Pharmaceutical compositions of PROTAC compounds and uses thereof

Abstract

Proteolytic targeting chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate target proteins by hijacking the ubiquitin-proteasome system (UPS). Pharmaceutical compositions are provided that include a mixture of a PROTAC, a hydrophilic polymer, a surfactant, and optionally an acid and an adsorbent. Methods for preparing and using such pharmaceutical compositions are also described. In one aspect, an amorphous solid dispersion comprising a PROTAC is disclosed herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of patent application No. PCT / CN2022 / 083105, filed March 25, 2022, and No. PCT / CN2023 / 079057, filed March 1, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention belongs to the pharmaceutical field, specifically to pharmaceutical compositions and their preparation methods and uses. [Background technology]

[0003] Protein degradation targeting chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate target proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to the use of small molecule inhibitors to knock down classical targets and disease-related proteins that have been classified as "undruggable" to date. However, PROTACs often suffer from poor cell permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA).

[0004] ARV-110 is a PROTAC® protein degrader that targets the androgen receptor (AR). ARV-110 is being developed by Arvinas for the potential treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on existing therapies. Its molecular weight is 812.29 and its calculated log P is approximately 4.18. It has been reported to be very difficult to dissolve in aqueous solutions and should be taken with food.

[0005] ARV-471 is a PROTAC® protein degrader that targets the estrogen receptor (ER). ARV-471 is being developed by Arvinas for the potential 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 is approximately 4-6. It is reported to be very difficult to dissolve in aqueous solutions and should be taken with food in clinical studies.

[0006] Poor water solubility and very low oral absorption are obstacles to developing RPOTAC molecules for in vivo applications. Furthermore, the bioavailability of nearly all PROTAC molecules is affected by the food effect. There is a significant need for PROTAC compositions that have improved oral bioavailability, allow for the administration of lower doses, reduce the variability in absorption caused by food intake, and reduce the variability in absorption between subjects in vitro.

[0007] Incorporation by Reference All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0008] Disclosed herein are pharmaceutical compositions comprising: a) an amorphous solid dispersion (ASD) comprising: i) a proteolysis targeted chimeric (PROTAC) compound or a pharmaceutically acceptable salt thereof; ii) a surfactant; iii) a hydrophilic polymer; iv) optionally an acid; and v) optionally an adsorbent; wherein the PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optional acid are present in the ADS in an amorphous state; and b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is one in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is measured by the total area under the curve (AUC) or maximum plasma concentration (C) following oral administration to fasted subjects. max ) is at least 2-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that ... max) is at least 3, 4, or 5-fold greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof, when the bioavailability is measured as the total area under the curve (AUC) or maximum plasma concentration (Cmax) following oral administration to a subject in a fed state, that is at least 1.5-fold greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability of a PROTAC compound or a pharmaceutically acceptable salt thereof, when the bioavailability is measured as the total area under the curve (AUC) or maximum plasma concentration (Cmax) following oral administration to a subject in a fed state, that is at least 2, 2.5, or 3-fold greater than the bioavailability of a corresponding composition comprising a PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is at least 5-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is at least 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof without being part of an ASD. In some embodiments, the corresponding composition comprises the PROTAC compound or a pharmaceutically acceptable salt thereof in an amorphous state. In some embodiments, the corresponding composition comprises the PROTAC compound or a pharmaceutically acceptable salt thereof in a crystalline form. In some embodiments, the pharmaceutical composition is one in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is measured by the total area under the curve (AUC) or maximum plasma concentration (C) following oral administration to a subject. max), exhibits a bioavailability that does not change by more than 100%, 50%, or 25% when orally administered to said subject in a fed state compared to a fasted state. In some embodiments, the bioavailability is measured in a canine model in a fasted or 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 moiety, ii) L is a linker, and iii) B is a moiety that binds to a target protein, wherein the target protein is degradable by an E3 ubiquitin ligase. In some embodiments, B is an androgen receptor (AR) binding moiety. In some embodiments, B is an estrogen receptor binding moiety. 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

[0009] [ka] or a pharmaceutically acceptable salt or enantiomer thereof. 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

[0010] [ka] or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the PROTAC compound has a log P in octanol-water of at least 2.0. In some embodiments, the PROTAC compound has a log P in octanol-water 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 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 comprises 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 dodecyl sulfate (SDS), polyvinyl caprolactam graft copolymer (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 the amorphous solid dispersion in an amount of about 1% to about 80% by weight. In some embodiments, the hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 15% to about 50% by weight.In some embodiments, the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl beta-cyclodextrin (HP-β-CD), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polymethacrylate, hypromellose phthalate (HPMCP), polyvinylcaprolactam, polyvinyl acetate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl acetate and polyvinylcaprolactam graft copolymer (PVAc-PVCap-PEG), polyvinylcaprolactam-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 vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl 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 pharmaceutically acceptable salt thereof to the hydrophilic polymer is from 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 povidone, sodium carboxymethylcellulose, 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% to about 35% by weight. In some embodiments, the amorphous solid dispersion has a particle size D50 value of 1 μm to 1000 μm. In some embodiments, the D50 value is about 1 μm to about 150 μm (e.g., 10 μm to 15 μm). In some embodiments, the amorphous solid dispersion further comprises an antioxidant (e.g., vitamin E). In some embodiments, the pharmaceutically acceptable carrier or excipient does not comprise an organic acid. In some embodiments, the pharmaceutically acceptable carrier or excipient comprises an external acid that is not present in the solid amorphous dispersion. In some embodiments, the pharmaceutical composition is shelf-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 pharmaceutically acceptable salt thereof at the end of that period. In some embodiments, the pharmaceutical composition is shelf-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 pharmaceutically acceptable salt thereof at the end of that period. In some embodiments, the pharmaceutical composition is shelf-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 a shelf-stable pharmaceutical composition retains at least 90% by weight of the PROTAC compound or pharmaceutically acceptable salt thereof at the end of that period.In some embodiments, the pharmaceutical composition is 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% to about 50% by weight of the ASD; (ii) a surfactant in an amount of about 1% to about 60% by weight of the ASD, the surfactant comprising 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; and (iii) a surfactant in an amount of about 5% to about 70% by weight of the ASD. an amount of a hydrophilic polymer, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., Eudragit), hypromellose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof; and (iv) optionally an acid in an amount of about 1% to about 50% by weight of the ASD; and b) optionally a pharmaceutically acceptable carrier or excipient.In some embodiments, the pharmaceutical composition comprises: a) an amorphous solid dispersion comprising: (i) 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, the surfactant comprising tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; and (iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, the hydrophilic polymer being selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., PEG-110), ... pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., PEG-110), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), PEG, polymethacrylate (e.g., PEG-110), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PV and (iv) an amorphous solid dispersion comprising: (a) a hydrophilic polymer comprising, for example, Eudragit), hypromellose phthalate (HPMCP), polyvinyl caprolactam, polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), or hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof; and (b) optionally, an acid in an amount of about 1% to about 50% by weight of the ASD, the acid comprising 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 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 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% to about 40% by weight of the ASD; a surfactant in an amount of about 5% to about 60% by weight of the ASD, where the surfactant is TPGS or lecithin, or a combination thereof; a hydrophilic polymer in an amount of about 10% to about 60% by weight of the ASD, where the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hypromellose 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% to about 40% by weight of the ASD, where 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, and a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, wherein the hydrophilic polymer is , vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hypromellose 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, the composition comprises ARV-471 or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 40% by weight of the ASD; a surfactant in an amount of about 5% to about 60% by weight of the ASD, where the surfactant is TPGS or lecithin; a hydrophilic polymer in an amount of about 10% to about 60% by weight of the ASD, where the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hypromellose 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 5% to about 40% by weight of the ASD, where 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, where the surfactant is TPGS or lecithin, a hydrophilic polymer in an amount of about 10% to about 50% by weight of the ASD, where the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, PEG, polymethacrylate (e.g., Eudragit), hypromellose 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, where 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 30-300 mg of a PROTAC compound or a pharmaceutically acceptable salt thereof, 10-500 mg of a surfactant, 10-500 mg of a hydrophilic polymer, optionally an acid in an amount of 1-500 mg, optionally an adsorbent in an amount of 1-500 mg, and optionally a pharmaceutically acceptable carrier or excipient.

[0011] Disclosed herein is an amorphous solid dispersion comprising (i) a proteolysis-targeting chimeric (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 are methods of treating a disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition or amorphous solid dispersion described herein. In some embodiments, the pharmaceutical composition is administered with or without food. In some embodiments, the subject is in a fasted 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 are methods for ubiquitinating or degrading a target protein in the cells of a subject, the methods comprising administering to the subject a pharmaceutical composition or amorphous solid dispersion described herein.

[0014] Disclosed herein are methods for preparing an amorphous solid dispersion, the method comprising: (a) combining (i) a proteolysis targeted chimeric (PROTAC) compound or a pharmaceutically acceptable salt thereof, (ii) a surfactant, (iii) a hydrophilic polymer, (iv) optionally an additive, and (v) a solvent, thereby forming a liquid mixture or solution; and b) removing the solvent from the mixture, thereby forming the amorphous solid dispersion. [Brief explanation of the drawings]

[0015] The novel features of the invention are set forth with particularity 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 that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0016] [Figure 1] 1 shows an X-ray powder diffraction study of the amorphous solid dispersion (ASD) of ARV-110 formulation batch number P210803. [Figure 2] 1 shows an X-ray powder diffraction study of particles of ARV-110. [Figure 3] FIG. 1 shows a comparison of plasma concentrations of the 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 given orally at a dose of 50 mg API, all under fasting conditions. [Figure 4] 1 shows a comparison of plasma concentrations of API (ARV-110) in a dog model when ARV-110 is given orally without being part of an ASD formulation at a dose of 45 mg API under fed and fasted conditions. [Figure 5] FIG. 1 shows a comparison of plasma concentrations of API (ARV-110) in a dog model when ASD composition batch number P210803 of ARV-110 was given orally at a dose of 45 mg API under fed and fasted conditions. [Figure 6]FIG. 1 shows a comparison of plasma concentrations of API (ARV-110) in a dog model when two ASD compositions of ARV-110 (batch numbers P220622-1 and P220622-2) and the API alone were given orally at a dose of 50 mg API under fed conditions. [Figure 7] FIG. 1 shows a comparison of plasma concentrations of API (ARV-110) in a dog model when an ASD composition of ARV-110 (Batch No. P220802-1) was given orally at doses of 50 mg API, 100 mg API, and 200 mg API, all under fed conditions. [Figure 8] 1 shows the X-ray powder diffraction of the ASD of ARV-471 composition batch number P220215-1. [Figure 9] 1 shows an X-ray powder diffraction study of particles of ARV-471. [Figure 10] FIG. 1 shows a comparison of plasma concentrations of the active pharmaceutical ingredient (API) ARV-471 in a dog model when ARV-471 was delivered intravenously (iv) at a dose of 6 mg API under fasted conditions or given orally at a dose of 60 mg API under both fasted and fed conditions. [Figure 11] FIG. 1 shows a comparison of plasma concentrations of API (ARV-471) in a dog model when two ASD compositions of ARV-471 (batch numbers P220215-1 and P220215-2) and the API alone were given orally at a dose of 60 mg API under fed conditions. [Figure 12] FIG. 1 shows a comparison of plasma concentrations of API (ARV-471) in a dog model when an ASD composition of ARV-471 (Batch No. P220215-1) was given orally at a dose of 60 mg API under fed and fasted conditions. [Figure 13] FIG. 1 shows a comparison of plasma concentrations of API (ARV-471) in a dog model when an ASD composition of ARV-471 (Batch No. P220419-1) was given orally at doses of 100 mg API, 150 mg API, and 200 mg API, all under fasting conditions. [Figure 14]1 shows a comparison of plasma concentrations of API (ARV-471) in a dog model when API alone is given orally at a high dose of 200 mg under fed and fasted conditions. [Figure 15] FIG. 1 shows a comparison of plasma concentrations of API (ARV-471) in a dog model when an ASD composition of ARV-471 (Batch No. P220525-1) was given orally at a high dose of 200 mg API under fed and fasted conditions. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure is generally directed to compositions comprising pharmaceutically active agents useful as therapeutic agents for alleviating, ameliorating, or eliminating one or more conditions in a subject in need of treatment, as further described herein. In particular, described herein are pharmaceutical compositions, processes for their manufacture, and uses, where the pharmaceutical compositions comprise a PROTAC, a hydrophilic polymer, and a surfactant in a combination such that the PROTAC has improved bioavailability compared to the PROTAC alone. In some embodiments, the PROTAC, the hydrophilic polymer, one or more surfactants, and optionally an acid are in an amorphous solid dispersion. Pharmaceutical compositions of the present disclosure, comprising an amorphous solid dispersion comprising a PROTAC and a suitable excipient or carrier, provide better bioavailability and a reduced food effect than crystalline forms of such PROTACs or other conventional dosage forms. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising the PROTAC in a crystalline form. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising the PROTAC in an amorphous state without being part of an ASD. In some embodiments, conventional dosage forms comprise the PROTAC in a crystalline form. In some embodiments, the conventional dosage form comprises a PROTAC in an amorphous state. In some embodiments, the conventional dosage form comprises a PROTAC compound filled into a capsule. In some embodiments, the conventional dosage form does not comprise an ASD. In some embodiments, the ASD comprises a PROTAC, a surfactant (e.g., lecithin or TPGS), and a hydrophilic polymer.

[0018] definition General terms used herein preferably have the following meanings within the context of this disclosure, unless otherwise indicated:

[0019] Unless otherwise specified or clear from the context, as used herein, the term "about" in connection with a number or range of numbers is understood to mean the stated number and + / - 10% of that number, or 10% below the recited lower limit and 10% above the recited upper limit of the recited values ​​for a range.

[0020] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to a "surfactant" includes a reference to one or more specific surfactants, and reference to an "antioxidant" includes a reference to one or more such additives.

[0021] The term "subject" as used herein refers to a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, or baboon).

[0022] As used herein, "AUC" or "AUC inf " refers to the area under the plasma drug concentration versus time curve extrapolated from time zero to infinity. As used herein, "AUC last "C" as used herein refers to the area under the curve from the time of administration to the time of the last measurable concentration. max " refers to the maximum drug concentration observed in plasma after an extravascular dose of the drug. As used herein, "T max " refers to the time after administration of the drug when the maximum plasma concentration is reached. In some cases, AUC, AUC inf , or C maxcan be used to measure the bioavailability of an API (e.g., a PROTAC) described herein. In some cases, improvements or differences in bioavailability of an API in various oral compositions (e.g., ASD compositions described herein) can be measured using AUC, AUC inf , or C max In some cases, the bioavailability of an API is assessed in subjects in the fed or fasted state. In some cases, the absolute bioavailability of an API is measured via the plasma concentration of the API achieved by intravenous injection.

[0023] "D10," "D50," and "D90" are used herein to describe particle size distribution. "D10," as used herein, refers to the diameter at which 10 percent of the total mass of particles are smaller and 90 percent are larger. "D50," as used herein, is the median diameter at which 50 percent of the total mass of particles are larger and 50% are smaller. "D90" defines the diameter at which 90 percent of the mass distribution has a smaller particle size and 10 percent has a larger particle size.

[0024] In some embodiments, an error band is included. The term "total error band" is used herein to identify all causes, including sampling and sample preparation, calculated at a 95% confidence level. An example is a D50 100 μm with a total error band of + / - 5% for size. Other statistics may be used to describe particle size distribution. The most common calculations are standard deviation and variance. Standard Deviation (St Dev.). The standard deviation specification defines a diameter such that approximately 68.27% of the total population is within + / - 1 St Dev and 95.45% is within + / - 2 St Dev.

