Formulation of therapeutic agents for improved permeability

Abstract

This disclosure provides compositions and methods for enhanced delivery of a therapeutic agent to a target, wherein the composition comprises a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 498,410, filed on 26 April 2023, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Routes of drug administration that do not require injection (e.g., intravenous, intramuscular, or subcutaneous injection) are often preferred due to the convenience of drug administration, cost-effectiveness, and ease of large-scale production of non-injectable formulations (e.g., oral formulations). Furthermore, patient compliance is generally high, at least in the case of oral formulations (see, for example, Khan, K., et al. (2008) J. Behav. Med. 31(3), 213-224). However, the effectiveness of therapeutic agents administered via routes that require crossing physiological barriers (e.g., the intestinal barrier) can be limited by their bioavailability (see, for example, Martinez, MN, et al. J. Clin. Pharmacol. 2002, 42, 620-643; Waring, MJ, et al. Nat. Rev. Drug Discov. 2015, 14, 475-486; Ward, KWIn Reducing Drug Attrition; Topics in Medicinal Chemistry; Springer: Berlin, Germany, 2012). For example, oral bioavailability depends at least in part on the physicochemical properties of the therapeutic agent, such as solubility and intestinal permeability. In fact, poor drug absorption in the small intestine presents a major challenge in the development of oral drug formulations (see, for example, Goldberg, et al (2003) Nat. Rev. Drug Discov. 2:289; Ensigna, et al (2012) Adv Drug Deliv Rev 64:557). Therefore, there is a need for formulations that improve the gastrointestinal (GI) permeability and bioavailability of therapeutic agents. [Overview of the Initiative]

[0003] In some embodiments, the present disclosure provides compositions comprising: i) a compound comprising a polypeptide having a molecular weight of about 1 kDa to about 250 kDa; and (ii) a certain amount of at least one bile acid or a salt thereof at an effective concentration higher than the critical micelle concentration (CMC) of a bile salt.

[0004] In some embodiments, the present disclosure provides compositions comprising (i) a nucleic acid-containing compound and (ii) at least one bile acid or a salt thereof in an effective concentration higher than the CMC of the bile salt.

[0005] In some embodiments, the present disclosure provides a composition comprising (i) a Class III or Class IV compound according to the Biopharmaceutical Classification System (BCS), and (ii) a certain amount of at least one bile acid or a salt thereof, wherein the amount of at least one bile acid or a salt thereof is at an effective concentration higher than the CMC of the bile acid or salt thereof.

[0006] In some embodiments of any of the aforementioned or related embodiments, the composition comprises a pharmaceutically acceptable salt of a bile acid. In some embodiments, the bile acid or a salt thereof comprises three, four, or five ring structures. In some embodiments, the bile acid or a salt thereof comprises a steroid nucleus. In some embodiments, the steroid nucleus comprises one, two, or three hydroxyl groups. In some embodiments, the 3-position of the steroid nucleus comprises a hydroxyl group. In some embodiments, the 7-position, 12-position, or both of the steroid nucleus comprises a hydroxyl group. In some embodiments, the 17-position of the steroid nucleus comprises a carboxylate side chain. In some embodiments, the 17-position of the steroid nucleus comprises an ester or amino side chain. In some embodiments, the amino side chain is selected from taurine and glycine. In some embodiments, the bile acid or its salt is selected from sodium taurocholate (STC), sodium glycocholate (GCA), sodium cholate (CHA), 3-[(3-collamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), sodium taurodeoxycholate (TDCA), sodium glycodeoxycholate (GDCA), sodium deoxycholate (DCA), sodium taurochenodeoxycholate (TCDCA), sodium glycochenodeoxycholate (GCDCA), and sodium chenodeoxycholate (CDCA). In some embodiments, the bile acid or its salt has a CMC of about 30 mg / mL, about 20 mg / mL, about 15 mg / mL, or less than about 5 mg / mL. In some embodiments, the CMC is measured by a method selected from potentiometric, spectroscopic, and light scattering methods.

[0007] In some embodiments, the present disclosure provides a composition comprising: i) a compound comprising a polypeptide having a molecular weight of about 1 kDa to about 250 kDa; and (ii) a certain amount of at least one bile acid or salt thereof in an effective concentration higher than the CMC of the bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof.

[0008] In some embodiments, the Disclosure provides a composition comprising (i) a nucleic acid-containing compound, and (ii) a certain amount of at least one bile acid or salt thereof in an effective concentration higher than the critical micelle concentration (CMC) of a bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof.

[0009] In some embodiments, the present disclosure provides a composition comprising (i) a Class III or Class IV compound according to the Biopharmaceutical Classification System (BCS), and (ii) a certain amount of at least one bile acid or salt thereof in an effective concentration higher than the CMC of the bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof.

[0010] In some embodiments of the aforementioned or related aspects, the composition comprises glycocholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises taurocholic acid or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments of any of the aforementioned or related aspects, the amount of at least one bile acid or a salt thereof is effective in increasing the GI permeability of the polypeptide compared to the GI permeability of the polypeptide alone. In some embodiments, the amount of at least one bile acid or a salt thereof is effective in increasing the intestinal permeability of the polypeptide compared to the intestinal permeability of the polypeptide alone. In some embodiments, the polypeptide has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. Some subscriptions, polypeptides are approximately 1kDa to 5kDa, approximately 2kDa to 5kDa, approximately 3kDa to 5kDa, approximately 1kDa to 10kDa, approximately 2kDa to 10kDa, approximately 5kDa to 10kDa, approximately 5kDa to 20kDa, approximately 5kDa to 50kDa, approximately 10kDa to 50kDa, approximately 10kDa to 20kDa, approximately 5kDa to 50kDa, approximately 10kDa to 20kDa, approximately 5kDa to 50kDa, approximately 10kDa to 20kDa, approximately 5kDa to 20kDa, approximately 5kDa to 20kDa, approximately 5kDa to 20kDa, approximately 10 The polypeptide has a molecular weight of 100 kDa, approximately 10 kDa to approximately 150 kDa, approximately 50 kDa to approximately 150 kDa, approximately 100 kDa to approximately 150 kDa, approximately 50 kDa to approximately 200 kDa, approximately 100 kDa to approximately 200 kDa, approximately 100 kDa to approximately 250 kDa, approximately 150 kDa to approximately 250 kDa, or approximately 200 kDa to approximately 250 kDa. In some embodiments, the polypeptide is selected from enzymes, antibodies or their antigen-binding fragments, antimicrobial agents, hormones, growth factors, chemokines, cell signaling factors, and cytokines. In some embodiments, the polypeptide is an enzyme. In some embodiments, the polypeptide is a hormone. In some embodiments, the polypeptide is an antibody or its antigen-binding fragment. In some embodiments, the polypeptide is a growth factor. In some embodiments, the polypeptide is a chemokine. In some embodiments, the polypeptide is a cytokine. In some embodiments, the polypeptide is a cell signaling factor. In some embodiments, the polypeptide is a recombinant protein. In some embodiments, the polypeptide is a therapeutic peptide.

[0012] In some embodiments of any of the aforementioned or related embodiments, the amount of at least one bile acid or a salt thereof is effective in increasing the GI permeability of the nucleic acid compared to the GI permeability of the nucleic acid alone. In some embodiments, the amount of at least one bile acid or a salt thereof is effective in increasing the intestinal permeability of the nucleic acid compared to the intestinal permeability of the nucleic acid alone. In some embodiments, the nucleic acid comprises a ribonucleoside, a deoxyribonucleoside, or a combination thereof. In some embodiments, the nucleic acid is selected from immunostimulatory oligonucleotides, mRNA, plasmid DNA, and RNA interfering oligonucleotides. In some embodiments, the nucleic acid is an immunostimulatory oligonucleotide. In some embodiments, the nucleic acid is mRNA. In some embodiments, the nucleic acid is plasmid DNA. In some embodiments, the nucleic acid is an RNA interfering oligonucleotide. In some embodiments, the RNA interfering oligonucleotide is selected from siRNA, shRNA, miRNA, and antisense oligonucleotides. In some embodiments, the antisense oligonucleotide is a gapmer. In some embodiments, the nucleic acid comprises one or more modified nucleosides. In some embodiments, the modifications are selected from modified sugar moieties, modified nucleoside bonds, modified nucleic acid bases, and combinations thereof. In some embodiments, the composition comprises a viral vector containing nucleic acids.

[0013] In some embodiments of any of the aforementioned or related embodiments, the amount of at least one bile acid or a salt thereof is effective in increasing the GI permeability of a class III or class IV compound compared to the GI permeability of the compound alone. In some embodiments, the amount of at least one bile acid or a salt thereof is effective in increasing the intestinal permeability of a class III or class IV compound compared to the intestinal permeability of the compound alone. In some embodiments, the composition comprises a class III compound by BCS. In some embodiments, the composition comprises a class IV compound by BCS. In some embodiments, the compound has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the compound has a molecular weight of about 0.1 to about 1 kDa. In some embodiments, the compound is selected from polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, and combinations thereof.

[0014] In some embodiments of any of the aforementioned or related aspects, the effective concentration of at least one bile acid or its salt is about 2 to about 200 times greater than that of CMC. In some embodiments, the effective concentration of at least one bile acid or its salt is at least about 3, 4, 5, 6, 7, 8, 9, or 10 times greater than that of CMC. In some embodiments, the effective concentration is about 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or about 200 times greater than that of CMC. In some embodiments, the effective concentration of at least one bile acid or its salt is about 32 mg / mL to 160 mg / mL. In some embodiments, the effective concentration of at least one bile acid or its salt is at least about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 90 mg / mL, about 95 mg / mL, or about 100 mg / mL. In some embodiments, the amount of at least one bile acid or its salt is effective in increasing the GI permeability of the compound compared to the GI permeability of the compound alone. In some embodiments, the amount of at least one bile acid or its salt is effective in increasing the intestinal permeability of the compound compared to the intestinal permeability of the compound alone. In some embodiments, the composition contains an effective amount of the compound. In some embodiments, the composition contains one, two, three, or four bile acids or their salts.

[0015] In some embodiments of any of the aforementioned or related aspects, the composition further comprises at least one co-excipient in a certain amount.

[0016] In some embodiments, at least one co-excipient is selected from chelating agents, polymers, dendrimers, nanoparticles, lipids, alkyl acids, and combinations thereof. In some embodiments, the amount of at least one co-excipient is effective in increasing compound permeability compared to the intestinal permeability of the control composition, and optionally, the control composition is formulated without at least one co-excipient. In some embodiments, at least one co-excipient is a chelating agent. In some embodiments, the chelating agent is selected from ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetate sodium (EGTA), ethylene dinitrilotetraacetate sodium (EDTA), sodium glutamate (AAE), and combinations thereof. In some embodiments, the composition contains a certain amount of chelating agent at a concentration of about 5 mg / mL to about 100 mg / mL.

[0017] In some embodiments, at least one co-excipient is a polymer. In some embodiments, the polymer is a homopolymer or copolymer, and optionally, the copolymer is selected from block copolymers, random copolymers, graft copolymers, and alternating copolymers. In some embodiments, the polymer includes poly(methacrylate), poly(ethyl acrylate), poly(ethylene glycol), hyaluronic acid, polysaccharides, chitosan, arginine, poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(ethyleneimine), poly(N-(2-hydroxypropyl)methacrylamide), poly(glycolic acid), poly(lactic acid), poly(lactic acid-coglycolic acid), poly(caprolactone), poly(orthoester), poly(anhydride), poly(amide), poly(esteramide), poly(phosphoester), poly(alkyanoacrylate), or combinations thereof. In some embodiments, the polymer has a molecular weight of about 0.5 kDa to about 100 kDa. In some embodiments, the polymer is branched, and optionally, the polymer includes star-shaped, H-shaped, pom-pom-shaped, or comb-shaped architectures. In some embodiments, the polymer is selected from Eudragit E PO (EPO), Eudragit RL100 (RL100), poly(ethylene glycol) 1kDa (PEG-1kDa), branched poly(ethyleneimine) 800Da (PEI:b0.8), Kollidon SR (KOLSR), poly(methacrylic acid) 5kDa (PMA:5), poly(aspartic acid) 2kDa (POLD:2), poly(2-ethyl oxazoline) 25kDa (POXZ:25), poly(glutamic acid) 50kDa (POLE:50), branched poly(ethyleneimine)-co-poly(ethylene glycol) 500Da (bPEIPPEG:0.5), and Vivacoat (VIVA). In some embodiments, the composition contains a polymer in an amount at a concentration of about 5 mg / mL to about 150 mg / mL.

[0018] In some embodiments, at least one co-excipient is a dendrimer. In some embodiments, the dendrimer comprises a poly(amidoamine), poly(propyleneimine), polyamide, polyether, polyester, or phosphorus-based architecture. In some embodiments, the dendrimer is a first-generation (G1), G2, G3, G4, G5, G6, G7, G8, G9, G10, or G11 dendrimer. In some embodiments, the dendrimer is selected from 3.5-generation carboxylate-terminated poly(amidoamine) dendrimers (DENDAC3.5) and 4th-generation amine-terminated poly(amidoamine) dendrimers (DENDAM4). In some embodiments, the composition contains an amount of dendrimer at a concentration of about 0.1 mg / mL to about 50 mg / mL.

