, about 5 wt % to about 15 wt %, about 5 wt % to about 20 wt %, about 5 wt % to about 25 wt %, about 5 wt % to about 30 wt %, about 5 wt % to about 35 wt %, about 5 wt % to about 40 wt %, about 5 wt % to about 45 wt %, about 5 wt % to about 50 wt %, about 5 wt % to about 55 wt %, about 5 wt % to about 60 wt %, about 10 wt % to about 15 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 25 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 35 wt %, about 10 wt % to about % to about 40% by weight, about 10% by weight to about 45% by weight, about 10% by weight to about 50% by weight, about 10% by weight to about 55% by weight, about 10% by weight to about 60% by weight, about 15% by weight to about 20% by weight, about 15% by weight to about 25% by weight, about 15% by weight to about 30% by weight, about 15% by weight to about 35% by weight, about 15% by weight to about 40% by weight, about 15% by weight to about 45% by weight, about 15% by weight to about 50% by weight, about 15% by weight to about 55% by weight, about 15% by weight to about 60% by weight, about 20% by weight to about 25% by weight, about 20% by weight to about 30% by weight, about 20% by weight to about 35% by weight, about 20% by weight to about % to about 40% by weight, about 20% to about 45% by weight, about 20% to about 50% by weight, about 20% to about 55% by weight, about 20% to about 60% by weight, about 25% to about 30% by weight, about 25% to about 35% by weight, about 25% to about 40% by weight, about 25% to about 45% by weight, about 25% to about 50% by weight, about 25% to about 55% by weight, about 25% to about 60% by weight, about 30% to about 35% by weight, about 30% to about 40% by weight, about 30% to about 45% by weight, about 30% to about 50% by weight, about 30% to about 55% by weight, From about 30% to about 60% by weight, from about 35% to about 40% by weight, from about 35% to about 45% by weight, from about 35% to about 50% by weight, from about 35% to about 55% by weight, from about 35% to about 60% by weight, from about 40% to about 45% by weight, from about 40% to about 50% by weight, from about 40% to about 55% by weight, from about 40% to about 60% by weight, from about 45% to about 50% by weight, from about 45% to about 55% by weight, from about 45% to about 60% by weight, from about 50% to about 55% by weight, from about 50% to about 60% by weight, or from about 55% to about 60% by weight is present in the amorphous solid dispersion.In some embodiments, the PROTAC is present in the amorphous solid dispersion at about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at at least about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt%. In some embodiments, PROTAC is present in the amorphous solid dispersion at up to about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt%. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 15 wt%. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 20 wt%. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 25 wt%. In some embodiments, PROTAC is present in the amorphous solid dispersion at about 30 wt%. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110 free base or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471 free base or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471.

[0294] In some embodiments, ASD described herein includes one or more surfactants. In some embodiments, one or more surfactants include block copolymers of lecithin, polyethylene glycol and polypropylene glycol, TGPS, graft copolymers (PVAc-PVCap-PEG) based on polyvinyl caprolactam, or combinations thereof. In some embodiments, one or more surfactants include lecithin and TPGS. In some embodiments, one or more surfactants include lecithin. In some embodiments, one or more surfactants include TPGS. In some embodiments, one or more surfactants are present in an amount of about 5% by weight to about 60% by weight of ASD. In some embodiments, surfactants are present in an amount of about 15% by weight to about 50% by weight of ASD. In some embodiments, surfactants are present in an amount of about 20% by weight to about 40% by weight of ASD.

[0295] In some embodiments, the ASD described herein comprises a hydrophilic polymer. In some embodiments, the hydrophilic polymer is nonionic. In some embodiments, the hydrophilic polymer is enteric. In some embodiments, the hydrophilic polymer is anionic. In some embodiments, the hydrophilic polymer is cationic. In some embodiments, the pharmaceutical composition described herein comprises an ASD containing a hydrophilic polymer, wherein the hydrophilic polymer is a polymethacrylate (e.g., Eudragit), HPMCP, VA64 or HPMCAS. In some embodiments, the hydrophilic polymer is present in an amount of about 1% by weight to about 80% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 10% by weight to about 70% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 15% by weight to about 60% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 20% by weight to about 50% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 25% by weight to about 45% by weight of the ASD.

[0296] In some embodiments, the ASD described herein optionally comprises an adsorbent. In some embodiments, the adsorbent is silicon dioxide. In some embodiments, the adsorbent is present in an amount of about 1% to about 40% by weight of the ASD. In some embodiments, the adsorbent is present in an amount of about 10% to about 30% by weight of the ASD. In some embodiments, the adsorbent is present in an amount of about 15% to about 25% by weight of the ASD.

[0297] In some embodiments, the ASD described herein optionally comprises an acid. In some embodiments, the acid is an organic acid. In some embodiments, the organic acid is tartaric acid. In some embodiments, the organic acid is present in an amount of about 1% to about 40% by weight of the ASD. In some embodiments, the organic acid is present in an amount of about 10% to about 30% by weight of the ASD. In some embodiments, the organic acid is present in an amount of about 15% to about 25% by weight of the ASD.

[0298] In some embodiments, the ASD described herein comprises an adsorbent. In some embodiments, the adsorbent is selected from silicon dioxide, activated carbon, magnesium aluminum silicate, diatomaceous earth, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sugar or sugar alcohol, such as sorbitol, mannitol, lactose, cyclodextrin and maltodextrin. In some embodiments, the adsorbent is silicon dioxide. In some embodiments, the adsorbent is present in an amorphous solid dispersion in an amount of about 5% by weight to about 80% by weight. In some embodiments, the average particle size of the amorphous solid dispersion is 1 μm to 1000 μm. In some embodiments, the average particle size (in terms of particle size) of the amorphous solid dispersion is about 10 μm to about 150 μm.

[0299] In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives include organic acids and inorganic acids. In some embodiments, the solid dispersion is a solid solution in which PROTAC (or its PROTAC salt) and a hydrophilic polymer are used as solute and solvent, respectively. Depending on the composition and sample processing history, the solid dispersion can form a variety of structures. When the PROTAC loading is lower than the equilibrium solubility of PROTAC in the hydrophilic polymer, the drug is dispersed in the polymer matrix in molecular form and forms a thermodynamically stable uniform solution. A uniform solution can usually only be obtained at very low PROTAC loading and / or high temperature. For higher loadings, the mixture becomes a supersaturated solution, and the drug precipitates out. This can result in the dispersion of crystalline PROTAC particles in a hydrophilic polymer matrix, where the drug concentration corresponds to its equilibrium solubility at that temperature. Alternatively, since PROTAC crystallization can be a slow process, an intermediate metastable structure can be formed in which amorphous PROTAC aggregates are dispersed in a hydrophilic polymer matrix containing PROTAC in a non-crystalline amorphous state. Such amorphous solid dispersions can provide superior dissolution properties compared to crystalline PROTACs. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0300] In some embodiments, the amorphous solid dispersion described herein comprises PROTAC, a hydrophilic polymer and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants. In some embodiments, the amorphous solid dispersion described herein is a uniform amorphous solid dispersion. In some embodiments, the components of the amorphous dispersion are mixed and heated in a solvent, and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the solvent is water. In some embodiments, the solvent is a polar organic solvent. In some embodiments, the solvent is a non-polar organic solvent. In some embodiments, the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, methyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide, dichloromethane (DCM), acetone, tetrahydrofuran (THF) and any combination thereof. In some embodiments, the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid and any combination thereof. In some embodiments, the solvent is selected from water, methanol, ethanol and isopropanol. In some embodiments, the solvent is selected from dichloromethane, methanol, THF and acetone. In some embodiments, the solvent is selected from a mixture of these solvents.

[0301] In some embodiments, the amorphous solid dispersion described herein comprises PROTAC, a hydrophilic polymer, a surfactant, and an optional adsorbent. In some embodiments, the components of the amorphous dispersion (such as PROTAC, a hydrophilic polymer, and a surfactant) are mixed and dissolved in a solvent with or without heating to form a solution. In some embodiments, the adsorbent is further added to the solution to form a uniform suspension and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the solution is sprayed onto the adsorbent and the solvent is removed to form an amorphous solid dispersion. In some embodiments, the adsorbent is selected from silicon dioxide (also known as silica), magnesium aluminum silicate (Neusilin), microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, sugars and sugar alcohols. In some embodiments, sugars and sugar alcohols include sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0302] In some embodiments, the ASD exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not change by more than about 5% to about 60% when orally administered to a subject in a fed state compared to a fasted state. In some embodiments, the ASD exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not change by more than about 25% to about 100% when orally administered to a subject in a fed state compared to a fasted state. In some embodiments, the ASD exhibits a bioavailability of a PROTAC compound, or a pharmaceutically acceptable salt thereof, that changes by no more than about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 5% to about 50%, about 10% to about 60%, about 15% to about 20%, about 15% to about 25%, about 10% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, to about 50%, about 15% to about 60%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 25% to about 60%, about 30% to about 35%, about 30% to about 40 %, about 30% to about 50%, about 30% to about 60%, about 35% to about 40%, about 35% to about 50%, about 35% to about 60%, about 40% to about 50%, about 40% to about 60%, about 50% to about 60%, about 55% to about 65%, about 60% to about 70%, about 65% to about 80%, about 75% to about 90%, about 80% to about 100%, or about 90% to about 100%. In some embodiments, the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof exhibited by the ASD does not change by more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, or about 60% when orally administered to a subject in a fed state compared to a fasted state. In some embodiments, the PROTAC is one selected from Table 1. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0303] The formation of an amorphous solid dispersion can result in the ASD having a certain particle size. In some embodiments, the particle size of the ASD is about 1 nm to 1 nm. In some embodiments, the particle size of the ASD is about 0.01 microns to 1000 microns. In some embodiments, the particle size of the ASD is about 0.01 microns to about 1,000 microns. In some embodiments, the particle size of the ASD is at least about 0.01 microns. In some embodiments, the particle size of the ASD is at most about 1,000 microns. In some embodiments, the particle size of the ASD is about 1 micron to about 50 microns. In some embodiments, the particle size of the ASD is at least about 1 micron. In some embodiments, the particle size of the ASD is at most about 50 microns. In some embodiments, the particle size of the ASD is about 10 microns to about 15 microns. In some embodiments, the ASD has a particle size of about 1 micron, to about 3 microns, about 1 micron, to about 7 microns, about 1 micron, to about 10 microns, about 1 micron, to about 13 microns, about 1 micron, to about 17 microns, about 1 micron, to about 20 microns, about 1 micron, to about 23 microns, about 1 micron, to about 27 microns, about 1 micron, to about 30 microns, about 1 micron, to about 40 microns, about 1 micron, to about 50 microns, about 10 microns to about 13 microns, about 10 microns to about 17 microns, about 10 microns to about 20 microns, about 10 microns to about 23 microns, about 10 microns to about 27 microns, about 10 microns to about 30 microns, about 10 microns to about 40 microns, about 10 microns to about 50 microns, about 20 microns to about 27 microns, about 20 microns to about 30 microns, about 20 microns to about 40 microns, about 20 microns to about 50 microns, about 30 microns to about 40 microns, about 30 microns to about 50 microns, and about 40 microns to about 50 microns. In some embodiments, the particle size of the ASD is about 1 micron to about 100 microns. In some embodiments, the particle size of the ASD is at least about 1 micron. In some embodiments, the particle size of the ASD is about 0.1 micron, 1 micron, 3 microns, 5 microns, 7 microns, 10 microns, 13 microns, 17 microns, 20 microns, 23 microns, 25 microns, 27 microns, 30 microns, 33 microns, 35 microns, 37 microns, 40 microns, 43 microns, 45 microns, 47 microns, 50 microns, 60 microns, 70 microns, 80 microns, 90 microns or 100 microns or less. In some embodiments, the particle size of the ASD is about 20 microns or less.

[0304] In some embodiments, a distribution of amorphous solid dispersion particle sizes is obtained. In some embodiments, the terms D10, D50 and / or D90 are used to describe the particle size distribution. In some embodiments, the D90 particle size of the ASD is equal to or less than about 1,000 μm, 950 μm, 900 μm, 800 μm, 700 μm, 600 μm, 500 μm, 400 μm, 300 μm, 200 μm, 100 μm, 75 μm, 65 μm, 50 μm, 25 μm, 20 μm, 15 μm or 10 μm. In some embodiments, the D50 particle size of the ASD is equal to or less than about 500 μm, 400 μm, 300 μm, 200 μm, 100 μm, 50 μm, 35 μm, 25 μm, 20 μm, 15 μm, 10 μm or 5 μm. In some embodiments, the ASD has a D10 particle size of equal to or less than about 200 μm, 100 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.

[0305] In some embodiments, a distribution of amorphous solid dispersion particle sizes is obtained. In some embodiments, the terms D10, D50, and / or D90 are used to describe the particle size distribution. In some embodiments, the D90 particle size of the ASD is from about 10 μm to about 1,000 μm. In some embodiments, the ASD has a D90 particle size of about 10 μm to about 20 μm, about 10 μm to about 30 μm, about 10 μm to about 50 μm, about 10 μm to about 100 μm, about 10 μm to about 150 μm, about 10 μm to about 200 μm, about 10 μm to about 500 μm, about 10 μm to about 750 μm, about 10 μm to about 1,000 μm, about 20 μm to about 30 μm, about 20 μm to about 50 μm, about 20 μm to about 100 μm, about 20 μm to about 150 μm, about 20 μm to about 200 μm, about 50 μm to about 100 μm, about 100 μm to about 1,000 μm, about 500 μm to about 1,000 μm, or about 750 μm to about 1,000 μm. In some embodiments, the D90 particle size is at least about 10 μm, about 20 μm, about 30 μm, about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 500 μm, or about 750 μm. In some embodiments, the D90 particle size is at most about 15 μm. In some embodiments, the D90 particle size is at most about 10 μm, 15 μm, 20 μm, about 30 μm, about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 500 μm, or about 1,000 μm.

[0306] In some embodiments, a distribution of amorphous solid dispersion particle sizes is obtained. In some embodiments, the terms D10, D50 and / or D90 are used to describe the particle size distribution. In some embodiments, the D50 value of the ASD is from about 1 μm to about 100 μm. In some embodiments, the D50 value of the ASD is from about 10 μm to about 15 μm. In some embodiments, the D50 particle size is from about 5 μm to about 10 μm, from about 5 μm to about 15 μm, from about 5 μm to about 20 μm, from about 5 μm to about 25 μm, from about 5 μm to about 30 μm, from about 5 μm to about 40 μm, from about 5 μm to about 50 μm, from about 5 μm to about 60 μm, from about 5 μm to about 75 μm, from about 5 μm to about 100 μm, from about 10 μm to about 15 ... μm to about 20 μm, about 10 μm to about 25 μm, about 10 μm to about 30 μm, about 10 μm to about 40 μm, about 10 μm to about 50 μm, about 10 μm to about 60 μm, about 10 μm to about 75 μm, about 10 μm to about 100 μm, about 15 μm to about 20 μm, about 15 μm to about 25 μm, about 15 μm to about 30 μm, about 15 μm to about 40 μm , about 15 μm to about 50 μm, about 15 μm to about 60 μm, about 15 μm to about 75 μm, about 15 μm to about 100 μm, about 20 μm to about 25 μm, about 20 μm to about 30 μm, about 20 μm to about 40 μm, about 20 μm to about 50 μm, about 20 μm to about 60 μm, about 20 μm to about 75 μm, about 20 μm to about 100 μm, about 25 μm to about In some embodiments, the D50 particle size is about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 75 μm, about 25 μm to about 100 μm, about 30 μm to about 40 μm, about 30 μm to about 50 μm, about 30 μm to about 60 μm, about 30 μm to about 75 μm, about 50 μm to about 100 μm, or about 75 μm to about 100 μm. In some embodiments, the D50 particle size is about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 75 μm, or about 100 μm. In some embodiments, the D50 particle size is at least about 0.5 μm, 5 μm, about 10 μm, about 15 μm, or about 20 μm. In some embodiments, the D50 particle size is at most about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 75 μm, or about 100 μm.