[0025] "Effective amount" and "sufficient amount" are used interchangeably and may refer to an amount of a substance that is sufficient to achieve an intended purpose or goal.

[0026] A "therapeutically effective amount," when used in connection with the pharmaceutical compositions described herein, is an amount of one or more pharmaceutically active agents sufficient to produce a therapeutic result in a subject in need thereof.

[0027] "Therapeutically equivalent" when used in connection with the pharmaceutical compositions described herein refers to the amount or quantity 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.

[0028] The prefix "lower" denotes a radical containing up to 7, especially up to 4, carbon atoms, said radical being either linear or branched, with single or multiple branches.

[0029] "Amino" refers to the -NH2 radical.

[0030] "Cyano" refers to the -CN radical.

[0031] "Nitro" refers to the -NO2 radical.

[0032] "Methoxyl" refers to the -O-Me radical.

[0033] "Oxa" refers to the -O radical.

[0034] "Oxo" refers to the =O radical.

[0035] "Thioxo" refers to the =S radical.

[0036] "Imino" refers to the =NH radical.

[0037] "Oximo" refers to the =N-OH radical.

[0038] "Hydrazino" refers to the =N-NH2 radical.

[0039] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0040] "Hydroxyamino" refers to the -NH-OH radical.

[0041] "Acyl" refers to a 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, where the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise in the specification, the alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, amide, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0042] "Acylsulfonamide" refers to a monovalent radical in which the carbon atom of the carbonyl is attached to a sulfonamide group. Exemplary acylsulfonamides 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)NR a C(O)N(R a )2, -C(O)NR a S(O)NR a C(O)N(R a )2, and -C(O)S(O)2N(R a ) 2, wherein each R aare 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).

[0043] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have 1 to about 20 carbon atoms, 1 to about 10 carbon atoms, or 1 to 6 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, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" 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 this definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of C1-C6 alkyls. 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless stated otherwise in the specification, an alkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, —NO2, or —C≡CH. In some embodiments, an alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkyl is optionally substituted with halogen.

[0044] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. The group can be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also covers occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl is a C2-C6 alkenyl. 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 stated otherwise in the specification, an alkenyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0045] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group has from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also covers occurrences of the term "alkynyl" where no numerical range is specified. In some embodiments, alkynyl is a C2-C6 alkynyl. 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 stated otherwise in the specification, alkynyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0046] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with 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, the alkylene is -CH2CH2CH2-.

[0047] "Alkylamino" refers to a group of the formula -N(R a )2, where R a is an alkyl radical as defined above, or two R a together with the nitrogen atom,

[0048] [ka] and the like. Unless stated otherwise in the specification, alkylamino groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylamino is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, alkylamino is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, alkylamino is optionally substituted with halogen.

[0049] "Alkoxy" means a group of the formula -OR a where R a is an alkyl radical as defined above. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0050] "Aminoalkyl" refers to an alkyl radical, as defined above, 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.

[0051] "Aryl" refers to a radical derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, aryl contains hydrogen and 6 to 30 carbon atoms. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, aryl is phenyl. Unless stated otherwise in the specification, aryl can be optionally substituted with, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)NH-Ci-C6 alkyl, etc. In some embodiments, aryl is halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH (In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF, —OH, or —OMe. In some embodiments, aryl is optionally substituted with halogen. In some embodiments, aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, and heteroalkyl is independently unsubstituted or substituted with halogen, methyl, ethyl, —CN, —CF, —OH, —OMe, —NH, or —NO.

[0052] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include cycloalkyls having 3 to 15 carbon atoms (C3-C4). 15 cycloalkyl), cycloalkyl having 3 to 10 carbon atoms (C3-C 10cycloalkyl), cycloalkyl having 3 to 8 carbon atoms (C3-C8 cycloalkyl), cycloalkyl having 3 to 6 carbon atoms (C3-C6 cycloalkyl), cycloalkyl having 3 to 5 carbon atoms (C3-C5 cycloalkyl), or cycloalkyl having 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, a cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycle includes, 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-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, cycloalkyl is optionally substituted with, 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.

[0053] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. Carbocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. 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 carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The term "unsaturated carbocyclic ring" refers to a carbocyclic ring having at least one degree of unsaturation and excluding aromatic carbocyclic rings. Examples of unsaturated carbocyclic rings include cyclohexadiene, cyclohexene, and cyclopentene. The term "saturated cycloalkyl" as used herein refers to a saturated carbocyclic ring. Exemplary saturated cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. The carbocyclic ring can be optionally substituted with one or more substituents, such as those described herein.

[0054] Where the plural is used for compounds, salts, etc., this is taken to mean a single compound, salt, etc. as well.

[0055] Any asymmetric carbon atom may be present in the (R)-, (S)-, or (R,S)-configuration, preferably in the (R)- or (S)-configuration. Thus, the compounds may be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.

[0056] The present disclosure also relates to possible tautomers of the compounds of formula (I).

[0057] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0058] "Heteroaryl" refers to a ring system radical containing carbon atoms, 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 radical containing 1 to 13 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 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 (i.e., thienyl). Unless stated otherwise in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0059] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to a stable 3- to 18-membered saturated, unsaturated, or aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including a fused, bridged, or spirocyclic ring system. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical can be partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, the term "heterocyclyl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, 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 -ORa , -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)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a )2, where t is 1 or 2, wherein each R aare 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); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R e is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise indicated.

[0060] Active Pharmaceutical Ingredients (API) The present disclosure relates to pharmaceutical compositions and methods of administration and use thereof, including compositions comprising an amorphous solid dispersion comprising an API, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the API is a PROTAC. Proteolysis-targeted chimeras (PROTACs) generally have poor water solubility and low oral absorption, even when the PROTAC compound is in amorphous form. Due to these characteristics, it is very difficult to develop PROTAC compositions with good oral bioavailability at lower doses and reduced absorption variability caused by food intake. The pharmaceutical compositions described herein exhibit significantly improved PROTAC oral bioavailability compared to conventional dosage forms. In some embodiments, the pharmaceutical composition for a 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, the PROTAC is one listed in Table 1. In some embodiments, the PROTAC is ARV-110, or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471, or a pharmaceutically acceptable salt or enantiomer thereof. In some embodiments, the PROTAC is ARV-471. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising PROTAC in crystalline form. In some embodiments, conventional dosage forms of PROTACs include dosage forms comprising PROTAC in an amorphous state without being part of an ASD. In some embodiments, conventional dosage forms do not include an ASD. In some embodiments, the ASD includes a PROTAC, a surfactant (e.g., lecithin or TPGS), and a hydrophilic polymer.

[0061] In some embodiments, a solid dispersion is a solid-state solution in which the API (or API salt) and hydrophilic polymer act as the solute and solvent, respectively. Solid dispersions can form multiple structures depending on the composition and sample processing history. When the API loading is lower than the equilibrium solubility of the API in the hydrophilic polymer, the drug is molecularly dispersed within the polymer matrix, forming a thermodynamically stable homogeneous solution. Homogeneous solutions are often achievable only at very low API loadings and / or elevated temperatures. At higher loadings, the mixture becomes a supersaturated solution, and the drug precipitates. This can result in a dispersion of crystalline API particles in the hydrophilic polymer matrix, with the drug concentration corresponding to the equilibrium solubility at that temperature. Alternatively, because API crystallization can be a slow process, an intermediate metastable structure can form in which amorphous API aggregates are dispersed in a hydrophilic polymer matrix containing the API in a non-crystalline, amorphous state. Such amorphous solid dispersions can offer superior dissolution properties compared to crystalline APIs.

[0062] The amorphous solid dispersions described herein may comprise an API, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include antioxidants. In some embodiments, the amorphous solid dispersions described herein are homogeneous 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 the 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 mixtures of these solvents.

[0063] The amorphous solid dispersions described herein may comprise an API, a hydrophilic polymer, a surfactant, and optionally an adsorbent. In some embodiments, the components of the amorphous dispersion, such as the API, hydrophilic polymer, and surfactant, are mixed and solubilized in a solvent, with or without heating, to form a solution. In some embodiments, an adsorbent is further added to the solution to form a homogeneous suspension, and the solvent is removed to form the amorphous solid dispersion. In some embodiments, the solution is sprayed onto the adsorbent, and the solvent is removed to form the amorphous solid dispersion. In some embodiments, the adsorbent is selected from silicon dioxide (also known as silica), magnesium aluminometasilicate (Neusilin), microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked povidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, sugars, and sugar alcohols. In some embodiments, the sugars and sugar alcohols include sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0064] PROTAC compounds Various embodiments described herein are directed to compositions comprising an effective amount of an active pharmaceutical ingredient (API). The terms "active pharmaceutical ingredient," "API," "drug," "pharmaceutically active agent," "bioactive agent," "therapeutic agent," and "active agent," etc., may be used interchangeably and refer to a substance, such as a chemical compound, complex, or PROTAC, that, when administered in an effective amount, has a measurable beneficial physiological effect on the body, such as a therapeutic effect in the treatment of a disease or disorder. Furthermore, when these terms are used, or when a particular active agent is specifically identified by name or category, it is understood that such reference 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, radioisotopes, etc.

[0065] The partition coefficient (P) as referred to herein is the ratio of the concentrations of a compound between two immiscible solvent phases at equilibrium. Most commonly, one of the solvents is water and the other is hydrophobic, typically 1-octanol. The logarithm of this ratio is log P (conventionally, the lipophilic phase is the numerator and the hydrophilic phase is the denominator), as shown below:

[0066]

number

[0067] 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 readily soluble in water ("water-loving") and polar solvents. Lipophilic compounds are poorly soluble in water and polar solvents ("water-phobic" or hydrophobic), but are highly soluble in organic solvents. Thus, Low hydrophilicity = high lipophilicity = high log P = poor water solubility = poor absorption. High hydrophilicity = low lipophilicity = low log P = good water solubility = good absorption.

[0068] The partition coefficient can be experimentally measured or estimated through calculation. Various methods for calculating (or predicting) log P have been developed, typically by matching calculated log P values ​​with experimentally measured log P values ​​for a training set of several thousand molecules, most of which are drug-like. Log P calculations are considered very robust and accurately handle many organic molecules. For example, more than 50% of molecules' log P values ​​are predicted with an error of less than 0.25, while more than 80% are predicted with an error of less than 0.5. Less than 3.5% of structures are predicted with an error of more than 1.0. To distinguish it from measured log P, calculated log P is sometimes referred to as clog P. Unless otherwise indicated, "log P" as used herein refers to the experimental log P value.

[0069] In some embodiments, the API is lipophilic. An API is considered lipophilic if its log P or calculated log P is 2.0 or greater. A log P of 2.0 or greater indicates that the API is 100 times more soluble in a lipophilic solvent than in water. In some embodiments, the API is insoluble in a polar solvent. In some embodiments, the API is insoluble in an aqueous medium. In some embodiments, the API is insoluble in water.

[0070] 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.

[0071] In some embodiments, the PROTACs described herein have low solubility. In some embodiments, the PROTAC has a solubility of less than 10 mg / mL in water at about 25°C. In some embodiments, the PROTAC has a solubility of at most 1 mg / mL in water at about 25°C. In some embodiments, the PROTAC has a solubility of less than 1 mg / mL in water at about 25°C. In some embodiments, the PROTAC has a solubility of less than 0.5 mg / mL in water at about 25°C. In some embodiments, the PROTAC has a solubility of less than 0.1 mg / mL in water at about 25°C. In some embodiments, the PROTAC has a solubility of less than 0.01 mg / mL in water at about 25°C.

[0072] In some embodiments, an API described herein is a heterobifunctional small molecule. In some embodiments, the heterobifunctional small molecule is a PROTAC. In some embodiments, the PROTAC contains 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 connects 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 to a target protein. In some embodiments, the target protein is targeted for degradation.

[0073] In some embodiments, PROTACs function by inducing selective intracellular protein degradation. In some embodiments, PROTACs bring together a target protein and an E3 ligase. In some embodiments, PROTACs recruit an E3 ligase and the target protein. In some embodiments, such recruitment by a PROTAC results in ubiquitination and subsequent degradation of the target protein via the proteasome. In some embodiments, PROTACs achieve target protein degradation by hijacking the cellular ubiquitin-proteasome system (UPS). In some embodiments, an E1 ligase activates and conjugates ubiquitin to an E2 ligase. In some embodiments, the E2 ligase then complexes with an E3 ligase. In some embodiments, the E3 ligase targets a protein of interest by covalently attaching ubiquitin to the protein of interest. In some embodiments, after the ubiquitin chain is formed, the protein of interest is recognized and degraded by the 26S proteasome. In some embodiments, PROTACs exploit the UPS cellular system by bringing a target protein into proximity with an E3 ligase that catalyzes the degradation of the target protein. In some embodiments, the PROTAC possesses a catalytic machinery that allows it to recycle itself after the target protein is degraded. As used herein, the terms "PROTAC" and "PROTAC compound" are used interchangeably.

[0074] 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 listed in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or greater. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise 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.

[0075] [Table 1-1]

[0076] [Table 1-2]

[0077] The acid dissociation constant Ka (or acidity constant) is a measure of the strength of an acid or base in solution, typically water. It is the equilibrium constant for the chemical dissociation of acids and bases. In aqueous solutions, the equilibrium for acid dissociation can be written as:

[0078]

number

[0079]

number

[0080] The equilibrium for the dissociation of the conjugate acid of a base can be written as:

[0081]

number

[0082]

number

[0083] K a pK is the logarithm of a is more often used to describe the strength or weakness of the conjugate acid of an acid or base. pK a =-log 10 (K a ) pK a The more positive the value of , the less dissociated the acid is and the weaker the acid is. pK a =-2~12 → Weak acid (hardly dissociates in water or only partially dissociates) pKa<-2 → Strong acid (completely or mostly dissociates in water) On the other hand, for bases, pK a <12 → Weak base (barely dissociates in water or only partially dissociates) pKa≧12 → Strong base (completely or mostly dissociates in water)

[0084] In some embodiments, the API is a weak base.

[0085] In some embodiments, the API comprises a weakly basic functional group.

[0086] In some embodiments, the API has a pKa of 3.0 or greater. In some embodiments, the API has a pKa of 3.5 or greater. In some embodiments, the API has a pKa of 4.0 or greater. In some embodiments, the API has a pKa of 4.5 or greater. In some embodiments, the API has a pKa of 5.0 or greater.

[0087] 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 metal salts such as calcium salts and magnesium salts; organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts; inorganic acid salts such as hydrochloride, hydrobromide salts, sulfate salts, and phosphate salts; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, and tartrate salts; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, and p-toluenesulfonate salts; and amino acid salts such as arginate salts, aspartate salts, and glutamate salts. 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, the PROTAC, hydrophilic polymer, and surfactant are formulated as 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 dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise 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.

[0088] Exemplary PROTAC Compounds Including ARV-110 and ARV-471 and Analogs Thereof Described herein are pharmaceutical compositions 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.

[0089] In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is a compound of formula (I): ALB Formula (I) During the ceremony, (i) A is an E3 ubiquitin ligase binding moiety; (ii) L is a linker; (iii) B is a moiety that binds to a target protein, and the target protein can be degraded by an E3 ubiquitin ligase.

[0090] 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, the CLM is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

[0091] In some embodiments, the CLM has a chemical structure represented by formula (A):

[0092] [ka] During the ceremony, W is selected from the group consisting of CH, CHR, C=O, SO, NH, and N-alkyl; each X is independently selected from the group consisting of O, S, and H2; Z is selected from the group consisting of O, S, and H2; G is independently selected from the group consisting of H, C1-C6 alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH, C1-C6 heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3, and Q4 are independently R n is a carbon atom or nitrogen atom bonded to A is selected from the group H, C1-C6 alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, and F; R is -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", - NR'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, 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;

[0093] [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R n contains a functional group, bond, or atom, where n is an integer from 4 to 10, and one R n is a bond covalently linking one of Q1, Q2, Q3, or Q4 to a linker (L), and any one of 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.