[0019] In some embodiments, at least one co-excipient is microparticles. In some embodiments, the microparticles are fine particles or nanoparticles. In some embodiments, the microparticles are selected from inorganic particles, carbon particles, ceramic particles, metal particles, polymer particles, liposomes, lipid nanoparticles, and combinations thereof. In some embodiments, the microparticles include metal oxides, metal salts, mineral colloids, inorganic salts, and combinations thereof. In some embodiments, the microparticles are carbon particles, optionally fullerenes, or carbon nanotubes. In some embodiments, the microparticles are selected from tribasic calcium phosphate nanoparticles (CaPO4), dibasic calcium phosphate nanoparticles (CaHPO4), 5 μm spherical hydroxyapatite nanoparticles (HAP:5U), 2.5 μm spherical hydroxyapatite nanoparticles (HAP:2.5U), zinc oxide nanoparticles (ZNO:r10n), hydroxyapatite rod-shaped nanoparticles with a diameter of 40 nm (HAP:r40n), and carbon black nanoparticles with a diameter of 13 nm (CB:13n). In some embodiments, the amount of microparticles is in an effective concentration of about 0.1 mg / mL to about 100 mg / mL.

[0020] In some embodiments of any of the aforementioned or related embodiments, the amount of at least one bile acid or a salt thereof (e.g., in milligrams (mg)) is substantially equal to the effective concentration (e.g., effective concentration in units of weight per volume, (e.g., mg / mL)) obtained by multiplying it by a dilution factor (e.g., dilution factor in volume (e.g., mL)). In some embodiments, the effective concentration of at least one bile acid or a salt thereof is determined using a method for measuring GI (e.g., intestinal) permeability described herein, e.g., a GI-ORIS screening assay. In some embodiments, the amount of at least one co-excipient (e.g., in milligrams (mg)) is substantially equal to the effective concentration (e.g., effective concentration in units of weight per volume, (e.g., mg / mL)) obtained by multiplying it by a dilution factor (e.g., dilution factor in volume (e.g., mL)). In some embodiments, the effective concentration of at least one co-excipient is determined using a method for measuring GI (e.g., intestinal) permeability described herein, e.g., a GI-ORIS screening assay. In some embodiments, the dilution factor is substantially equal to the liquid volume of the GI tube. In some embodiments, the dilution factor is substantially equal to the liquid volume of the GI tube from which the contents of the composition are released after administration. In some embodiments, the dilution factor is substantially equal to the liquid volume of the stomach, the liquid volume of the small intestine, or the sum of both. In some embodiments, the dilution factor (mL) is about 2 mL to about 30 mL. In some embodiments, the dilution factor (mL) is about 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL. In some embodiments, the composition is formulated for immediate release, and the dilution factor is less than about 30 mL, less than about 25 mL, less than about 20 mL, or less than about 15 mL. In some embodiments, the composition is formulated for immediate release, with dilution ratios of approximately 10 mL to approximately 20 mL, or approximately 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL.In some embodiments, the composition is formulated for delayed release, with dilution factors of less than about 15 mL, less than about 10 mL, or less than about 5 mL. In some embodiments, the composition is formulated for delayed release, with dilution factors of about 2 mL to about 15 mL, or about 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, or 15 mL. In some embodiments, the amount of at least one bile acid or its salt is about 60 mg to about 1,200 mg. In some embodiments, the amount of at least its co-excipient is about 0.1 mg to about 600 mg.

[0021] In some embodiments, the present disclosure provides dosage forms comprising compositions described herein. In some embodiments, the amount of at least one bile acid or a salt thereof is sufficient to achieve an effective concentration at the absorption site in the GI tubule. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a liquid dosage form. In some embodiments, the solid dosage form is formulated for immediate release. In some embodiments, the solid dosage form is formulated for delayed release. In some embodiments, the solid dosage form includes an enteric coating. In some embodiments, the solid dosage form is formulated to release its contents in the stomach after oral administration. In some embodiments, the solid dosage form is formulated to release its contents in the small intestine after oral administration.

[0022] In some embodiments, this disclosure provides a pharmaceutical composition comprising a composition or dosage form described herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for enteral administration. In some embodiments, the pharmaceutical composition is formulated for rectal administration. In some embodiments, the pharmaceutical composition is formulated for intragastric or intraduodenal administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for sublingual or buccal administration. In some embodiments, the pharmaceutical composition is formulated for ophthalmic or nasal administration. In some embodiments, the pharmaceutical composition is formulated for topical administration.

[0023] In some embodiments, the Disclosure provides a method for enhancing the GI permeability of a compound, the method comprising administering a composition, dosage form, or pharmaceutical composition described herein to a GI tissue. In some embodiments, the GI tissue includes gastric tissue, intestinal tissue, rectal tissue, or a combination thereof. In some embodiments, the GI permeability of the compound is increased compared to the GI permeability of a control composition. In some embodiments, the control composition includes the compound alone. In some embodiments, the GI permeability of the compound is increased by at least about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 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 compared to the GI permeability of a control composition. In some embodiments, the GI permeability of the compound is increased by approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or 300 times compared to the GI permeability of the control composition.

[0024] In some embodiments, the Disclosure provides a method for enhancing the intestinal permeability of a compound, the method comprising administering a composition, dosage form, or pharmaceutical composition described herein into intestinal tissue. In some embodiments, the intestinal permeability of the compound is increased compared to the intestinal permeability of a control composition. In some embodiments, the control composition comprises the compound alone. In some embodiments, the intestinal permeability of the compound is increased by at least about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 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 compared to the intestinal permeability of a control composition. In some embodiments, the intestinal permeability of the compound is increased by approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or 300 times compared to the intestinal permeability of the control composition.

[0025] In some embodiments of the aforementioned or related aspects, GI permeability (e.g., intestinal permeability) is measured in vivo or in vitro using a Transwell permeability assay, a Ussing chamber assay, or a GI tube-organ robot interface system (GI-ORIS) based permeability assay.

[0026] In some embodiments, the Disclosure provides a method for increasing the bioavailability of a compound in a subject, the method comprising administering a composition, dosage form, or pharmaceutical composition described herein into a GI tube of the subject, wherein the composition, dosage form, or pharmaceutical composition comprises an effective dose of the compound.

[0027] In some embodiments of the aforementioned or related aspects, administration is in vivo. In some embodiments, administration is enteral. In some embodiments, administration is transrectal, intraduodenal, or oral. In some embodiments, administration is sublingual or buccal.

[0028] In some embodiments, the Disclosure provides a method for increasing the bioavailability of a compound in a subject, the method comprising orally administering a composition, dosage form, or pharmaceutical composition described herein to the subject, wherein the composition, dosage form, or pharmaceutical composition comprises an effective dose of the compound.

[0029] In some embodiments of the aforementioned or related aspects, the bioavailability of the compound is increased compared to the bioavailability of the control composition. In some embodiments, the control composition comprises the compound alone. In some embodiments, the plasma peak of the compound is increased compared to the plasma peak of the control composition. In some embodiments, the control composition comprises the compound alone.

[0030] In some embodiments, the Disclosure provides a method for preventing or treating a disease or disorder in a subject, comprising administering to the subject a composition, dosage form, or pharmaceutical composition described herein, wherein the composition, dosage form, or pharmaceutical composition comprises an effective dose of the compound. In some embodiments, the administration is enteral. In some embodiments, the administration is transrectal. In some embodiments, the administration is intraduodenal. In some embodiments, the administration is oral. In some embodiments, the administration is sublingual or buccal. In some embodiments, the administration is topical. In some embodiments, the administration is transdermal. In some embodiments, the administration is nasal. In some embodiments, the administration is ophthalmic.

[0031] In some embodiments, the Disclosure provides a method for preventing or treating a disease or disorder in a subject, comprising orally administering to the subject a composition, dosage form, or pharmaceutical composition described herein, wherein the composition, dosage form, or pharmaceutical composition comprises an effective dose of a compound.

[0032] In some embodiments, the Disclosure provides the use of the compositions, dosage forms, or pharmaceutical compositions described herein to increase the bioavailability of a compound in a subject.

[0033] In some embodiments, this disclosure provides the use of the compositions, dosage forms, or pharmaceutical compositions described herein in the manufacture of agents for increasing the bioavailability of compounds in a subject.

[0034] In some embodiments, this disclosure provides the use of a composition, dosage form, or pharmaceutical composition described herein for the prevention or treatment of a disease or disorder of interest.

[0035] In some embodiments, this disclosure provides the use of the compositions, dosage forms, or pharmaceutical compositions described herein in the manufacture of agents for preventing or treating diseases or disorders in a subject.

[0036] In some embodiments, the Disclosure provides a kit comprising a container containing a composition, a dosage form, or a pharmaceutical composition as described herein, and a package insert containing instructions for administering the composition or pharmaceutical composition to increase the bioavailability of the compound in a subject from a GI tube.

[0037] In some embodiments, the Disclosure provides a kit comprising a container containing a composition, a dosage form, or a pharmaceutical composition as described herein, and a package insert containing instructions for orally administering the composition or pharmaceutical composition for increasing the bioavailability of the compound in a subject.

[0038] In some embodiments, the Disclosure provides a kit comprising a container containing a composition, a dosage form, or a pharmaceutical composition as described herein, and a package insert containing instructions for administering the composition or pharmaceutical composition for the prevention or treatment of a disease or disorder in a subject.

[0039] In some embodiments, the Disclosure provides a kit comprising a container containing a composition, a dosage form, or a pharmaceutical composition as described herein, and a package insert containing instructions for orally administering the composition or pharmaceutical composition for the prevention or treatment of a disease or disorder in a subject. [Brief explanation of the drawing]