[0307] In some embodiments, a distribution of amorphous solid dispersion particle sizes is obtained. In some embodiments, the terms D10, D50 and / or D90 are used to describe the particle size distribution. In some embodiments, the D10 value of the ASD is from about 0.1 μm to about 50 μm. In some embodiments, the D10 particle size is about 0.1 μm to about 1 μm, about 0.1 μm to about 2 μm, about 0.1 μm to about 3 μm, about 0.1 μm to about 4 μm, about 0.1 μm to about 5 μm, about 0.1 μm to about 7 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 30 μm, about 0.1 μm to about 40 μm, about 0.1 μm to about 50 μm, about 1 μm to about 2 μm, about 1 μm to about 3 μm, about 1 μm to about 4 μm, about 1 μm to about 5 μm, about 1 μm to about 7 μm, about 1 μm to about 10 μm, about 1 μm to about 20 μm, or 1 μm to about 50 μm. In some embodiments, the D10 particle size is about 0.1 μm, about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 7 μm, about 10 μm, about 20 μm, about 30 μm, about 40 μm, or about 50 μm. In some embodiments, the D10 particle size is at least about 0.1 μm, about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 7 μm, about 10 μm, about 20 μm, about 30 μm, or about 40 μm. In some embodiments, the D10 particle size is at most about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 7 μm, about 10 μm, about 20 μm, about 30 μm, about 40 μm, or about 50 μm.

[0308] In some embodiments, the ASD described herein comprises a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the ASD comprises ARV-110 or ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0309] In some embodiments, the amorphous solid dispersion described herein comprises a surfactant. In some embodiments, the surfactant is selected from a polymerized nonionic surfactant and a phospholipid. In some embodiments, the surfactant is a polymerized nonionic surfactant. In some embodiments, the surfactant comprises a block copolymer of polyethylene glycol and polypropylene glycol. In some embodiments, the polymerized nonionic surfactant has a number average molecular weight of about 7000Da to about 10,000Da. In some embodiments, the amorphous solid dispersion described herein comprises a surfactant TPGS. In some embodiments, the amorphous solid dispersion described herein comprises a surfactant, and the surfactant comprises one or more phospholipids, such as lecithin. In some embodiments, the surfactant comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin and phosphatidic acid. In some embodiments, one or more phospholipids comprise greater than 50% by weight, 60% by weight, 70% by weight, 80% by weight or 90% by weight of phosphatidylcholine. In some embodiments, the surfactant comprises lecithin. In some embodiments, the surfactant is present in the amorphous solid dispersion in an amount of about 5% to about 70% by weight based on solids. In some embodiments, the surfactant is present in the amorphous solid dispersion in an amount of about 20% to about 60% by weight based on solids. In some embodiments, the surfactant is present in the amorphous solid dispersion in an amount of about 10% to about 30% by weight based on solids.

[0310] In some embodiments, the present disclosure discloses an ASD comprising i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof, ii) a surfactant, iii) a hydrophilic polymer, and iv) optionally an acid. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471. In some embodiments, the ASD comprises i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof, ii) a surfactant, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutyl ether-β-cyclodextrin, hydroxypropyl β-cyclodextrin (HP-β-CD), or a combination thereof, and iv) an optional acid. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471. In some embodiments, the ASD comprises i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof, in an amount of about 5 wt % to about 50 wt % of the ASD, ii) a surfactant, in an amount of about 1 wt % to about 60 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer, in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutyl ether-β-cyclodextrin, hydroxypropyl β-cyclodextrin (HP-β-CD), or a combination thereof, and iv) an optional acid, in an amount of about 1 wt % to about 50 wt % of the ASD. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0311] In some embodiments, the ASD of the present disclosure comprises i) ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413, or a pharmaceutically acceptable salt thereof, in an amount of about 5 wt % to about 50 wt % of the ASD, ii) a surfactant in an amount of about 1 wt % to about 60 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer includes vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof, and iv) an optional acid in an amount of about 1 wt % to about 50 wt % of the ASD.

[0312] In some embodiments, the ASD of the present disclosure comprises i) ARV-110 or ARV-471 or a pharmaceutically acceptable salt thereof in an amount of about 5 wt % to about 50 wt % of the ASD, ii) a surfactant in an amount of about 1 wt % to about 60 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof. The neutral hydrophilic polymer includes vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutyl ether-β-cyclodextrin or hydroxypropyl β-cyclodextrin (HP-β-CD), and iv) optionally an acid in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the acid includes tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof.

[0313] In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) or a pharmaceutically acceptable salt thereof, a surfactant, a hydrophilic polymer, optionally an adsorbent, and optionally an organic acid. In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) or a pharmaceutically acceptable salt thereof. In some embodiments, the ASD comprises a surfactant. In some embodiments, the ASD comprises a hydrophilic polymer. In some embodiments, the ASD comprises an adsorbent. In some embodiments, the ASD comprises an acid. In some embodiments, the surfactant comprises lecithin or TPGS or a combination thereof. In some embodiments, the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer or HPMCAS or a combination thereof. In some embodiments, the adsorbent is silica. In some embodiments, the acid is tartaric acid or citric acid or a combination thereof. In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) in an amount of about 10% to about 40% by weight of the ASD. In some embodiments, the ASD comprises a surfactant in an amount of about 5% to about 60% by weight of the ASD. In some embodiments, the surfactant is TPGS or lecithin or a combination thereof. In some embodiments, the ASD comprises a hydrophilic polymer in an amount of about 10% to about 60% by weight of the ASD. In some embodiments, the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer or HPMCAS or a combination thereof. In some embodiments, the ASD comprises an acid in an amount of about 5% to 40% by weight of the ASD. In some embodiments, the acid is tartaric acid or citric acid or a combination thereof. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) in an amount of about 15% to about 35% by weight of the ASD. In some embodiments, the ASD comprises a surfactant in an amount of about 10% to about 55% by weight of the ASD. In some embodiments, the surfactant is TPGS or lecithin or a combination thereof. In some embodiments, the ASD comprises a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD. In some embodiments, the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer or HPMCAS or a combination thereof. In some embodiments, the ASD comprises an acid in an amount of about 10% to 35% by weight of the ASD. In some embodiments, the acid is tartaric acid or citric acid or a combination thereof. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) in an amount of about 25% by weight of the ASD. In some embodiments, the ASD comprises a surfactant in an amount of about 25% by weight of the ASD. In some embodiments, the surfactant is TPGS or lecithin or a combination thereof. In some embodiments, the ASD comprises a hydrophilic polymer in an amount of about 25% by weight of the ASD. In some embodiments, the hydrophilic polymer is VA64 or HPMCAS. In some embodiments, the ASD comprises an acid in an amount of about 25% by weight of the ASD. In some embodiments, the acid is tartaric acid. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the present disclosure discloses an ASD comprising a PROTAC (e.g., ARV-110 and ARV-471) in an amount of about 20% by weight of the ASD. In some embodiments, the ASD comprises a surfactant in an amount of about 40% by weight of the ASD. In some embodiments, the surfactant is lecithin or phospholipid. In some embodiments, the ASD comprises a hydrophilic polymer in an amount of about 40% by weight of the ASD. In some embodiments, the hydrophilic polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS) or vinylpyrrolidone-vinyl acetate copolymer. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, when measured by AUC, AUC inf or AUC last When measured by AUC after oral administration, the ASDs described herein have a bioavailability that is superior to that of a corresponding reference composition comprising a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in the ASD. In some embodiments, the ASD exhibits a bioavailability that is at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher than that of a corresponding composition comprising a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in the ASD. In some embodiments, when measured by AUC after oral administration, the ASD exhibits a bioavailability that is at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher than that of a corresponding composition comprising a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in the ASD. maxWhen measured, the ASD exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in the ASD. In some embodiments, the ASD exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in an ASD capsule comprising ARV-110 when measured by AUC after oral administration. In some embodiments, when measured by AUC after oral administration, the bioavailability of the ASD is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in an ASD capsule comprising ARV-110. maxWhen measured, the ASD exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of ARV-110 not present in an ASD capsule comprising ARV-110. In some embodiments, the ASD exhibits a bioavailability that is about 1.1-fold to about 10-fold greater than a crystalline PROTAC (e.g., ARV-110 and ARV-471) or an amorphous PROTAC not present in an ASD. In some embodiments, the ASD exhibits a bioavailability that is about 1.1-fold to about 2-fold, about 1.1-fold to about 3-fold, about 1.1-fold to about 4-fold, about 1.1-fold to about 5-fold, about 1.1-fold to about 6-fold, about 1.1-fold to about 7-fold, about 1.1-fold to about 8-fold, about 1.1-fold to about 10-fold, about 1.1-fold to about 12-fold, about 1.1-fold to about 13-fold, about 1.1-fold to about 15-fold, about 1.1-fold to about 16-fold, about 1.1-fold to about 17-fold, about 1.1-fold to about 18-fold, about 1.1-fold to about 19-fold, about 1.1-fold to about 20-fold, about 1.1- In some cases, PROTACs (e.g., ARV-110 and ARV-471) that are not present in an ASD capsule comprising PROTACs are in an amorphous state. In some embodiments, PROTACs are one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTACs have a log P of 2.0 or more. In some embodiments, PROTACs are ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the bioavailability of a PROTAC (e.g., ARV-110 and ARV-471) compound or a pharmaceutically acceptable salt thereof exhibited by an ASD is at least 2 times greater than the bioavailability of a corresponding composition comprising a PROTAC (e.g., ARV-110 and ARV-471) compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (e.g., in crystalline form, or in an amorphous state but not as part of an ASD). In some embodiments, the AUC or maximum plasma concentration (C max) is used to measure bioavailability. In some embodiments, the bioavailability of a PROTAC (e.g., ARV-110 and ARV-471) compound or a pharmaceutically acceptable salt thereof exhibited by an ASD is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising a PROTAC (e.g., ARV-110 and ARV-471) compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (e.g., in crystalline form, or in an amorphous state but not as part of an ASD). In some embodiments, the AUC or maximum plasma concentration (C max ) is used to measure bioavailability. In some embodiments, the bioavailability of a PROTAC (e.g., ARV-110 and ARV-471) or a pharmaceutically acceptable salt thereof exhibited by an ASD is at least 6 times greater than the bioavailability of a corresponding composition comprising a PROTAC (e.g., ARV-110 and ARV-471) compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (e.g., in crystalline form, or in an amorphous state but not as part of an ASD). In some embodiments, the maximum plasma concentration (C max ) to measure bioavailability. In some embodiments, the subject comprises a dog. In some embodiments, the subject comprises six beagles. In some embodiments, the PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, when measured by AUC after oral administration last or C maxWhen measured, the ASD described herein exhibits a bioavailability that is about 100% to about 1500%, 120% to about 1000%, 125% to about 500%, about 130% to about 450%, 140% to about 400%, or about 150% to about 300% of the bioavailability of a corresponding reference composition comprising a PROTAC (e.g., ARV-110 and ARV-471), wherein the corresponding reference pharmaceutical composition does not contain an amorphous solid dispersion. In some embodiments, the reference composition is about 1.1 times to about 10 times the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1 times to about 2 times, about 1.1 times to about 5 times, about 1.1 times to about 10 times, about 1.5 times to about 2 times, about 2 times to about 5 times, about 2 times to about 10 times, about 2.5 times to about 3 times, or about 5 times to about 10 times the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the dose of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an ASD, which comprises a PROTAC (e.g., ARV-110 and ARV-471) free base or a pharmaceutically acceptable salt thereof. In some embodiments, the reference composition comprises a PROTAC (e.g., ARV-110 and ARV-471) free base or a pharmaceutically acceptable salt thereof, wherein the reference composition does not comprise an ASD. In some embodiments, bioavailability is measured under fasting conditions. In some embodiments, bioavailability is measured under fed conditions. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or more. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0320] Surfactants

[0321] In one aspect, disclosed herein is a pharmaceutical composition comprising an amorphous solid dispersion (ASD) comprising a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the ASD comprises a PROTAC, a hydrophilic polymer, and a surfactant. The surfactant may be present in the ASD in an amorphous state. In some embodiments, the PROTAC is a PROTAC of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0322] In some embodiments, surfactant is a compound or a mixture of compounds comprising a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group. They can play one or more roles, including solubility enhancers, bioavailability enhancers, stability enhancers, antioxidants and emulsifiers. Other terms in the surfactant field include emulsifiers, emulsifying agents, surfactants, wetting agents, suspending agents, etc. Examples of surfactants include, but are not limited to, phospholipids, lecithin, kolliphor series (rh40), sorbitan oleate, SDS, Solutol, Soluplus, sucrose esters of fatty acids, polyoxyethylene stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol glyceryl hydroxystearate oil, peg-40 castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbates, glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG), lauryl polyethylene glycol esters, poloxamer, labrafil, labrasol, tween 80, tocopheryl polyethylene glycol succinate (TPGS or vitamin E In some embodiments, the surfactant is a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG). In some embodiments, the surfactant is tocopherol polyethylene glycol 1000 succinate. In some embodiments, PROTAC is ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC is a pharmaceutically acceptable salt of ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC has a calculated log P or log P of at least 2.0. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC, hydrophilic polymer and surfactant are formulated into an amorphous solid dispersion.In some embodiments, PROTAC, hydrophilic polymer, surfactant, and optional acid are formulated as an amorphous solid dispersion. In some embodiments, PROTAC, hydrophilic polymer, surfactant, and acid are formulated as an amorphous solid dispersion.

[0323] The surfactant used in the present disclosure can be one or more nonionic surfactants, one or more ionic surfactants or their mixture. In some embodiments, the nonionic surfactant does not have a charged group at its head. Exemplary nonionic surfactants include but are not limited to fatty alcohols, cetyl alcohol, stearyl alcohol, cetearyl alcohol and oleyl alcohol. Exemplary nonionic surfactants include but are not limited to polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, polyoxyglycerol esters (such as caprylocaproyl polyethylene glycol-8 glycerides or PEG-8 caprylic acid / capric acid glycerides sold under the trade name Labrasol), pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ethers (such as Triton In some embodiments, the surfactant is tocopherol polyethylene glycol 1000 succinate. In some embodiments, the nonionic surfactant comprises one or more of fatty alcohol, cetyl alcohol, stearyl alcohol, cetearyl alcohol and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (such as Triton X-100), polyethylene glycol alkylphenyl ether (such as nonenol-9), glycerol alkyl esters (such as lauric acid glyceryl), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamer), polyethoxylated tallow amine (POEA), and tocopherol polyethylene glycol succinate (TPGS or vitamin E TPGS). In some embodiments, the surfactant is tocopherol polyethylene glycol 1000 succinate.