[0094] In some embodiments, the CLM has a chemical structure represented by Formula (A), wherein W is selected from the group consisting of CH, C=O, and NH; each X is independently selected from the group consisting of O and S; Z is selected from the group consisting of O and S; G is independently selected from the group consisting of H, C1-C3 alkyl (straight chain, branched, optionally substituted), and OH; Q1, Q2, Q3, and Q4 are independently R n is a carbon atom bonded to A is selected from the group consisting of H, C1-C3 alkyl (linear or branched), Cl, and F;

[0095] [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R n contains a functional group, bond, or atom, where n is an integer from 4 to 10, and one R n is a bond covalently linking one of Q1, Q2, Q3, or Q4 to a linker (L), and any other R n is optionally selected from the group consisting of H, C1-C3 alkyl, and halogen.

[0096] In some embodiments, the CLM has a chemical structure represented by Formula (A), wherein W is selected from the group consisting of CH and C=O; each X is O; Z is O, G is H, Q1, Q2, Q3, and Q4 are independently R n is a carbon atom bonded to A is H,

[0097] [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R n comprises a functional group, bond, or atom, where n is 4, and each R nis bonded to one of Q1, Q2, Q3, or Q4, and one R n is a bond covalently connecting Q2 or Q3 to the linker (L), and any other R n is optionally selected from the group consisting of H and F.

[0098] In some embodiments, the CLM has a chemical structure represented by Formula (A), wherein W is C=O, each X is O, Z is O, G is H, and Q, Q, Q, and Q are independently selected from the group consisting of R n and A is H.

[0099] [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R n comprises a functional group, bond, or atom, where n is 4, and each R n is bonded to one of Q1, Q2, Q3, or Q4, and one of R n is the bond covalently connecting Q3 to the linker (L), while R n is F bonded to Q2, and any multi-sided R n is H.

[0100] In some embodiments, the CLM has a chemical structure represented by Formula (A), wherein W is CH, each X is O, Z is O, G is H, and Q, Q, Q, and Q are independently selected from R n and A is H.

[0101] [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R n comprises a functional group, bond, or atom, where n is 4, and each R nis bonded to one of Q1, Q2, Q3, or Q4, and one of R n is the bond covalently connecting Q2 to the linker (L), and any of the R n is H.

[0102] In some embodiments, the CLM has a chemical structure represented by:

[0103] [ka]

[0104] In some embodiments, the CLM has a chemical structure represented by:

[0105] [ka]

[0106] In some embodiments, L is a linker. In some embodiments, the linker is a bond. In some embodiments, the linker is a chemical linking moiety connecting A and B.

[0107] In some embodiments, L is selected from:

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka] In the formula, m=1 or 2, and n=0 or 1;

[0114] [ka] indicates the point of attachment to A or B.

[0115] In some embodiments, L is selected from:

[0116] [ka] In the formula, m=1 or 2, and n=0 or 1;

[0117] [ka] indicates the point of attachment to A or B.

[0118] In some embodiments, L is selected from:

[0119] [ka] During the ceremony,

[0120] [ka] indicates the point of attachment to A or B.

[0121] In some embodiments, L is

[0122] [ka] wherein:

[0123] [ka] indicates the point of attachment to A or B.

[0124] In some embodiments, L is

[0125] [ka] wherein L is a group A and B in formula (I).

[0126] [ka] The following order is used:

[0127] In some embodiments, B is an androgen receptor (AR) binding moiety. In some embodiments, the PROTAC is an AR PROTAC degrader. In some embodiments, B is an estrogen receptor (ER) binding moiety. In some embodiments, the PROTAC is an ER PROTAC degrader.

[0128] In some embodiments, the AR binding moiety is represented by the structure of formula (B1):

[0129] [ka] During the ceremony, Y 3 , Y 4 , Y 5 are each independently a bond, O, C═O, NR, CR′, CHR′, heteroaryl, or aryl;

[0130] [ka] indicates the point of attachment to the linker group L, R' is independently H or C 1~6 Alkyl (straight chain, branched, one More halo, C 1~6 Alkoxyl, C 1~6 Cyclic, or C 1~6 optionally substituted by heterocyclyl; R Q3 is H, halo, hydroxyl, nitro, CN, C=CH, C 1~6 Alkyl (straight chain, branched, one or more halogens, C 1~6 optionally substituted with alkoxyl), C 1~6 Alkoxyl (linear, branched, optionally substituted with one or more halo), C 1~6 Alkenyl, C 1~6 alkynyl, or CF3; R Q2 H, halogen, C 1~6 alkyl (straight chain, branched chain, optionally substituted with one or more halo, or C4 alkoxyl), or R Q2 and R Q3 together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms, X 1 , X 2 , X 3 , and X 4 are each independently N or CR'.

[0131] In some embodiments, the AR binding moiety is represented by the structure of formula (B1): During the ceremony, R Q3 is H, halogen, hydroxyl, nitro, CN, C=CH, C 1~3 Alkyl, C 1~3 Alkenyl, C 1~3 alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently O, C=O, or NR';

[0132] [ka] indicates the point of attachment to the linker group L, R' is independently H or C 1~3 Alkyl (straight chain, branched, one More than halogens, C 1~3 Alkoxyl, C 1~6 Cyclic, or C 1~6 optionally substituted by heterocyclyl; R Q2 is H or a halogen, Each X is independently N or CH.

[0133] In some embodiments, the AR binding moiety is represented by the structure of formula (B1): During the ceremony, R Q3 is H, halogen, CN, or CF3, Y 3 , Y 4 , Y 5 are each independently O, C=O, or NH;

[0134] [ka] indicates the point of attachment to the linker group L, R Q2 is a halogen, X 1 and X 2 is N, X 1 and X 2 is CH.

[0135] In some embodiments, the AR binding moiety is represented by the structure of formula (B1): During the ceremony, R Q3 is CN, Y 3 is O, Y 4 is NH, Y 5 is C=O,

[0136] [ka] indicates the point of attachment to the linker group L, and R Q2 is Cl and X 1 and X 2 is N and X 1 and X 2 is CH.

[0137] In some embodiments, the AR binding moiety is:

[0138] [ka] wherein:

[0139] [ka] indicates the point of attachment to the linker group L.

[0140] In some embodiments, the AR binding moiety is:

[0141] [ka] wherein:

[0142] [ka] indicates the point of attachment to the linker group L, where L is

[0143] [ka] is.

[0144] In some embodiments, the ER binding moiety is represented by the structure of formula (B2):

[0145] [ka] Formula (B2) During the ceremony, each X is independently CH or N;

[0146] [ka] indicates the point of attachment to the linker group L, each R1 is independently H, OH, halogen, alkoxy, methoxy, ethoxy, O(CO)R', which may be mono-, di-, or tri-substituted, and R' is an alkyl or cycloalkyl group having 1 to 6 carbons or an aryl group; each R2 is independently H, halogen, CN, CF, linear or branched alkyl, alkoxy, methoxy, ethoxy, and the substitution may be mono- or di-substituted; Each R3 is independently H, halogen, and the substitution can be mono- or di-substituted.

[0147] In some embodiments, the ER binding moiety is represented by the structure of formula (B2): During the ceremony, each X is independently CH;

[0148] [ka] indicates the point of attachment to the linker group L, each R1 is independently H, OH, or halogen; each R2 is independently H, halogen, CN, or CF; Each R3 is independently H or halogen.

[0149] In some embodiments, the ER binding moiety is represented by the structure of formula (B2): During the ceremony, each X is independently CH;

[0150] [ka] indicates the point of attachment to the linker group L, each R1 is independently H or OH; each R2 is H; Each R3 is H.

[0151] In some embodiments, the ER binding moiety is represented by the structure of formula (B2): During the ceremony, each X is independently CH;

[0152] [ka] indicates the point of attachment to the linker group L, each R1 is independently H or OH, wherein one R1 is OH; each R2 is independently H; Each R3 is independently H.

[0153] In some embodiments, the ER binding moiety is

[0154] [ka] wherein:

[0155] [ka] indicates the point of attachment to the linker group L.

[0156] In some embodiments, the ER binding moiety is

[0157] [ka] wherein:

[0158] [ka] indicates the point of attachment to the linker group L, where L is

[0159] [ka] is.

[0160] In some embodiments, salts of compounds of Formula (I) are formed from compounds of Formula I having a basic nitrogen atom, e.g., pharmaceutically acceptable salts, e.g., as acid addition salts (e.g., with organic or inorganic acids). Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids, or sulfamic acids, acetic acid, propionic acid, octanoic acid, decanoic 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, and cinnamic acid. , methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid, or 4-methylbenzenesulfonic acid, methyl sulfate, ethyl sulfate, dodecyl sulfate, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid, or N-propylsulfamic acid, or other organic protonic acids such as ascorbic acid.

[0161] In the presence of negatively charged radicals such as carboxy or sulfo, salts can also be formed with bases, for example metal or ammonium salts, for example alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium, or calcium salts, or ammonium salts with ammonia or suitable organic amines, for example tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'-dimethylpiperazine.

[0162] When a basic group and an acidic group are present in the same molecule, the compounds of formula I can also form internal salts.

[0163] For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, such as picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (if applicable in the form of pharmaceutical preparations) and are therefore preferred.

[0164] In some embodiments, the PROTAC is an AR PROTAC degrader. In some embodiments, the PROTAC has a B group that is an AR binding moiety. In some embodiments, the AR PROTAC degrader is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the 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-dioxoisoindolin-S-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide. In some embodiments, the ARV-110 compound is

[0165] [ka] It is represented by the structure:

[0166] In some embodiments, the PROTAC is an ER PROTAC degrader. In some embodiments, the PROTAC has a B group that is an ER binding moiety. In some embodiments, the ER PROTAC degrader is ARV-471 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-471. In some embodiments, the ARV-471 compound is (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione. In some embodiments, the ARV-471 compound is represented by the following structure:

[0167] [ka]

[0168] 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, mucate, oleate, dibasic phosphate, monobasic phosphate, acetate trihydrate, bis(heptafluorobutyrate), bis(pentafluoropropionate), bis(pyridinecarboxylate), bis(trifluoroacetate), chlorhydrate, and sulfate pentahydrate.Other representative pharmaceutically acceptable salts include, for example, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodine ... Examples of suitable salts include ammonium salts, ammonium salts, ammonium nitrate ... The XXX hydrate is another example of a pharmaceutically acceptable salt.

[0169] In some embodiments, the API has low solubility at a pH of about 6-8. In some embodiments, the API has a solubility of less than 10 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 1.0 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.5 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.1 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.05 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.04 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.03 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.02 mg / ml in a solution having a pH between about 6-8. In some embodiments, the API has a solubility of less than 0.01 mg / ml in a solution having a pH between about 6 and 8. In some embodiments, the API has a solubility of less than 0.001 mg / ml in a solution having a pH between about 6 and 8. In some embodiments, the API has low solubility at a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 10 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 1.0 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.5 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.1 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.05 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.04 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.03 mg / ml in a solution having a pH between about 4 and 8.In some embodiments, the API has a solubility of less than 0.02 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.01 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has a solubility of less than 0.001 mg / ml in a solution having a pH between about 4 and 8. In some embodiments, the API has low solubility at a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 10 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 1.0 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.5 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.1 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.05 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.04 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.03 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.02 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.01 mg / ml in a solution having a pH between about 6 and 10. In some embodiments, the API has a solubility of less than 0.001 mg / ml in a solution having a pH between about 6 and 10.

[0170] In some embodiments, the API is a PROTAC. In some embodiments, the PROTAC is one 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0171] In some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions described herein do not include an organic acid, hi some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions do not include any acid.

[0172] In some embodiments, pharmaceutical compositions comprising an ASD, including a PROTAC described herein (e.g., ARV-110 or ARV-471), have acceptable shelf stability. In some embodiments, the pharmaceutical composition is shelf-stable at 40°C / 75% RH for at least 6 months, where a shelf-stable pharmaceutical composition has less than 0.5% of any impurities at the end of the storage period. In some embodiments, the pharmaceutical composition is shelf-stable at 25°C / 60% RH for at least 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, where a shelf-stable pharmaceutical composition has less than 0.5% of any impurities at the end of the storage period. In some embodiments, the pharmaceutical compositions described herein comprise a PROTAC (e.g., ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof), a surfactant, and a non-ionic or ionic hydrophilic polymer. 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 greater. In some embodiments, the PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 10 mg to about 500 mg. In some embodiments, the PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 20 mg to about 200 mg. In some embodiments, the PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof is present in the 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 non-ionic polymer. In some embodiments, the hydrophilic polymer is an ionic polymer such as sulfobutylether-β-cyclodextrin. In some embodiments, the hydrophilic polymer is copovidone (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), hypromellose phthalate (HPMCP), HPMCAS, cellulose phthalate hydroxypropyl methyl ether, hydroxypropyl methylcellulose benzene-1,2-dicarboxylate, 2-hydroxypropyl methylcellulose phthalate, hypromellose phthalas, Mantrocel HP-55, methylhydroxypropyl cellulose phthalate, or Soluplus. In some embodiments, the hydrophilic polymer comprises PEG, polymethacrylate (e.g., sold under the trade name Eudragit), hypromellose 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.

[0173] In some embodiments, the weight ratio of the 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 the 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 1:10, or about 1:10. :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 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 0, about 1:1 to about 1:2, about 1:1 to about 1:4, about 1:1 to about 1:6, about 1:1 to about 1:8, about 1:1 to about 1:10, about 1:2 to about 1:4, about 1:2 to about 1:6, about 1:2 to about 1:8, about 1:2 to about 1:10, about 1:4 to about 1:6, about 1:4 to about 1:8, about 1:4 to about 1:10, about 1:6 to about 1:8, about 1:6 to about 1:10, or about 1:8 to about 1:10. In some embodiments, the weight ratio of the 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, or about 1:10. In some embodiments, the weight ratio of the 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 the 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, 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 greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0174] In some embodiments, the pharmaceutical compositions described herein have a therapeutic efficacy of at least 200 mg / kg / day, with a mean AUC, AUC inf , or AUC last The composition has a bioavailability, measured as a function of time, that is superior to the bioavailability of a corresponding reference composition comprising a crystalline form of the 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, measured as AUC after oral administration, 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 C maxThe composition exhibits a bioavailability, measured as a function of time, 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 form of the PROTAC (e.g., ARV-110 or ARV-471) or a corresponding composition comprising an amorphous PROTAC (e.g., ARV-110 or ARV-471) that is not in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability, measured as AUC after oral administration, 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 amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in the ASD capsule containing the amorphous PROTAC (e.g., ARV-110 or ARV-471). maxIn some embodiments, the pharmaceutical composition exhibits a bioavailability, measured as a percent bioavailability (e.g., 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 amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in the ASD capsule containing 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 the amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in the ASD. In some embodiments, the pharmaceutical composition has 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 2 ... 5-fold to about 4-fold, about 2-fold to about 5-fold, about 2-fold to about 6-fold, about 2-fold to about 7-fold, about 2-fold to about 8-fold, about 2-fold to about 10-fold, about 3-fold to about 4-fold, about 3-fold to about 5-fold, about 3-fold to about 6-fold, about 3-fold to about 7-fold, about 3-fold to about 8-fold, about 3-fold to about 10-fold, about 4-fold to about 5-fold, about 4-fold to about 6-fold, about 4-fold to about 7-fold, about 4-fold to about 8-fold, about 4-fold to about 10-fold, about 5-fold to about 6-fold, about 5-fold to about 7-fold, about 5-fold to about 8-fold, about 5-fold to about 10-fold, about 6-fold to about 7-fold, about 6-fold to about 8-fold, about 6-fold to about 10-fold, about 7-fold to about 8-fold, about 7-fold to about 10-fold, or about 8-fold to about 10-fold higher bioavailability. 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 greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0175] In some embodiments, the pharmaceutical compositions described herein have an AUC or C max The pharmaceutical composition exhibits a bioavailability, measured as a function of time, that is at least about 1.1-fold, about 1.3-fold, about 1.5-fold, about 1.8-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold greater than the bioavailability of the amorphous PROTAC (e.g., ARV-110 or ARV-471) not present in an ASD described herein. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 2-fold greater than the bioavailability of the 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 at least about 4-fold greater than the bioavailability of the 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 up to about 1.3-fold, about 1.5-fold, about 1.8-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, or 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 bioavailability is measured in a fasted dog model. In some embodiments, the bioavailability is measured in a fed dog model. In some embodiments, the bioavailability of the pharmaceutical composition, as measured as AUC after oral administration, does not change by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, or 10% when administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition is measured as the C maxWhen measured as a function of time, 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 administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 100% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 90% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 80% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 70% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 50% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 50% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 40% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 20% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 10% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability is measured in a dog model. In some embodiments, the dog model is a beagle dog. 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 greater. In some embodiments, the PROTAC is ARV-110.In some embodiments, the PROTAC is ARV-471.