[0040] [Figure 1] Table 3 provides bar graphs showing enhanced intestinal permeability measured in vitro using the GI-Tube-Organ Robot Interface System (GI-ORIS) for human calcitonin (A), human insulin (B), semaglutide (C), or vancomycin (D) formulated with the bile acids or combinations of bile acids specified in Table 3. Enhanced peptide permeability is expressed as an increased change in permeability ratio compared to the unformulated buffer control (bars represent the mean of 6 replicates, and error bars represent the standard deviation). [Figure 2A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with sodium glycocholate (GCA) at different concentrations (the formulations corresponding to the formulation IDs in B are provided in Table 4). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (darker shades indicate increased vancomycin permeability, and dashed lines indicate vancomycin permeability at the lowest concentration (GCA at 128 mg / mL) where the greatest effect was observed). [Figure 2B]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with sodium glycocholate (GCA) at different concentrations (the formulations corresponding to the formulation IDs in B are provided in Table 4). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (darker shades indicate increased vancomycin permeability, and dashed lines indicate vancomycin permeability at the lowest concentration (GCA at 128 mg / mL) where the greatest effect was observed). [Figure 3A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with sodium taurocholate (STC) at different concentrations (formulations corresponding to formulation IDs in B are provided in Table 5). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (darker shades indicate increased vancomycin permeability, and dashed lines indicate vancomycin permeability at the lowest concentration (STC at 128 mg / mL) where the greatest effect was observed). [Figure 3B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with sodium taurocholate (STC) at different concentrations (formulations corresponding to formulation IDs in B are provided in Table 5). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (darker shades indicate increased vancomycin permeability, and dashed lines indicate vancomycin permeability at the lowest concentration (STC at 128 mg / mL) where the greatest effect was observed). [Figure 4A]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and chelating agents (the formulations corresponding to the formulation IDs in B are provided in Table 6). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 4B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and chelating agents (the formulations corresponding to the formulation IDs in B are provided in Table 6). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 5A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and chelating agents (formulations corresponding to formulation IDs in B are provided in Table 7). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 5B]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and chelating agents (formulations corresponding to formulation IDs in B are provided in Table 7). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 6A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and polymer (formulations corresponding to formulation IDs in B are provided in Table 8). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 6B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and polymer (formulations corresponding to formulation IDs in B are provided in Table 8). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 7A]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and polymer (formulations corresponding to formulation IDs in B are provided in Table 9). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 7B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and polymer (formulations corresponding to formulation IDs in B are provided in Table 9). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 8A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and dendrimers (formulations corresponding to formulation IDs in B are provided in Table 10). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 8B]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and dendrimers (formulations corresponding to formulation IDs in B are provided in Table 10). The enhancement of vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 9A] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and nanoparticles (formulations corresponding to formulation IDs in B are provided in Table 11). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 9B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with GCA and nanoparticles (formulations corresponding to formulation IDs in B are provided in Table 11). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with GCA alone at 128 mg / mL). [Figure 10A]Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and nanoparticles (formulations corresponding to formulation IDs in B are provided in Table 12). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 10B] Beeswamp and bar plots are provided to quantify the permeability measured by GI-ORIS for vancomycin formulated with STC and nanoparticles (formulations corresponding to formulation IDs in B are provided in Table 12). Enhanced vancomycin permeability is expressed as the logarithmic mean of vancomycin permeability scaled across experiments, with each circle or bar corresponding to the mean of all experimental data for a given formulation over 1 to 5 experiments (n=6 to 30) (dark shading indicates increased vancomycin permeability, and dashed lines indicate vancomycin permeability formulated with STC alone at 128 mg / mL). [Figure 11] This provides a two-dimensional heatmap quantifying the permeability of vancomycin, as measured by GI-ORIS, for vancomycin formulated with bile salts alone (GCA or STC) or in combination with bioceramic nanoparticles (hydroxyapatite microparticles, zinc oxide microparticles) at different concentrations. The values ​​are the mean logarithm of inter-experiment scaled vancomycin permeability, aggregated over 2–4 experiments (n=12–24). Cells are shaded brighter as vancomycin permeability increases. [Figure 12A]This provides a two-dimensional heatmap quantifying the permeability of vancomycin, as measured by GI-ORIS, for vancomycin formulated with bile salts (GCA or STC) alone or in combination with chelating agents (egtazic acid or glutamic acid) at different concentrations. The values ​​are the mean logarithm of inter-experiment scaled vancomycin permeability, aggregated over 2–4 experiments (n=12–24). Cells are shaded brighter as vancomycin permeability increases. [Figure 12B] This two-dimensional heatmap quantifies the permeability of human insulin formulated with bile salts (GCA or STC) alone, or in combination with chelating agents (egtazic acid or glutamic acid) at different concentrations, as measured by GI-ORIS. The value represents the mean magnification increase in permeability compared to the unformulated buffer control (n=6). Cells are shaded brighter as insulin permeability increases. [Figure 12C] This provides a two-dimensional heatmap quantifying the permeability of semaglutide, formulated with bile salts (GCA or STC) alone or in combination with chelating agents (egtazuic acid or glutamic acid) at different concentrations, as measured by GI-ORIS. The value represents the average percentage permeability of semaglutide (n=6). Cells are shaded brighter as semaglutide permeability increases. [Figure 12D] This provides a two-dimensional heatmap quantifying the permeability of human calcitonin, as measured by GI-ORIS, for bile salts alone (STC) or in combination with chelating agents (egtazuic acid) at multiple concentrations. The value represents the average percentage permeability of calcitonin (n=6). Cells are shaded brighter as calcitonin permeability increases. [Figure 13]This bar graph quantifies the permeability of vancomycin formulated with STCs and chelating agents, as measured by GI-ORIS (formulations corresponding to formulation IDs are provided in Table 13). The values ​​are the mean logarithm of vancomycin permeability scaled across experiments and aggregated over a single experiment (n=6). [Figure 14] This bar graph quantifies the in vivo bioavailability of semaglutide after intraduodenal administration in rats of a benchmark formulation of semaglutide containing sodium caprate, or a semaglutide formulation containing bile acids (STCs) and additional co-excipients (formulations corresponding to formulation IDs are identified in Table 14). Control rats received intravenous injection of the formulations. Bioavailability is expressed as the percentage of plasma peptide concentration after intraduodenal administration compared to plasma peptide concentration (%F) after intravenous administration (** indicates a p-value of less than 0.01 compared to the benchmark formulation). [Figure 15] This document provides bar graphs quantifying the in vivo bioavailability of vancomycin after intraduodenal administration in rats, comparing unformulated vancomycin or vancomycin formulated with bile acids (GCA or STC) and additional co-excipients, in a buffered control (formulations corresponding to formulation IDs are identified in Table 15). Control rats received intravenous injection of the formulations. Bioavailability is expressed as the percentage of plasma peptide concentration after intraduodenal administration compared to plasma peptide concentration (%F) after intravenous administration (* indicates a p-value of less than 0.05 compared to the unformulated vancomycin buffered control). [Figure 16] This document provides plots quantifying the permeability measured by GI-ORIS for antisense oligonucleotides formulated with bile acids alone or with bile acids and additional co-excipients (formulations corresponding to formulation IDs are identified in Table 18). The values ​​represent the percentage permeability for individual replicates in a single GI-ORIS screening experiment. [Figure 17]This paper provides plots of oral bioavailability of vancomycin solid formulations in dogs and intestinal permeability measured by GI-ORIS for the corresponding liquid formulations. Bivariate linear regression fitted to the data showed very high correlations when a 15 mL dilution factor was applied. [Figure 18] This provides a plot quantifying the dose-normalized area under the curve (AUC) of semaglutide in plasma after oral administration of an immediate-release solid dosage form containing semaglutide and the indicated excipients to dogs. Positive control animals received oral administration of Rybelsus (a commercially available oral semaglutide immediate-release solid dosage form). [Figure 19] This document provides plots quantifying the bioavailability of vancomycin after oral administration in dogs for immediate-release (uncoated) or delayed-release (enteric-coated) solid dosage forms containing vancomycin and indicated excipients. Comparisons are made with the bioavailability of oral-administered vancomycin solid dosage forms without excipients ("unformulated"). Bioavailability is expressed as the percentage of post-oral vancomycin concentration compared to post-intravenous plasma vancomycin concentration. [Modes for carrying out the invention]

[0041] This disclosure is at least in part based on the discovery of formulations for effective delivery of therapeutic agents into the gastrointestinal (GI) tract. As described herein, an automated, high-throughput screening assay based on a GI-tube-organ robotic interface system (GI-ORIS) was used to evaluate formulations for improving the GI permeability of therapeutic agents, e.g., therapeutic agents characterized by poor intestinal permeability, wherein the formulation comprises at least one bile acid or a salt thereof and optionally one or more co-excipients. GI-ORIS has several advantages for screening compositions for the intestinal permeability of the therapeutic agents contained therein. Firstly, GI-ORIS has been shown to have higher predictive ability for human oral drug absorption compared to conventional in vitro monolayer assays using tumor-derived cancer cell lines from the colon or intestine (e.g., Caco-2 cell-based systems) (see, e.g., von Erlach et al (2020) Nat Biomed Eng 4:544). Secondly, without being constrained by theory, the GI-ORIS cell architecture remains substantially viable in the presence of high concentrations of bile acids or their salts (e.g., concentrations exceeding the critical micelle concentration (CMC) of bile acids or their salts). In contrast, conventional cell-based in vitro screening systems (e.g., Caco-2 cell-based systems) are considered susceptible to cytotoxicity in the presence of such concentrations. As demonstrated herein, these features of GI-ORIS allow for the evaluation of compositions effective in improving the GI (e.g., intestinal and / or gastric) permeability of therapeutic agents, the compositions comprising the therapeutic agent and at least one bile acid or its salt at a concentration higher than the CMC. It has also been found that such compositions further comprising one or more co-excipients (e.g., chelating agents) provide increased GI (e.g., intestinal and / or gastric) permeability. For example, as described herein, the compositions of the present disclosure have been found to increase intestinal permeability by at least twofold compared to control compositions (e.g., compositions comprising a therapeutic agent having at least one bile acid or a salt thereof and one or more optional co-excipients).Furthermore, the compositions of this disclosure, characterized by having GI-ORIS-enhanced GI permeability, were found to be effective in increasing the systemic bioavailability of therapeutic agents after in vivo administration to the GI tube.

[0042] Accordingly, in some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents to the GI duct, including those characterized by poor intestinal permeability. In some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents across skin or mucosal barriers. In some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents via administration routes that do not require direct injection into body tissues and / or the circulatory system (e.g., via administration routes that do not require injection via parenteral routes such as intramuscular, subcutaneous, or intravenous injection). In some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents by enteral administration (e.g., oral, transduodenal, or transrectal administration). In some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents by oral, buccal, or sublingual administration. In some embodiments, the Disclosure provides compositions and methods for improving the delivery of therapeutic agents by nasal or ophthalmic administration.

[0043] In some embodiments, the Disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients, wherein the compositions are effective in increasing the gastrointestinal (GI) permeability (e.g., intestinal permeability and / or gastric permeability) of the therapeutic agent after enteral administration (e.g., oral, duodenal, or transrectal administration) to a subject. In some embodiments, the GI permeability of the therapeutic agent is increased compared to the GI permeability of a control composition containing the therapeutic agent but lacking at least one bile acid or a salt thereof and optionally one or more co-excipients. In some embodiments, the intestinal permeability of the therapeutic agent is increased compared to the intestinal permeability of a control composition. In some embodiments, the gastric permeability of the therapeutic agent is increased compared to the gastric permeability of a control composition. In some embodiments, the administration is oral. In some embodiments, the administration is transduodenal (e.g., via a feeding tube). In some embodiments, the administration is transrectal.

[0044] In some embodiments, the Disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients, wherein the compositions are effective in increasing the permeability of the therapeutic agent across the skin barrier after transdermal or topical administration to a subject. In some embodiments, the permeability of the therapeutic agent across the skin barrier is increased compared to the permeability of a control composition containing the therapeutic agent but lacking at least one bile acid or a salt thereof and optionally one or more co-excipients.

[0045] In some embodiments, the Disclosure provides a composition comprising a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients, wherein the composition is effective in increasing the permeability of the therapeutic agent across the mucosal barrier after intranasal or ophthalmic administration to a subject. In some embodiments, administration is intranasal (e.g., via inhalation). In some embodiments, administration is ophthalmic. In some embodiments, the Disclosure provides a composition comprising a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients, wherein the composition is effective in increasing the permeability of the therapeutic agent across the mucosal barrier after buccal or sublingual administration to a subject. In some embodiments, the permeability of the therapeutic agent across the mucosal barrier is increased compared to the permeability of a control composition containing the therapeutic agent but lacking at least one bile acid or a salt thereof and optionally one or more co-excipients.

[0046] In some embodiments, the composition is formulated as a solid or liquid dosage form. In some embodiments, the composition is formulated as a solid or liquid dosage form for enteral administration (e.g., oral, duodenal, or rectal administration). In some embodiments, the solid dosage form is an immediate-release formulation. In some embodiments, the solid dosage form is a delayed-release formulation. In some embodiments, the solid dosage form includes an enteric coating for delayed release. Methods for formulating dosage forms for enteral administration are known in the art and are further described herein. In some embodiments, the dosage form contains at least one bile acid or salt thereof in an amount sufficient to achieve an effective concentration of at least one bile acid or salt thereof at the site of absorption (e.g., a GI tube). For example, in some embodiments, the amount is sufficient to achieve an effective concentration at the absorption site despite dilution occurring in vivo between administration and transport to the absorption site. In some embodiments, the effective concentration is higher than the critical micelle concentration (CMC) of at least one bile acid or salt thereof. In some embodiments, the effective concentration of at least one bile acid or a salt thereof is determined using a method for measuring GI (e.g., intestinal) permeability as described herein, such as a GI-ORIS screening assay.

[0047] In some embodiments, the present disclosure relates to a method for increasing the GI (e.g., intestinal and / or gastric) permeability of a therapeutic agent after enteral administration (e.g., oral, duodenal, or transrectal administration) to a subject, the method comprising formulating a dosage form (e.g., solid or liquid dosage form) comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt thereof, and a certain amount of bile acid or salt thereof sufficient to achieve an effective concentration of at least one bile acid or salt thereof at the absorption site (e.g., effective concentration The present invention provides a method comprising: formulating a dosage form (determined using the methods herein for measuring GI permeability, such as GI-ORIS), and optionally containing a certain amount of one or more co-excipients; and administering the dosage form enterally (e.g., orally, duodenodenally, or transrectally) to the target, wherein the GI (e.g., intestinal and / or gastric) permeability of the therapeutic agent is increased compared to the GI permeability of a dosage form containing a control composition (e.g., a composition lacking at least one bile acid or a salt thereof and one or more co-excipients). In some embodiments, the increased GI (e.g., intestinal and / or gastric) permeability of the therapeutic agent is effective in increasing its bioavailability after enteral administration. Without being constrained by theory, one or more advantages of increasing the bioavailability of a therapeutic agent are: (i) reduced doses are required to achieve a minimum effective concentration threshold, thereby reducing or mitigating the risk of undesirable effects (e.g., toxicity, adverse symptoms) associated with high doses of the therapeutic agent; (ii) the need to administer the therapeutic agent by needle injection is avoided, thereby improving patient compliance and adherence; and / or (iii) the need for hospitalization, such as in the case of intravenous injection, is avoided.

[0048] Compositions for Enhanced Permeability This disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof, and optionally one or more co-excipients. In some embodiments, this disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof. In some embodiments, this disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof, and one or more co-excipients.

[0049] In some embodiments, the composition comprises one or more doses of the therapeutic agent. In some embodiments, the composition comprises one bile acid or a salt thereof. In some embodiments, the composition comprises two or more bile acids or salts thereof. In some embodiments, the composition comprises two bile acids or salts thereof. In some embodiments, the composition comprises three bile acids or salts thereof. In some embodiments, the composition comprises four bile acids or salts thereof. In some embodiments, the composition comprises five bile acids or salts thereof.