[0324] In some embodiments, the nonionic surfactant comprises a block copolymer of vitamin E TPGS, polyethylene glycol and polypropylene glycol, or any combination thereof. In some embodiments, the surfactant comprises more than two repeating units, such as polyoxyalkylene units. In some embodiments, the surfactant comprises polyoxyglycerol esters (such as caprylocaproyl polyethylene glycol-8 glycerides or PEG-8 caprylic / capric glycerides). In some embodiments, the surfactant is a nonionic surfactant comprising polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol. In some embodiments, ASD comprises two surfactants. In some embodiments, ASD comprises two or more surfactants. In some embodiments, ASD comprises a surfactant, wherein the surfactant is lecithin. In some embodiments, ASD comprises a surfactant, wherein the surfactant is TPGS. In some embodiments, ASD comprises one or more surfactants, wherein the surfactant comprises lecithin and TPGS.

[0325] In some embodiments, the ionic surfactant has a charged group in its head. In some embodiments, the ionic surfactant has an anionic head group or a cationic head group. In some embodiments, exemplary ionic surfactants include sodium lauryl sulfate (SLS), sodium dodecyl sulfate, calcium oleate, triethanolamine oleate, sodium docusate, benzalkonium chloride and cetylpyridinium chloride. In some embodiments, the pharmaceutical composition or amorphous solid dispersion comprises SLS. In some embodiments, the surfactant is a mixture of one or more nonionic surfactants and one or more ionic surfactants. In some embodiments, the surfactant comprises SLS and TPGS.

[0326] In some embodiments, the number average molecular weight of the nonionic surfactant is about 1000Da to about 100,000Da, 2000Da to about 20,000Da, about 4000Da to about 15,000Da, about 6000Da to about 12,000Da or about 7000Da to about 10,000Da. In some embodiments, the number average molecular weight of the nonionic surfactant is about 7000Da to about 10,000Da. In some embodiments, the ethylene glycol content of the nonionic surfactant is about 30% by weight to about 99% by weight, about 50% by weight to about 95% by weight, about 60% by weight to about 95% by weight, about 75% by weight to about 90% by weight or about 80% by weight to about 85% by weight. In some embodiments, the ethylene glycol content of the nonionic surfactant is about 80% by weight to about 85% by weight.

[0327] In some embodiments, the surfactant is selected from fatty acids, phospholipids, sphingolipids, glycolipids, polyketides, sterol lipids, isoprenoid lipids, etc. In some embodiments, phospholipids are composed of glycerol connected to a phosphate group and two fatty acids. Other terms in the field of phospholipids include glycerophospholipids, phosphoglycerides, diacylglycerides, etc. The phosphate group can be unmodified (i.e., in a structure below R=H) or modified by being connected (i.e., in a structure below R≠H) to a simple organic molecule, such as but not limited to choline, ethanolamine, or serine. Phospholipids can be further modified by substitution on one or more hydrocarbon chains.

[0328]

[0329] Phospholipids

[0330] In one aspect, the pharmaceutical compositions described herein comprise an ASD comprising a surfactant that is a phospholipid. In some embodiments, the phospholipid is selected from a glycerophospholipid, a sphingolipid, and / or a phospholipid derivative. In some embodiments, the glycerophospholipid includes, but is not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and mixtures thereof. Phospholipid derivatives according to the present disclosure include but are not limited to dioleoylphosphatidylcholine, dimyristylphosphatidylcholine, divalerylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidonylphosphatidylcholine (DAPC), dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE) and distearoylphosphatidylethanolamine (DSPE), distearoylphosphatidylglycerol (DSPG), phosphatidylinositol, dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA) etc., and mixtures thereof. In some embodiments, phospholipids include at least 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight or 95% by weight of phosphatidylcholine. In some embodiments, phospholipids include greater than 80% of phosphatidylcholine.

[0331] In some embodiments, the phospholipid is present in the pharmaceutical composition in an amount of about 25 mg to about 200 mg. In some embodiments, the phospholipid is present in an amount of about 50 mg to 150 mg. In some embodiments, the phospholipid accounts for 2.5%-20% of the total weight of the pharmaceutical composition. In some embodiments, the phospholipid accounts for 5%-17% of the total weight of the pharmaceutical composition. In some embodiments, the phospholipid contains greater than 80% phosphatidylcholine.

[0332] In some embodiments, the phosphatidylcholine is a phosphatidylcholine in which the choline group (Me3N +-CH2-CH2-O-) attached to a phospholipid with a phosphate group.

[0333]

[0334] Phosphatidylcholine

[0335] In some embodiments, the ASD comprises phosphatidylcholine. A non-limiting example of phosphatidylcholine is 1-oleoyl-2-palmitoyl-phosphatidylcholine, as shown below:

[0336]

[0337] In some embodiments, the surfactant is lecithin. The USP 40 definition of lecithin is "a complex mixture of acetone-insoluble phospholipids, which is mainly composed of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidic acid, and exists together with various amounts of other substances (such as triglycerides, fatty acids and carbohydrates), such as separated from natural vegetable oil sources". In some embodiments, lecithin is a mixture of phospholipids. In some embodiments, lecithin comprises a mixture of phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidic acid. In some embodiments, lecithin comprises a mixture of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine and phosphatidic acid. Lecithin can be separated from various sources, including but not limited to eggs, soybeans, milk, seafood, rapeseed, cottonseed and sunflower. In some embodiments, the lecithin used in the disclosed amorphous solid dispersion and / or pharmaceutical composition is separated from egg yolk. Lecithin can be E322. The lecithin may be egg lecithin. The lecithin may be LSC 5050. The lecithin may be LSC 6040. The lecithin may be a mixed soy lecithin. The lecithin may be ovolecithin. The lecithin may be 53MCT lecithin. The lecithin may be Phospholipon 100H. The lecithin may be ProKote LSC. The lecithin may be soy lecithin. The lecithin may be soy lecithin. The lecithin may be Sternpur. The lecithin may be a vegetable lecithin. The lecithin may be 1,2-diacyl-sn-glycero-3-phosphocholine. In some embodiments, the lecithin contains more than 25% phosphatidylcholine. In some embodiments, the lecithin contains more than 50% phosphatidylcholine. In some embodiments, the lecithin contains more than 60% phosphatidylcholine. In some embodiments, the lecithin contains more than 70% phosphatidylcholine. In some embodiments, the lecithin is derived from an extract of soybean (eg, CAS [8030-76-0]). In some embodiments, the lecithin comprises egg yolk lecithin (eg, CAS [93685-90-6]).

[0338] In some embodiments, lecithin contains about 10% to about 95% phosphatidylcholine. In some embodiments, lecithin contains about 15% to about 80% phosphatidylcholine. In some embodiments, lecithin contains about 20% to about 75% phosphatidylcholine. In some embodiments, lecithin contains about 25% to about 70% phosphatidylcholine. In some embodiments, lecithin contains about 30% to about 65% phosphatidylcholine. In some embodiments, lecithin contains about 35% to about 60% phosphatidylcholine. In some embodiments, lecithin contains about 40% to about 55% phosphatidylcholine. In some embodiments, the lecithin contains about 10%, about 15%, about 20%, about 21%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 69%, about 70%, about 75%, about 85%, about 90% phosphatidylcholine. In some embodiments, the lecithin contains about 69% phosphatidylcholine. In some embodiments, the lecithin contains about 21% phosphatidylcholine. In some embodiments, the lecithin contains about 1% to about 55%, about 1% to about 50%, about 2% to about 40%, about 3% to about 36%, about 5% to about 35%, about 10% to about 30%, about 15% to about 25% phosphatidylethanolamine. In some embodiments, lecithin contains about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 22%, about 24%, about 26%, about 29%, about 30%, about 35%, about 36%, about 40%, about 45%, about 50% or about 55% phosphatidylethanolamine. In some embodiments, lecithin contains about 21% phosphatidylcholine, about 22% phosphatidylethanolamine and about 19% phosphatidylinositol. In some embodiments, lecithin contains about 69% phosphatidylcholine and about 24% phosphatidylethanolamine. In some embodiments, lecithin is egg yolk lecithin. In some embodiments, in some embodiments, phosphatidylcholine comes from an egg source. In some embodiments, phosphatidylcholine comes from a soybean source.

[0339] In some embodiments, the surfactant is a phospholipid. In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid is a mixture comprising phosphatidylcholine. In some embodiments, the surfactant is lecithin. In some embodiments, lecithin is a mixture of phospholipids. In some embodiments, lecithin consists of phosphatidylcholine. In some embodiments, lecithin contains more than 25% phosphatidylcholine. In some embodiments, lecithin contains more than 80% phosphatidylcholine. In some embodiments, phosphatidylcholine is from an egg source. In some embodiments, phosphatidylcholine is from a soybean source.

[0340] In some embodiments, the surfactant is present in the ASD described herein at about 10% by weight to about 70% by weight. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 10% by weight to about 60% by weight. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 10% by weight to about 50% by weight. In some embodiments, the surfactant is present in the ASD at about 15% by weight to about 45% by weight. In some embodiments, the surfactant is present in the ASD at about 20% by weight to about 40% by weight. In some embodiments, the surfactant is present in the ASD at about 20% by weight to about 30% by weight. In some embodiments, the surfactant is present in the ASD at about 30% by weight to about 40% by weight. In some embodiments, the surfactant is present in an amount of about 10% to about 15% by weight, about 10% to about 20% by weight, about 10% to about 25% by weight, about 10% to about 30% by weight, about 10% to about 35% by weight, about 10% to about 40% by weight, about 10% to about 45% by weight, about 10% to about 50% by weight, about 15% to about 20% by weight, about 15% to about 25% by weight, about 15% to about 30% by weight, about 15% to about 35% by weight, about 15% to about 40% by weight, about 15% to about 45% by weight, about 15% to about 50% by weight, about 20% to about 25% by weight, about 20% to about 30% by weight, about 20% to about 35% by weight, about 20% to about 40% by weight %, about 20 wt % to about 45 wt %, about 20 wt % to about 50 wt %, about 25 wt % to about 30 wt %, about 25 wt % to about 35 wt %, about 25 wt % to about 40 wt %, about 25 wt % to about 45 wt %, about 25 wt % to about 50 wt %, about 30 wt % to about 35 wt %, about 30 wt % to about 40 wt %, about 30 wt % to about 45 wt %, about 30 wt % to about 50 wt %, about 35 wt % to about 40 wt %, about 35 wt % to about 45 wt %, about 35 wt % to about 50 wt %, about 40 wt % to about 45 wt %, about 40 wt % to about 50 wt %, about 45 wt % to about 50 wt %, about 50 wt % to about 60 wt %, or about 60 wt % to about 70 wt % is present in the amorphous solid dispersion. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight.In some embodiments, the surfactant is present in the amorphous solid dispersion at least about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt% or about 45 wt%. In some embodiments, the surfactant is present in the amorphous solid dispersion at most about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt% or about 50 wt%. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 20 wt%. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 25 wt%. In some embodiments, the surfactant is present in the amorphous solid dispersion at 40 wt%. In some embodiments, the surfactant is TPGS. In some embodiments, the surfactant is lecithin.

[0341] In some embodiments, the surfactant is present in an ASD described herein in an amount of about 5 mg to about 5,000 mg. In some embodiments, the surfactant is present in an amount of about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg to about 50 mg, about 5 mg to about 80 mg, about 5 mg to about 100 mg, about 5 mg to about 150 mg, about 5 mg to about 200 mg, about 5 mg to about 300 mg, about 5 mg to about 500 mg, about 5 mg to about 5,000 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg, about 10 mg to about 50 mg, about 10 mg to about 80 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about to about 200 mg, about 10 mg to about 300 mg, about 10 mg to about 500 mg, about 10 mg to about 5,000 mg, about 20 mg to about 30 mg, about 20 mg to about 50 mg, about 20 mg to about 80 mg, about 20 mg to about 100 mg, about 20 mg to about 150 mg, about 20 mg to about 200 mg, about 20 mg to about 300 mg, about 20 mg to about 500 mg, about 20 mg to about 5,000 mg, about 30 mg to about 50 mg, about 30 mg to about 80 mg, about 30 mg to about 100 mg, about 30 mg to about 150 mg, about 30 mg to about 2 00mg, about 30mg to about 300mg, about 30mg to about 500mg, about 30mg to about 5,000mg, about 50mg to about 80mg, about 50mg to about 100mg, about 50mg to about 150mg, about 50mg to about 200mg, about 50mg to about 300mg, about 50mg to about 500mg, about 50mg to about 5,000mg, about 80mg to about 100mg, about 80mg to about 150mg, about 80mg to about 200mg, about 80mg to about 300mg, about 80mg to about 500mg, about 80mg to about 5,000mg, about 100m In some embodiments, the present invention provides an amount of about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 500 mg, about 100 mg to about 5,000 mg, about 150 mg to about 200 mg, about 150 mg to about 300 mg, about 150 mg to about 500 mg, about 150 mg to about 5,000 mg, about 200 mg to about 300 mg, about 200 mg to about 500 mg, about 200 mg to about 5,000 mg, about 300 mg to about 500 mg, about 300 mg to about 5,000 mg, or about 500 mg to about 5,000 mg.In some embodiments, the surfactant is present in the ASD in an amount of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or about 5,000 mg. In some embodiments, the surfactant is present in the ASD in an amount of at least about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 500 mg. In some embodiments, the surfactant is present in the ASD in an amount of at most about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or about 5,000 mg. In some embodiments, the surfactant is or comprises a phospholipid. In some embodiments, the phospholipid is or comprises lecithin. In some embodiments, the surfactant is TPGS. In some embodiments, the surfactant is lecithin. In some embodiments, the surfactant is TPGS and lecithin. In some embodiments, ASD is formulated into unit dosage forms, such as capsules or tablets. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of 10 mg to 500 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of 20 mg to 300 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of 30 mg to 100 mg. In some embodiments, the surfactant is present in the pharmaceutical composition in an amount of 40 mg to 80 mg.

[0342] In some embodiments, a surfactant (such as TPGS, SLS, lecithin, or a combination thereof) is present in the ASD in an amount of no less than 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 225, or 250 mg. In some embodiments, lecithin is present in an amorphous solid dispersion or pharmaceutical composition disclosed herein in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, or 250 mg. In some embodiments, the PROTAC is ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP, or KT-413. In some embodiments, PROTAC is a pharmaceutically acceptable salt of ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, other additives include antioxidants, such as vitamin E.