[0176] In some embodiments, the pharmaceutical compositions exhibit a bioavailability of the 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-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a dosage form, wherein the PROTAC is in a crystalline form. In some embodiments, the pharmaceutical compositions exhibit a bioavailability of the 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-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a dosage form, wherein the PROTAC is in an amorphous form without being part of an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 2-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a dosage form (such as a crystalline form of the PROTAC or an amorphous form of the PROTAC that is not part of an ASD). In some embodiments, the bioavailability is measured as the AUC or maximum plasma concentration (C) following oral administration to subjects in a fasted state. max In some embodiments, the pharmaceutical composition exhibits a bioavailability of the 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 compound or a pharmaceutically acceptable salt thereof in amorphous form in a conventional dosage form (e.g., without being part of an ASD). In some embodiments, bioavailability is measured as the AUC or maximum plasma concentration (C) following oral administration to subjects in a fasted state. max) in a dosage form. In some embodiments, conventional dosage forms of PROTACs include dosage forms that include the PROTAC in a crystalline form. In some embodiments, conventional dosage forms of PROTACs include dosage forms that include the PROTAC in an amorphous state without being part of an ASD. In some embodiments, conventional dosage forms do not include an ASD. In some embodiments, conventional dosage forms include a PROTAC compound filled into a capsule. In some embodiments, the pharmaceutical composition exhibits a bioavailability of the 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 that includes a PROTAC compound or a pharmaceutically acceptable salt thereof in a dosage form (such as a crystalline form of the PROTAC or an amorphous form of the PROTAC without being part of an ASD). In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC (e.g., ARV-110 or ARV-471) or a pharmaceutically acceptable salt thereof that is at least 6-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a dosage form (such as a crystalline form of the PROTAC or an amorphous form of the PROTAC that is not part of an ASD). In some embodiments, the bioavailability is measured as the maximum plasma concentration (C) following oral administration to subjects in a fasted state. max ) In some embodiments, the subject comprises a dog. In some embodiments, the subject comprises six beagle dogs. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0177] In some embodiments, the pharmaceutical compositions described herein have an AUC last or C maxThe bioavailability, measured as a function of time, 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 or ARV-471) (e.g., an amorphous PROTAC that is not in a crystalline form or part of an ASD), 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 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, and 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 amorphous form without being part of an ASD. In some embodiments, the bioavailability is measured under fasted conditions. In some embodiments, the bioavailability is measured under fed conditions. 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 greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0178] In some embodiments, a salt of a PROTAC (e.g., ARV-110 or ARV-471) compound is formed from a compound of ARV-110 having a basic nitrogen atom, e.g., a pharmaceutically acceptable salt, e.g., as an acid addition salt (e.g., with an organic or inorganic acid). Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, acetic acid, propionic acid, octanoic acid, decanoic 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-naphthalene-disulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid, or 4-methylbenzenesulfonic acid, methyl sulfate, ethyl sulfate, dodecyl sulfate, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid, or N-propylsulfamic acid, or other organic protonic acids such as ascorbic acid.

[0179] In the presence of negatively charged radicals such as carboxy or sulfo, salts can also be formed with bases, for example metal or ammonium salts, for example alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium, or calcium salts, or ammonium salts with ammonia or suitable organic amines, for example tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'-dimethylpiperazine.

[0180] When a basic group and an acidic group are present in the same molecule, PROTAC compounds may also form internal salts.

[0181] For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, such as picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (if applicable in the form of pharmaceutical preparations) and are therefore preferred.

[0182] Amorphous Solid Dispersions The present disclosure relates to pharmaceutical compositions comprising amorphous solid dispersions, methods for preparing the described pharmaceutical compositions, and methods for treating diseases or conditions by administering the same. In some embodiments, the pharmaceutical compositions comprising the amorphous solid dispersions further comprise a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the pharmaceutical compositions optionally comprise an adsorbent, an acid, or both.

[0183] In one aspect, disclosed herein is an amorphous solid dispersion, the amorphous solid dispersion comprising: a) a PROTAC or a pharmaceutically acceptable salt thereof, wherein the PROTAC has a log P in octanol-water of 2.0 or greater; b) a surfactant, wherein the surfactant is selected from a polymeric surfactant and a phospholipid; c) a hydrophilic polymer; and d) optionally an adsorbent, and optionally an acid.

[0184] In some embodiments, the PROTAC or a pharmaceutically acceptable salt thereof is a PROTAC, hi some embodiments, the PROTAC is represented by a compound of formula (I): ALB Formula (I) During the ceremony, -A is an E3 ubiquitin ligase binding moiety, -L is a linker, -B is a moiety that binds to a target protein, where the target protein can be degraded by an E3 ubiquitin ligase. 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, and the compound is

[0185] [ka] or a pharmaceutically acceptable salt or enantiomer thereof.

[0186] In some embodiments, the PROTAC compound is an ER PROTAC degrader. In some embodiments, the estrogen receptor PROTAC degrader is ARV-471, which is represented by the following structure:

[0187] [ka]

[0188] In some embodiments, the 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, their corresponding free bases, and pharmaceutically acceptable salts thereof. In some embodiments, the PROTAC is selected from Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC or a pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 5% to about 70% by weight based on the 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 combinations 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% to about 70% by weight.

[0189] In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 5% to about 60%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 15% to about 50%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 15% to about 30%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 15% to about 25%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 20% to about 30%. In some embodiments, the PROTAC is 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 45%, about 5% to about 50%, about 5% to about 55%, 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 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 55%, about 10% to about 60%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, 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 45%, about 20% to about 50%, about 20% to about 55%, about 20% to about 60%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about It is present in the amorphous solid dispersion at a weight percent of 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 50% to about 55%, about 50% to about 60%, or about 55% to about 60%.In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 55%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at a weight percent of at most about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%. In some embodiments, the PROTAC is present in the amorphous solid dispersion at about 15% weight percent. In some embodiments, the PROTAC is present in the amorphous solid dispersion at about 20% weight percent. In some embodiments, the PROTAC is present in the amorphous solid dispersion at about 25% weight percent. In some embodiments, the PROTAC is present in the amorphous solid dispersion at about 30% weight percent. 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 greater. In some embodiments, the 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.

[0190] In some embodiments, the ASDs described herein comprise one or more surfactants. In some embodiments, the one or more surfactants comprise lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, TGPS, a polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof. In some embodiments, the one or more surfactants comprise lecithin and TPGS. In some embodiments, the one or more surfactants comprise lecithin. In some embodiments, the one or more surfactants comprise TPGS. In some embodiments, the one or more surfactants are present in an amount of about 5% to about 60% by weight of the ASD. In some embodiments, the surfactant is present in an amount of about 15% to about 50% by weight of the ASD. In some embodiments, the surfactant is present in an amount of about 20% to about 40% by weight of the ASD.

[0191] In some embodiments, the ASD described herein comprises a hydrophilic polymer. In some embodiments, the hydrophilic polymer is non-ionic. 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 comprising 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% to about 80% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 10% to about 70% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 15% to about 60% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 20% to about 50% by weight of the ASD. In some embodiments, the hydrophilic polymer is present in an amount of about 25% to about 45% by weight of the ASD.

[0192] 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.

[0193] 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.

[0194] 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 povidone, sodium carboxymethylcellulose, 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 5 to about 80% by weight. In some embodiments, the average particle size of the amorphous solid dispersion is between 1 μm and 1000 μm. In some embodiments, the average particle size of the amorphous solid dispersion, in terms of particle size, is between about 10 μm and about 150 μm.

[0195] In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more other additives. In some embodiments, the other additives include an organic acid and an inorganic acid. In some embodiments, the solid dispersion is a solid-state solution in which the PROTAC (or its PROTAC salt) and hydrophilic polymer act as the solute and solvent, respectively. Solid dispersions can form multiple structures depending on the composition and sample processing history. When the PROTAC loading is lower than the equilibrium solubility of the PROTAC in the hydrophilic polymer, the drug is molecularly dispersed within the polymer matrix, forming a thermodynamically stable homogeneous solution. Homogeneous solutions are often only achievable at very low PROTAC loadings and / or elevated temperatures. At higher loadings, the mixture becomes a supersaturated solution and the drug precipitates. This can result in a dispersion of crystalline PROTAC particles in the hydrophilic polymer matrix, with the drug concentration corresponding to the equilibrium solubility at that temperature. Alternatively, because crystallization of PROTACs can be a slow process, an intermediate metastable structure may form in which amorphous PROTAC aggregates are dispersed in a hydrophilic polymer matrix containing the PROTAC in a non-crystalline, amorphous state. Such amorphous solid dispersions can provide superior dissolution properties compared to crystalline PROTACs. 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 greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0196] In some embodiments, the amorphous solid dispersions described herein comprise a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise 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. In some embodiments, the amorphous solid dispersions described herein are homogeneous 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 the 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 mixtures of these solvents.

[0197] In some embodiments, the amorphous solid dispersion described herein comprises a PROTAC, a hydrophilic polymer, a surfactant, and optionally an adsorbent. In some embodiments, the components of the amorphous dispersion, such as the PROTAC, the hydrophilic polymer, and the surfactant, are mixed and solubilized in a solvent, with or without heating, to form a solution. In some embodiments, an adsorbent is further added to the solution to form a homogeneous suspension, and the solvent is removed to form the amorphous solid dispersion. In some embodiments, the solution is sprayed onto the adsorbent, and the solvent is removed to form the amorphous solid dispersion. In some embodiments, the adsorbent is selected from silicon dioxide (also known as silica), magnesium aluminometasilicate (Neusilin), microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), talc, cross-linked povidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, sugars, and sugar alcohols. In some embodiments, the sugars and sugar alcohols include sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0198] 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 the PROTAC compound or a pharmaceutically acceptable salt thereof that does not change by 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 10% to about 50%, about 10% 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 25%, about 10% to about 35%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 25%, about 10% to about 30%, about 10% to about 25%, about 10% to about % to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% 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 3 The ASD exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not change by more than 5% 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 ASD exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that 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 selected from Table 1.In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0199] Formation of an amorphous solid dispersion can result in a particular particle size of the ASD. In some embodiments, the particle size of the ASD is about 1 nm to 1 mm. In some embodiments, the particle size of the ASD is about 0.01 to 1000 micrometers. In some embodiments, the particle size of the ASD is about 0.01 micrometer to about 1,000 micrometers. In some embodiments, the particle size of the ASD is at least about 0.01 micrometer. In some embodiments, the particle size of the ASD is at most about 1,000 micrometers. In some embodiments, the particle size of the ASD is about 1 micrometer to about 50 micrometers. In some embodiments, the particle size of the ASD is at least about 1 micrometer. In some embodiments, the particle size of the ASD is at most about 50 micrometers. In some embodiments, the particle size of the ASD is about 10 micrometers to about 15 micrometers.In some embodiments, the particle size of the ASD is about 1 micrometer to about 3 micrometers, about 1 micrometer to about 7 micrometers, about 1 micrometer to about 10 micrometers, about 1 micrometer to about 13 micrometers, about 1 micrometer to about 17 micrometers, about 1 micrometer to about 20 micrometers, about 1 micrometer to about 23 micrometers, about 1 micrometer to about 27 micrometers, about 1 micrometer to about 30 micrometers, about 1 micrometer to about 40 micrometers, about 1 micrometer to about 50 micrometers, about 10 micrometers to about 13 micrometers, or about 10 micrometers to about 17 micrometers. , about 10 micrometers to about 20 micrometers, about 10 micrometers to about 23 micrometers, about 10 micrometers to about 27 micrometers, about 10 micrometers to about 30 micrometers, about 10 micrometers to about 40 micrometers, about 10 micrometers to about 50 micrometers, about 20 micrometers to about 27 micrometers, about 20 micrometers to about 30 micrometers, about 20 micrometers to about 40 micrometers, about 20 micrometers to about 50 micrometers, about 30 micrometers to about 40 micrometers, about 30 micrometers to about 50 micrometers, or about 40 micrometers to about 50 micrometers. In some embodiments, the particle size of the ASD is from about 1 micrometer to about 100 micrometers. In some embodiments, the particle size of the ASD is from at least about 1 micrometer. In some embodiments, the particle size of the ASD is less than or equal to about 0.1, 1, 3, 5, 7, 10, 13, 17, 20, 23, 25, 27, 30, 33, 35, 37, 40, 43, 45, 47, 50, 60, 70, 80, 90, or 100 micrometers, hi some embodiments, the particle size of the ASD is less than or equal to about 20 micrometers.

[0200] In some embodiments, a particle size distribution of the amorphous solid dispersion 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 less than or equal to 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 less than or equal to 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 D10 particle size of the ASD is less than or equal to 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.

[0201] In some embodiments, a particle size distribution of the amorphous solid dispersion 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 about 10 μm to about 1,000 μm. In some embodiments, the D90 particle size of the ASD is 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. In some embodiments, the D90 particle size is at least about 10 μm, about 20 μm, 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.

[0202] In some embodiments, a particle size distribution of the amorphous solid dispersion 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 about 1 μm to about 100 μm. In some embodiments, the D50 value of the ASD is about 10 μm to about 15 μm. In some embodiments, the D50 particle size is about 5 μm to about 10 μm, about 5 μm to about 15 μm, about 5 μm to about 20 μm, about 5 μm to about 25 μm, about 5 μm to about 30 μm, about 5 μm to about 40 μm, about 5 μm to about 50 μm, about 5 μm to about 60 μm, about 5 μm to about 75 μm, about 5 μm to about 100 μm, about 10 μm to about 15 μm, about 10μm to about 20μm, about 10μm to about 25μm, about 10μm to about 30μm, about 10μm to about 40μm, about 10μm to about 50μm, about 10μm to about 60μm, Approximately 10μm to approximately 75μm, approximately 10μm to approximately 100μm, approximately 15μm to approximately 20μm, approximately 15μm to approximately 25μm, approximately 15μm to approximately 30μm, approximately 15μm to approximately 40μm , 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, approximately 20 μm to approximately 40 μm, approximately 20 μm to approximately 50 μm, approximately 20 μm to approximately 60 μm, approximately 20 μm to approximately 75 μm, approximately 20 μm to approximately 100 μm, approximately 25 μm to approximately 3 In some embodiments, the D50 particle size is about 5 μm, about 10 μm, about 25 μm to about 40 μm, about 25 μm to about 50 μm, about 25 μm to about 60 μm, about 25 μm to 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, hi 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.