[0050] In some embodiments, at least one bile acid or a salt thereof, along with one or more optional co-excipients, enhances the GI (e.g., intestine and / or stomach) permeation of the therapeutic agent in a subject (e.g., a human subject). In some embodiments, at least one bile acid or a salt thereof, along with one or more optional co-excipients, enhances the intestinal permeation of the therapeutic agent in a subject (e.g., a human subject). In some embodiments, at least one bile acid or a salt thereof, along with one or more optional co-excipients, enhances the GI (e.g., intestine and / or stomach) permeation of the therapeutic agent in a subject (e.g., a human subject). In some embodiments, at least one bile acid or a salt thereof, along with one or more co-excipients, enhances the GI (e.g., intestine and / or stomach) permeation of the therapeutic agent in a subject (e.g., a human subject). In some embodiments, at least one bile acid or a salt thereof, along with one or more co-excipients, enhances the GI (e.g., intestine and / or stomach) permeation of the therapeutic agent in a subject (e.g., a human subject). In some embodiments, GI (e.g., intestinal and / or gastric) permeability is enhanced compared to GI (e.g., intestinal and / or gastric) permeability of a control composition, and the control composition lacks at least one bile acid or a salt thereof, and optionally one or more co-excipients.

[0051] Therapeutic drugs In some embodiments, the therapeutic agents of the compositions described herein are characterized by having poor permeability across one or more physiological barriers. In some embodiments, the therapeutic agent is a macromolecule (e.g., a therapeutic agent having a molecular weight greater than about 1 kDa) having poor permeability across one or more physiological barriers. In some embodiments, the therapeutic agent is a polypeptide (e.g., a polypeptide having a molecular weight of about 1 kDa to about 250 kDa) having poor permeability across one or more physiological barriers. In some embodiments, the therapeutic agent is a nucleic acid having poor permeability across one or more physiological barriers. In some embodiments, the therapeutic agent is a compound having a molecular weight of less than 1 kDa having poor permeability across one or more physiological barriers. In some embodiments, the physiological barrier includes the gastrointestinal barrier (e.g., the stomach and / or intestinal barrier). In some embodiments, the physiological barrier includes the skin. In some embodiments, the physiological barrier includes the mucosal barrier, cell lining (e.g., epithelial cell lining), and / or chemical lining (e.g., lining containing digestive secretions, antimicrobial peptides, and / or cell secretions).

[0052] In some embodiments, the therapeutic agents of the compositions described herein are characterized by having poor GI (e.g., gastric and / or intestinal) permeability. In some embodiments, the therapeutic agents are characterized by having poor GI permeability due to size (e.g., molecular weight greater than 1 kDa), charge, hydrophobicity, or a combination thereof. In some embodiments, the therapeutic agents are characterized by having poor GI permeability according to the Biopharmaceutical Classification System (BCS) system.

[0053] In some embodiments, the therapeutic agent is a macromolecule (e.g., a therapeutic agent having a molecular weight greater than about 1 kDa) with poor GI (e.g., gastric and / or intestinal) permeability. In some embodiments, the therapeutic agent is a polypeptide (e.g., a polypeptide having a molecular weight of about 1 kDa to about 250 kDa) with poor GI (e.g., gastric and / or intestinal) permeability. In some embodiments, the therapeutic agent is a nucleic acid with poor GI (e.g., gastric and / or intestinal) permeability. In some embodiments, the therapeutic agent is a small molecule (e.g., a therapeutic agent having a molecular weight less than about 1 kDa, e.g., a BSC class III or class IV compound) with poor GI (e.g., gastric and / or intestinal) permeability.

[0054] As used herein, the term “therapeutic agent” includes any compound having a therapeutic effect, including conventional drugs and their analogues, that is suitable for administration to a subject (e.g., a human subject). In some embodiments, a therapeutic agent is a compound having in vivo pharmacological activity for, for example, mediating the diagnosis, cure, improvement, treatment, or prevention of a disease or disorder in a subject, or for affecting the structure or function of a body in a subject. In some embodiments, a therapeutic agent includes a compound that is poorly absorbed via the enteral (e.g., oral, duodenal, or transrectal) route, including hydrophilic or macromolecule drugs such as polypeptides, nucleic acids, oligosaccharides, polysaccharides, lipids, or hormones. In some embodiments, a therapeutic agent includes a compound having poor permeability across the lining of the intestine and / or stomach. In some embodiments, a therapeutic agent includes a compound having poor permeability across the skin. In some embodiments, a therapeutic agent includes a compound having poor permeability across the mucosal barrier.

[0055] polypeptide In some embodiments, the therapeutic agent comprises a polypeptide. In some embodiments, the therapeutic agent is a polypeptide. In some embodiments, the polypeptide has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 1 kDa to a maximum of about 300 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 10 kDa to a maximum of about 300 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 50 kDa to a maximum of about 300 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 100 kDa to a maximum of about 300 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 1 kDa to a maximum of about 200 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 10 kDa to a maximum of about 200 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 50 kDa to a maximum of about 200 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 100 kDa to a maximum of about 200 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 1 kDa to a maximum of about 100 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 10 kDa to a maximum of about 100 kDa. In some embodiments, the polypeptide has a molecular weight of at least about 50 kDa to a maximum of about 100 kDa. In some embodiments, the polypeptide has a molecular weight of more than about 0.1 kDa to a maximum of about 1 kDa.

[0056] In some embodiments, the polypeptide is naturally occurring. In some embodiments, the polypeptide is synthetic. In some embodiments, the polypeptide comprises a protein (e.g., a recombinant protein) or an engineered variant of a fragment thereof.

[0057] In some embodiments, the polypeptide comprises an enzyme. In some embodiments, the polypeptide comprises an antibody or its antigen-binding fragment. In some embodiments, the polypeptide comprises a hormone. In some embodiments, the polypeptide comprises an immunoglobulin. In some embodiments, the polypeptide comprises a growth factor. In some embodiments, the polypeptide comprises a cell signaling ligand. In some embodiments, the polypeptide comprises a cytokine. In some embodiments, the polypeptide comprises a chemokine. In some embodiments, the polypeptide comprises an antimicrobial agent.

[0058] In some embodiments, the polypeptide comprises one or more modifications. In some embodiments, one or more modifications are selected from any post-translational modifications known in the art. Non-limiting examples of post-translational modifications include glycosylation, acylation, prenylation, lipoylation, phosphorylation, ubiquitination, S-nitrosylation, methylation, N-acetylation, lipidation, S-glutathioneation, succinylation, sulfation, glycation, carbamylation, carbonylation, biotination, oxidation, pegylation, SUMOylation, racemization, iodization, hydroxylation, malonylation, propionylation, butyrylation, and carboxylation.

[0059] nucleic acid In some embodiments, the therapeutic agent comprises a nucleic acid. In some embodiments, the therapeutic agent is a nucleic acid. In some embodiments, the nucleic acid has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the nucleic acid has a molecular weight of about 0.1 to about 1 kDa.

[0060] In some embodiments, the nucleic acid includes DNA. In some embodiments, the nucleic acid includes plasmid DNA.

[0061] In some embodiments, the nucleic acid includes RNA. In some embodiments, the RNA is single-stranded. In some embodiments, the single-stranded RNA includes a duplex. In some embodiments, the single-stranded RNA includes RNA secondary structures (e.g., hairpin loops, stem loops). In some embodiments, the RNA is double-stranded RNA. In some embodiments, the double-stranded RNA includes a duplex and one or more overhangs. In some embodiments, the double-stranded RNA includes a duplex and one or more bulges.

[0062] In some embodiments, RNA includes small hairpin RNA (shRNA) molecules. In some embodiments, RNA includes small interfering RNA (siRNA) molecules. In some embodiments, RNA includes microRNA (miRNA) molecules. In some embodiments, RNA includes messenger RNA (mRNA) molecules. In some embodiments, RNA includes transfer RNA (tRNA) molecules. In some embodiments, RNA includes micronuclear RNA (snRNA) molecules. In some embodiments, RNA includes non-coding RNA (ncRNA).

[0063] In some embodiments, nucleic acids include oligonucleotides. As used herein, the term “oligonucleotide” includes RNA agents and DNA agents, as well as chimeric oligonucleotides containing both RNA and DNA elements (e.g., gapmers). Furthermore, the term “oligonucleotide” includes naturally occurring nucleotides, nucleotides not naturally occurring (e.g., nucleotide analogs), or compounds containing combinations of naturally occurring and nucleotides not naturally occurring. In one embodiment, the oligonucleotide is an RNA agent (i.e., an oligonucleotide whose sugar-phosphate backbone contains ribose or a chemical analog thereof). In one embodiment, the oligonucleotide is a DNA agent (i.e., an oligonucleotide whose sugar-phosphate backbone contains deoxyribose or a chemical analog thereof). In one embodiment, the oligonucleotide is a modified RNA agent, a non-limiting example of which is a locked nucleic acid (LNA)-containing RNA oligonucleotide. In some embodiments, the RNA agent includes single-stranded RNA, double-stranded RNA (dsRNA), or molecules that are partially double-stranded RNA, i.e., molecules having a double-stranded portion and a single-stranded portion. In some embodiments, the RNA molecule is a cyclic RNA molecule or a linear RNA molecule. Such oligonucleotides are well established in the art.

[0064] Non-exclusive examples of RNA agents include messenger RNA (mRNA) (e.g., encoding a protein of interest), modified mRNA (mmRNA) containing at least one chemical modification compared to naturally occurring RNA, mRNA incorporating microRNA binding sites (or miR binding sites), modified RNA containing functional RNA elements, microRNA (miRNA), antagonists, small (short) interfering RNA (siRNA) (including shortmer and dicer substrate RNA), RNA interference (RNAi) molecules, antisense RNA, ribozymes, small hairpin RNA (shRNA), and locked nucleic acids (LNA). Such RNA agents are well established in the art.

[0065] In some embodiments, the DNA agent includes double-stranded DNA, single-stranded DNA (ssDNA), or a molecule that is partially double-stranded DNA, i.e., a molecule having a double-stranded portion and a single-stranded portion. In some embodiments, the DNA molecule is triple-stranded or partially triple-stranded, i.e., having a triple-stranded portion and a double-stranded portion. In some embodiments, the DNA molecule is a circular DNA molecule or a linear DNA molecule. Such oligonucleotides are well established in the art.

[0066] In one embodiment, the oligonucleotide is an antisense oligonucleotide, such as antisense RNA. In some embodiments, antisense RNA (asRNA), also called an antisense transcript, is a naturally occurring or synthetically produced single-stranded RNA molecule that hybridizes with the protein-coding messenger RNA (mRNA) with which it blocks the translation of mRNA into protein. Antisense transcripts are classified into short (less than 200 nucleotides) and long (more than 200 nucleotides) non-coding RNAs (ncRNAs). The primary natural function of asRNA is to regulate gene expression, and synthetic versions are widely used as research tools for gene knockdown and therapeutic applications. Antisense RNA and its functions have been described in the art (see, for example, Weiss et al. (1999) Cell. Molec. Life Sci. 55:334-358; Wahlstedt (2013) Nat. Rev. Drug Disc. 12:433-446; Pelechano and Steinmetz (2013) Nat. Rev. Genet. 14:880-893). Therefore, in some embodiments, the compositions of this disclosure include agents for antisense therapy. In one embodiment, the agent for antisense therapy is an RNA agent or chimeric oligonucleotide (e.g., a gapmer) comprising at least one modification, such as at least one chemical analogue of a naturally occurring ribonucleic acid, compared to a naturally occurring ribonucleic acid. In some embodiments, the modification of the RNA agent comprises the incorporation of at least one locked nucleic acid compared to a naturally occurring ribonucleic acid.

[0067] In some embodiments, oligonucleotides contain one or more locked nucleic acids. Locked nucleic acids, also referred to as inaccessible RNA, are modified RNA nucleotide molecules in which the ribose portion of the LNA is modified with additional crosslinks connecting the 2' oxygen and 4' carbon atoms. These crosslinks "lock" the ribose in a 3'-endo(North) conformation. The LNA nucleotide can be mixed with DNA or RNA residues in the oligonucleotide as needed and hybridize with the DNA or RNA according to the Watson-Crick base pairing rules. The locked ribose conformation enhances base stacking and backbone pre-organization. This significantly increases the hybridization properties (e.g., melting temperature) of oligonucleotides containing LNA nucleotides. LNA molecules and their properties have been described in the relevant art (e.g., Obika et al. (1997) Tetrahedron Lett. 38:8735-8738; Koshkin et al. (1998) Tetrahedron 54:3607-3630; Elmen et al. (2005) Nucl. Acids Res. 33:439-447).

[0068] In some embodiments, the antisense RNA is a gapmer. The gapmer is a chimeric antisense oligonucleotide containing a central block of deoxynucleotide monomers long enough to induce RNAase H cleavage. Such gapmers are well established in the art. In some embodiments, the gapmer is a locked nucleic acid (LNA)-containing gapmer. The use of LNA-containing gapmer antisense oligonucleotides for antisense therapy is well established in the art (see, for example, Wahlestedt et al. (2000) Proc. Natl. Acad. Sci. USA 97: 5633-5638; Kurreck et al. (2002) Nucl. Acids Res. 30: 1911-1918; Fluiter et al. (2009) Mol. Biosyst. 5: 838-843; Pendergraff et al. (2017) Mol. Therap. Nucl. Acids 8: 158-168).