[0343] In some embodiments, the weight ratio of PROTAC to surfactant is from about 2:1 to about 1:10. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:0.5 to about 1:6. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:0.8 to about 1:5. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:0.8 to about 1:3. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:1 to about 1:3. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:0.8 to about 1:2.8. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:0.8 to about 1:2.5. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:1 to about 1:2.5. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:1 to about 1:2. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:1 to about 1:2. In some embodiments, the weight ratio of PROTAC to surfactant is from about 1:1 to about 1:1.5. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:1 to about 1:4. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:1 to about 1:3.5. In some embodiments, the surfactant is TPGS. In some embodiments, the surfactant is lecithin. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0344] In some embodiments, the surfactant accounts for 0.1%-60% of the total weight of the pharmaceutical composition described herein. In some embodiments, the surfactant accounts for 0.1%-50% of the total weight of the pharmaceutical composition described herein. In some embodiments, the pharmaceutical composition is an amorphous solid dispersion. In some embodiments, the surfactant accounts for 1%-40% of the total weight of the composition. In some embodiments, the surfactant accounts for 1%-30% of the total weight of the composition. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the surfactant accounts for 5%-20% of the total weight of the composition. In some embodiments, the surfactant accounts for 10%-17% of the total weight of the composition. In some embodiments, the surfactant accounts for about 15% of the total weight of the composition. In some embodiments, the surfactant accounts for about 16% of the total weight of the composition. In some embodiments, the surfactant accounts for about 17% of the total weight of the composition. In some embodiments, the surfactant accounts for about 15-30% of the total weight of the composition. In some embodiments, the surfactant accounts for about 10-35% of the total weight of the composition. In some embodiments, the surfactant accounts for about 20-40% of the total weight of the composition. In some embodiments, the surfactant is TPGS or lecithin or a combination thereof. In some embodiments, the surfactant is a phospholipid. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 0.75. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.0. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.1. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.2. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.3. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.4. In some embodiments, the weight ratio of the hydrophilic polymer to the surfactant (e.g., lecithin or TPGS) is greater than 1.5. In some embodiments, the pharmaceutical composition described herein comprises PROTAC, a hydrophilic polymer and a surfactant. In some embodiments, the pharmaceutical compositions described herein comprise PROTAC, a hydrophilic polymer, and a surfactant or poloxamer. In some embodiments, the pharmaceutical compositions described herein comprise PROTAC, a hydrophilic polymer, and lecithin. In some embodiments, the pharmaceutical compositions described herein comprise PROTAC, a hydrophilic polymer, and lecithin. In some embodiments, the pharmaceutical compositions described herein comprise PROTAC, an ionic hydrophilic polymer, and lecithin.In some embodiments, the PROTAC is ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP, or KT-413. In some embodiments, PROTAC is a pharmaceutically acceptable salt of ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0345] In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants (e.g., vitamin E).

[0346] Hydrophilic polymer

[0347] In one aspect, described herein is a pharmaceutical composition comprising an ASD comprising a PROTAC, a hydrophilic polymer, a surfactant, and an optional adsorbent. The hydrophilic polymer may be present in the ASD in an amorphous state. In some embodiments, PROTAC is a PROTAC of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC is a pharmaceutically acceptable salt of ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP or KT-413. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-471 or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, a pharmaceutical composition comprises an ASD comprising a hydrophilic polymer. In some embodiments, the hydrophilic polymer comprises at least one of polyvinyl pyrrolidone (povidone or PVP), vinyl pyrrolidone-vinyl acetate copolymer (copovidone), sulfobutyl ether-β-cyclodextrin, oligosaccharides, polysaccharides, HEC, HPC, PEO, HP-β-CD, PEG, hydroxypropyl methylcellulose phthalate (HPMCP), polymethacrylate (e.g., sold under the trade name Eudragit), HPMC, PVP, polyvinyl pyrrolidone (PVPP), vinyl pyrrolidone-vinyl acetate copolymer or Kollidon VA64 (VA64), PVA, hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCP, sulfobutyl ether-β-cyclodextrin and polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG, also known as ). In some embodiments, PVP comprises PVP K30. In some embodiments, HMPC comprises HPMC E5 and HMPC E50. In some embodiments, the hydrophilic polymer is sulfobutyl ether-β-cyclodextrin. In some embodiments, the hydrophilic polymer is a nonionic polymer. In some embodiments, the hydrophilic polymer is an ionic polymer, such as sulfobutyl ether-β-cyclodextrin. In some embodiments, the hydrophilic polymer comprises copolyvidone. In some embodiments, the hydrophilic polymer comprises povidone. In some embodiments, the hydrophilic polymer comprises sulfobutyl ether-β-cyclodextrin. In some embodiments, HPMCAS is HPMCAS-LF. In some embodiments, the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer or Kollidon VA64 (VA64). In some embodiments, the hydrophilic polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as HPMCAS-LS. In some embodiments, the hydrophilic polymer is a polymethacrylate, such as Eudragit. In some embodiments, the hydrophilic polymer is hypromellose phthalate (HPMCP).

[0349] In some embodiments, the amorphous solid dispersion described herein comprises a hydrophilic polymer. In some embodiments, the hydrophilic polymer is a nonionic polymer. In some embodiments, the hydrophilic polymer is an ionic polymer. In some embodiments, the hydrophilic polymer is a cationic polymer. In some embodiments, the hydrophilic polymer is an anionic polymer. In some embodiments, the hydrophilic polymer comprises polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam-based graft copolymers (PVAc-PVCap-PEG) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG, also known as ), polyethylene oxide, hydroxypropyl beta-cyclodextrin (HP-β-CD) or a combination thereof. In some embodiments, the nonionic hydrophilic polymer is HPMC, PVP, HP-β-CD or PVA. In some embodiments, the hydrophilic polymer is an enteric polymer. In some embodiments, the enteric polymer comprises a methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate or cellulose acetate phthalate. In some embodiments, the enteric polymer remains unionized at low pH and remains insoluble. In some embodiments, the enteric polymer comprises polymethacrylate (e.g., Eudragit), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCAS or Soluplus. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the polymethacrylate comprises quaternary ammonium methacrylate copolymer (type A), quaternary ammonium methacrylate copolymer (type B), basic butylated methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer (1:1), dispersion 30%, methacrylic acid-methyl methacrylate copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (1:2), polyacrylate dispersion (30%), poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate In some cases, the enteric polymer comprises cellulose phthalate hydroxypropyl methyl ether; HPMCP; hydroxypropyl methylcellulose benzene-1,2-dicarboxylate; 2-hydroxypropyl methylcellulose phthalate; hypromellose phthalate; Mantrocel HP-55; or methylhydroxypropyl cellulose phthalate.

[0350] In some embodiments, the hydrophilic polymer is present in the ASD described herein in an amount of about 5% to about 90% by weight. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 5% to about 70%. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 15% to about 50%. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 20% to about 30%. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 25% to about 40%. In some embodiments, the hydrophilic polymer is present in an amount of about 5 wt % to about 10 wt %, about 5 wt % to about 20 wt %, about 5 wt % to about 30 wt %, about 5 wt % to about 40 wt %, about 5 wt % to about 50 wt %, about 5 wt % to about 60 wt %, about 5 wt % to about 70 wt %, about 5 wt % to about 80 wt %, about 5 wt % to about 90 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 60 wt %, about 10 wt % to about 70 wt %, about 10 wt % to about 80 wt %, about 10 wt % to about 90 wt %, about 20 wt % to about 30 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 60 wt %, about 20 wt % to about 70 wt %, about 2 ... 0 wt %, about 20 wt % to about 90 wt %, about 30 wt % to about 40 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 60 wt %, about 30 wt % to about 70 wt %, about 30 wt % to about 80 wt %, about 30 wt % to about 90 wt %, about 40 wt % to about 50 wt %, about 40 wt % to about 60 wt %, about 40 wt % to about 70 wt %, about 40 wt % to about 80 wt %, about 40 % by weight to about 90% by weight, about 50% by weight to about 60% by weight, about 50% by weight to about 70% by weight, about 50% by weight to about 80% by weight, about 50% by weight to about 90% by weight, about 60% by weight to about 70% by weight, about 60% by weight to about 80% by weight, about 60% by weight to about 90% by weight, about 70% by weight to about 80% by weight, about 70% by weight to about 90% by weight or about 80% by weight to about 90% by weight are present in the amorphous solid dispersion. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone VA64. In some embodiments, the hydrophilic polymer comprises hydroxypropylmethylcellulose acetate succinate (HPMCAS).In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises polymethacrylate (e.g., Eudragit). In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, ASD comprises two or more hydrophilic polymers. In some embodiments, two or more hydrophilic polymers are selected from copolyvidone, HPMCAS and HPMC.

[0351] In some embodiments, the weight ratio of PROTAC or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10:1 to about 1:10. In some embodiments, the hydrophilic polymer is selected from PVA, oligosaccharides, polysaccharides, PVP, HPMC, HEC, HPC, PEO, HP-β-CD, HPMCAS, PEG, HPMCP, Eudragit and Soluplus or a combination thereof. In some embodiments, the hydrophilic polymer is non-ionic. In some embodiments, the hydrophilic polymer comprises polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG) or a combination thereof. In some embodiments, the hydrophilic polymer is HPMC, PVP, HP-β-CD, PVA, HPMCAS or PCL-PVAc-PEG. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 5% by weight to about 70% by weight based on solids. In some embodiments, the weight ratio of PROTAC or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10: 1 to about 1: 10. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0352] In some embodiments, the ASD is formulated into a unit dosage form, such as a capsule or tablet. In some embodiments, the hydrophilic polymer is present in the ASD in an amount of about 10 mg to about 6,000 mg. In some embodiments, the hydrophilic polymer is present in the ASD in an amount of about 10 mg to about 500 mg. In some embodiments, the hydrophilic polymer is present in the ASD in an amount of about 20 mg to about 300 mg. In some embodiments, the hydrophilic polymer is present in the ASD in an amount of about 25 mg to about 100 mg. In some embodiments, the hydrophilic polymer is present in the ASD in an amount of about 30 mg to about 80 mg. In some embodiments, the hydrophilic polymer is present in an amount of about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 200 mg, about 10 mg to about 300 mg, about 10 mg to about 500 mg, about 10 mg to about 800 mg, about 10 mg to about 1,000 mg, about 10 mg to about 2,000 mg, about 10 mg to about 4,000 mg, about 10 mg to about 6,000 mg, about 50 mg to about 100 mg, about 50 mg to about 150 mg, about 500 mg to about 1000 mg, about 500 mg to about 2000 mg, about 1000 mg to about 3000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 1,0000 mg, about 1000 mg to about 2,0000 mg, about 1000 mg to about 4,000 mg, about 1000 mg to about 6,000 mg, about 500 mg to about 1000 mg, about 500 mg to about 1500 mg, about 5000 mg to about 1 mg to about 200 mg, about 50 mg to about 300 mg, about 50 mg to about 500 mg, about 50 mg to about 800 mg, about 50 mg to about 1,000 mg, about 50 mg to about 2,000 mg, about 50 mg to about 4,000 mg, about 50 mg to about 6,000 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 500 mg, about 100 mg to about 800 mg, about 100 mg to about 1,000 mg, From about 100 mg to about 2,000 mg, from about 100 mg to about 4,000 mg, from about 100 mg to about 6,000 mg, from about 150 mg to about 200 mg, from about 150 mg to about 300 mg, from about 150 mg to about 500 mg, from about 150 mg to about 800 mg, from about 150 mg to about 1,000 mg, from about 150 mg to about 2,000 mg, from about 150 mg to about 4,000 mg, from about 150 mg to about 6,000 mg, from about 200 mg to about 300 mg, from about 200 mg to about 500 mg , about 200 mg to about 800 mg, about 200 mg to about 1,000 mg, about 200 mg to about 2,000 mg, about 200 mg to about 4,000 mg, about 200 mg to about 6,000 mg, about 300 mg to about 500 mg, about 300 mg to about 800 mg, about 300 mg to about 1,000 mg, about 300 mg to about 2,000 mg, about 300 mg to about 4,000 mg, about 300 mg to about 6,000 mg, about 500 mg to about 800 mg, about 500 mg to about 1,In some embodiments, the present invention relates to an amount of at least one molecule of the present invention to amorphous solid dispersion. In some embodiments, the present invention relates to an amount of at least one molecule of the present invention to amorphous solid dispersion. In some embodiments, the present invention relates to an amount of at least one molecule of the present invention to amorphous solid dispersion. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1,000 mg, about 2,000 mg, about 4,000 mg, or about 6,000 mg. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of at least about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1,000 mg, about 2,000 mg, or about 4,000 mg. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of up to about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1,000 mg, about 2,000 mg, about 4,000 mg or about 6,000 mg. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone K30. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone (such as VA64). In some embodiments, the hydrophilic polymer includes hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer includes HPMCP. In some embodiments, the hydrophilic polymer includes polymethacrylate (e.g., Eudragit). In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone HPMC. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone HPMC E5. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone HPMC E50.

[0353] In some embodiments, a pharmaceutical composition is provided, which comprises about 1mg to about 500mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 10mg to about 400mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 25mg to about 200mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 50mg to about 150mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 75mg to about 125mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 75mg to about 100mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 100mg to about 125mg of a hydrophilic polymer. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone, such as VA64. In some embodiments, the hydrophilic polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises polymethacrylate (e.g., Eudragit). In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, ASD comprises two or more hydrophilic polymers. In some embodiments, two or more hydrophilic polymers are selected from copolyvidone, HPMCAS and HPMC.

[0354] In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 55 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 60 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 65 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 70 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 75 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 80 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 85 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 90 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 95 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 100 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 105 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 110 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 115 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 120 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 125 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 130 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 135 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 140 mg to about 150 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, which comprises about 145mg to about 150mg hydrophilic polymer. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone VA64.In some embodiments, the hydrophilic polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises polymethacrylate. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, ASD comprises two or more hydrophilic polymers. In some embodiments, two or more hydrophilic polymers are selected from copolyvidone, HPMCAS and HPMC.

[0355] In some embodiments, the hydrophilic polymer accounts for about 5% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 10% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 15% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 20% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 25% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 30% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 40% of the total weight of the composition. In some embodiments, the hydrophilic polymer accounts for about 50% of the total weight of the composition. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone. In some embodiments, the hydrophilic polymer is polyvinyl pyrrolidone VA64. In some embodiments, the hydrophilic polymer includes hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer includes HPMCP. In some embodiments, the hydrophilic polymer comprises polymethacrylate. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, the ASD comprises two or more hydrophilic polymers. In some embodiments, the two or more hydrophilic polymers are selected from copovidone, HPMCAS and HPMC.

[0356] In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 99% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 80% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 60% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 40% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 20% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 10% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 1% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 20% by weight to about 99% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 20% by weight to about 80% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 20% to about 60% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 20% to about 40% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 99% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 80% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 60% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 40% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 99% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 80% by weight of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 60% by weight of a hydrophilic polymer. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone. In some embodiments, the composition is an amorphous solid dispersion described herein. In some embodiments, the composition is a pharmaceutical composition described herein.

[0357] In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion comprises about 1% by weight to about 90% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 1% by weight to about 80% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 10% by weight to about 60% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 20% by weight to about 50% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 20% by weight to about 40% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 1%, about 10%, about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 80% or about 90% by weight of a hydrophilic polymer. In some embodiments, amorphous solid dispersion comprises at least about 1 wt %, about 10 wt %, about 20 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt % or about 80 wt % hydrophilic polymer. In some embodiments, amorphous solid dispersion comprises at most about 10 wt %, about 20 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt %, about 80 wt % or about 90 wt % hydrophilic polymer. In some embodiments, hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose HMPC. In some embodiments, hydrophilic polymer is polyvinylpyrrolidone. In some embodiments, hydrophilic polymer is polyvinylpyrrolidone, such as VA64. In some embodiments, the hydrophilic polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises polymethacrylate. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. In some embodiments, ASD comprises two or more hydrophilic polymers. In some embodiments, two or more hydrophilic polymers are selected from copolyvidone, HPMCAS and HPMC.