[0203] In some embodiments, a particle size distribution of the amorphous solid dispersion 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.

[0204] 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0205] In some embodiments, the amorphous solid dispersions described herein comprise a surfactant. In some embodiments, the surfactant is selected from a polymeric nonionic surfactant and a phospholipid. In some embodiments, the surfactant is a polymeric nonionic surfactant. In some embodiments, the surfactant comprises a block copolymer of polyethylene glycol and polypropylene glycol. In some embodiments, the polymeric nonionic surfactant has a number average molecular weight of about 7000 to about 10,000 Da. In some embodiments, the amorphous solid dispersions described herein comprise the surfactant TPGS. In some embodiments, the amorphous solid dispersions described herein comprise a surfactant comprising 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, the one or more phospholipids comprise more than 50%, 60%, 70%, 80%, or 90% phosphatidylcholine by weight. 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.

[0206] 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, the surfactant comprising 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, the hydrophilic polymer comprising vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutylether-β-cyclodextrin, hydroxypropyl beta-cyclodextrin (HP-β-CD), or a combination thereof; 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 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 60% by weight of the ASD, wherein the surfactant comprises tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; and iii) a surfactant in an amount of about 5% to about 60% by weight of the ASD. The present invention also provides a method for preparing a PROTAC (Protactic Drug Substance) comprising: (i) providing a hydrophilic polymer in an amount of 70% by weight, the hydrophilic polymer comprising vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutylether-β-cyclodextrin, hydroxypropyl beta-cyclodextrin (HP-β-CD), or a combination thereof; and (ii) optionally providing an acid in an amount of about 1% to about 50% by weight of the ASD. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0207] 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% to about 50% by weight of the ASD; and ii) a surfactant in an amount of about 1% to about 60% by weight of the ASD, wherein the surfactant is selected from the group consisting of tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinyl caprolactam, and the like. iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl beta cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin, or a combination thereof; and iv) optionally an acid in an amount of about 1% to about 50% by weight of the ASD.

[0208] 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% to about 50% by weight of the ASD; ii) a surfactant in an amount of about 1% to about 60% by weight of the ASD, the surfactant comprising tocopherol polyethylene glycol succinate (TPGS), lecithin, a block copolymer of polyethylene glycol and polypropylene glycol, polyvinyl caprolactam-based graft copolymer (PVAc-PVCap-PEG), or a combination thereof; and iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, the hydrophilic polymer being vinylpyrrolidone-vinyl acetate. copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutylether-β-cyclodextrin, or hydroxypropyl beta-cyclodextrin (HP-β-CD); and iv) optionally an acid in an amount of about 1% to about 50% by weight of the ASD, the acid comprising 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.

[0209] 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 vinylpyrrolidone-vinyl acetate copolymer or HPMCAS, or a combination thereof. In some embodiments, the adsorbent is silicon dioxide. 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, 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 greater. 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.

[0210] 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, 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 greater. 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. 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 greater. 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.

[0211] 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, 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 greater. 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.

[0212] 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 a 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 hydroxypropyl methylcellulose acetate succinate (HPMCAS) or vinylpyrrolidone-vinyl acetate copolymer. 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 greater. 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.

[0213] In some embodiments, the ASDs described herein have a mean AUC, AUC inf , or AUC last The ASD has a bioavailability, measured as AUC after oral administration, 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 a corresponding reference composition comprising an amorphous PROTAC not present in an ASD. In some embodiments, the ASD exhibits a bioavailability, measured as AUC after oral administration, 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 a corresponding composition comprising an amorphous PROTAC not present in an ASD. In some embodiments, the ASD exhibits a C max The PROTACs exhibit a bioavailability, measured as a function of time, 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 a corresponding composition comprising an amorphous PROTAC that is not present in an ASD. In some embodiments, the ASD exhibits a bioavailability, measured as AUC after oral administration, 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 containing ARV-110. ... maxThe ASD exhibits a bioavailability, measured as a function of time, 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 the ASD capsule containing 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 the ASD. In some embodiments, the ASD 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 100-fold, or about 100-fold more soluble in the ASD than the crystalline PROTAC (e.g., ARV-110 and ARV-471) or the amorphous PROTAC not present in the ASD. The bioavailability may be 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 2-fold to about 4-fold, about 2-fold to about 5-fold, about 2-fold to about 6-fold, about 2-fold to about 7-fold, about 2-fold to about 8-fold, about 2-fold to about 10-fold, about 5-fold to about 10-fold, or about 8-fold to about 10-fold higher. In some cases, the PROTAC (e.g., ARV-110 and ARV-471) not present in the PROTAC-containing ASD capsule is in an amorphous state. In some embodiments, the PROTAC is listed in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or greater. 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.

[0214] In some embodiments, the ASD exhibits a bioavailability of the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof that is at least 2-fold greater than the bioavailability of a corresponding composition comprising the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof in a conventional dosage form (e.g., in a crystalline form or in an amorphous state without being part of an ASD). In some embodiments, bioavailability is measured as the AUC or maximum plasma concentration (C) following oral administration to subjects in a fasted state. max In some embodiments, the ASD exhibits a bioavailability of the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof in a conventional dosage form (e.g., in a crystalline form or in an amorphous state without being part of an ASD). In some embodiments, bioavailability is measured as the AUC or maximum plasma concentration (C) following oral administration to subjects in a fasted state. max In some embodiments, the ASD exhibits a bioavailability of the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof that is at least six-fold greater than the bioavailability of a corresponding composition comprising the PROTAC (e.g., ARV-110 and ARV-471) compounds or pharmaceutically acceptable salts thereof in a conventional dosage form (e.g., in a crystalline form or in an amorphous state without being part of the ASD). In some embodiments, the bioavailability is measured as the maximum plasma concentration (C) following oral administration to subjects in a fasted state. max) in a subject. In some embodiments, the subject comprises a dog. In some embodiments, the subject comprises six beagle dogs. 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 greater. 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.

[0215] In some embodiments, the ASD described herein has an AUC last or C maxThe bioavailability, measured as a function of time, 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 comprise an amorphous solid dispersion. In some embodiments, the reference composition is about 1.1-fold to about 10-fold the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1-fold to about 2-fold, about 1.1-fold to about 5-fold, about 1.1-fold to about 10-fold, about 1.5-fold to about 2-fold, about 2-fold to about 5-fold, about 2-fold to about 10-fold, about 2.5-fold to about 3-fold, or about 5-fold to about 10-fold the dose of the pharmaceutical composition. In some embodiments, the reference composition is at least about 1.1-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold the dose of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an ASD comprising 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, and the reference composition does not comprise an ASD. In some embodiments, the bioavailability is measured under fasted conditions. In some embodiments, the bioavailability is measured under fed conditions. In some embodiments, the PROTAC is listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC has a log P of 2.0 or greater. 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.

[0216] surfactants 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 in Table 1 or a pharmaceutically acceptable salt thereof. 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.

[0217] In some embodiments, surfactants are compounds or mixtures of compounds that contain a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group. They may serve one or more functions, including solubility enhancer, bioavailability enhancer, stability enhancer, antioxidant, emulsifier. Other terms in the art for surfactants include emulsifier, emulsifier, surface active agent, wetting agent, suspending agent, etc. Examples of surfactants include phospholipids, lecithin, Kolliphor series (RH40), sorbitan oleate, SDS, Solutol, Soluplus, sucrose esters of fatty acids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, macrogol glycerol hydroxystearic acid oil, PEG-40 castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, polyvinylated protease graft copolymer (PVAc-PVCap-PEG), lauromacrogol arlasolve, poloxamer, labrafil, labrasol, Tween 80, tocopherol polyethylene glycol succinate (TPGS or vitamin E). In some embodiments, the surfactant is a polyvinylcaprolactam-based graft copolymer (PVAc-PVCap-PEG). In some embodiments, the surfactant is tocopheryl polyethylene glycol 1000 succinate. 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, the 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, the PROTAC has a calculated log P or log P of at least 2.0. In some embodiments, the PROTAC is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC, hydrophilic polymer, and surfactant are formulated as an amorphous solid dispersion. In some embodiments, the PROTAC, hydrophilic polymer, surfactant, and optionally an acid are formulated as an amorphous solid dispersion. In some embodiments, the PROTAC, hydrophilic polymer, surfactant, and acid are formulated as an amorphous solid dispersion.

[0218] The surfactant used in the present disclosure can be one or more nonionic surfactants, one or more ionic surfactants, or a mixture thereof. 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, cetostearyl alcohol, and oleyl alcohol. Exemplary nonionic surfactants include polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, polyoxylglycerides (caprylocaproyl macrogol-8 glycerides or PEG-8 caprylic / capric 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 ether (Triton Examples of surfactants include, but are not limited to, polyethylene glycol alkyl phenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), polyethoxylated tallow amine (POEA), and tocopherol polyethylene glycol succinate (i.e., TPGS or vitamin E TPGS). In some embodiments, the surfactant is tocopheryl polyethylene glycol 1000 succinate. In some embodiments, the nonionic surfactant comprises one or more of a fatty alcohol, cetyl alcohol, stearyl alcohol, cetostearyl 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 ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbates), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), polyethoxylated tallow amine (POEA), and tocopherol polyethylene glycol succinate (TPGS or vitamin E TPGS). In some embodiments, the surfactant is tocopheryl polyethylene glycol 1000 succinate.

[0219] In some embodiments, the nonionic surfactant comprises vitamin E TPGS, a block copolymer of polyethylene glycol and polypropylene glycol, or any combination thereof. In some embodiments, the surfactant comprises two or more repeating units, such as polyoxyalkylene units. In some embodiments, the surfactant comprises a polyoxylglyceride (such as caprylocaproyl macrogol-8 glyceride or PEG-8 caprylic / capric glyceride). 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, the ASD comprises two surfactants. In some embodiments, the ASD comprises two or more surfactants. In some embodiments, the ASD comprises a surfactant and the surfactant is lecithin. In some embodiments, the ASD comprises a surfactant and the surfactant is TPGS. In some embodiments, the ASD comprises one or more surfactants and the surfactant comprises lecithin and TPGS.

[0220] In some embodiments, the ionic surfactant has a charged group at 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, docusate sodium, 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.

[0221] In some embodiments, the nonionic surfactant has a number average molecular weight of about 1000 to about 100,000 Da, 2000 to about 20,000 Da, about 4000 to about 15,000 Da, about 6000 to about 12,000 Da, or about 7000 to about 10,000 Da. In some embodiments, the nonionic surfactant has a number average molecular weight of about 7,000 to about 10,000 Da. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 30% to about 99% by weight, about 50% to about 95% by weight, about 60% to about 95% by weight, about 75% to about 90% by weight, or about 80% to about 85% by weight. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 80% to about 85% by weight.

[0222] In some embodiments, the surfactant is selected from fatty acids, phospholipids, sphingolipids, glycolipids, polyketides, sterol lipids, prenol lipids, etc. In some embodiments, the phospholipid is composed of glycerol with a phosphate group attached and two fatty acids. Other terms in the art for phospholipids include glycerophospholipid, phosphoglyceride, diacylglyceride, etc. The phosphate group can be unmodified (i.e., in the structure below, R=H) or modified by attachment to a simple organic molecule, such as, but not limited to, choline, ethanolamine, or serine (i.e., in the structure below, R≠H). The phospholipid can be further modified by one or more substitutions on the hydrocarbon chain.

[0223] [ka]

[0224] phospholipids In one aspect, the pharmaceutical compositions described herein include 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, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and mixtures thereof. Phospholipid derivatives according to the present disclosure include, but are not limited to, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidonoylphosphatidylcholine (DAPC), dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), and distearoylphosphatidylethanolamine (DSPE), distearoylphosphatidylglycerol (DSPG), phosphatidylinositol, dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), and the like, and combinations thereof. In some embodiments, the phospholipids comprise at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% by weight of phosphatidylcholine, hi some embodiments, the phospholipids comprise more than 80% phosphatidylcholine.

[0225] 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 comprises 2.5% to 20% of the total weight of the pharmaceutical composition. In some embodiments, the phospholipid comprises 5% to 17% of the total weight of the pharmaceutical composition. In some embodiments, the phospholipid comprises greater than 80% phosphatidylcholine.

[0226] In some embodiments, the phosphatidylcholine contains a choline group (MeN + It is a phospholipid in which a phosphate group is attached to the lipid bilayer (-CH2-CH2-O-).

[0227] [ka]

[0228] phosphatidylcholine In some embodiments, the ASD comprises a phosphatidylcholine. A non-limiting example of a phosphatidylcholine is 1-oleoyl-2-palmitoyl-phosphatidylcholine, as shown below.

[0229] [ka]

[0230] In some embodiments, the surfactant is lecithin. The USP 40 definition of lecithin is "a complex mixture of acetone-insoluble phospholipids, isolated from crude vegetable oil sources, consisting primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid, along with varying amounts of other substances, such as triglycerides, fatty acids, and carbohydrates." In some embodiments, the lecithin is a mixture of phospholipids. In some embodiments, the lecithin comprises a mixture of phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid. In some embodiments, the lecithin comprises a mixture of phospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. Lecithin can be isolated from a variety of sources, including, but not limited to, eggs, soybeans, milk, marine sources, rapeseed, cottonseed, and sunflower. In some embodiments, the lecithin used in the disclosed solid amorphous dispersions and / or pharmaceutical compositions is isolated from egg yolk. The lecithin can be E322. The lecithin can be egg lecithin. The lecithin can be LSC 5050. The lecithin can be LSC 6040. The lecithin can be mixed soy phosphatides. The lecithin can be ovolecithin. The lecithin can be Phosal 53 MCT. The lecithin can be Phospholipon 100 H. The lecithin can be ProKote LSC. The lecithin can be soy lecithin. The lecithin can be soy phospholipid. The lecithin can be Sternpur. The lecithin can be vegetable lecithin. The lecithin can be 1,2-diacyl-sn-glycero-3-phosphocholine. In some embodiments, the lecithin contains greater 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 soybean extract (e.g., CAS[8030-76-0]). In some embodiments, the lecithin comprises egg yolk lecithin (e.g., CAS[93685-90-6]).

[0231] In some embodiments, the lecithin contains about 10% to about 95% phosphatidylcholine. In some embodiments, the lecithin contains about 15% to about 80% phosphatidylcholine. In some embodiments, the lecithin contains about 20% to about 75% phosphatidylcholine. In some embodiments, the lecithin contains about 25% to about 70% phosphatidylcholine. In some embodiments, the lecithin contains about 30% to about 65% phosphatidylcholine. In some embodiments, the lecithin contains about 35% to about 60% phosphatidylcholine. In some embodiments, the 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%, or 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%, or about 15% to about 25% phosphatidylethanolamine. In some embodiments, the 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, the lecithin contains about 21% phosphatidylcholine, about 22% phosphatidylethanolamine, and about 19% phosphatidylinositol. In some embodiments, the lecithin contains about 69% phosphatidylcholine and about 24% phosphatidylethanolamine. In some embodiments, the lecithin is egg yolk lecithin. In some embodiments, the phosphatidylcholine is derived from an egg source.In some embodiments, the phosphatidylcholine is derived or is of soybean origin.

[0232] In some embodiments, the surfactant is a phospholipid. In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid is a mixture that includes phosphatidylcholine. In some embodiments, the surfactant is lecithin. In some embodiments, the lecithin is a mixture of phospholipids. In some embodiments, the lecithin is composed of phosphatidylcholine. In some embodiments, the lecithin contains more than 25% phosphatidylcholine. In some embodiments, the lecithin contains more than 80% phosphatidylcholine. In some embodiments, the phosphatidylcholine is derived from an egg source. In some embodiments, the phosphatidylcholine is derived from or is derived from a soybean source.