[0069] BCS The Biopharmaceutical Classification System (BCS) classifies therapeutic agents (e.g., oral dosage forms of therapeutic agents) into different classes (BCSI~IV) based on parameters that determine water solubility, intestinal permeability, and the proportion of the therapeutic agent absorbed after oral ingestion (see, for example, Amidon, GLPharm.Res.12,413-420(1995); Benet, LZ, AAPS J.13,519-547(2011); Dahan, A., et al. Mol.Pharm.9,1847-1851(2012); Lobenberg, R. et al. Eur.J.Pharm.Biopharm.Off.J.50,3-12(2000)).

[0070] The characteristics of therapeutic agents under BCS (e.g., oral dosage forms of therapeutic agents) are known in the art (see, for example, Khan GM. The Science (2001) 1:350-54; Lobenberg R, et al. Eur J Pharm Biopharm (2000) 50:3-12; Draft Guidance for Industry, “Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms containing certain Active Moieties / Active Ingredients based on a Biopharmaceutic Classification System” CDER / FDA (2017)). Class I therapeutic agents under BCS are characterized by high water solubility and high intestinal permeability. Class II therapeutic agents under BCS are characterized by low water solubility and high intestinal permeability. Class III therapeutic agents under BCS are characterized by high water solubility and low intestinal permeability. Class IV therapeutic agents under BCS are characterized by low water solubility and low intestinal permeability.

[0071] The BCS includes class boundaries for defining the water solubility of therapeutic agents. Water solubility refers to the process by which a compound enters an aqueous solution via mass transfer from a solid surface to the liquid phase (see Sharma, J.L., *Dictionary of Chemistry*, *New Delhi India*: CBS Publishers and Distributors; 1997, pp. 558-60). Solubility is the concentration of a solute in a saturated solution at a given temperature. Dissolution rate is the amount of solid substance that enters a solution per unit time under standard conditions of temperature, pH, solvent composition, and a constant solid surface area. Under the BCS, the therapeutic agent has "high water solubility" if the maximum dose strength is soluble (e.g., at least 90% of the dose is soluble) in an aqueous medium of approximately 250 mL or less at approximately 37°C (e.g., ±1°C, ±2°C, ±3°C, ±4°C, ±5°C, ±6°C, ±7°C, ±8°C, ±9°C, or ±10°C) within a pH range of approximately 1 to approximately 7.5 (see, for example, Draft Guidance for Industry, “Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms containing certain Active Moieties / Active Ingredients based on a Biopharmaceutic Classification System”. CDER / FDA (2017)). The 250 mL volume estimate for (i) is derived from a standard bioequivalence study protocol that prescribes administration of the drug product in a glass (approximately 8 ounces) of water to fasted human volunteers. In some embodiments, the evaluation is performed by exposing the highest dose intensity of the therapeutic agent to approximately 250 mL of an aqueous medium (e.g., water or aqueous buffer), and an assay is performed to measure solubility after equilibrium has been established. The pH solubility profile of the drug is determined in the aqueous medium at approximately 37°C (e.g., ±1°C, ±2°C, ±3°C, ±4°C, ±5°C, ±6°C, ±7°C, ±8°C, ±9°C, or ±10°C) with a pH in the range of approximately 1 to approximately 7.5.In some embodiments, the aqueous medium is one described in the Art (see, for example, British Pharmacopoeia Electronic version: Appendix I D. Buffer Solutions. London: The Stationary Office; 2003). Methods for measuring water solubility are known in the Art and include analysis by shaking flask or titration, or by approved stability indicator assays. In some embodiments, a solubility indicator assay is selected to distinguish the therapeutic agent from its degradation products.

[0072] The BCS includes class boundaries for defining the intestinal permeability of therapeutic agents. As further described herein, the GI tubule is characterized by an intestinal barrier that prevents the loss of water and electrolytes, as well as the entry of antigens or microorganisms into the systemic circulation, while allowing the exchange of compounds and absorption of nutrients from the diet between the external environment and the host. The intestinal wall consists of four layers: mucosa, submucosa, muscularis, and serosa. The outermost layer of the GI tubule is the serosa, a smooth membrane containing a thin layer of serous-secreting cells and a thin layer of connective tissue. The next layer is the muscularis, which includes two muscular layers that contribute to intestinal movement (peristalsis). The next layer is the submucosa, which includes a layer of dense, irregular or loose connective tissue that supports the mucosa and connects it to the underlying smooth muscle. The innermost layer of the GI tubule facing the lumen is the mucosa. The mucosa includes the physical barrier of the GI tubule (e.g., including vascular endothelium, epithelial cell lining, and mucus layer), as well as layers of secreted digestive substances, immune molecules, and cell products (e.g., inflammatory mediators, antimicrobial peptides, and cytokines). As used herein, the term “intestinal permeability” refers to the ability of a compound to pass from the lumen of the GI tubule into the submucosa, for example, by entering or passing through the epithelium or mucus layer, respectively. According to the BCS, a therapeutic agent is considered to have “high intestinal permeability” if, for example, based on mass balance determination as described herein, or compared to an intravenous reference dose, the systemic bioavailability is determined to be at least about 85% of the administered dose.

[0073] Methods for measuring intestinal permeability are known in the art. In some embodiments, permeability is measured using a mass balance test. For example, a radiolabeled drug is administered to one or more subjects (e.g., one or more human subjects), and the degree of absorption of the drug into the systemic circulation is measured (e.g., by detecting the amount of radiolabeled drug present in a tissue sample such as blood or urine). In some embodiments, permeability is measured based on the degree of absorption of the therapeutic agent in a subject (e.g., a human subject) (e.g., the percentage of the dose absorbed). Methods for measuring the degree of absorption are known in the art and include absolute bioavailability tests and intestinal perfusion tests (e.g., in vivo intestinal perfusion tests in humans, in vivo or in situ perfusion tests in animals). In some embodiments, permeability is measured in vitro, using excised human or animal intestinal tissue, or using an epithelial cell monolayer. Preferred methods are described in the Examples section of this specification. For example, in some embodiments, permeability is measured using in vitro tissue explants with GI-ORIS, as described in U.S. Patent Publication 2019 / 0064153, which is incorporated herein by reference. In another example, the Caco2 cell line, derived from human colon cancer, is used for permeability determination. Initial screening can also be performed using parallel-membrane permeability analysis (PAMPA) performed on microplates. This measures the permeability of compounds through phospholipid-coated filter media that mimic intestinal cell structure. When determining drug permeability, known permeability reference standards can be used in absorption assays.

[0074] In some embodiments, the therapeutic agent is characterized as an immediate-release (IR) drug according to the BCS. In some embodiments, the IR drug is characterized by having rapid or very rapid dissolution. According to the BCS, a therapeutic agent is considered to have "rapid dissolution" if, using the United States Pharmacopeia (USP) apparatus 1 at 100 rpm or the apparatus 2 at 50 rpm with a volume of aqueous dissolving medium of 500 mL or less, an average of 85% or more of the labeled amount of the drug dissolves within 30 minutes, and "very rapid dissolution" if an average of 85% or more of the labeled amount dissolves within 15 minutes under the aforementioned conditions. In some embodiments, the aqueous dissolving medium is 0.1N HCl. In some embodiments, the aqueous dissolving medium is enzyme-free artificial gastric juice (SGF). In some embodiments, the aqueous dissolving medium is a pH 4.5 buffer. In some embodiments, the aqueous dissolving medium is a pH 6.8 buffer. In some embodiments, the aqueous dissolving medium is enzyme-free artificial intestinal fluid (SIF). In some embodiments, the aqueous dissolving medium contains SGF and a surfactant. In some embodiments, the aqueous dissolving medium contains milk with 3.5% fat. In some embodiments, the aqueous dissolving medium contains a small amount of SIF. In some embodiments, the aqueous dissolving medium contains a large amount of SIF.

[0075] In some embodiments, the therapeutic agent is characterized as Class III according to BCS. In some embodiments, the Class III therapeutic agent has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the Class III therapeutic agent has a molecular weight of about 0.1 to about 1 kDa. In some embodiments, the Class III therapeutic agent comprises polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, or combinations thereof. In some embodiments, the Class III therapeutic agent is a biological formulation characterized by good water solubility and poor GI permeability, such as proteins, peptides, polysaccharides, nucleic acids, nucleic acid oligomers, and viruses. Examples of Class III therapeutic agents include, but are not limited to, acyclovir, neomycin B, captopril, atenolol, valproic acid, stabuzin, salbutamol, methotrexate, lamivudine, ergometrine, ciprocgloxacin, amiloride, and caspofungin.

[0076] In some embodiments, the therapeutic agent is characterized as Class IV according to BCS. In some embodiments, the Class IV therapeutic agent has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the Class IV therapeutic agent has a molecular weight of about 0.1 to about 1 kDa. In some embodiments, the Class IV therapeutic agent comprises polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, or combinations thereof. In some embodiments, the Class IV therapeutic agent is a lipophilic compound having poor GI permeability. Examples of Class IV drugs include, but are not limited to, nalidixic acid, chlorothiazide, tobramycin, cyclosporine, allopurinol, acetazoleamide, doxycycline, dapsone, sulfamethoxazole, tacrolimus, paclitaxel, doxorubicin, brimicin, and griseofulvin.

[0077] Additional non-limiting examples of BCS Class III and Class IV therapeutic agents include abacavir sulfate, acetylsalicylic acid, amoxicillin, atropine sulfate, azathioprine, benznidazole, chloramphenicol, cimetidine, codeine phosphate, colchicine, cyclophosphamide, dapsone, dexamethasone, didanosine, diethylcarbamazine citrate, digoxin, ethambutol hydrochloride, ethosuximide, fluconazole, folic acid, furosemide, griseofulvin, and hydrara. Examples include din hydrochloride, hydrochlorothiazide, isoniazid, methyldopa, metoclopramide hydrochloride, metronidazole, nicotinamide, nifurtimox, nitrofurantoin, nystatin, paracetamol, penicillamine, penicillin V potassium, phenobarbital, primaquine phosphate, propylthiouracil, pyrazinamide, pyridostigmine bromide, pyridoxine hydrochloride, pyrimethamine, sulfate, sulfadiazine, theophylline, trimethoprim, and zidovudine.

[0078] In some embodiments, the therapeutic agent (e.g., a BCS class III or IV therapeutic agent) comprises polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, and combinations thereof (e.g., complexes or conjugates). In some embodiments, the therapeutic agent comprises a complex or conjugate of a protein and a nucleic acid. In some embodiments, the therapeutic agent comprises a complex or conjugate of a protein and an oligosaccharide. In some embodiments, the therapeutic agent comprises a complex or conjugate of a protein and a small molecule. In some embodiments, the therapeutic agent comprises a complex or conjugate of a nucleic acid and a lipid. In some embodiments, the therapeutic agent comprises a complex or conjugate of a nucleic acid and a small molecule. In some embodiments, the therapeutic agent comprises a complex or conjugate of a protein and a small molecule.

[0079] In some embodiments, the therapeutic agent (e.g., a BCS class III or IV therapeutic agent) has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or greater than about 30 kDa. In some embodiments, the therapeutic agent has a molecular weight of about 0.1 to about 1 kDa.

[0080] Additional treatments In some embodiments, the therapeutic agent (e.g., a BCS class III or IV therapeutic agent) comprises an oligosaccharide. In some embodiments, the therapeutic agent is an oligosaccharide. In some embodiments, the therapeutic agent (e.g., a BCS class III or IV therapeutic agent) comprises a lipid.

[0081] In some embodiments, the therapeutic agent (e.g., a BCS class III or IV therapeutic agent) comprises small molecules. In some embodiments, the small molecules have a molecular weight of less than 1,000 g / mol. As used herein, the unit "g / mol" is used synonymously with Dalton (Da). In some embodiments, the small molecules have a molecular weight of at least about 100 g / mol to a maximum of about 1,000 g / mol. In some embodiments, the small molecules have molecular weights (g / mol) of about 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900, 1000 or less, or a range including and / or extending to the aforementioned values. In some embodiments, the small molecules are chemically synthesized by one or more chemical reactions (e.g., synthesis).

[0082] In some embodiments, the small molecule is in a crystalline dosage form. In some embodiments, the small molecule is in an amorphous dosage form. As used herein, “amorphous” refers to a solid form of a molecule and / or ion that is not crystalline. As used herein, the term “small molecule” encompasses all its forms, including optically pure enantiomers or mixtures of enantiomers, racemics or otherwise, as well as derivative forms such as salts, acids, and esters.

[0083] Bile acids or their salts Bile acids or their salts are generally ionic amphiphilic compounds containing a steroid skeleton, carbon side chains (e.g., side chains containing 4 to 8 carbon atoms), and hydroxyl groups. The steroid skeleton contains four rings labeled from left to right as rings A, B, C, and D. Ring D has one less carbon than rings A, B, and C. The "beta" hydroxyl group is positioned at the top (i.e., usually depicted as a solid line), and the "alpha" hydroxyl group is positioned at the bottom (i.e., usually depicted as a dashed line).

[0084] Bile acids often originate from cholesterol in the liver (see, for example, Chiang JY.J Hepatol.2004;40:539-551;Chiang JYL.Front Biosci.1998;3:D176-D193;Russell DW.Annu Rev Biochem.2003;72:1370174). For example, the synthesis of bile acids or their salts is the main pathway for removing cholesterol from the body. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the major primary bile acids synthesized in the human liver. CA and CDCA are conjugated with taurine or glycine for secretion into bile. Bile salts form micelles mixed with phospholipids and cholesterol and are secreted into the GI ducts to promote digestion and nutrient absorption.