[0358] acid

[0359] In some embodiments, the amorphous solid dispersion further comprises an inorganic acid or an organic acid. The inorganic acid or organic acid may be present in the ASD in an amorphous state. In some embodiments, the organic acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid and p-toluenesulfonic acid. In some embodiments, the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid. In some embodiments, PROTAC is a PROTAC of Table 1 or a pharmaceutically acceptable salt thereof.

[0360] In one aspect, an amorphous solid dispersion is described herein, comprising an API and one or more acids. Also described herein is a pharmaceutical composition comprising an API and one or more acids. In some embodiments, the amorphous solid dispersion comprises an API, one or more acids, and a hydrophilic high molecular weight material. In some embodiments, the API is at least partially protonated. In some embodiments, the API is a PROTAC (e.g., a PROTAC of Table 1 or a pharmaceutically acceptable salt thereof).

[0361] In some embodiments, amorphous solid dispersion disclosed herein and / or pharmaceutical composition include one or more organic acids. In some embodiments, one or more organic acids include one or more of the following: acetic acid, acrylic acid, adipic acid, alginic acid, amino acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, carbonic acid, citric acid, formic acid, fumaric acid, gluconic acid, isoascorbic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, fluorinated acid, trifluoromethanesulfonic acid, trifluoroacetic acid, oxalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, aliphatic sulfonic acid (for example, methanesulfonic acid, methanedisulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid), aromatic sulfonic acid (for example, benzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid) and uric acid. In some embodiments, one or more organic acids include methanesulfonic acid, tartaric acid or both. In some embodiments, the one or more organic acids comprise methanesulfonic acid and tartaric acid. In some embodiments, the one or more organic acids do not comprise acetic acid.

[0362] In some embodiments, the organic acid or inorganic acid is present in the ASD at about 1% to about 60% by weight. In some embodiments, the organic acid or inorganic acid is present in the ASD at about 5% to about 50% by weight. In some embodiments, the organic acid or inorganic acid is present in the ASD at about 10% to about 40% by weight. In some embodiments, the organic acid or inorganic acid is present in the ASD at about 15% to about 30% by weight. In some embodiments, the organic acid or inorganic acid is present in the ASD at about 15% to about 25% by weight. In some embodiments, the organic acid or inorganic acid is present in the ASD at about 20% to about 30% by weight. In some embodiments, the organic acid or inorganic acid is present in an amount of about 1 wt % to about 5 wt %, about 1 wt % to about 10 wt %, about 1 wt % to about 15 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 25 wt %, about 1 wt % to about 30 wt %, about 1 wt % to about 35 wt %, about 1 wt % to about 40 wt %, about 1 wt % to about 50 wt %, about 1 wt % to about 60 wt %, about 5 wt % to about 10 wt %, about 5 wt % to about 15 wt %, about 5 wt % to about 20 wt %, about 5 wt % to about 25 wt %, %, about 5 wt % to about 30 wt %, about 5 wt % to about 35 wt %, about 5 wt % to about 40 wt %, about 5 wt % to about 50 wt %, about 5 wt % to about 60 wt %, about 10 wt % to about 15 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 25 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 35 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 60 wt %, about 15 ...%. %, about 15 wt % to about 25 wt %, about 15 wt % to about 30 wt %, about 15 wt % to about 35 wt %, about 15 wt % to about 40 wt %, about 15 wt % to about 50 wt %, about 15 wt % to about 60 wt %, about 20 wt % to about 25 wt %, about 20 wt % to about 30 wt %, about 20 wt % to about 35 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 60 wt %, about 25 wt % to about 30 wt %, about 25 wt % to about 3 %, about 25 wt % to about 40 wt %, about 25 wt % to about 50 wt %, about 25 wt % to about 60 wt %, about 30 wt % to about 35 wt %, about 30 wt % to about 40 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 60 wt %, about 35 wt % to about 40 wt %, about 35 wt % to about 50 wt %, about 35 wt % to about 60 wt %, about 40 wt % to about 50 wt %, about 40 wt % to about 60 wt %, or about 50 wt % to about 60 wt % are present in the ASD.In some embodiments, the organic acid or inorganic acid is present in the ASD at about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 50 wt%, or about 60 wt%. In some embodiments, the organic acid or inorganic acid is present in the ASD at least about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, or about 50 wt%. In some embodiments, the organic acid or inorganic acid is present in the ASD at most about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 50 wt%, or about 60 wt%. In some embodiments, the organic acid or inorganic acid is present in the pharmaceutical composition and is not present in the ASD. In some embodiments, the organic acid is malic acid. In some embodiments, the organic acid is citric acid. In some embodiments, the organic acid is tartaric acid. In some embodiments, the organic acid is succinic acid.

[0363] In some embodiments, one or more organic acids are present in amorphous solid dispersions and / or pharmaceutical compositions in an amount of about 0.1% by weight to about 99% by weight of a total composition. In some embodiments, one or more organic acids are present in amorphous solid dispersions and / or pharmaceutical compositions in an amount of about 1% by weight to about 80% by weight, about 1% by weight to about 60% by weight, about 1% by weight to about 50% by weight, about 1% by weight to about 25% by weight, about 1% by weight to about 10% by weight, about 1% by weight to about 5% by weight, about 10% by weight to about 80% by weight, about 10% by weight to about 60% by weight, about 10% by weight to about 50% by weight, about 20% by weight to about 80% by weight, about 20% by weight to about 60% by weight, about 20% by weight to about 50% by weight, about 30% by weight to about 80% by weight, about 30% by weight to about 60% by weight, about 30% by weight to about 50% by weight, or about 30% by weight to about 40% by weight of a total composition. In some embodiments, one or more organic acids are present in amorphous solid dispersions and / or pharmaceutical compositions in an amount of about 25 % by weight, about 26 % by weight, about 27 % by weight, about 28 % by weight, about 29 % by weight, about 30 % by weight, about 31 % by weight, about 32 % by weight, about 33 % by weight, about 34 % by weight, about 35 % by weight, about 36 % by weight, about 37 % by weight, about 38 % by weight, about 39 % by weight, about 40 % by weight, about 41 % by weight, about 42 % by weight, about 43 % by weight, about 44 % by weight or about 45 % by weight of the total composition. In some embodiments, one or more organic acids include tartaric acid. In some embodiments, one or more organic acids include methanesulfonic acid.In some embodiments, the one or more organic acids are present in an amount of about 1.0 mg to about 1000 mg, including but not limited to about 5.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 200 mg, 201 In some embodiments, the amount of one or more organic acids is 1mg to 500mg. In some embodiments, one or more organic acids are present in an amount of about 10 mg to about 400 mg, 20 mg to about 300 mg, about 25 mg to about 200 mg, about 50 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 1 mg to about 200 mg, or about 50 mg to about 200 mg. In some embodiments, one or more organic acids are present in an amount of 25 mg to 250 mg. In some embodiments, one or more organic acids are present in an amount of 150 mg to 250 mg. In some embodiments, one or more organic acids are present in an amount of 150 mg to 200 mg. In some embodiments, one or more organic acids are present in an amount of 50 mg to 200 mg. In some embodiments, amorphous solid dispersions and / or pharmaceutical compositions are formulated into unit dosage forms, such as capsules or tablets. In some embodiments, organic acids are present in pharmaceutical compositions in an amount of 1 mg to 500 mg. In some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 10 mg to 300 mg. In some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 30 mg to 100 mg. In some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 30 mg to 80 mg.

[0364] In some embodiments, the one or more organic acids are present in a molar ratio to the API of greater than 0.5: 1, greater than 1: 1, greater than 1.5: 1, greater than 2: 1, greater than 2.5: 1, or greater than 3: 1. In some embodiments, the one or more organic acids are present in a molar ratio to the API of about 0.5: 1 to about 1: 1, about 0.5: 1 to about 1.5: 1, about 0.5: 1 to about 2: 1, about 0.5: 1 to about 2.5: 1, about 0.5: 1 to about 3: 1, about 1: 1 to about 1.5: 1, about 1: 1 to about 2: 1, about 1: 1 to about 2.5: 1, about 1: 1 to about 3: 1, about 1.5: 1 to about 2: 1, about 1.5: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 2: 1 to about 3: 1, or about 2.5: 1 to about 3: 1. In some embodiments, the one or more organic acids comprise tartaric acid and methanesulfonic acid.

[0365] In some embodiments, the amorphous solid dispersion described herein comprises an API, one or more acids, and a hydrophilic high molecular weight material. In some embodiments, the one or more acids comprise a first acid and a second acid. In some embodiments, the molar ratio of the first acid to the API is from about 0.1:1 to about 10:1, from about 0.5:1 to about 5:1, from about 0.5:1 to about 3:1, from about 0.5:1 to about 1:1, from about 0.5:1 to about 1.5:1, from about 0.5:1 to about 2:1, from about 0.5:1 to about 2.5:1, from about 0.5:1 to about 3:1, from about 1:1 to about 1.5:1, from about 1:1 to about 2:1, from about 1:1 to about 2.5:1, from about 1:1 to about 3:1, from about 1.5:1 to about 2:1, from about 1.5:1 to about 2.5:1, from about 1.5:1 to about 3:1, from about 2:1 to about 2.5:1, from about 2:1 to about 3:1, or from about 2.5:1 to about 3:1. In some embodiments, the molar ratio of the second acid to the API is present at a molar ratio to the API of about 0.1:1 to about 10:1, about 1:1 to about 8:1, about 2:1 to about 7:1, about 4:1 to about 7:1, about 0.5:1 to about 3:1, about 0.5:1 to about 1:1, about 0.5:1 to about 1.5:1, about 0.5:1 to about 2:1, about 0.5:1 to about 2.5:1, about 0.5:1 to about 3:1, about 1:1 to about 1.5:1, about 1:1 to about 2:1, about 1:1 to about 2.5:1, about 1:1 to about 3:1, about 1.5:1 to about 2:1, about 1.5:1 to about 2.5:1, about 1.5:1 to about 3:1, about 2:1 to about 2.5:1, about 2:1 to about 3:1, or about 2.5:1 to about 3:1. In some embodiments, the mass ratio of the second acid to the API is present in a molar ratio to the API of about 0.1:1 to about 10:1, about 0.2:1 to about 5:1, about 0.5:1 to about 3:1, about 0.2:1 to about 1.2:1, about 0.4:1 to about 1:1, about 0.5:1 to about 1:1, about 0.5:1 to about 1.5:1, about 0.5:1 to about 2:1, about 0.5:1 to about 2.5:1, about 0.5:1 to about 3:1, about 1:1 to about 1.5:1, about 1:1 to about 2:1, about 1:1 to about 2.5:1, about 1:1 to about 3:1, about 1.5:1 to about 2:1, about 1.5:1 to about 2.5:1, about 1.5:1 to about 3:1, about 2:1 to about 2.5:1, about 2:1 to about 3:1, or about 2.5:1 to about 3:1. In some embodiments, the molar ratio of the first acid to the API is about 0.1: 1 to 1.5: 1. In some embodiments, the first acid is an inorganic acid. In some embodiments, the first acid is an organic acid.

[0366] In some embodiments, the mass ratio of the second acid to the API is about 0.05:1 to about 20:1, about 0.5:1 to about 10:1, about 0.5:1 to about 1:1, about 0.5:1 to about 1.5:1, about 0.5:1 to about 2:1, about 0.5:1 to about 2.5:1, about 0.5:1 to about 3:1, about 1:1 to about 1.5:1, about 1:1 to about 2:1, about 1:1 to about 2.5:1, about 1:1 to about 3:1, about 1.5:1 to about 2:1, about 1.5:1 to about 2.5:1, about 1.5:1 to about 3:1, about 2:1 to about 2.5:1, about 2:1 to about 3:1, or about 2.5:1 to about 3:1. In some embodiments, the mass ratio of the second acid to the API is about 0.5:1 to about 10:1. In some embodiments, the first acid is an inorganic acid. In some embodiments, the first acid is an organic acid.

[0367] In some embodiments, the amorphous solid dispersion and / or pharmaceutical composition disclosed herein comprises one or more inorganic acids. In some embodiments, the one or more inorganic acids comprise one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid. In some embodiments, the one or more inorganic acids comprise hydrochloric acid. In some embodiments, the inorganic acid is fully ionized. In some embodiments, the inorganic acid is partially ionized. In some embodiments, partial ionization refers to a balance in which 1% or more of the inorganic acid is ionized.

[0368] In some embodiments, one or more inorganic acids are present in amorphous solid dispersions and / or pharmaceutical compositions in an amount of about 0.1 % by weight to about 99 % by weight of a total composition. In some embodiments, one or more inorganic acids are present in amorphous solid dispersions and / or pharmaceutical compositions in an amount of about 0.1 % by weight to about 80 % by weight, 1 % by weight to about 80 % by weight, about 1 % by weight to about 60 % by weight, about 1 % by weight to about 50 % by weight, about 10 % by weight to about 80 % by weight, about 10 % by weight to about 60 % by weight, about 10 % by weight to about 50 % by weight, about 20 % by weight to about 80 % by weight, about 20 % by weight to about 60 % by weight, about 20 % by weight to about 50 % by weight, about 30 % by weight to about 80 % by weight, about 30 % by weight to about 60 % by weight, about 30 % by weight to about 50 % by weight, or about 30 % by weight to about 40 % by weight of a total composition. In some embodiments, one or more inorganic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of about 0.1 wt %, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, about 35 wt %, about 40 wt % or about 45 wt % of the total composition. In some embodiments, one or more inorganic acids comprise hydrochloric acid. In some embodiments, the one or more inorganic acids are present in an amount of about 1.0 mg to about 1000 mg, including but not limited to about 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 170 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 235 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 510 mg, 510 mg, 510 mg, 510 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg or 350 mg is present in the amorphous solid dispersion and / or the pharmaceutical composition.In some embodiments, one or more inorganic acids are present in an amount of about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, about 2 mg to about 20 mg, about 5 mg to about 15 mg, about 7 mg to about 25 mg, about 7 mg to about 20 mg, or 10 mg to about 18 mg. In some embodiments, amorphous solid dispersions and / or pharmaceutical compositions are formulated into unit dosage forms, such as capsules or tablets. In some embodiments, inorganic acids are present in pharmaceutical compositions in an amount of 1 mg to 500 mg. In some embodiments, inorganic acids are present in pharmaceutical compositions in an amount of 10 mg to 300 mg. In some embodiments, inorganic acids are present in pharmaceutical compositions in an amount of 30 mg to 100 mg. In some embodiments, inorganic acids are present in pharmaceutical compositions in an amount of 30 mg to 80 mg.

[0369] In some embodiments, the amorphous solid dispersion disclosed herein comprises a first acid and a second acid. In some embodiments, the molar ratio of the second acid to the first acid is from about 0.05:1 to about 20:1. In some embodiments, the molar ratio of the second acid to the first acid is from about 0.5:1 to about 10:1. In some embodiments, the molar ratio of the second acid to the first acid is from about 1:1 to about 4:1. In some embodiments, the molar ratio of the second acid to the first acid is about 2:1. In some embodiments, the molar ratio of API to the first acid is from about 0.1:1 to about 10:1. In some embodiments, the molar ratio of API to the first acid is from about 0.2:1 to about 5:1 or from about 0.5:1 to about 2:1. In some embodiments, the molar ratio of API to the first acid is about 1:1. In some embodiments, the molar ratio of API to the second acid is from about 0.05:1 to about 20:1. In some embodiments, the molar ratio of API to the second acid is from about 0.1:1 to about 5:1 or from about 0.2:1 to about 1:1. In some embodiments, the molar ratio of API to second acid is about 0.5:1.