[0233] In some embodiments, the surfactant is present in the ASD described herein at about 10% to about 70% weight percent. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 10% to about 60% weight percent. In some embodiments, the surfactant is present in the amorphous solid dispersion at about 10% to about 50% weight percent. In some embodiments, the surfactant is present in the ASD at about 15% to about 45% weight percent. In some embodiments, the surfactant is present in the ASD at about 20% to about 40% weight percent. In some embodiments, the surfactant is present in the ASD at about 20% to about 30% weight percent. In some embodiments, the surfactant is present in the ASD at about 30% to about 40% weight percent. In some embodiments, the surfactant is 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 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, 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%. The amorphous solid dispersion is present in an amorphous solid dispersion at a weight percent of about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, about 45% to about 50%, about 50% to about 60%, or about 60% to about 70%. In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of 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%. In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%.In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of up to about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of about 20%. In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of about 25%. In some embodiments, the surfactant is present in the solid amorphous dispersion at a weight percent of 40%. In some embodiments, the surfactant is TPGS. In some embodiments, the surfactant is lecithin.

[0234] In some embodiments, the surfactant is present in the 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 15 ... mg~200mg, 10mg~300mg, 10mg~500mg, 10mg~5,000mg, 20mg~30mg, 20mg~50mg, 20mg~80mg, 20mg~100mg, 20mg~150mg, Approximately 20mg to approximately 200mg, approximately 20mg to approximately 300mg, approximately 20mg to approximately 500mg, approximately 20mg to approximately 5,000mg, approximately 30mg to approximately 50mg, approximately 30mg to approximately 80mg, approximately 30mg to approximately 100mg, approximately 30mg to approximately 150mg, approximately 30mg to approximately 20 0mg, 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 50 mg ~ about 500mg, about 50mg - about 5,000mg, about 80mg - about 100mg, about 80mg - about 150mg, about 80mg - about 200mg, about 80mg - about 300mg, about 80mg - about 500mg, about 80mg - about 5,000mg, about 100mg - about It is present in the ASD in an amount of 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 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 up to 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 includes 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, the ASD is formulated in a unit dosage form, such as a capsule or tablet. 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.

[0235] In some embodiments, the surfactant, such as TPGS, SLS, lecithin, or a combination thereof, is present in the ASD in an amount of 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 or more. In some embodiments, lecithin is present in the 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, the 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, 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 greater. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more other additives.In some embodiments, other additives include organic and inorganic acids, hi some embodiments, other additives include antioxidants such as vitamin E.

[0236] In some embodiments, the weight ratio of PROTAC to surfactant is about 2:1 to about 1:10. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:0.5 to about 1:6. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:0.8 to about 1:5. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:0.8 to about 1:3. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:1 to about 1:3. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:0.8 to about 1:2.8. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:0.8 to about 1:2.5. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:1 to about 1:2.5. In some embodiments, the weight ratio of PROTAC to surfactant is about 1:1 to about 1:2. In some embodiments, the weight ratio of PROTAC to surfactant is 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, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0237] In some embodiments, the surfactant comprises 0.1% to 60% of the total weight of the pharmaceutical composition described herein. In some embodiments, the surfactant comprises 0.1% to 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 comprises 1% to 40% of the total weight of the composition. In some embodiments, the surfactant comprises 1% to 30% of the total weight of the composition. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the surfactant comprises 5% to 20% of the total weight of the composition. In some embodiments, the surfactant comprises 10% to 17% of the total weight of the composition. In some embodiments, the surfactant comprises about 15% of the total weight of the composition. In some embodiments, the surfactant comprises about 16% of the total weight of the composition. In some embodiments, the surfactant comprises about 17% of the total weight of the composition. In some embodiments, the surfactant comprises about 15% to 30% of the total weight of the composition. In some embodiments, the surfactant comprises about 10% to 35% of the total weight of the composition. In some embodiments, the surfactant comprises 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 compositions described herein comprise a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the pharmaceutical compositions described herein comprise a PROTAC, a hydrophilic polymer, and a surfactant or poloxamer. In some embodiments, the pharmaceutical compositions described herein comprise a PROTAC, a hydrophilic polymer, and lecithin. In some embodiments, the pharmaceutical compositions described herein comprise a PROTAC, a hydrophilic polymer, and lecithin. In some embodiments, the pharmaceutical compositions described herein comprise a 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, the 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, 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 greater. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0238] 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally comprises one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include an antioxidant (e.g., vitamin E).

[0239] hydrophilic polymer In one aspect, described herein is a pharmaceutical composition comprising an ASD, the ASD comprising a PROTAC, a hydrophilic polymer, a surfactant, and optionally an adsorbent. The hydrophilic polymer may be present in the ASD in an amorphous state. In some embodiments, the PROTAC is a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof. 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, the 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, 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.

[0240] In some embodiments, the pharmaceutical composition comprises an ASD comprising a hydrophilic polymer, in some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (povidone or PVP), vinylpyrrolidone-vinyl acetate copolymer (copovidone), sulfobutylether-β-cyclodextrin, oligosaccharides, polysaccharides, HEC, HPC, PEO, HP-β-CD, PEG, hypromellose phthalate (HPMCP), polymethacrylates (e.g., sold under the trade name Eudragit), HPMC, PVP, polyvinylpolypyrrolidone (PVPP), vinylpyrrolidone-vinyl acetate copolymer, or Kollidon. The hydrophilic polymer may include VA64 (VA64), PVA, hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCP, sulfobutylether-β-cyclodextrin, and at least one of polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG, also known as Soluplus®). In some embodiments, the PVP includes PVP K30. In some embodiments, the HMPC includes HPMC E5 and HMPC E50. In some embodiments, the hydrophilic polymer is sulfobutylether-β-cyclodextrin. In some embodiments, the hydrophilic polymer is a non-ionic polymer. In some embodiments, the hydrophilic polymer is an ionic polymer, such as sulfobutylether-β-cyclodextrin. In some embodiments, the hydrophilic polymer includes copovidone. In some embodiments, the hydrophilic polymer includes povidone. In some embodiments, the hydrophilic polymer comprises sulfobutylether-β-cyclodextrin. In some embodiments, the HPMCAS is HPMCAS-LF. In some embodiments, the hydrophilic polymer comprises vinylpyrrolidone-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).

[0241] In some embodiments, the solid amorphous dispersions described herein comprise a hydrophilic polymer. In some embodiments, the hydrophilic polymer is a non-ionic 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, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG), or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG, also known as Soluplus®), 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 non-ionized and insoluble at low pH. In some embodiments, the enteric polymer comprises a polymethacrylate (e.g., Eudragit), hypromellose phthalate (HPMCP), HPMCAS, or Soluplus. In some embodiments, the polymethacrylate comprises Eudragit.In some embodiments, the polymethacrylate is selected from the group consisting of ammonio methacrylate copolymer (Type A), ammonio 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, methacrylic acid poly(methyl acrylate) 1:2:1, poly(ethyl acrylate, methyl methacrylate) 2:1, poly(methacrylic acid, methyl methacrylate) 1:1, poly(methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, or poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1. In some cases, the enteric polymer comprises cellulose phthalate hydroxypropyl methyl ether, HPMCP, hydroxypropyl methylcellulose benzene-1,2-dicarboxylate, 2-hydroxypropyl methylcellulose phthalate, hypromellosi phthalas, Mantrocel HP-55, or methylhydroxypropyl cellulose phthalate.

[0242] In some embodiments, the hydrophilic polymer is present in the ASD described herein in a weight percent of about 5% to about 90%. 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 from about 5% to about 10%, from about 5% to about 20%, from about 5% to about 30%, from about 5% to about 40%, from about 5% to about 50%, from about 5% to about 60%, from about 5% to about 70%, from about 5% to about 80%, from about 5% to about 90%, from about 10% to about 20%, from about 10% to about 30%, from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 10% to about 70%, from about 10% to about 80%, from about 10% to about 90%, from about 20% to about 30%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%, from about 20% to about 70%, from about 20% to about 80%, It is present in the amorphous solid dispersion at a weight percent of 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP.In some embodiments, the hydrophilic polymer comprises a polymethacrylate (e.g., Eudragit). In some embodiments, the hydrophilic polymer comprises polyvinylcaprolactam-polyvinylacetate-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.

[0243] In some embodiments, the weight ratio of PROTAC or a pharmaceutically acceptable salt thereof to 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 combinations thereof. In some embodiments, the hydrophilic polymer is non-ionic. In some embodiments, the hydrophilic polymer comprises polyvinyl alcohol (PVA), oligosaccharides, polysaccharides, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxide, hydroxypropyl beta-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam 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% to about 70% by weight based on the solids. In some embodiments, the weight ratio of the PROTAC or pharmaceutically acceptable salt thereof to the hydrophilic polymer is about 10:1 to about 1:10. In some embodiments, the PROTAC is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0244] In some embodiments, the ASD is formulated in 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 from about 10 mg to about 50 mg, from about 10 mg to about 100 mg, from about 10 mg to about 150 mg, from about 10 mg to about 200 mg, from about 10 mg to about 300 mg, from about 10 mg to about 500 mg, from about 10 mg to about 800 mg, from about 10 mg to about 1,000 mg, from about 10 mg to about 2,000 mg, from about 10 mg to about 4,000 mg, from about 10 mg to about 6,000 mg, from about 50 mg to about 10 0mg, about 50mg to about 150mg, about 50mg to about 200mg, about 50mg to about 300mg, about 50mg to about 500mg, about 50mg to about 800mg, about 50mg to about 1,000mg, about 50mg to about Approximately 2,000mg, approximately 50mg to approximately 4,000mg, approximately 50mg to approximately 6,000mg, approximately 100mg to approximately 150mg, approximately 100mg to approximately 200mg, approximately 100mg to approximately 300mg, approximately 100mg to approximately 50 0mg, about 100mg to about 800mg, about 100mg to about 1,000mg, about 100mg to about 2,000mg, about 100mg to about 4,000mg, about 100mg to about 6,000mg, about 150mg to about 200mg, about 150mg to about 300mg, about 150mg to about 500mg, about 150mg to about 800mg, about 150mg to about 1,000mg, about 150mg to about 2,000mg, about 150mg to about 4,0 00mg, about 150mg to about 6,000mg, about 200mg to about 300mg, about 200mg to about 500mg, about 200mg to about 800mg, about 200mg to about 1,000mg, about 200mg to about 2,0 00mg, about 200mg to about 4,000mg, about 200mg to about 6,000mg, about 300mg to about 500mg, about 300mg to about 800mg, about 300mg to about 1,000mg, about 300mg to about 2,000mg, about 300mg to about 4,000mg, about 300mg to about 6,000mg, about 500mg to about 800mg, about 500mg to about 1,000mg, about 500mg to about 2,000mg, about 500mg to about 4,000mg, about 500mg to about 6,000mg, about 800mg to about 1,000mg, about 800mg to about 2,000mg, about 800m 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 1000 mg, about 2000 mg, about 4000 mg, about 4000 mg, about 6000 mg, about 800 mg, about 1000 mg, about 2000 mg, about 4000 mg, or about 6000 mg. In some embodiments, the hydrophilic polymer is present in the solid amorphous 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 solid amorphous dispersion in an amount of at most 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.The solid amorphous dispersion is present in an amount of 000 mg. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone K30. 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 polyvinylcaprolactam-polyvinylacetate-polyethylene glycol. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone HPMC. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone HPMC E5. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone HPMC E50.

[0245] In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 500 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 400 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 200 mg of a hydrophilic polymer. 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 75 mg to about 125 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 100 mg of a hydrophilic polymer. In some embodiments, a pharmaceutical composition is provided comprising about 100 mg to about 125 mg of a hydrophilic polymer. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose 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, the ASD comprises two or more hydrophilic polymers. In some embodiments, the two or more hydrophilic polymers are selected from copovidone, HPMCAS, and HPMC.

[0246] 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 comprising about 145 mg to about 150 mg of a hydrophilic polymer.In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose HMPC. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises a polymethacrylate. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinylcaprolactam-polyvinylacetate-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.

[0247] In some embodiments, the hydrophilic polymer comprises about 5% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 10% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 15% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 20% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 25% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 30% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 40% of the total weight of the composition. In some embodiments, the hydrophilic polymer comprises about 50% of the total weight of the composition. In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the hydrophilic polymer comprises HPMCP. In some embodiments, the hydrophilic polymer comprises a polymethacrylate. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinylcaprolactam-polyvinylacetate-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.

[0248] In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 99% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 80% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 60% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 40% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 20% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 10% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 0.1% to about 1% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 20% to about 99% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are provided comprising about 20% to about 80% by weight of a hydrophilic polymer. In some embodiments, pharmaceutical compositions are 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.

[0249] In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion comprises about 1% to about 90% weight percent of the hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 1% to about 80% weight percent of the hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 10% to about 60% weight percent of the hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 20% to about 50% weight percent of the hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises about 20% to about 40% weight percent of the 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% weight percent of the hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises at least about 1%, about 10%, about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 80% by weight of a hydrophilic polymer. In some embodiments, the amorphous solid dispersion comprises at most 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, the hydrophilic polymer is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose 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. In some embodiments, the polymethacrylate comprises Eudragit. In some embodiments, the hydrophilic polymer comprises polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol. 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.

[0250] acid In some embodiments, the amorphous solid dispersion additionally comprises an inorganic or organic acid. The inorganic 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, the PROTAC is a PROTAC in Table 1 or a pharmaceutically acceptable salt thereof.

[0251] In one aspect, described herein are amorphous solid dispersions comprising an API and one or more acids. Also described herein are pharmaceutical compositions comprising the 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 in Table 1 or a pharmaceutically acceptable salt thereof).

[0252] In some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions disclosed herein comprise one or more organic acids. In some embodiments, the one or more organic acids comprise one or more of acetic acid, acrylic acid, adipic acid, alginic acid, amino acids, 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 acids (e.g., methanesulfonic acid, methanedisulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid), aromatic sulfonic acids (e.g., benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid), and uric acid. In some embodiments, the one or more organic acids include methanesulfonic acid, tartaric acid, or both. In some embodiments, the one or more organic acids include methanesulfonic acid and tartaric acid. In some embodiments, the one or more organic acids exclude acetic acid.

[0253] In some embodiments, the organic or inorganic acid is present in the ASD at about 1% to about 60% by weight. In some embodiments, the organic or inorganic acid is present in the ASD at about 5% to about 50% by weight. In some embodiments, the organic or inorganic acid is present in the ASD at about 10% to about 40% by weight. In some embodiments, the organic or inorganic acid is present in the ASD at about 15% to about 30% by weight. In some embodiments, the organic or inorganic acid is present in the ASD at about 15% to about 25% by weight. In some embodiments, the organic or inorganic acid is present in the ASD at about 20% to about 30% by weight.In some embodiments, the organic acid is from about 1% to about 5% by weight, from about 1% to about 10% by weight, from about 1% to about 15% by weight, from about 1% to about 20% by weight, from about 1% to about 25% by weight, from about 1% to about 30% by weight, from about 1% to about 35% by weight, from about 1% to about 40% by weight, from about 1% to about 50% by weight, from about 1% to about 60% by weight, from about 5% to about 10% by weight, from about 5% to about 15% by weight, from about 5% to about 20% by weight, from about 5% to about 25% by weight Weight%, about 5% to about 30% by weight, about 5% to about 35% by weight, about 5% to about 40% by weight, about 5% to about 50% by weight, about 5% to about 60% by weight, 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 50% by weight, about 10% to about 60% 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 50% by weight, about 15% to about 60% 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% to about 50% by weight, about 20% to about 60% by weight, about 25% to about 30% by weight, about 25% to about 35% by weight In some embodiments, the organic 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 40 wt%, about 50 wt%, about 60 wt%, about 25 wt%, about 40 wt%, about 50 wt%, about 60 wt%, about 25 wt%, about 40 wt%, about 50 wt%, or about 60 wt%. In some embodiments, the organic acid is present in the ASD at 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 is present in the ASD at up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, or about 60% by weight. In some embodiments, the organic acid or inorganic acid is present in the pharmaceutical composition but not 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.