[0085] In some embodiments, the bile acids or salts thereof of this disclosure are converted from cholesterol. The structure of cholesterol is shown by compound A. The structure has a beta-hydroxyl group at position 3, and the four steroid rings are flat. The human liver has two major bile acid biosynthetic pathways, the neutral bile acid pathway (also known as the “classic pathway”) and the acidic pathway (see, e.g., Chiang, et al (2013) Compr Physiol 3:1191; Pellicoro, et al (2007) Aliment Pharmacol Ther 26(Suppl2) 149-160). These pathways convert cholesterol to CA or CDCA by a combination of (i) hydroxylation of the steroid nucleus (e.g., introduction of an alpha-hydroxyl group at position 7) and (ii) oxidative cleavage of the side chain at position 17 of the steroid nucleus. The neutral bile acid pathway converts cholesterol to CA or CDCA by a series of enzymatic steps including (i) then (ii). The acidic pathway, involving a series of enzymatic steps, includes (i) and then (ii). In the transformation, the junction between ring A and ring B is altered, and the hydroxyl group at position 3 is converted to an alpha orientation. The bile acid is further amidated at the carboxyl group with glycine or taurine. [ka]

[0086] In some embodiments, the bile acids or salts thereof of this disclosure are converted from cholesterol by hydroxylation, saturation of a double bond at C5-C6, epimerization of a 3-hydroxyl group, oxidative cleavage of a 3-carbon unit from a side chain (i.e., C25-C27), or a combination thereof. In some embodiments, the bile acids or salts thereof are converted from cholesterol by one or more enzymes in the neutral bile acid pathway. In some embodiments, the bile acids or salts thereof are converted from cholesterol by one or more enzymes in the acidic bile acid pathway. In some embodiments, the bile acids or salts thereof contain a carboxylate at position 24. In some embodiments, the bile acids or salts thereof contain an ester at position 24. In some embodiments, the bile acids or salts thereof contain an amide at position 24. In some embodiments, the bile acids or salts thereof are amidated with taurine at position 24. In some embodiments, the bile acids or salts thereof are amidated with glycine at position 24.

[0087] In some embodiments, the bile acids of this disclosure include a steroid nucleus. As used herein, “steroid nucleus” refers to a perhydrocyclopentanophenanthrene nucleus shared by a steroid, for example, a compound of formula (I) further described herein. As shown below, the steroid nucleus comprises four rings: three hexacarbon rings (A, B, and C) and one quinacarbon ring (D). [ka] During the ceremony, [ka] R 1 , R 2 , R 3 , R 4 , R 5 , and X are further defined as follows:

[0088] In some embodiments, the bile acid comprises a steroid nucleus. In some embodiments, the bile acid comprises a steroid nucleus having one, two, or three hydroxyl groups. In some embodiments, the bile acid comprises a steroid nucleus having one hydroxyl group. In some embodiments, the hydroxyl group is beta or alpha. In some embodiments, the hydroxyl group is at any open position on the steroid nucleus (e.g., position 3, position 7, or position 12). In some embodiments, the hydroxyl group is at position 3 on the steroid nucleus. In some embodiments, the hydroxyl group at position 3 is beta. In some embodiments, the hydroxyl group is at position 7 on the steroid nucleus. In some embodiments, the hydroxyl group is at position 12 on the steroid nucleus.

[0089] In some embodiments, the bile acid comprises a steroid nucleus having first and second hydroxyl groups. In some embodiments, the first and second hydroxyl groups are located at any open position on the steroid nucleus (e.g., positions 3, 7, and / or 12). In some embodiments, the first and second hydroxyl groups are independently alpha or beta. In some embodiments, the first hydroxyl group is at position 3 of the steroid nucleus and the second hydroxyl group is at position 7. In some embodiments, both the first hydroxyl group at position 3 and the second hydroxyl group at position 7 are beta. In some embodiments, the first hydroxyl group is at position 3 of the steroid nucleus and the second hydroxyl group is at position 12. In some embodiments, both the first hydroxyl group at position 3 and the second hydroxyl group at position 12 are beta. In some embodiments, the first hydroxyl group is at position 7 of the steroid nucleus and the second hydroxyl group is at position 12. In some embodiments, both the first hydroxyl group at position 7 and the second hydroxyl group at position 12 are beta.

[0090] In some embodiments, the bile acid comprises a steroid nucleus having first, second, and third hydroxyl groups. In some embodiments, the first, second, and third hydroxyl groups are located at any open position of the steroid nucleus (e.g., positions 3, 7, and / or 12). In some embodiments, the first, second, and third hydroxyl groups are independently alpha or beta. In some embodiments, the first, second, and third hydroxyl groups are located at positions 3, 7, and 12 of the steroid nucleus, respectively. In some embodiments, the first, second, and third hydroxyl groups at positions 3, 7, and 12 are beta.

[0091] In some embodiments, the bile acid contains a side chain at position 17 of the steroid nucleus. In some embodiments, the side chain contains a carboxylate. In some embodiments, the side chain contains an ester. In some embodiments, the side chain contains an amide. In some embodiments, the side chain contains a conjugate to any naturally occurring or synthetic amino acid known in the art. In some embodiments, the side chain contains a conjugate to taurine. In some embodiments, the side chain contains a conjugate to glycine.

[0092] In some embodiments, the composition comprises a pharmaceutically acceptable salt of a bile acid. In some embodiments, the composition comprises a sodium salt of a bile acid. In some embodiments, the composition comprises a potassium salt of a bile acid.

[0093] In some embodiments, the compositions of the present disclosure comprise one or more trihydroxyconjugated bile acids or salts thereof. Examples of trihydroxyconjugated bile acids include, but are not limited to, glycocholic acid (GC), taurocholate (TC), glycohyocholate (GHC), taurohyocholate (THC), tauro-α-mulicolate (T-α-MC), 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), and tauro-β-mulicolate (T-β-MC). In some embodiments, the composition comprises a trihydroxyconjugated bile acid. In some embodiments, the composition comprises a pharmaceutically acceptable salt of a trihydroxyconjugated bile acid. In some embodiments, the composition comprises a sodium salt of a trihydroxyconjugated bile acid. In some embodiments, the composition comprises a potassium salt of a trihydroxyconjugated bile acid.

[0094] In some embodiments, the compositions of the present disclosure comprise one or more dihydroxyconjugated bile acids or salts thereof. Exemplary dihydroxyconjugated bile acids include, but are not limited to, tauroursodeoxycholic acid (TUDC), taurohyodeoxycholic acid (THDC), glycohyodeoxycholic acid (GHDC), glycochenodeoxycholic acid (GCDC), taurodeoxycholic acid (TDC), taurochenodeoxycholic acid salt (TCDC), glycodeoxycholic acid (GDC), and glycoursodeoxycholic acid (GUDC). In some embodiments, the composition comprises a dihydroxyconjugated bile acid. In some embodiments, the composition comprises a pharmaceutically acceptable salt of a dihydroxyconjugated bile acid. In some embodiments, the composition comprises a sodium salt of a dihydroxyconjugated bile acid. In some embodiments, the composition comprises a potassium salt of a dihydroxyconjugated bile acid.

[0095] In some embodiments, the compositions of the present disclosure include one or more unconjugated bile acids or salts thereof. Exemplary unconjugated bile acids include, but are not limited to, deoxycholic acid (DC), cholic acid, and chenodeoxycholic acid (CDC). In some embodiments, the composition includes an unconjugated bile acid. In some embodiments, the composition includes a pharmaceutically acceptable salt of an unconjugated bile acid. In some embodiments, the composition includes a sodium salt of an unconjugated bile acid. In some embodiments, the composition includes a potassium salt of an unconjugated bile acid.

[0096] Exemplary bile acids or salts thereof In some embodiments, the bile acid or salt thereof is of formula (I):

Chemical formula

Chemical formula

[0097] (i) Variable R 1 , R 2 , and R 3 In some embodiments, R 1 H is H.

[0098] In some embodiments, R 1 These are halogens, -CN, -NO2, -OH, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), or -NH(C1~C6 alkyl)2.

[0099] In some embodiments, R 1 is a halogen (e.g., F, Cl, or Br). In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NO2. In some embodiments, R 1 is -OH. In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -O(C1~C6 alkyl). In some embodiments, R 1 is -NH(C1~C6 alkyl). In some embodiments, R 1 It is -NH(C1~C6 alkyl)2.

[0100] In some embodiments, R 2 H is H.

[0101] In some embodiments, R 2 These are halogens, -CN, -NO2, -OH, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), or -NH(C1~C6 alkyl)2.

[0102] In some embodiments, R 2 is a halogen (e.g., F, Cl, or Br). In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NO2. In some embodiments, R 2 is -OH. In some embodiments, R 2 is -NH2. In some embodiments, R 2 is -O(C1~C6 alkyl). In some embodiments, R 2 is -NH(C1~C6 alkyl). In some embodiments, R 2 It is -NH(C1~C6 alkyl)2.

[0103] In some embodiments, R 3 H is H.

[0104] In some embodiments, R 3 These are halogens, -CN, -NO2, -OH, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), or -NH(C1~C6 alkyl)2.

[0105] In some embodiments, R 3 is a halogen (e.g., F, Cl, or Br). In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NO2. In some embodiments, R 3 is -OH. In some embodiments, R 3 is -NH2. In some embodiments, R 3 is -O(C1~C6 alkyl). In some embodiments, R 3 is -NH(C1~C6 alkyl). In some embodiments, R 3 It is -NH(C1~C6 alkyl)2.

[0106] In some embodiments, R1 , R 2 , and R 3 at least one of which is -OH. In some embodiments, R 1 is -OH. In some embodiments, R 2 is -OH. In some embodiments, R 3 is -OH.

[0107] In some embodiments, one of R 1 , R 2 , and R 3 is -OH. In some embodiments, R 1 is -OH, and R 2 and R 3 are each independently H, halogen, -CN, -NO2, -NH2, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2. In some embodiments, R 2 is -OH, and R 1 and R 3 are each independently H, halogen, -CN, -NO2, -NH2, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2. In some embodiments, R 3 is -OH, and R 1 and R 2 are each independently H, halogen, -CN, -NO2, -NH2, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2.

[0108] In some embodiments, at least two of R 1 , R 2 , and R 3 are -OH. In some embodiments, R 1 and R 2 are each -OH. In some embodiments, R 2 and R 3 are each -OH. In some embodiments, R 1 and R 3Each of these is -OH.

[0109] In some embodiments, R 1 , R 2 , and R 3 Two of them are -OH. In some embodiments, R 1 and R 2 These are -OH and R 3 These are H, halogen, -CN, -NO2, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), and -NH(C1~C6 alkyl)2. In some embodiments, R 1 and R 3 Each of them is -OH, and R 2 These are H, halogen, -CN, -NO2, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), and -NH(C1~C6 alkyl)2. In some embodiments, R 2 and R 3 These are -OH and R 1 These are H, halogen, -CN, -NO2, -NH2, -O(C1~C6 alkyl), -NH(C1~C6 alkyl), and -NH(C1~C6 alkyl)2.

[0110] In some embodiments, R 1 , R 2 , and R 3 These are both -OH groups.

[0111] (ii) Variable R 4 and R 5 In some embodiments, R 4 H is H.

[0112] In some embodiments, R 4The C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2.

[0113] In some embodiments, R 4 is a halogen (e.g., F, Cl, or Br). In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NO2. In some embodiments, R 4 is -OH. In some embodiments, R 4 is -NH2. In some embodiments, R 4 is -O(C1~C6 alkyl), and the C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 4 is -NH(C1~C6 alkyl), where C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 4 R is -NH(C1~C6 alkyl)2, where C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 4 is a C1-C6 alkyl group optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 groups. In some embodiments, R 4 is a C2-C6 alkenyl optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 4 This is a C2-C6 alkynyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 molecules.

[0114] In some embodiments, R 5 H is H.

[0115] In some embodiments, R 5 The C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2.

[0116] In some embodiments, R 5 is a halogen (e.g., F, Cl, or Br). In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NO2. In some embodiments, R 5 is -OH. In some embodiments, R 5 is -NH2. In some embodiments, R 5 is -O(C1~C6 alkyl), and the C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 5 is -NH(C1~C6 alkyl), where C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 5 R is -NH(C1~C6 alkyl)2, where C1~C6 alkyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 5 is a C1-C6 alkyl group optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 groups. In some embodiments, R 5is a C2-C6 alkenyl optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2. In some embodiments, R 5 This is a C2-C6 alkynyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 molecules.

[0117] In some embodiments, R 4 and R 5 Each of these is independently a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo.

[0118] In some embodiments, R 4 R is optionally a C1-C6 alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo. In some embodiments, R 5 R is optionally a C1-C6 alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo. In some embodiments, R 4 and R 5 Each is independently a C1-C6 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo. In some embodiments, R 4 R is optionally substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo. In some embodiments, R 5 R is optionally substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo. In some embodiments, R 4 and R 5Each of these is independently a methyl molecule optionally substituted with one or more halogens, -CN, -NO2, -OH, -NH2, or oxo groups.