[0370] Adsorbent

[0371] In one aspect, a pharmaceutical composition disclosed herein comprises an ASD comprising a PROTAC, a hydrophilic polymer, a surfactant, and an optional adsorbent. The adsorbent may be present in the ASD in an amorphous state. In some embodiments, the adsorbent is present in the ASD in an amorphous state. In some embodiments, the adsorbent is not present in the ASD in an amorphous state, and the amorphous composition is adsorbed onto the adsorbent. In some embodiments, PROTAC is a PROTAC of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the ASD optionally comprises an adsorbent. In some embodiments, the ASD optionally comprises one or more adsorbents.

[0372] Many adsorbents are solid, porous or superporous adsorbent materials. They contain many micropores or nanopores in their structure, resulting in very large surface areas, for example greater than 500 m 2 / g. Exemplary adsorbents include, but are not limited to, silicon dioxide, activated carbon, magnesium aluminum silicate, diatomaceous earth, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0373] In some embodiments, the adsorbent, such as silica, is present in the ASD at about 1 wt % to about 70 wt %. In some embodiments, the adsorbent is present in the ASD at about 1 wt % to about 5 wt %, about 1 wt % to about 10 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 30 wt %, about 1 wt % to about 40 wt %, about 1 wt % to about 50 wt %, about 1 wt % to about 60 wt %, about 1 wt % to about 70 wt %, about 5 wt % to about 10 wt %, about 5 wt % to about 20 wt %, about 5 wt % to about 30 wt %, about 5 wt % to about 40 wt %, about 5 wt % to about 50 wt %, about 5 wt % to about 60 wt %, about 5 wt % to about 70 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about In some embodiments, the adsorbent is present in the ASD at about 5 wt % to about 40 wt %. In some embodiments, the adsorbent is present in the ASD at about 10 wt % to about 50 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 60 wt %, about 20 wt % to about 70 wt %, about 30 wt % to about 40 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 60 wt %, about 30 wt % to about 70 wt %, about 40 wt % to about 50 wt %, about 40 wt % to about 60 wt %, about 40 wt % to about 70 wt %, about 50 wt % to about 60 wt %, about 50 wt % to about 70 wt %, or about 60 wt % to about 70 wt %. In some embodiments, the adsorbent is present in the ASD at about 5 wt % to about 40 wt %. In some embodiments, the adsorbent is present in the ASD at about 10 wt % to about 35 wt %. In some embodiments, the adsorbent is present in the ASD at about 15% to about 30% by weight. In some embodiments, the adsorbent is present in the ASD at about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% by weight. In some embodiments, the adsorbent is present in the ASD at at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, or about 60% by weight. In some embodiments, the adsorbent is present in the ASD at most about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% by weight. In some embodiments, the adsorbent is SiO2.

[0374] In some embodiments, the adsorbent is present in the ASD in an amount of about 1 mg to about 5,000 mg. In some embodiments, the adsorbent is present in the ASD in an amount of about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 30 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 1 mg to about 200 mg, about 1 mg to about 500 mg, about 1 mg to about 1,000 mg, about 1 mg to about 3,000 mg, about 1 mg to about 5,000 mg, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg to about 50 mg, about 5 mg to about 100 mg, about 5 mg to about 200 mg, about 5 mg to about 500 mg, about 5 mg to about 1,000 mg, about 5 mg to about 3,000 mg, about 5 mg to about 5,000 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 200 mg, about 10 mg to about 500 mg, about 10 mg to about 1,000 mg, about 10 mg to about 3,000 mg, about 10 mg to about 5,000 mg, about 20 mg to about 30 mg, about 20 mg to about 50 mg, about 20 mg to about 100 mg, about 20 mg to about 200 mg, about 20 mg to about 500 mg, about 20 mg to about 1,000 mg mg, about 20 mg to about 3,000 mg, about 20 mg to about 5,000 mg, about 30 mg to about 50 mg, about 30 mg to about 100 mg, about 30 mg to about 200 mg, about 30 mg to about 500 mg, about 30 mg to about 1,000 mg, about 30 mg to about 3,000 mg, about 30 mg to about 5,000 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 500 mg, about 50 mg to about 1,000 mg, about 50 mg to about 3,000 mg, about 50 mg to about 5,000 mg, about 100 mg to about 200 mg, about 100 The ASD may be present in an amount from about 100 mg to about 500 mg, from about 100 mg to about 1,000 mg, from about 100 mg to about 3,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 500 mg, from about 200 mg to about 1,000 mg, from about 200 mg to about 3,000 mg, from about 200 mg to about 5,000 mg, from about 500 mg to about 1,000 mg, from about 500 mg to about 3,000 mg, from about 500 mg to about 5,000 mg, from about 1,000 mg to about 3,000 mg, from about 1,000 mg to about 5,000 mg, or from about 3,000 mg to about 5,000 mg.In some embodiments, the adsorbent is present in the ASD in an amount of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1,000 mg, about 3,000 mg, or about 5,000 mg. In some embodiments, the adsorbent is present in the ASD in an amount of at least about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1,000 mg, or about 3,000 mg. In some embodiments, the adsorbent is present in the ASD in an amount of at most about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1,000 mg, about 3,000 mg, or about 5,000 mg. In some embodiments, the ASD is formulated into a unit dosage form, such as a capsule or tablet. In some embodiments, the adsorbent is present in the pharmaceutical composition in an amount of 1 mg to 500 mg. In some embodiments, the adsorbent is present in the pharmaceutical composition in an amount of 10 mg to 300 mg. In some embodiments, the adsorbent is present in the pharmaceutical composition in an amount of 30 mg to 100 mg. In some embodiments, the adsorbent is present in the pharmaceutical composition in an amount of 30 mg to 80 mg.

[0375] In some embodiments, the adsorbent is present in the ASD. In some embodiments, the adsorbent powder described herein has a D50 value of 1nm-1000nm. In some embodiments, the D50 value of the adsorbent is about 0.01nm to 1000nm. In some embodiments, the D50 value of the adsorbent is about 0.01nm to about 1,000nm. In some embodiments, the D50 value of the adsorbent is at least about 0.01nm. In some embodiments, the D50 value of the adsorbent is at most about 1,000nm. In some embodiments, the D50 value of the adsorbent is about 1nm to about 500nm. In some embodiments, the D50 value of the adsorbent is at least about 1nm. In some embodiments, the D50 value of the adsorbent is at most about 500nm. In some embodiments, the D50 value of the adsorbent is from about 1 nm to about 300 nm, from about 1 nm to about 700 nm, from about 1 nm to about 100 nm, from about 1 nm to about 130 nm, from about 1 nm to about 170 nm, from about 1 nm to about 200 nm, from about 1 nm to about 230 nm, from about 1 nm to about 270 nm, from about 1 nm to about 30 nm, from about 1 nm to about 400 nm, from about 1 nm to about 500 nm, from about 10 nm to about 130 nm, from about 10 nm to about 170 nm, from about 10 ... In some embodiments, the adsorbent has a D50 value of about 1 nm to about 100 nm. In some embodiments, the adsorbent has a D50 value of at least about 1 nm. In some embodiments, the D50 value of the adsorbent is about 0.1nm, 1nm, 30nm, 50nm, 70nm, 100nm, 130nm, 170nm, 200nm, 230nm, 250nm, 270nm, 300nm, 330nm, 350nm, 370nm, 400nm, 430nm, 450nm, 470nm, 500nm, 600nm, 700nm, 800nm, 900nm or 1000nm or less. In some embodiments, the adsorbent is a silica powder having an average diameter of 1nm-1000nm. In some embodiments, the D50 value of silica is about 0.01nm to 1000nm. In some embodiments, the D50 value of silica is about 0.01nm to about 1,000nm. In some embodiments, the D50 value of silica is about 1nm to about 100nm.In some embodiments, the silica has a D50 value of at least about 1 nm. In some embodiments, the silica has a D50 value of about 0.1 nm, 1 nm, 30 nm, 50 nm, 70 nm, 100 nm, 130 nm, 170 nm, 200 nm, 230 nm, 250 nm, 270 nm, 300 nm, 330 nm, 350 nm, 370 nm, 400 nm, 430 nm, 450 nm, 470 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, or 1000 nm or less.

[0376] In some embodiments, the ASD includes an adsorbent, wherein the adsorbent is silicon dioxide. In some embodiments, the silicon dioxide is present in the amorphous solid dispersion. In some embodiments, the amorphous solid dispersion is granulated and incorporated into the pharmaceutical composition with additional particle additives. In some embodiments, the silicon dioxide is present outside the amorphous solid dispersion as an extragranular additive. In some embodiments, the silicon dioxide is present in the amorphous solid dispersion and is an extragranular additive.

[0377] PROTAC drug composition

[0378] Disclosed herein are pharmaceutical compositions comprising an API. In some embodiments, the API is present in the pharmaceutical composition in an amount of at least 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the API is present in the pharmaceutical composition in an amount of about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg or 200 mg. In some embodiments, the API is present in the pharmaceutical composition in an amount of no more than 1000 mg, 750 mg, 500 mg, 400 mg, 300 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 75 mg, 60 mg, 55 mg or 50 mg. In some embodiments, the API is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the API is ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, the API is a PROTAC. In some embodiments, the API is ARV-110. In some embodiments, the API is ARV-471. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion comprising a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants.

[0379] Disclosed herein are pharmaceutical compositions comprising PROTACs, e.g., PROTAC compounds of Table 1. In some embodiments, the pharmaceutical composition is formulated into a unit dosage form, such as a tablet or capsule. In some embodiments, PROTAC is present in a pharmaceutical composition in an amount of 10 mg to 1000 mg. In some embodiments, PROTAC is present in an amount of 20 mg to 500 mg. In some embodiments, PROTAC is present in an amount of 20 mg to 400 mg. In some embodiments, PROTAC is present in an amount of 30 mg to 300 mg in a pharmaceutical composition. In some embodiments, PROTAC is present in an amount of 20 mg to 300 mg. In some embodiments, PROTAC is present in an amount of 25 mg to 250 mg. In some embodiments, PROTAC is present in an amount of 30 mg to 200 mg. In some embodiments, PROTAC is present in an amount of about 50 mg, about 100 mg, or about 150 mg. In some embodiments, PROTAC is present in an amount of 50 mg, 100 mg, or 150 mg. In some embodiments, PROTAC is present in an amount of 50 mg. In some embodiments, PROTAC is present in an amount of 60 mg. In some embodiments, PROTAC is present in an amount of 100 mg. In some embodiments, PROTAC is present in an amount of 150 mg. In some embodiments, PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is PROTAC. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0380] In some embodiments, a pharmaceutical composition is provided, comprising a PROTAC present in a dose of about 1.0 mg to about 1000 mg. In some embodiments, PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants.

[0381] In some embodiments, a pharmaceutical composition is provided, comprising ARV-110 or ARV-471 or a pharmaceutically acceptable salt thereof present in a dosage of about 1.0 mg to about 1000 mg. In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion, which includes ARV-110 or ARV-471 or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants.

[0382] In some embodiments, a pharmaceutical composition is provided, comprising about 1 mg to about 500 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 10 mg to about 400 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 25 mg to about 200 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 75 mg to about 125 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 75 mg to about 100 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 100 mg to about 125 mg PROTAC. In some embodiments, PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise an organic acid and an inorganic acid. In some embodiments, the other additives comprise an antioxidant.

[0383] In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 55 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 60 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 65 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 70 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 75 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 80 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 85 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 90 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 95 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 100 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 105 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 110 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 115 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 120 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 125 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 130 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 135 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 140 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 145 mg to about 150 mg PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 50 mg of PROTAC.

[0384] In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 40 mg of PROTAC.

[0385] In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 30 mg of PROTAC.

[0386] In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 25 mg of PROTAC.

[0387] In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 50 mg of PROTAC.

[0388] In some embodiments, a pharmaceutical composition is provided comprising about 20 mg to about 40 mg of PROTAC.

[0389] In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 25 mg of PROTAC.

[0390] In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 20 mg of PROTAC.

[0391] In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 10 mg of PROTAC.

[0392] In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 20 mg of PROTAC.

[0393] In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof.

[0394] In some embodiments, the PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0395] In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives.

[0396] In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include antioxidants.

[0397] In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 145 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 140 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 135 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 130 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 125 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 120 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 115 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 110 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 105 mg PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 50 mg to about 100 mg PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 95 mg of PROTAC.

[0398] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 90 mg of PROTAC.

[0399] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 85 mg of PROTAC.

[0400] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 80 mg of PROTAC.

[0401] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 75 mg of PROTAC.

[0402] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 70 mg of PROTAC.

[0403] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 65 mg of PROTAC.

[0404] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 60 mg of PROTAC.

[0405] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 55 mg of PROTAC.

[0406] In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 50 mg of PROTAC.

[0407] In some embodiments, a pharmaceutical composition is provided comprising about 40 mg to about 80 mg of PROTAC.

[0408] In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 125 mg PROTAC. In some embodiments, a pharmaceutical composition is provided comprising a PROTAC in an amount of about 25 mg to about 200 mg. In some embodiments, PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is one of the ones listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, other additives comprise organic acids and inorganic acids. In some embodiments, other additives comprise antioxidants.