[0254] In some embodiments, the one or more organic acids are present in the solid amorphous dispersion and / or pharmaceutical composition in an amount of from about 0.1% to about 99% by weight of the total composition. In some embodiments, the one or more organic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of about 1% to about 80%, about 1% to about 60%, about 1% to about 50%, about 1% to about 25%, about 1% to about 10%, about 1% to about 5%, about 10% to about 80%, about 10% to about 60%, about 10% to about 50%, about 20% to about 80%, about 20% to about 60%, about 20% to about 50%, about 30% to about 80%, about 30% to about 60%, about 30% to about 50%, or about 30% to about 40% by weight of the total composition. In some embodiments, the one or more organic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45% by weight of the total composition. In some embodiments, the one or more organic acids comprise tartaric acid. In some embodiments, the one or more organic acids comprise methanesulfonic acid.In some embodiments, the one or more organic acids are at least 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, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg In some embodiments, the one or more organic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of from about 1.0 mg to about 1000 mg, including, but not limited to, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, or 350 mg. In some embodiments, the one or more organic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of from 1 mg to 500 mg. In some embodiments, the 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, the one or more organic acids are present in an amount of 25 mg to 250 mg. In some embodiments, the one or more organic acids are present in an amount of 150 mg to 250 mg. In some embodiments, the one or more organic acids are present in an amount of 150 mg to 200 mg. In some embodiments, the one or more organic acids are present in an amount of 50 mg to 200 mg. In some embodiments, the amorphous solid dispersion and / or pharmaceutical composition is formulated in a unit dosage form, such as a capsule or tablet. In some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 1 mg to 500 mg. In some embodiments, the organic acid is present in the pharmaceutical composition in an amount between 10 mg and 300 mg.In some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 30 mg to 100 mg, hi some embodiments, the organic acid is present in the pharmaceutical composition in an amount of 30 mg to 80 mg.

[0255] In some embodiments, the one or more organic acids are present in a molar ratio to 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 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 include tartaric acid and methanesulfonic acid.

[0256] In some embodiments, the solid amorphous dispersions described herein comprise 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 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 API is from about 0.1:1 to about 10:1, from about 1:1 to about 8:1, from about 2:1 to about 7:1, from about 4:1 to about 7:1, 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, or from about 0.5:1 The compound is present in a molar ratio to API of about 1:1 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 weight ratio of the second acid to the API is from about 0.1:1 to about 10:1, from about 0.2:1 to about 5:1, from about 0.5:1 to about 3:1, from about 0.2:1 to about 1.2:1, from about 0.4:1 to about 1:1, 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, or from about 0. The first acid is present in a molar ratio to the API of 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.

[0257] In some embodiments, the weight ratio of the second acid to API is from about 0.05:1 to about 20:1, from about 0.5:1 to about 10:1, 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 weight ratio of the second acid to the API is from 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.

[0258] In some embodiments, the amorphous solid dispersions and / or pharmaceutical compositions disclosed herein comprise 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 an equilibrium state in which 1% or more of the inorganic acid is ionized.

[0259] In some embodiments, the one or more inorganic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of about 0.1% to about 99% by weight of the total composition, hi some embodiments, the one or more inorganic acids are present in the amorphous solid dispersion and / or pharmaceutical composition in an amount of about 0.1% to about 80%, 1% to about 80%, about 1% to about 60%, about 1% to about 50%, about 10% to about 80%, about 10% to about 60%, about 10% to about 50%, about 20% to about 80%, about 20% to about 60%, about 20% to about 50%, about 30% to about 80%, about 30% to about 60%, about 30% to about 50%, or about 30% to about 40% by weight of the total composition. In some embodiments, the one or more inorganic acids are present in the solid amorphous dispersion and / or pharmaceutical composition in an amount of about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% by weight of the total composition. In some embodiments, the one or more inorganic acids comprise hydrochloric acid.In some embodiments, the one or more inorganic acids are at least 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, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg The amorphous solid dispersion and / or pharmaceutical composition may be present in an amount of from about 1.0 mg to about 1000 mg, including, but not limited to, 190 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, or 350 mg. In some embodiments, the 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 about 10 mg to about 18 mg. In some embodiments, the amorphous solid dispersion and / or pharmaceutical composition is formulated in a unit dosage form such as a capsule or tablet. In some embodiments, the inorganic acid is present in the pharmaceutical composition in an amount of 1 mg to 500 mg. In some embodiments, the inorganic acid is present in the pharmaceutical composition in an amount of 10 mg to 300 mg. In some embodiments, the inorganic acid is present in the pharmaceutical composition in an amount of 30 mg to 100 mg. In some embodiments, the inorganic acid is present in the pharmaceutical composition in an amount of 30 mg to 80 mg.

[0260] In some embodiments, the amorphous solid dispersions disclosed herein comprise 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 the API to the first acid is from about 0.1:1 to about 10:1. In some embodiments, the molar ratio of the 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 the API to the first acid is about 1:1. In some embodiments, the molar ratio of API to second acid is from about 0.05:1 to about 20:1. In some embodiments, the molar ratio of API to 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.

[0261] Adsorbent In one aspect, the pharmaceutical composition disclosed herein comprises an ASD comprising a PROTAC, a hydrophilic polymer, a surfactant, and optionally an 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, the PROTAC is a PROTAC in 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.

[0262] Many adsorbents are solid, porous, or ultraporous adsorbent materials. The adsorbent has numerous micropores or nanopores within its structure, e.g., 500 mm 2It has a very large surface area exceeding / 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, crosslinked povidone, sodium carboxymethyl cellulose, sodium starch carboxymethyl, and sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin. In some embodiments, the adsorbent is silicon dioxide.

[0263] In some embodiments, the adsorbent, such as silicon dioxide, is present in the ASD at about 1% to about 70% by weight. In some embodiments, the adsorbent is present in the ASD at about 1% to about 5%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 40%, or about 10%. In some embodiments, the adsorbent is present in the ASD at about 5% to about 50% by weight, about 10% to about 60% by weight, about 10% to about 70% by weight, about 20% to about 30% by weight, about 20% to about 40% by weight, about 20% to about 50% by weight, about 20% to about 60% by weight, about 20% to about 70% by weight, about 30% to about 40% by weight, about 30% to about 50% by weight, about 30% to about 60% by weight, about 30% to about 70% by weight, about 40% to about 50% by weight, about 40% to about 60% by weight, about 40% to about 70% by weight, about 50% to about 60% by weight, about 50% to about 70% by weight, or about 60% to about 70% by weight. In some embodiments, the adsorbent is present in the ASD at about 5% to about 40% by weight. In some embodiments, the adsorbent is present in the ASD at about 10% to about 35% by weight. 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 up to 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.

[0264] 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, or about 5 mg ~ about 1,000mg, about 5mg to about 3,000mg, about 5mg to about 5,000mg, about 10mg to about 20mg, about 10mg to about 30mg, about 10mg to about 50mg, about 10mg to about 100mg, about 10mg to about 200mg, about 10mg to about 500mg, about 10mg to about 1,000mg, about 10mg to about 3,000mg, about 10mg to about 5,000mg, about 20mg to about 30mg, about 20mg to about 50mg, about 20mg to about 100mg, about 20mg to about 200mg, about 20mg to about 500mg, about 20mg to about 1,000mg 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 3 0mg to about 5,000mg, about 50mg to about 100mg, about 50mg to about 200mg, about 50mg to about 500mg, about 50mg to about 1,000mg, about 50mg to about 3,000mg, about 50mg to about 5,000mg, about 100mg to about 200mg, about 100mg about 500 mg, about 100 mg to about 1,000 mg, about 100 mg to about 3,000 mg, about 100 mg to about 5,000 mg, about 200 mg to about 500 mg, about 200 mg to about 1,000 mg, about 200 mg to about 3,000 mg, about 200 mg to about 5,000 mg, about 500 mg to about 1,000 mg, about 500 mg to about 3,000 mg, about 500 mg to about 5,000 mg, about 1,000 mg to about 3,000 mg, about 1,000 mg to about 5,000 mg, or 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 in 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.

[0265] In some embodiments, the adsorbent is present in an ASD. In some embodiments, the adsorbent powders described herein have a D50 value of 1 to 1,000 nm. In some embodiments, the adsorbent has a D50 value of about 0.01 to 1,000 nm. In some embodiments, the adsorbent has a D50 value of about 0.01 to about 1,000 nm. In some embodiments, the adsorbent has a D50 value of at least about 0.01 nm. In some embodiments, the adsorbent has a D50 value of at most about 1,000 nm. In some embodiments, the adsorbent has a D50 value of about 1 nm to about 500 nm. In some embodiments, the adsorbent has a D50 value of at least about 1 nm. In some embodiments, the adsorbent has a D50 value of at most about 500 nm. 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 100 nm to about 250 nm, from about 100 nm to about 300 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 100 nm to about 250 nm, from about 100 nm to about 350 nm, from about 100 nm to about 450 nm, from about 100 nm to about 550 nm, from about 100 nm to about 260 nm, from about 100 nm to about 360 nm, from about 100 nm to about 470 nm, from about 100 nm to about 590 nm, from about 100 nm to about 600 nm, from about 100 nm to about 650 nm, from about 100 nm to about 700 nm, from about 100 nm to about 800 nm, from about 100 nm to about 900 nm, from about 100 nm to about 1200 nm, from about 100 nm to about 1400 nm, from about 100 nm to about 260 nm, nm to about 200 nm, about 100 nm to about 230 nm, about 100 nm to about 270 nm, about 100 nm to about 300 nm, about 100 nm to about 400 nm, about 100 nm to about 500 nm, about 200 nm to about 270 nm, about 200 nm to about 300 nm, about 200 nm to about 400 nm, about 200 nm to about 500 nm, about 300 nm to about 400 nm, about 300 nm to about 500 nm, or about 400 nm to about 500 nm. In some embodiments, the D50 value of the adsorbent is about 1 nm to about 100 nm. In some embodiments, the D50 value of the adsorbent is at least about 1 nm. In some embodiments, the adsorbent has a D50 value of about 0.1, 1, 30, 50, 70, 100, 130, 170, 200, 230, 250, 270, 300, 330, 350, 370, 400, 430, 450, 470, 500, 600, 700, 800, 900, or 1000 nm or less. In some embodiments, the adsorbent is a silicon dioxide powder having an average diameter of 1 to 1000 nm. In some embodiments, the silicon dioxide has a D50 value of about 0.01 to 1000 nm.In some embodiments, the silicon dioxide has a D50 value of about 0.01 nm to about 1,000 nm. In some embodiments, the silicon dioxide has a D50 value of about 1 nm to about 100 nm. In some embodiments, the silicon dioxide has a D50 value of at least about 1 nm. In some embodiments, the silicon dioxide has a D50 value of about 0.1, 1, 30, 50, 70, 100, 130, 170, 200, 230, 250, 270, 300, 330, 350, 370, 400, 430, 450, 470, 500, 600, 700, 800, 900, or 1000 nm or less.

[0266] In some embodiments, the ASD comprises an adsorbent, and 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 a pharmaceutical composition with an extra granular additive. In some embodiments, the silicon dioxide is present outside the amorphous solid dispersion as an extra granular additive. In some embodiments, the silicon dioxide is present in the amorphous solid dispersion and is an extra granular additive.

[0267] PROTAC pharmaceutical compositions 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 less than or equal to 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, 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0268] Disclosed herein are pharmaceutical compositions comprising a PROTAC, e.g., a PROTAC compound in Table 1. In some embodiments, the pharmaceutical composition is formulated in a unit dosage form, such as a tablet or capsule. In some embodiments, the PROTAC is present in the pharmaceutical composition in an amount of 10 mg to 1000 mg. In some embodiments, the PROTAC is present in an amount of 20 mg to 500 mg. In some embodiments, the PROTAC is present in an amount of 20 mg to 400 mg. In some embodiments, the PROTAC is present in an amount of 30 mg to 300 mg. In some embodiments, the PROTAC is present in an amount of 20 mg to 300 mg. In some embodiments, the PROTAC is present in an amount of 25 mg to 250 mg. In some embodiments, the PROTAC is present in an amount of 30 mg to 200 mg. In some embodiments, the PROTAC is present in an amount of about 50 mg, about 100 mg, or about 150 mg. In some embodiments, the PROTAC is present in an amount of 50 mg, 100 mg, or 150 mg. In some embodiments, the PROTAC is present in an amount of 50 mg. In some embodiments, the PROTAC is present in an amount of 60 mg. In some embodiments, the PROTAC is present in an amount of 100 mg. In some embodiments, the PROTAC is present in an amount of 150 mg. In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. 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, the PROTAC has a log P of 2.0 or greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0269] In some embodiments, pharmaceutical compositions are provided comprising a PROTAC present in a dose of about 1.0 mg to about 1000 mg. 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 greater. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include antioxidants.

[0270] In some embodiments, a pharmaceutical composition is provided comprising about ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof, present in a dose of about 1.0 mg to about 1000 mg. In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion comprising 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally comprises one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include antioxidants.

[0271] In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 500 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 400 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 200 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 150 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 125 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 100 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 100 mg to about 125 mg of a PROTAC. In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally comprises one or more other additives. In some embodiments, the other additives include organic acids and inorganic acids. In some embodiments, the other additives include antioxidants.

[0272] In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 55 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 60 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 65 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 70 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 80 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 85 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 90 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 95 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 100 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 105 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 110 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 115 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 120 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 125 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 130 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 135 mg to about 150 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 140 mg to about 150 mg of PROTAC. In some embodiments, pharmaceutical compositions are provided comprising about 145 mg to about 150 mg of a PROTAC, hi some embodiments, pharmaceutical compositions are provided comprising about 1 mg to about 50 mg of a PROTAC.In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 40 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 30 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 25 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 50 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 20 mg to about 40 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 10 mg to about 25 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 5 mg to about 20 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 10 mg of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 1 mg to about 20 mg of a PROTAC. In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0273] In some embodiments, a pharmaceutical composition comprising about 50 mg to about 145 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 140 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 135 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 130 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 125 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 120 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 115 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 110 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 105 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition comprising about 50 mg to about 100 mg of PROTAC is provided. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 95 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 90 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 85 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 80 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 75 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 70 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 65 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 60 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 50 mg to about 55 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 25 mg to about 50 mg of PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 40 mg to about 80 mg of a PROTAC.In some embodiments, a pharmaceutical composition is provided comprising about 75 mg to about 125 mg of a 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, the PROTAC is ARV-110 or a pharmaceutically acceptable salt thereof. In some embodiments, the PROTAC is ARV-110. 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0274] In some embodiments, the PROTAC comprises about 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50% of the total weight of the composition. In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. 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 greater. 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 additionally comprises one or more adsorbents. In some embodiments, the amorphous solid dispersion described herein additionally 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.