[0119] In some embodiments, R 4 is a C1-C6 alkyl group (e.g., methyl, ethyl, or propyl). In some embodiments, R 5 is a C1-C6 alkyl group (e.g., methyl, ethyl, or propyl). In some embodiments, R 4 and R 5 Each of these is independently a C1-C6 alkyl group (e.g., methyl, ethyl, or propyl). In some embodiments, R 4 is methyl. In some embodiments, R 5 is methyl. In some embodiments, R 4 and R 5 These are methyl compounds, respectively.

[0120] (iii) Variables X, R X , R Xa , and R Xb In some embodiments, X is -(C1~C 12 Alkylene)-R X ,-(C2~C 12 Alkenylene)-R X , or -(C2~C 12 Alkinylene)-R X And C1~C 12 Alkylene, C2~C 12 Alkenylene, or C2~C 12 Alkynylene is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 molecules.

[0121] In some embodiments, X is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 -(C1~C 12 Alkylene)-R XIn some embodiments, X is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 -(C2~C 12 Alkenylene)-R X In some embodiments, X is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 -(C2~C 12 Alkinylene)-R X That is the case.

[0122] In some embodiments, X is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 -(C1~C 12 Alkylene)-R X (For example, alkylenes are methylene, ethylene, propylene, or butylene). In some embodiments, X is -(C1~C 12 Alkylene)-R X (For example, alkylenes are methylene, ethylene, propylene, or butylene). In some embodiments, X is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2 -(butylene)-R X In some embodiments, X is -(butylene)-R X That is the case.

[0123] In some embodiments, R X is -C(=O)OR Xa or -C(=O)N(R Xa )2. In some embodiments, R X is -C(=O)R Xa In some embodiments, R X is -C(=O)OR Xa In some embodiments, R X is -OC(=O)R Xa In some embodiments, R X is -N(R Xa )C(=O)(R Xa ) is. In some embodiments, R Xis -C(=O)N(R Xa )2. In some embodiments, R X is -OS(=O)2R Xa In some embodiments, R X is -S(=O)2OR Xa That is the case.

[0124] In some embodiments, at least one R Xa is H. In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)R Xb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb )3, -C(=O)N(R Xb )2, -OS(=O)2R Xb , or -S(=O)2OR Xb C1~C replaced by 12 Alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)R Xb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb )3, -C(=O)N(R Xb )2, -OS(=O)2R Xb , or -S(=O)2OR Xb C2~C replaced by 12 It is an alkenyl. In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)RXb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb )3, -C(=O)N(R Xb )2, -OS(=O)2R Xb、 Or -S(=O)2OR Xb C2~C replaced by 12 It is alkinyl.

[0125] In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)R Xb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb )3, -C(=O)N(R Xb )2, -OS(=O)2R Xb , or -S(=O)2OR Xb It is a methyl substituted with R. In some embodiments, at least one R Xa This is an optional choice of one or more -C(=O)OR Xb It is a methyl substituted with R. In some embodiments, at least one R Xa This is one or more -C(=O)OR Xb It is a methyl substituted with R. In some embodiments, at least one R Xa is -C(=O)OR Xb It is a methyl substituted with [a specific methyl compound].

[0126] In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)R Xb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb)3, -C(=O)N(R Xb )2, -OS(=O)2R Xb , or -S(=O)2OR Xb It is ethyl substituted with R. In some embodiments, at least one R Xa This is an optional choice of one or more -S(=O)2OR Xb It is ethyl substituted with R. In some embodiments, at least one R Xa This is one or more -S(=O)2OR Xb It is ethyl substituted with R. In some embodiments, at least one R Xa is -S(=O)2OR Xb It is ethyl substituted with [a specific compound].

[0127] In some embodiments, at least one R Xa This can be any one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)R Xb , -C(=O)OR Xb -OC(=O)R Xb , -N(R Xb )C(=O)(R Xb ), -N + (R Xb )3, -C(=O)N(R Xb )2, -OS(=O)2R Xb , or -S(=O)2OR Xb It is a propyl substituted with R. In some embodiments, at least one R Xa This is an optional choice of one or more -N values. + (R xb )3 is a propyl substituted with 3. In some embodiments, at least one R Xa is one or more -N + (R Xb )3 is a propyl substituted with 3. In some embodiments, at least one R Xa is, -N + (R Xb It is a propyl substituted with 3.

[0128] In some embodiments, at least one R xbis H. In some embodiments, at least one R Xb C1~C is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. 12 It is alkyl. In some embodiments, at least one R Xb C2~C is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. 12 It is an alkenyl. In some embodiments, at least one R Xb C2~C is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. 12 It is alkinyl.

[0129] Several embodiments, each R Xb H is H.

[0130] In some embodiments, at least one R Xb is a methyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, at least two R Xb is a methyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, at least two R Xb It is methyl.

[0131] In some embodiments, two R Xb is a methyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, two R Xb It is methyl.

[0132] In some embodiments, at least one RXb is a propyl molecule optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, at least one R Xb is a propyl substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, at least one R Xb is a propyl substituted with one or more -S(=O)2OH groups. In some embodiments, at least one R Xb This is a propyl derivative substituted with one -S(=O)2OH group.

[0133] In some embodiments, one R Xb C1~C is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. 12 It is alkyl. In some embodiments, one R Xb is a propyl substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH, optionally. In some embodiments, one R Xb is a propyl substituted with one or more oxo, halogen, -CN, -NO2, -OH, -NH2, -C(=O)OH, or -S(=O)2OH. In some embodiments, one R Xb is a propyl substituted with one or more -S(=O)2OH groups. In some embodiments, one R Xb This is a propyl derivative substituted with one -S(=O)2OH group.

[0134] (iv) Exemplary embodiments of compounds In some embodiments, the compound is of formula (I-1-a): [ka] The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0135] In some embodiments, the compound is of formula (I-1-b): [ka] The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0136] In some embodiments, the compounds are of formula (I-1-c), (I-1-d), (I-1-e): [ka] The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0137] In some embodiments, the compound is of formula (I-1-f): [ka] The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0138] In some embodiments, the compound is of formula (I-2-a): [ka] The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0139] In some embodiments, the compound is of formula (I-2-b): [ka] is a compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0140] In some embodiments, the compound is of formula (I-2-c), (I-2-d), or (I-2-e):

Chemical formula

[0141] In some embodiments, the compound is of formula (I-2-f):

Chemical formula

[0142] In some embodiments, the compound is of formula (I-1-a’):

Chemical formula

[0143] In some embodiments, the compound is of formula (I-1-b’):

Chemical formula

[0144] In some embodiments, the compound is of formula (I-1-c’), (I-1-d’), (I-1-e’):

Chemical formula

[0145] In some embodiments, the compound is of formula (I-1-f’):

Chemical Formula

[0146] In some embodiments, the compound is of formula (I-2-a’):

Chemical Formula

[0147] In some embodiments, the compound is of formula (I-2-b’):

Chemical Formula

[0148] In some embodiments, the compound is of formula (I-2-c’), (I-2-d’), or (I-2-e’):

Chemical Formula

[0149] In some embodiments, the compound is of formula (I-2-f’):

Chemical Formula

[0150] In some embodiments, the compound is selected from the compounds listed in Table A, as well as their pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, and tautomers.

[0151] In some embodiments, the compounds are selected from the compounds listed in Table A and their pharmaceutically acceptable salts.

[0152] In some embodiments, the compound is selected from the compounds listed in Table A. [ka] [ka]

[0153] (v) Definition The term "independently" is used herein to indicate that variables such as atoms or functional groups, which are applied independently, differ independently from application to application. For example, if two or more substituents or atoms (such as carbon or heteroatoms like oxygen (O), sulfur (S), or nitrogen (N)) are produced, each substituent or atom is independent of the other substituent or atom, and such substituents or atoms may alternate.

[0154] As used herein, the term “alkyl” refers, in certain embodiments, to saturated, linear, or branched hydrocarbon radicals containing 1 to 20 (including 1 to 10 or 1 to 6) carbon atoms. Branching means that one or more lower C1-C6 alkyl groups, such as methyl, ethyl, or propyl, are bonded to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, and n-hexyl radicals, and examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals. 20 Examples of alkyl radicals include, but are not limited to, hexadecamethyl, hexadecaethyl, hexadecopropyl, octadecamethyl, octadecaethyl, and octadecapropyl.

[0155] When used herein, the term “alkenyl” refers, in certain embodiments, to a monovalent linear or branched group derived from a hydrocarbon moiety containing 2 to 6, 2 to 8, or 2 to 20 carbon atoms having at least one carbon-carbon double bond. The double bond may or may not be a bond to another group. Examples of C2-C8 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-l-yl, heptenyl, and octenyl. As defined herein, “alkenyl” groups include both cis and trans isomers.

[0156] When used herein, the term "alkynyl" refers, in certain embodiments, to a monovalent linear or branched group derived from a hydrocarbon moiety containing 2 to 6, 2 to 8, or 2 to 20 carbon atoms having at least one carbon-carbon triple bond. The triple bond may or may not be a bond to another group. Examples of C2-C8 alkynyl groups include, but are not limited to, ethynyl, propynyl, and butynyl.

[0157] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the monovalent alkyl groups described above can become an alkylene by removing a second hydrogen atom from the alkyl group. As defined herein, alkylenes may also be C1-C6 alkylenes. Alkylenes may further be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0158] Similarly, the terms "alkenylene," "alkynylene," "cycloalkylene," "arylene," "heteroarylene," and "heterocyclene" refer to divalent radicals derived from monovalent alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclene, respectively, by removing a second hydrogen atom from the respective monovalent radical.

[0159] The terms "halo," "halo," or "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0160] As used herein, the term "oxo" is understood to refer to a carbonyl group (i.e., C(O)).

[0161] When used herein as an adjective, the terms “pharmaceutical” or “pharmaceutically acceptable” mean substantially non-toxic and substantially harmless to the recipient. As used herein, “pharmaceutically acceptable” means a compound, material, composition, carrier and / or dosage form suitable, within the bounds of sound medical judgment, for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0162] The compounds disclosed herein include the compounds themselves, and, where applicable, their salts and solvates. Salts can be formed, for example, between an anion on a compound of the disclosure and a positively charged group (e.g., protonated amino acids). Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a compound of the disclosure and a charged group (e.g., carboxylates). Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. The compounds of this disclosure also include salts thereof that contain quaternary nitrogen atoms.

[0163] Furthermore, physiologically acceptable, i.e., pharmaceutically compatible, salts may be salts of the compounds disclosed herein with inorganic or organic acids. Salts having inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts having organic carboxylic acids or sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or naphthalenedisulfonic acid are preferred.

[0164] Other pharmaceutically compatible salts that may be mentioned are salts with conventional bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), or ammonium salts, derived from ammonia or organic amines, such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, or methylpiperidine.

[0165] As used herein, “pharmaceutically acceptable salt” may refer to a derivative of the disclosed compound obtained by modifying the parent compound to an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts, as well as quaternary ammonium salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoenoic acid, isethionic acid, lactic acid, lactobio Examples of inorganic and organic acids include, but are not limited to, ammonium acids, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinous acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amine acids, such as glycine, alanine, phenylalanine, and arginine.

[0166] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octo-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid. The disclosure also includes salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, or an alkaline earth metal ion, such as an aluminum ion, or by an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylamine, diethylaminoethanol, ethylenediamine, imidazole, lysine, arginine, morpholine, 2-hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, or tetramethylammonium hydroxide.

[0167] It should be understood that all references to pharmaceutically acceptable salts include the solvated form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0168] Furthermore, the compounds of this disclosure, for example, salts of the compounds, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0169] Some of the compounds of this disclosure may exist in the form of non-solvates, such as hydrates, as well as solvates.

[0170] A “solvate” refers to a solvation form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in their crystalline solid state and can therefore form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one of the substances in which water retains its molecular state as H2O, and such combinations can form one or more hydrates. In hydrates, water molecules are bonded through sub-valences by intermolecular forces, particularly hydrogen bridges. Solid hydrates contain water in stoichiometric ratios as so-called crystal water, and the water molecules do not need to be equivalent in terms of their bonding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, or trihydrates. Equally preferred are the hydrates of salts of the compounds of this disclosure.

[0171] Critical micelle concentration In some embodiments, the bile acids or salts thereof of this disclosure are characterized by a critical micelle concentration (CMC). In some embodiments, the bile acids or salts thereof aggregate and / or form micelles at concentrations above the CMC. Methods for measuring the CMC of the bile salts described herein are known in the art; see, for example, Natalini, et al J Pharm Biomed Anal. (2014) 87:62-81. In some embodiments, the methods include potentiometric, spectroscopic, nuclear magnetic resonance, viscometric, turbidimetry, microcalorimetry, refractive index, conductivity, cholesterol solubilization, bilirubin monoglucuronide solubilization, dye solubilization, fluorescence, capillary electrophoresis, reverse-phase HPLC, freezing point depression, surface tension, and / or light scattering methods. In some embodiments, the CMC value is the average of at least 3 to 50 iterations measured by a single technique (e.g., 3 to 50 iterations measured by potentiometrics, 3 to 50 iterations measured by spectroscopics, or 3 to 50 iterations measured by light scattering). In some embodiments, the CMC value is the average of repetitions measured by two or more techniques, with at least 3, 4, 5, 6, 7, 8, 9, or 10 repetitions measured for each technique (e.g., (i) the average of at least 3, 4, 5, 6, 7, 8, 9, or 10 repetitions measured by potentiometrics, (ii) the average of at least 3, 4, 5, 6, 7, 8, 9, or 10 repetitions measured by spectroscopics, (iii) the average of at least 3, 4, 5, 6, 7, 8, 9, or 10 repetitions measured by light scattering, (iv) repetitions from any pairwise combination of (i) to (iii), or (v) repetitions from any pairwise combination of repetitions from the combinations of (i) to (iii)).