[0409] In some embodiments, PROTAC accounts for about 5%, 10%, 15%, 20%, 25%, 30%, 40% or 50% of the total weight of the composition. In some embodiments, PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0410] In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 99% by weight of PROTAC, or any amount and range therebetween. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 80% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 60% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 40% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 20% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 10% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 0.1% by weight to about 1% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 20% by weight to about 99% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 20% by weight to about 80% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 20% to about 60% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 20% to about 40% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 99% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 80% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 60% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 30% to about 40% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 99% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 80% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising about 40% to about 60% by weight of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 5 wt % to about 70 wt % PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 5 wt % to about 35 wt % PROTAC.In some embodiments, a pharmaceutical composition is provided, comprising about 5% to about 10% by weight, about 5% to about 15% by weight, about 5% to about 18% by weight, about 5% to about 19% by weight, about 5% to about 20% by weight, about 5% to about 21% by weight, about 5% to about 22% by weight, about 5% to about 24% by weight, about 5% to about 25% by weight, about 5% to about 30% by weight, about 5% to about 35% by weight, about 10% to about 15% by weight, about 10% to about 18% by weight, about 10% to about 19% by weight, about 10% to about 20% by weight, about 10% to about 21% by weight %, about 10 wt % to about 22 wt %, about 10 wt % to about 24 wt %, about 10 wt % to about 25 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 35 wt %, about 15 wt % to about 18 wt %, about 15 wt % to about 19 wt %, about 15 wt % to about 20 wt %, about 15 wt % to about 21 wt %, about 15 wt % to about 22 wt %, about 15 wt % to about 24 wt %, about 15 wt % to about 25 wt %, about 15 wt % to about 30 wt %, about 15 wt % to about 35 wt %, about 18 wt % to about 19 wt %, about 18 wt % to about 20 wt %, about 18 wt % to about 21 wt %. %, about 18 wt % to about 22 wt %, about 18 wt % to about 24 wt %, about 18 wt % to about 25 wt %, about 18 wt % to about 30 wt %, about 18 wt % to about 35 wt %, about 19 wt % to about 20 wt %, about 19 wt % to about 21 wt %, about 19 wt % to about 22 wt %, about 19 wt % to about 24 wt %, about 19 wt % to about 25 wt %, about 19 wt % to about 30 wt %, about 19 wt % to about 35 wt %, about 20 wt % to about 21 wt %, about 20 wt % to about 22 wt %, about 20 wt % to about 24 wt %, about 20 ...20 wt % to about %, about 20 wt % to about 35 wt %, about 21 wt % to about 22 wt %, about 21 wt % to about 24 wt %, about 21 wt % to about 25 wt %, about 21 wt % to about 30 wt %, about 21 wt % to about 35 wt %, about 22 wt % to about 24 wt %, about 22 wt % to about 25 wt %, about 22 wt % to about 30 wt %, about 22 wt % to about 35 wt %, about 24 wt % to about 25 wt %, about 24 wt % to about 30 wt %, about 24 wt % to about 35 wt %, about 25 wt % to about 30 wt %, about 25 wt % to about 35 wt %, or about 30 wt % to about 35 wt % of a PROTAC.In some embodiments, a pharmaceutical composition is provided, comprising about 5 wt%, about 10 wt%, about 15 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 24 wt%, about 25 wt%, about 30 wt%, or about 35 wt% PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising at least about 5 wt%, about 10 wt%, about 15 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 24 wt%, about 25 wt%, or about 30 wt% PROTAC. In some embodiments, a pharmaceutical composition is provided, comprising up to about 10 wt%, about 15 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 24 wt%, about 25 wt%, about 30 wt%, or about 35 wt% of PROTAC. In some embodiments, PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC is one of those listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, PROTAC has a log P of 2.0 or higher. In some embodiments, the amorphous solid dispersion comprises PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersion described herein further comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein further comprises one or more other additives. In some embodiments, the other additives comprise organic acids and inorganic acids. In some embodiments, the other additives comprise antioxidants.

[0411] In one aspect, disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and an ASD, comprising i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof, ii) one or more surfactants, iii) a hydrophilic polymer, and iv) optionally, an acid.

[0412] In some embodiments, the ASD comprises i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof, ii) one or more surfactants, wherein the one or more surfactants comprise tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutyl ether-β-cyclodextrin, hydroxypropyl β-cyclodextrin (HP-β-CD), or a combination thereof, and iv) an acid.

[0413] In some embodiments, the ASD comprises i) a PROTAC listed in Table 1, or a pharmaceutically acceptable salt thereof, in an amount of about 5 wt % to about 50 wt % of the ASD, ii) one or more surfactants in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the one or more surfactants comprise tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl β-cyclodextrin (HP-β-CD), or a combination thereof, and iv) an acid in an amount of about 1 wt % to about 50 wt % of the ASD.

[0414] In some embodiments, the ASD comprises i) ARV-110, ARV-471, CFT7455, AC0682, ARV-766, BGB-16673, DT2216, FHD-609, GT20029, HP518, HSK29116, KT-474, NX-2127, NX-5948, AC0176, BRD4-CHAMP, KT-413, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to about 50% by weight of the ASD, and ii) one or more surfactants in an amount of about 1% to about 60% by weight of the ASD, wherein the one or more surfactants comprise ASD comprising tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), HPMCAS, hydroxypropyl β-cyclodextrin (HP-β-CD), or a combination thereof, and iv) an acid in an amount of about 1 wt % to about 50 wt % of the ASD.

[0415] In some embodiments, the ASD comprises i) ARV-110, ARV-471, or a pharmaceutically acceptable salt thereof, in an amount of about 5 wt % to about 50 wt % of the ASD, ii) one or more surfactants, in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the one or more surfactants comprise tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof, iii) a hydrophilic polymer, in an amount of % to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), HPMCAS or hydroxypropyl β-cyclodextrin (HP-β-CD), and iv) an acid in an amount of about 1% to about 50% by weight of the ASD, wherein the acid comprises tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof.

[0416] In some embodiments, when measured by AUC, AUC inf or AUC lastThe pharmaceutical compositions described herein have a bioavailability that is superior to that of a crystalline PROTAC or a corresponding reference composition comprising a PROTAC that is not present in an ASD when measured by AUC. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher than that of a corresponding composition comprising a crystalline PROTAC or a PROTAC that is not present in an ASD when measured by AUC after oral administration. In some embodiments, when measured by AUC after oral administration, the bioavailability of the pharmaceutical composition is at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher than that of a corresponding composition comprising a crystalline PROTAC or a PROTAC that is not present in an ASD. max The pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising a crystalline PROTAC or a PROTAC not present in an ASD, when measured. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of the PROTAC not present in the ASD capsule comprising ARV-110 when measured by AUC after oral administration. In some embodiments, when measured by AUC after oral administration, the bioavailability of the PROTAC is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of the PROTAC not present in the ASD capsule comprising ARV-110. maxWhen measured, the pharmaceutical composition exhibits a bioavailability that is at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 7 times, 8 times, 9 times, or 10 times greater than the bioavailability of the PROTAC not present in the ASD capsule comprising ARV-110. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is about 1.1 times to about 10 times greater than the bioavailability of the PROTAC not present in the ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is about 1.1 times to about 2 times, about 1.1 times to about 3 times, about 1.1 times to about 4 times, about 1.1 times to about 5 times, about 1.1 times to about 6 times, about 1.1 times to about 7 times, about 1.1 times to about 8 times, about 1.1 times to about 10 times, about 1.5 times to about 2 times, about 1.5 times to about 3 times, about 1.5 times to about 4 times, about 1.5 times to about 5 times, about 1.5 times to about 6 times, about 1.5 times to about 7 times, about 1.5 times to about 8 times, about 1.5 times to about 10 times, about 2 times to about 4 times greater than the bioavailability of the PROTAC not present in the ASD. , about 2 times to about 5 times, about 2 times to about 6 times, about 2 times to about 7 times, about 2 times to about 8 times, about 2 times to about 10 times, about 3 times to about 4 times, about 3 times to about 5 times, about 3 times to about 6 times, about 3 times to about 7 times, about 3 times to about 8 times, about 3 times to about 10 times, about 4 times to about 5 times, about 4 times to about 6 times, about 4 times to about 7 times, about 4 times to about 8 times, about 4 times to about 10 times, about 5 times to about 6 times, about 5 times to about 7 times, about 5 times to about 8 times, about 5 times to about 10 times, about 6 times to about 7 times, about 6 times to about 8 times, about 6 times to about 10 times, about 7 times to about 8 times, about 7 times to about 10 times, or about 8 times to about 10 times.

[0417] In some embodiments, when measured by AUC or C maxWhen measured, the pharmaceutical compositions described herein exhibit a bioavailability that is at least about 1.1 times, about 1.3 times, about 1.5 times, about 1.8 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, or about 8 times higher than the bioavailability of a PROTAC that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 2 times higher than the bioavailability of a PROTAC that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 4 times higher than the bioavailability of a PROTAC that is not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at most about 1.3 times, about 1.5 times, about 1.8 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, or about 10 times higher than the bioavailability of a PROTAC that is not present in an ASD. In some embodiments, the bioavailability is measured in a dog model in a fasted state. In some embodiments, bioavailability is measured in a dog model in the fed state. In some embodiments, the bioavailability of the pharmaceutical composition when administered orally in the fed state, when measured as AUC after oral administration, does not vary by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, or 10% compared to administration in the fasted state. In some embodiments, when measured as AUC after oral administration, the bioavailability of the pharmaceutical composition when administered orally in the fed state, when compared to administration in the fasted state, does not vary by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, or 10%. maxWhen measured, the bioavailability of the pharmaceutical composition does not change by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15% or 10% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 100% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 90% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 80% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 70% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 60% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 50% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 40% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 20% when orally administered in the fed state compared to administration in the fasted state. In some embodiments, the bioavailability is measured in a dog model. In some embodiments, the dog model is a beagle.

[0418] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 2-fold greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a crystalline form), wherein the bioavailability is measured as AUC or maximum plasma concentration (C ) after oral administration to a subject in a fasting state. max In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a crystalline form), wherein the bioavailability is measured as AUC or maximum plasma concentration (C max ). In some embodiments, the PROTAC is one listed in Table 1. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0419] In some embodiments, the bioavailability of the PROTAC compound or its pharmaceutically acceptable salt exhibited by the pharmaceutical composition is at least 1.5 times the bioavailability of the corresponding composition comprising the PROTAC compound or its pharmaceutically acceptable salt in a conventional dosage form, and the bioavailability is measured by the total area under the curve (AUC) or the maximum plasma concentration (Cmax) after oral administration to a subject in a fed state. A pharmaceutical composition as described in any one of claims 1 to 3, wherein the bioavailability of the PROTAC compound or its pharmaceutically acceptable salt exhibited by the pharmaceutical composition is at least 2 times, 2.5 times or 3 times the bioavailability of the corresponding composition comprising the PROTAC compound or its pharmaceutically acceptable salt in a conventional dosage form, and the bioavailability is measured by the total area under the curve (AUC) or the maximum plasma concentration (Cmax) after oral administration to a subject in a fed state. In some embodiments, PROTAC is one of those listed in Table 1. In some embodiments, PROTAC is ARV-110. In some embodiments, PROTAC is ARV-471.

[0420] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 5 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form, wherein the bioavailability is measured as AUC or maximum plasma concentration (C ) after oral administration to a subject in a fasting state. max ). In some embodiments, the PROTAC is one listed in Table 1. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0421] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 5 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form. In some embodiments, the PROTAC is one listed in Table 1. In some embodiments, the PROTAC has a log P of 2.0 or greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0422] In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 1.1 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form. In some embodiments, the PROTAC is one listed in Table 1. In some embodiments, the PROTAC has a log P of 2.0 or greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0423] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not vary by more than about 5% to about 60% when orally administered to a subject in a fed state compared to a fasted state. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not vary by more than about 25% to about 100% when orally administered to a subject in a fed state compared to a fasted state. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound, or a pharmaceutically acceptable salt thereof, that changes by no more than about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 5% to about 50%, about 10% to about 60%, about 15% to about 20%, about 15% to about 25%, about 10% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, % to about 50%, about 15% to about 60%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 25% to about 60%, about 30% to about 35%, about 30% to about 40%, about 25% to about 50%, about 25% to about 60%, about 30% to about 35%, about 30% to about 40% 0%, about 30% to about 50%, about 30% to about 60%, about 35% to about 40%, about 35% to about 50%, about 35% to about 60%, about 40% to about 50%, about 40% to about 60%, about 50% to about 60%, about 55% to about 65%, about 60% to about 70%, about 65% to about 80%, about 75% to about 90%, about 80% to about 100%, or about 90% to about 100%. In some embodiments, the pharmaceutical composition exhibits a bioavailability change of no more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, or about 60%. In some embodiments, the PROTAC is one selected from Table 1.

[0424] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof of no more than 50% change when orally administered to a subject in a fed state compared to a fasted state, wherein the bioavailability is measured as AUC or C after oral administration to the subject.max In some embodiments, the PROTAC is one selected from Table 1. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0425] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof of no more than 25% when orally administered to a subject in a fed state compared to a fasted state, wherein the bioavailability is measured as AUC or C after oral administration to the subject. max In some embodiments, the PROTAC is one selected from Table 1. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0426] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof of no more than 10% when orally administered to a subject in a fed state compared to a fasted state, wherein the bioavailability is measured as AUC or C after oral administration to the subject. max In some embodiments, the PROTAC is one selected from Table 1. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0427] In some embodiments, when measured by AUC after oral administration last or C maxWhen measured, the pharmaceutical compositions described herein exhibit a bioavailability that is about 100% to about 1500%, 120% to about 1000%, 125% to about 500%, about 130% to about 450%, 140% to about 400%, or about 150% to about 300% of the bioavailability of a corresponding reference composition comprising a PROTAC, wherein the corresponding reference pharmaceutical composition does not comprise an amorphous solid dispersion. In some embodiments, the reference composition is at least about 1.1 times the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, or about 10 times the dose of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an ASD comprising a PROTAC free base or a pharmaceutically acceptable salt thereof. In some embodiments, the reference composition comprises a PROTAC free base or a pharmaceutically acceptable salt thereof, wherein the reference composition does not comprise an ASD. In some embodiments, the bioavailability is measured under fasting conditions. In some embodiments, the bioavailability is measured under fed conditions. In some embodiments, the PROTAC is one of those listed in Table 1. In some embodiments, the PROTAC has a log P of 2.0 or higher. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0428] In some embodiments, the bioavailability of the compositions described herein is determined using a dog model. In some embodiments, the bioavailability of the compositions described herein is determined according to the conditions described in Example 1. In some embodiments, the bioavailability of the compositions described herein is determined in humans.

[0429] In some embodiments, the pharmaceutical compositions described herein are storage stable at 5±3°C for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months, wherein the storage-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical compositions described herein are storage stable at 25±2°C for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months, wherein the storage-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical compositions described herein are storage stable at 25±2°C for a period of at least 12 months, wherein the storage-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or a pharmaceutically acceptable salt thereof at the end of the period. In some embodiments, the pharmaceutical compositions described herein are storage stable at 40±2°C for a period of...

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises: a) an amorphous solid dispersion (ASD) comprising: A proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; Surfactants; Hydrophilic polymers; optional acid; as well as optional adsorbent; wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in the ASD in an amorphous state; as well as b) optional pharmaceutically acceptable carriers or excipients.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max ) measured.

3. The pharmaceutical composition of claim 1 or Error! No reference source was found., wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max ) measured.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 1.5 times the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max ) measured.

5. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2, 2.5 or 3 times the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max ) measured.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 5 times the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 1.1 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD.

8. A pharmaceutical composition according to any one of claims ERRO! Reference source not found. -ERRO! Reference source not found., wherein the corresponding composition comprises the PROTAC compound or the pharmaceutically acceptable salt thereof in a crystalline form or in an amorphous state.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is not changed by more than 100% when orally administered to a subject in a fed state compared to a fasted state, wherein the bioavailability is measured as the total area under the curve (AUC) or the maximum plasma concentration (C max ) measured.

10. The pharmaceutical composition of any one of claims 1 to False! Reference source not found., wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof does not change by more than 50% when orally administered to a subject in a fed state compared to a fasted state.

11. The pharmaceutical composition of any one of claims 1 to False! Reference source not found. , wherein the bioavailability of the PROTAC compound does not change by more than 25% when orally administered to a subject in a fed state compared to a fasted state.

12. The pharmaceutical composition of any one of claims ERRORS! Reference source not found. -ERRORS! Reference source not found., wherein the bioavailability is measured in a dog model in a fasted state or in a fed state.

13. The pharmaceutical composition of any one of claims 1 to False! Reference source not found., wherein the pharmaceutical composition is in the form of a tablet.

14. The pharmaceutical composition of any one of claims 1 to False! Reference source not found., wherein the pharmaceutical composition is in the form of a capsule.