[0275] In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 99% by weight of a PROTAC, or any number and range therebetween. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 80% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 60% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 40% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 20% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 10% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 0.1% to about 1% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 20% to about 99% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 20% to about 80% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 20% to about 60% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 20% to about 40% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 30% to about 99% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 30% to about 80% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 30% to about 60% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 30% to about 40% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 40% to about 99% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 40% to about 80% by weight of a PROTAC. In some embodiments, a pharmaceutical composition is provided comprising about 40% to about 60% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise about 5% to about 70% by weight of a PROTAC, and in some embodiments, pharmaceutical compositions are provided that comprise about 5% to about 35% by weight of a PROTAC.In some embodiments, about 5% to about 10%, about 5% to about 15%, about 5% to about 18%, about 5% to about 19%, about 5% to about 20%, about 5% to about 21%, about 5% to about 22%, about 5% to about 24%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 10% to about 15%, about 10% to about 18%, about 10% to about 19%, about 10% to about 20%, about 10% to about 21%, about 10% to about 22%, about 10% to about 24%, about 10% to about 25%, about 10% to about 30%, about 10 ...25%, about 10% to about 25%, about 10% to about 25%, about 10% to about 25%, about 10% to about 25%, about 10% to about 25%, about 10% to about 25%, about 10% to about 25%, about 0% to about 24%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 15% to about 18%, about 15% to about 19%, about 15% to about 20%, about 15% to about 21%, about 15% to about 22%, about 15% to about 24%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 18% to about 19%, about 18% to about 20%, about 18% to about 21%, about 18% to about 22%, about 18% to About 24%, about 18% to about 25%, about 18% to about 30%, about 18% to about 35%, about 19% to about 20%, about 19% to about 21%, about 19% to about 22%, about 19% to about 24%, about 19% to about 25%, about 19% to about 30%, about 19% to about 35%, about 20% to about 21%, about 20% to about 22%, about 20% to about 24%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 21% to about 22 %, about 21% to about 24%, about 21% to about 25%, about 21% to about 30%, about 21% to about 35%, about 22% to about 24%, about 22% to about 25%, about 22% to about 30%, about 22% to about 35%, about 24% to about 25%, about 24% to about 30%, about 24% to about 35%, about 25% to about 30%, about 25% to about 35%, or about 30% to about 35% by weight of a PROTAC. In some embodiments, pharmaceutical compositions are provided that comprise a PROTAC at about 5%, about 10%, about 15%, about 18%, about 19%, about 20%, about 21%, about 22%, about 24%, about 25%, about 30%, or about 35% by weight. In some embodiments, pharmaceutical compositions are provided that comprise a PROTAC in a weight percentage of at least about 5%, about 10%, about 15%, about 18%, about 19%, about 20%, about 21%, about 22%, about 24%, about 25%, or about 30%. In some embodiments, pharmaceutical compositions are provided that comprise a PROTAC in a weight percentage of at most about 10%, about 15%, about 18%, about 19%, about 20%, about 21%, about 22%, about 24%, about 25%, about 30%, or about 35%.In some embodiments, the PROTAC is ARV-110 or ARV-471, or a pharmaceutically acceptable salt thereof. 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 greater. In some embodiments, the amorphous solid dispersion comprises a PROTAC, a hydrophilic polymer, and a surfactant. In some embodiments, the amorphous solid dispersions described herein additionally comprise one or more adsorbents. In some embodiments, the amorphous solid dispersions described herein additionally comprise 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.

[0276] 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.

[0277] 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 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 vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sulfobutylether-β-cyclodextrin, hydroxypropyl beta-cyclodextrin (HP-β-CD), or a combination thereof; and iv) an acid.

[0278] In some embodiments, the ASD comprises: i) a PROTAC listed in Table 1 or a pharmaceutically acceptable salt thereof in an amount between about 5% and about 50% by weight of the ASD; ii) one or more surfactants in an amount between about 1% and about 50% by weight of the ASD, wherein the one or more surfactants comprise 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; and iii) a hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), sulfobutylether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl beta-cyclodextrin (HP-β-CD), or a combination thereof; and iv) an acid in an amount of about 1% to about 50% by weight of the ASD.

[0279] 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 are selected from the group consisting of tocopherol polyethylene glycol succinate (TPGS), lecithin, polyethylene glycol, and polypropylene glycol. iii) one or more surfactants, including a block copolymer of ethylene glycol, a polyvinyl caprolactam-based graft copolymer (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 includes a vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), HPMCAS, hydroxypropyl beta cyclodextrin (HP-β-CD), or a combination thereof; and iv) an acid in an amount of about 1% to about 50% by weight of the ASD.

[0280] In some embodiments, the ASD comprises: i) 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) one or more surfactants in an amount of about 1% to about 50% by weight of the ASD, wherein the one or more surfactants comprise 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; and iii) a hydrophilic poly(Asp- ... and iv) optionally 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.

[0281] In some embodiments, the pharmaceutical compositions described herein have a therapeutic efficacy of at least 200 mg / kg / day, with a mean AUC, AUC inf , or AUC last The pharmaceutical composition has a bioavailability, measured as AUC, that is greater than the bioavailability of a corresponding reference composition comprising the crystalline PROTAC or the PROTAC not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability, measured as AUC after oral administration, 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 the crystalline PROTAC or the PROTAC not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a Cmax The crystalline PROTAC exhibits a bioavailability, measured as a function of time, 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 crystalline PROTAC or the corresponding composition comprising the PROTAC not present in an ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability, measured as AUC after oral administration, 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 absent from the ASD capsule comprising ARV-110. In some embodiments, the pharmaceutical composition exhibits a C maxThe ASD capsules containing ARV-110 exhibit a bioavailability, measured as a function of time, 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. In some embodiments, the pharmaceutical compositions exhibit a bioavailability that is about 1.1-fold to about 10-fold greater than the bioavailability of the PROTAC not present in the ASD. In some embodiments, the pharmaceutical composition may be 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 2-fold to about 4-fold, about 2-fold to about 5-fold, fold, about 2 to about 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 10 times, about 3 to about 4 times, about 3 to about 5 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 10 times, about 4 to about 5 times, about 4 to about 6 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 10 times, about 5 to about 6 times, about 5 to about 7 times, about 5 to about 8 times, about 5 to about 10 times, about 6 to about 7 times, about 6 to about 8 times, about 6 to about 10 times, about 7 to about 8 times, about 7 to about 10 times, or about 8 to about 10 times higher bioavailability.

[0282] In some embodiments, the pharmaceutical compositions described herein have an AUC or C maxThe bioavailability of the PROTAC may be at least about 1.1-fold, about 1.3-fold, about 1.5-fold, about 1.8-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold greater than the bioavailability of the PROTAC not present in the ASD, as measured by a fasted bioavailability (Abstract). In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 2-fold greater than the bioavailability of the PROTAC not present in the ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is at least about 4-fold greater than the bioavailability of the PROTAC not present in the ASD. In some embodiments, the pharmaceutical composition exhibits a bioavailability that is up to about 1.3-fold, about 1.5-fold, about 1.8-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, or about 10-fold greater than the bioavailability of the PROTAC not present in the ASD. In some embodiments, the bioavailability is measured in a fasted dog model. In some embodiments, bioavailability is measured in a fed dog model. In some embodiments, the bioavailability of the pharmaceutical composition, as measured as AUC after oral administration, does not change by more than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, or 10% when administered in a fed state compared to when administered in a fasted state ... maxWhen measured as a function of time, 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 administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 100% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 90% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 80% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 70% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 60% when administered orally in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 50% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 40% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability of the pharmaceutical composition does not change by more than 20% when orally administered in a fed state compared to when administered in a fasted state. In some embodiments, the bioavailability is measured in a dog model. In some embodiments, the dog model is a beagle dog.

[0283] In some embodiments, the pharmaceutical composition may be one in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is determined by the AUC or maximum plasma concentration (C max), which is at least 2-fold higher than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a crystalline form). In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that ... max ), that is at least 3, 4, or 5 times greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form (such as a crystalline form). 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.

[0284] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof, measured as the total area under the curve (AUC) or maximum plasma concentration (Cmax) after oral administration to a subject in a fed state, that is at least 1.5-fold greater than the bioavailability of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof in a conventional dosage form. The pharmaceutical composition of any one of claims 1-3, wherein the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof, measured as the total area under the curve (AUC) or maximum plasma concentration (Cmax) after oral administration to a subject in a fed state, is at least 2-, 2.5-, or 3-fold greater than the bioavailability of a corresponding composition comprising the 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 is ARV-110. In some embodiments, the PROTAC is ARV-471.

[0285] In some embodiments, the pharmaceutical composition may be one in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is determined by the AUC or maximum plasma concentration (C max ), which is at least 5-fold greater than the bioavailability of a corresponding composition comprising the 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.

[0286] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 5-fold greater than the bioavailability of a corresponding composition comprising the 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.

[0287] In some embodiments, the pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that is at least 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold greater than the bioavailability of a corresponding composition comprising the 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.

[0288] In some embodiments, the pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition exhibits a bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof that does not change by 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 10% to about 50%, about 10% to about 60%, about 10% to about 15%, about 10% to about 20%, about 10% to about 20%, about 10% to about 20%, about 10% to about 20%, or about 20%. 0% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, about 15% to about 60%, about 20% to about 25%, about 20% to about 30%, about 2 0% 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 3 The bioavailability of the PROTAC compound or pharmaceutically acceptable salt thereof does not change by more than 5% 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 of the PROTAC compound or pharmaceutically acceptable salt thereof that 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%. In some embodiments, the PROTAC is selected from Table 1.

[0289] In some embodiments, the pharmaceutical composition may be a composition in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is measured by AUC or C max In some embodiments, the PROTAC is selected from 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.

[0290] In some embodiments, the pharmaceutical composition may be a composition in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is measured by AUC or C max In some embodiments, the PROTAC is selected from 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.

[0291] In some embodiments, the pharmaceutical composition may be a composition in which the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof is measured by AUC or C max In some embodiments, the PROTAC is selected from 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.

[0292] In some embodiments, the pharmaceutical compositions described herein have an AUC last or C max The bioavailability, measured as a function of time, 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, and the reference composition does not comprise an ASD. In some embodiments, the bioavailability is measured under fasted conditions. In some embodiments, the bioavailability is measured under fed conditions. 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.

[0293] 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.

[0294] 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 pharmaceutically acceptable salt thereof at the end of that 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 pharmaceutically acceptable salt thereof at the end of that 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 pharmaceutically acceptable salt thereof at the end of that period. In some embodiments, the pharmaceutical compositions described herein are shelf-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 pharmaceutically acceptable salt thereof at the end of that period. In some embodiments, the pharmaceutical compositions described herein are shelf-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 contains at most 0.5% by weight of total impurities at the end of that period. In some embodiments, the pharmaceutical compositions described herein are shelf-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 contains at most 0.5% by weight of total impurities at the end of that period. In some embodiments, the pharmaceutical compositions described herein are shelf-stable at 25±2° C. for a period of at least 12 months, and the shelf-stable pharmaceutical composition contains at most 0.5% by weight of total impurities at the end of that period.In some embodiments, the pharmaceutical compositions described herein are shelf-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 shelf-stable pharmaceutical composition contains at most 0.5% by weight of total impurities at the end of that period.

[0295] In one aspect, disclosed herein is a pharmaceutical composition comprising an ASD, the ASD comprising an API, a surfactant, a hydrophilic polymer, optionally an acid, and optionally an adsorbent. In one aspect, disclosed herein is a pharmaceutical composition comprising ...

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition is a) Amorphous solid dispersion (ASD), A proteolytically targeted chimeric (PROTAC) compound or a pharmaceutically acceptable salt thereof, Surfactants and Hydrophilic polymers and Selectively, an acid and It optionally includes an adsorbent, The PROTAC compound or a pharmaceutically acceptable salt thereof, the surfactant, the hydrophilic polymer, and the optionally selected acid are present in the ASD in an amorphous state, and the ASD b) A pharmaceutical composition comprising an optionally pharmaceutically acceptable carrier or excipient.

2. The bioavailability of the PROTAC compound or its pharmaceutically acceptable salt is such that the total area under the curve (AUC) or maximum plasma concentration (C) after oral administration to fasted subjects is such that the bioavailability of the PROTAC compound or its pharmaceutically acceptable salt is such that the bioavailability is such that the total area under the curve (AUC) or maximum plasma concentration (C) is such that the bioavailability of the PROTAC compound or its pharmaceutically acceptable salt ｍａｘ The pharmaceutical composition according to claim 1, which, when measured as ), exhibits a bioavailability that is at least twice that of a corresponding composition comprising the PROTAC compound or a pharmaceutically acceptable salt thereof, without being part of the ASD.

3. The pharmaceutical composition according to claim 1, wherein the bioavailability of the PROTAC compound or the pharmaceutically acceptable salt thereof, when measured as the total area under the curve (AUC) or maximum plasma concentration (C max) after oral administration to a feeding subject, is at least 1.5 times that of a corresponding composition containing the PROTAC compound or the pharmaceutically acceptable salt thereof, without being part of the ASD.

4. The pharmaceutical composition according to claim 1, wherein the bioavailability of the PROTAC compound or a pharmaceutically acceptable salt thereof, when measured as the total area under the curve (AUC) or maximum plasma concentration (C max) after oral administration to a subject, exhibits a bioavailability that does not change by more than 100% when orally administered to a fed subject compared to a fasted subject.

5. The pharmaceutical composition according to claim 1, wherein the PROTAC compound is an androgen receptor PROTAC degrading agent or an estrogen receptor PROTAC degrading agent.

6. The pharmaceutical composition according to claim 1, wherein the PROTAC compound has at least 2.0 log P in octanol-water.

7. The pharmaceutical composition according to any one of claims 1 to 6, 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.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the surfactant is present in the pharmaceutical composition in an amount of about 10% to 60% by weight.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the surfactant comprises a nonionic surfactant, an anionic surfactant, a phospholipid, or any combination thereof, and optionally 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), polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG), or a combination thereof.

10. The pharmaceutical composition according to any one of claims 1 to 6, wherein the surfactant comprises lecithin.

11. The hydrophilic polymer is present in the amorphous solid dispersion in an amount of about 1% to about 80% by weight, wherein the hydrophilic polymer is vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), oligosaccharide, polysaccharide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), polymethacrylate, hypromellose phthalate (HPMCP), polyethylene oxide, hydroxypropyl A pharmaceutical composition according to any one of claims 1 to 6, comprising ropylbeta cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene glycol (PEG), polyvinyl acetate and polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PCL-PVAc-PEG), or a combination thereof.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the amorphous solid dispersion contains an acid, and optionally 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.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the ASD comprises the adsorbent, and the adsorbent is silicon dioxide.

14. The pharmaceutical composition according to any one of claims 1 to 6, wherein the adsorbent is present in the amorphous solid dispersion in an amount of about 10% by weight to about 60% by weight.

15. The pharmaceutical composition according to any one of claims 1 to 6, wherein the adsorbent is present in the amorphous solid dispersion in an amount of about 10% by weight to about 40% by weight.

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is storage stable for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or 24 months at 5 ± 3°C, 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, and the storage stable pharmaceutical composition contains a maximum of 0.5% by weight of total impurities at the end of the period.

17. The pharmaceutical composition is a) Amorphous solid dispersion, The PROTAC compound or a pharmaceutically acceptable salt thereof in an amount of approximately 5% to approximately 50% by weight of the ASD, The surfactant in an amount of about 1% to about 50% by weight of the ASD, 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, The hydrophilic polymer in an amount of about 5% to about 70% by weight of the ASD, wherein the hydrophilic polymer comprises vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polymethacrylate, hypromellose phthalate (HPMCP), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl beta-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin, or a combination thereof, An amorphous solid dispersion comprising an acid in an amount of approximately 1% to approximately 50% by weight of the ASD, b) A pharmaceutical composition according to any one of claims 1 to 6 or 16, comprising an optionally pharmaceutically acceptable carrier or excipient.

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