15. The pharmaceutical composition of any one of claims 1 to 1, wherein the PROTAC compound is represented by the structure of formula (I): ALB Formula (I) in -A is the E3 ubiquitin ligase binding part; -L is a linker; and -B is the moiety that binds to a target protein, wherein the target protein can be degraded by an E3 ubiquitin ligase.

16. The pharmaceutical composition of claim 1, wherein B is an androgen receptor (AR) binding moiety.

17. The pharmaceutical composition of claim 1, wherein B is an estrogen receptor binding moiety.

18. The pharmaceutical composition of any one of claims 1 to 1, wherein the PROTAC compound is an androgen receptor PROTAC degrader.

19. The pharmaceutical composition of any one of claims 1 to False! Reference source not found. or False! Reference source not found., wherein the PROTAC compound is an estrogen receptor PROTAC degrader.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the PROTAC compound has a log P of at least 2.0 in octanol-water.

21. The pharmaceutical composition of any one of claims 1 to 19, wherein the PROTAC compound has a log P of at least 2.0, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or at least 5 in octanol-water.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 10% to 30% by weight.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the surfactant is present in the pharmaceutical composition in an amount of about 25 mg to about 250 mg.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the surfactant is present in the pharmaceutical composition in an amount of about 10% to 60% by weight.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the surfactant is present in the pharmaceutical composition in an amount of about 15% to 55% by weight.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the surfactant comprises a nonionic surfactant, an anionic surfactant, a phospholipid, or any combination thereof.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), a block copolymer of polyethylene glycol and polypropylene glycol, polysorbate, lecithin, polyethylene glycol castor oil, hydrogenated castor oil, sorbitan oleate, sodium dodecyl sulfate (SDS), a graft copolymer based on polyvinyl caprolactam (PVAc-PVCap-PEG), or a combination thereof.

28. The pharmaceutical composition of any one of claims 1 to 26, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS) or lecithin, or a combination thereof.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein the hydrophilic polymer is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg.

30. The pharmaceutical composition of any one of claims 1 to 29, wherein the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 1% to about 80% by weight.

31. The pharmaceutical composition of any one of claims 1 to 29, wherein the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 15% to about 50% by weight.

32. The pharmaceutical composition of any one of claims 1 to 31, wherein the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC or hydroxypropylmethylcellulose), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), polymethacrylate, hydroxypropylmethylcellulose phthalate (HPMCP), polyethylene oxide, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG), or a combination thereof.

33. The pharmaceutical composition of any one of claims 1 to 31, wherein the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate, hydroxypropylmethylcellulose phthalate (HPMCP), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol, or hydroxypropylmethylcellulose acetate succinate (HPMCAS).

34. The pharmaceutical composition of any one of claims 1 to 33, wherein the amorphous solid dispersion comprises an acid.

35. The pharmaceutical composition of claim 34, wherein the acid is an organic acid.

36. The pharmaceutical composition of claim 34, wherein the acid is an inorganic acid.

37. An amorphous solid dispersion as described in any one of claims 34 to 36, wherein the acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid.

38. The amorphous solid dispersion of any one of claims 34 to 36, wherein the acid is tartaric acid, citric acid or succinic acid.

39. The amorphous solid dispersion of any one of claims 1 to 38, wherein the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is from about 10:1 to about 1:

10.

40. The pharmaceutical composition of any one of claims 1 to 39, wherein the ASD comprises an adsorbent.

41. The pharmaceutical composition of claim 40, wherein the adsorbent is selected from the group consisting of silicon dioxide, activated carbon, magnesium aluminum silicate, diatomaceous earth, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, crospovidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, and sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin.

42. The pharmaceutical composition of claim 40, wherein the adsorbent is silicon dioxide.

43. The pharmaceutical composition of any one of claims 40 to 42, wherein the adsorbent is present in the amorphous solid dispersion in an amount of about 10% to about 35% by weight.

44. The pharmaceutical composition of any one of claims 43 to 44, wherein the particle size D50 value of the amorphous solid dispersion is 1 μm to 1000 μm.

45. The pharmaceutical composition of claim 44, wherein the D50 value is from about 1 μm to about 150 μm (eg, 10 μm to 15 μm).

46. ​​A pharmaceutical composition as described in any one of claims 1 to 45, wherein the amorphous solid dispersion further comprises an antioxidant (e.g., vitamin E).

47. A pharmaceutical composition as described in any one of claims 1 to 46, wherein the pharmaceutically acceptable carrier or excipient does not contain an organic acid.

48. A pharmaceutical composition as described in any one of claims 1 to 46, wherein the pharmaceutically acceptable carrier or excipient comprises an external acid that is not present in the amorphous solid dispersion.

49. The pharmaceutical composition of any one of claims 1 to 48, wherein the pharmaceutical composition is storage stable at 5±3°C for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months or 24 months, wherein the storage stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period.

50. The pharmaceutical composition of any one of claims 1 to 48, wherein the pharmaceutical composition is storage stable at 25±2°C for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months or 24 months, wherein the storage stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period.

51. The pharmaceutical composition of any one of claims 1 to 48, wherein the pharmaceutical composition is storage stable at 40±2°C for a period of at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months or 24 months, wherein the storage stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or the pharmaceutically acceptable salt thereof at the end of the period.

52. A pharmaceutical composition as described in any one of the preceding claims, wherein the pharmaceutical composition comprises: a) an amorphous solid dispersion comprising: The PROTAC compound or a pharmaceutically acceptable salt thereof is in an amount of about 5% to about 50% by weight of the ASD; the surfactant in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; the hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polymethacrylate, hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof; and an optional acid in an amount from about 1 wt % to about 50 wt % of the ASD; and b) optional pharmaceutically acceptable carriers or excipients.

53. A pharmaceutical composition as described in any one of the preceding claims, wherein the pharmaceutical composition comprises: a) an amorphous solid dispersion comprising: a PROTAC compound of Table 1 or a pharmaceutically acceptable salt thereof, in an amount of about 5 wt % to about 50 wt % of the ASD; the surfactant in an amount of about 1 wt % to about 50 wt % of the ASD, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; the hydrophilic polymer in an amount of about 5 wt % to about 70 wt % of the ASD, wherein the hydrophilic polymer comprises vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polymethacrylate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl β-cyclodextrin (HP-β-CD) or sulfobutyl ether-β-cyclodextrin; and an optional acid in an amount from about 1% to about 50% by weight of the ASD, wherein the acid comprises tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof; and b) optional pharmaceutically acceptable carriers or excipients.

54. The pharmaceutical composition of any of the preceding claims, wherein the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the surfactant is from about 1:0.5 to about 1:6, from about 1:0.8 to about 1:5, or from about 1:1 to about 1:

3.

55. The pharmaceutical composition of any of the preceding claims, wherein the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is from about 1:0.5 to about 1:6, from about 1:0.8 to about 1:5, or from about 1:1 to about 1:

3.

56. A pharmaceutical composition as described in any of the preceding claims, wherein the pharmaceutical composition is formulated in unit dosage form.

57. The pharmaceutical composition of claim 56, wherein the unit dosage form comprises: 30 mg to 300 mg of the PROTAC compound or a pharmaceutically acceptable salt thereof; 10 mg to 500 mg of the surfactant; 10 mg to 500 mg of the hydrophilic polymer; optional acid in an amount ranging from 1 mg to 500 mg; and Optional adsorbent, in an amount ranging from 1 mg to 500 mg; Optional pharmaceutically acceptable carriers or excipients.

58. An amorphous solid dispersion, wherein the amorphous solid dispersion comprises: A proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof; Surfactants; Hydrophilic polymers; optionally an acid; and Optional adsorbent, wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer and the optional acid are present in an amorphous state in the ASD.

59. The amorphous solid dispersion of claim 58, wherein the amorphous solid dispersion exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as total area under the curve (AUC) or maximum plasma concentration (C ) following oral administration to subjects in a fasting state. max ) measured.

60. The amorphous solid dispersion of claim 58 or 59, wherein the amorphous solid dispersion exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as total area under the curve (AUC) or maximum plasma concentration (C ) following oral administration to subjects in the fasting state. max ) measured.

61. The amorphous solid dispersion of any one of claims 58 to 60, wherein the amorphous solid dispersion exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 1.5 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as the total area under the curve (AUC) or maximum plasma concentration (C ) following oral administration to a subject in a fed state. max ) measured.

62. The amorphous solid dispersion of any one of claims 58 to 60, wherein the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is at least 2, 2.5, or 3 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD, wherein the bioavailability is measured as total area under the curve (AUC) or maximum plasma concentration (C ) following oral administration to a subject in a fed state. max ) measured.

63. The amorphous solid dispersion of any one of claims 58 to 62, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 5 times the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD.

64. The amorphous solid dispersion of any one of claims 58 to 62, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or the pharmaceutically acceptable salt thereof but not as part of an ASD.

65. The pharmaceutical composition of any one of claims 58 to 64, wherein the respective composition comprises the PROTAC compound or the pharmaceutically acceptable salt thereof in a crystalline form or in an amorphous state.

66. The amorphous solid dispersion of any one of claims 58 to 65, wherein the amorphous solid dispersion exhibits a bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof that is not changed by more than 100% when orally administered to a subject in a fed state compared to a fasted state, as measured by the total area under the curve (AUC) or maximum plasma concentration (C max ) measured.

67. The amorphous solid dispersion of any one of claims 58 to 66, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof does not change by more than 50% when orally administered to a subject in a fed state compared to a fasted state.

68. The amorphous solid dispersion of any one of claims 58 to 67, wherein the bioavailability of the PROTAC compound does not change by more than 25% when orally administered to a subject in a fed state compared to a fasted state.

69. The amorphous solid dispersion of any one of claims 58 to 67, wherein the bioavailability is measured in a dog model in a fasted state or in a fed state.

70. The amorphous solid dispersion of any one of claims 58 to 69, wherein the PROTAC compound is represented by the structure of formula (I): ALB Formula (I) in -A is the E3 ubiquitin ligase binding part; -L is a linker; and -B is the moiety that binds to a target protein, wherein the target protein can be degraded by an E3 ubiquitin ligase.

71. The amorphous solid dispersion of claim 70, wherein B is an androgen receptor binding moiety.

72. The amorphous solid dispersion of claim 70, wherein B is an estrogen receptor binding moiety.

73. The amorphous solid dispersion of any one of claims 58 to 71, wherein the PROTAC compound is an androgen receptor PROTAC degrader.

74. The amorphous solid dispersion of any one of claims 58 to 70 or 72, wherein the PROTAC compound is an estrogen receptor PROTAC degrader.

75. The amorphous solid dispersion of any one of claims 58 to 74, wherein the PROTAC compound has a log P of at least 2.0 in octanol-water.

76. The amorphous solid dispersion of any one of claims 58 to 75, wherein the surfactant is present in the amorphous solid dispersion in an amount of about 10% to 60% by weight.

77. The amorphous solid dispersion of any one of claims 58 to 76, wherein the surfactant comprises a nonionic surfactant, an anionic surfactant, a phospholipid, or any combination thereof.

78. The amorphous solid dispersion of any one of claims 58 to 77, wherein the surfactant comprises tocopheryl polyethylene glycol succinate (TPGS), a block copolymer of polyethylene glycol and polypropylene glycol, polysorbate, lecithin, polyethylene glycol castor oil, hydrogenated castor oil, sorbitan oleate, sodium dodecyl sulfate (SDS), a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof.

79. The amorphous solid dispersion of any one of claims 58 to 78, wherein the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 10 mg to about 500 mg.

80. The amorphous solid dispersion of any one of claims 58 to 79, wherein the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 1 wt% to about 80 wt%.

81. An amorphous solid dispersion as described in any one of claims 58 to 80, wherein the hydrophilic polymer is vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polymethacrylate, hydroxypropyl methylcellulose phthalate (HPMCP), polyethylene oxide, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG), or a combination thereof.

82. The amorphous solid dispersion of any one of claims 58 to 81, wherein the amorphous solid dispersion further comprises an acid.

83. The amorphous solid dispersion of claim 82, wherein the acid is an organic acid.

84. The amorphous solid dispersion of claim 82, wherein the acid is an inorganic acid.

85. The amorphous solid dispersion of any one of claims 82 to 84, wherein the acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

86. The amorphous solid dispersion of any one of claims 58 to 85, wherein the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10:1 to about 1:10, about 1:0.5 to about 1:6, about 1:0.8 to about 1:5, or about 1:1 to about 1:

3.

87. The amorphous solid dispersion of any one of claims 58 to 86, wherein the weight ratio of the PROTAC compound or a pharmaceutically acceptable salt thereof to the surfactant is about 10:1 to about 1:10, about 1:0.5 to about 1:6, about 1:0.8 to about 1:5, or about 1:1 to about 1:

3.

88. The amorphous solid dispersion of any one of claims 58 to 87, further comprising an adsorbent.

89. The amorphous solid dispersion of claim 88, wherein the adsorbent is selected from the group consisting of silicon dioxide, activated carbon, magnesium aluminum silicate, diatomaceous earth, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, crospovidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin.

90. The amorphous solid dispersion of any one of claims 58 to 89, wherein the adsorbent is present in the amorphous solid dispersion in an amount of about 10% to about 35% by weight.

91. The amorphous solid dispersion of any one of claims 58 to 90, wherein the amorphous solid dispersion further comprises an antioxidant (eg, vitamin E).

92. The amorphous solid dispersion of any one of claims 58 to 91, wherein the particle size of the amorphous solid dispersion has a D50 value of 1 μm to 1000 μm.

93. The amorphous solid dispersion of claim 92, wherein the particle size of the amorphous solid dispersion has a D50 value of about 1 μm to about 150 μm in particle size.

94. A method of treating a disease or condition comprising administering to a subject in need thereof a pharmaceutical composition or amorphous solid dispersion as described in any one of claims 1 to 93.

95. A method for ubiquitinating or degrading a target protein in a cell of a subject, comprising administering to the subject the pharmaceutical composition or amorphous solid dispersion of any one of claims 1 to 93.

96. The method of claim 94 or 95, wherein the pharmaceutical composition is administered with or without food.

97. The method of claim 94 or 95, wherein the subject is in a fasting state.

98. The method of claim 94 or 95, wherein the subject is in a fed state.

99. The method of any one of claims 94 or 96 to 98, wherein the disease or disorder is cancer.

100. The method of claim 99, wherein the cancer is prostate cancer or breast cancer.

101. A method for preparing an amorphous solid dispersion, comprising the steps of: a) combining the following substances: (i) a proteolysis targeting chimera (PROTAC) compound or a pharmaceutically acceptable salt thereof, (ii) a surfactant, (iii) a hydrophilic polymer, (iv) optionally an additive and (v) a solvent, thereby producing a liquid mixture or solution, and b) removing the solvent from the mixture, thereby producing an amorphous solid dispersion.

102. The method of claim 101, wherein the solvent is an organic solvent or a mixture of organic solvents.

103. The method of claim 101, wherein the solvent is or contains an alcohol.

104. The method of any one of claims 101 to 103, wherein the combination comprises dissolving the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, and the hydrophilic polymer in the solvent.

105. The method of any one of claims 101 to 104, wherein said removing comprises vacuum drying, spray drying or rotary evaporation.

106. The method of any one of claims 101 to 104, wherein said removing comprises spraying said solution onto an adsorbent and drying in a fluidized bed apparatus.

Images