[0172] The CMC values ​​of exemplary bile salts of this disclosure, measured according to this method, are shown in Table 2.

[0173] In some embodiments, the bile acids or salts described herein are characterized by a CMC of at least about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM, as measured, for example, using the method described herein. In some embodiments, the bile acids or salts are characterized by a CMC of about 30 mM, about 25 mM, about 20 mM, about 18 mM, about 16 mM, about 14 mM, or about 12 mM or less, as measured, for example, using the method described herein. In some embodiments, the bile acid or its salt is characterized by a CMC of about 1 mM to about 10 mM, about 2 mM to about 10 mM, about 3 mM to about 10 mM, about 4 mM to about 10 mM, about 5 mM to about 15 mM, or about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM, as measured, for example, using the method described herein.

[0174] In some embodiments, the bile acid or its salt is characterized by a CMC of at least about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL, as measured using, for example, the method described herein. In some embodiments, the bile acid or its salt is characterized by a CMC of about 15 mg / mL, about 14 mg / mL, about 13 mg / mL, about 12 mg / mL, about 11 mg / mL, about 10 mg / mL, about 9 mg / mL, about 8 mg / mL, about 7 mg / mL, or about 6 mg / mL or less, as measured using, for example, the method described herein. In some embodiments, the bile acid or its salt is characterized by a CMC of about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 5 mg / mL, or about 1 mg / mL to about 5 mg / mL, as measured using, for example, the method described herein.

[0175] Co-excipients In some embodiments, the Disclosure provides compositions comprising a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more co-excipients. As used herein, the term “co-excipient” refers to a component of the composition other than the therapeutic agent or its bile acid or salt. In some embodiments, one or more co-excipients enhance the intestinal permeability of the therapeutic agent in a subject (e.g., a human subject) after oral administration, compared, for example, (i) a therapeutic agent without one or more co-excipients, or (ii) a control composition comprising the therapeutic agent and at least one bile acid or a salt thereof without one or more co-excipients. In some embodiments, one or more co-excipients are selected from chelating agents, polymers, dendrimers, nanoparticles, lipids, alkyl acids, and combinations thereof.

[0176] In some embodiments, one or more co-excipients provide additional properties to facilitate systemic delivery of the therapeutic agent after oral administration. For example, in some embodiments, one or more co-excipients are selected from bulking agents, binders, surfactants, bioadhesives, lubricants, disintegrants, stabilizers, solubilizers, flow enhancers, and additives or factors that affect dissolution or disintegration time. In some embodiments, one or more co-excipients are effective in providing enhanced mucosal permeability, protection of the therapeutic agent from gastric proteases, and enhanced cellular uptake.

[0177] Chelating agents In some embodiments, the present disclosure provides a composition comprising a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more chelating agents.

[0178] Chelating agents, also known as scavengers, are molecules capable of forming stable complexes with metal ions, particularly divalent and trivalent metal ions, including trace and heavy metals (e.g., calcium, magnesium, zinc, iron, chromium, and lead). As used herein, “chelating agent,” “scavenger,” “scavenger,” or “scavenger” are used interchangeably to refer to polydendritic (i.e., multiple-bound) ligands that form a single central atom with two or more distinct coordinate bonds.

[0179] In some embodiments, the chelating agent forms a complex with a copper salt (e.g., a copper(I) or copper(II) salt). In some embodiments, the chelating agent forms a complex with an iron salt (e.g., an iron(II) or iron(III) salt). In some embodiments, the chelating agent forms a complex with a zinc salt (e.g., a zinc(II) salt).

[0180] In some embodiments, the chelating agent is selected from mannitol, sorbitol, saccharose, sucrose, trehalose, calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, disodium phosphate dihydrate), amino acids (e.g., any one of 20 standard proteinogenic α-amino acids), EDTA, EGTA, citrate, complexing peptides (e.g., GHK, i.e., glycyl-histidyl-lysine peptide), polyacrylic acid, polyacrylic acid derivatives, carbomer, carbomer derivatives, sodium alginate, silicates (e.g., kaolin), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), glycerol, sodium dodecyl sulfate, calcium sulfate, calcium carbonate, and any pharmaceutically acceptable salt of any of the above. In some embodiments, the chelating agent is an analog or derivative of one of the aforementioned agents.

[0181] In some embodiments, the chelating agent is as described in Fernane F et al., Interactions between calcium phosphate and heavy metal ions in aqueous solution, MATEC Web of Conferences, Vol. 5, EDP Sciences, 2013; US8, 193, 291; and Giertsen E et al. Caries Res. 1989; 23(4): 278-83.

[0182] In some embodiments, the chelating agent may be a polyol (e.g., mannitol, sorbitol, or glycerol), a sugar-based surfactant (e.g., those mentioned in Ferrin N et al., J Surfact Deterg. 2012;15(3):259-264), a carboxylate (e.g., citrate, tartrate, gluconate, oxalate, malate, or salcaprozate), a phosphate (e.g., sodium triphosphate or tetrapotassium pyrophosphate), a sulfate (e.g., sodium dodecyl sulfate), an amine (e.g., ethylenediamine, chlorophyll, or choline), an amino acid or complexed peptide (e.g., lysine, glycine, histidine, or Kober PA et al., Journal of Biological Chemistry. 1912;13(1):1-13 or Trzaskowski B et al., J Biol Inorg). The compounds include peptides (as mentioned in Chem. 2008;13(1):133-7), aminopolycarboxylic acids (e.g., EDTA, EGTA, pentec acid, or diethylenetriaminepentaacetic acid (DTPA), or humic acid), polymeric complexing agents (e.g., HPMC (which may be in the form of HPMC capsules such as QualiV, VCaps, or VCaps plus), pullulan (which may be in the form of pullulan capsules), polycarboxylates, carbomers or carbopols, chitosan, alginates, povidone, polyvinyl alcohol (PVA), or any complexing agent or polymer as mentioned in US8,193,291), cyclodextrins, or any mixture of two or more of the aforementioned agents.

[0183] In some embodiments, the chelating agent comprises ethylenediaminetetraacetic acid (EDTA) or a salt thereof. In some embodiments, the chelating agent comprises the free acid of EDTA. In some embodiments, the chelating agent comprises a salt of EDTA (e.g., disodium EDTA, tetrasodium EDTA, dipotassium EDTA, calcium disodium EDTA).

[0184] In some embodiments, the chelating agent comprises ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) or a salt thereof. In some embodiments, the chelating agent comprises the free acid of EGTA. In some embodiments, the chelating agent comprises a salt of EGTA (e.g., disodium EGTA, tetrasodium EGTA, dipotassium EGTA).

[0185] In some embodiments, the chelating agent comprises glutamic acid. In some embodiments, the chelating agent comprises any known salt of glutamic acid. In some embodiments, the chelating agent comprises sodium glutamate.

[0186] polymer In some embodiments, the Disclosure provides a composition comprising a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more polymers. In some embodiments, the composition comprises a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more hydrophilic polymers. In some embodiments, the composition comprises a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more hydrophobic polymers. In some embodiments, the composition comprises a therapeutic agent, at least one bile acid or a salt thereof as described herein, one or more hydrophilic polymers, and one or more hydrophobic polymers.

[0187] In some embodiments, the polymer is a non-biodegradable polymer. In some embodiments, the polymer is a biodegradable polymer. As used herein, the term “biodegradable” means a polymer that dissolves or decomposes when exposed to a physiological solution with a pH of about 6–8 at a temperature of about 25°C–38°C within a period acceptable for the desired application (e.g., vivotherapy), typically less than about 5 years, more preferably less than about 1 year.

[0188] In some embodiments, the polymer is naturally occurring (i.e., extracted or derived from a natural source). In some embodiments, the polymer is synthetic (i.e., synthesized from one or more chemical reactions). In some embodiments, the polymer is naturally occurring and further modified by one or more chemical reactions.

[0189] In some embodiments, the polymer is a naturally occurring polymer selected from albumin, collagen, gelatin, and prolamin, e.g., zein, as well as polysaccharides such as alginic acid, cellulose derivatives, and polyhydroxyalkanoates, e.g., polyhydroxybutyrate. In some embodiments, the polymer comprises cellulose or its derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose). In some embodiments, the polymer comprises natural gums (e.g., guar gum, xanthan gum, locust bean gum, karaya gum, bee gum, etc.). In some embodiments, the polymer comprises alginic acid. In some embodiments, the polymer comprises dextran. In some embodiments, the polymer comprises polysaccharides.

[0190] In some embodiments, the polymer is poly(hydroxy acid) (e.g., poly(lactic acid), poly(glycolic acid), and poly(lactic acid-coglycolic acid)), poly(lactide), poly(glycolide), poly(lactide-coglycolide), polyan anhydride, polyoltoester, polyamide, polycarbonate, polyalkylene (e.g., polyethylene and polypropylene), polyalkylene glycol (e.g., poly(ethylene glycol)), polyalkylene oxide (e.g., poly(ethylene oxide)), polyalkylene terephthalate (e.g., poly(terephthalate ethylene)), polyvinyl alcohol, polyvinyl ether, polyvinyl ester, polyvinyl halide (e.g., polyvinyl chloride), polyvinylpyrrolidone, polysiloxane, polyvinyl alcohol, polyvinyl acetate, polystyrene, polyurethane and its copolymers, alkylcellulose, hydroxyalkylcellulose, cellulose ether, cellulose ester, nitrocellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose Derivatized celluloses such as lurose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxyethylcellulose, cellulose triacetate, and sodium cellulose sulfate (collectively referred to as "synthetic cellulose" in this specification), acrylic acid, methacrylic acid or copolymer polymers, or esters, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate) Polyacrylic acids are selected from those comprising poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl methacrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate), their derivatives (collectively referred to herein as "polyacrylic acids"), poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), their copolymers and blends. As used herein, "derivatives" refers to polymers having substitutions, additions of chemical groups, and other modifications that are routinely prepared by those skilled in the art.

[0191] In some embodiments, the polymer comprises polyacrylate (e.g., carbopol, polycarbophil). In some embodiments, the polymer comprises polyoxyethylene. In some embodiments, the polymer comprises polyethylene glycol (PEG). In some embodiments, the PEG has a molecular weight of 1,000 Da to 40,000 Da. In some embodiments, the PEG is branched. In some embodiments, the PEG is linear. In some embodiments, the polymer comprises polycarbophil (e.g., Noveon AA-I, Noveon CA-I, Noveon CA-2). In some embodiments, the polymer comprises poly(alkyl methacrylate). In some embodiments, the polymer comprises poly(vinyl acetate).

[0192] In some embodiments, the polymer is a homopolymer. In some embodiments, the polymer is a copolymer. In some embodiments, the copolymer is a block copolymer. In some embodiments, the block copolymer includes lactic acid and glycolic acid (e.g., poly(dl-lactide-co-glycolide) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA)). In some embodiments, the block copolymer includes PEG and polypropylene (e.g., Pluronic®, Tektronix, or Genapol block copolymers). In some embodiments, the polymer includes a combination of one or more block copolymers (e.g., PEG-PLA or PEG-PLGA copolymer). In some embodiments, the copolymer is a random copolymer. In some embodiments, the copolymer is a graft copolymer. In some embodiments, the copolymer is an alternating copolymer.

[0193] In some embodiments, the homopolymer or copolymer includes poly(methacrylate), poly(ethyl acrylate), poly(ethylene glycol), hyaluronic acid, polysaccharides, chitosan, arginine, poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(ethyleneimine), poly(N-(2-hydroxypropyl)methacrylamide), poly(glycolic acid), poly(lactic acid), poly(lactic acid-coglycolic acid), poly(caprolactone), poly(orthoester), poly(anhydride), poly(amide), poly(esteramide), poly(phosphoester), poly(alkylcyanoacrylate), or combinations thereof.

[0194] In some embodiments, the polymer has a molecular weight of at least about 0.5 kDa, about 1 kDa, about 1.5 kDa, about 2 kDa, about 2.5 kDa, about 3 kDa, about 3.5 kDa, about 4 kDa, about 4.5 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, or about 100 kDa. In some provisions, the polymer has a molecular weight of approximately 0.5 kDa to approximately 10 kDa, approximately 1 kDa to approximately 10 kDa, approximately 5 kDa to approximately 10 kDa, approximately 0.5 kDa to approximately 20 kDa, approximately 1 kDa to approximately 20 kDa, approximately 5 kDa to approximately 20 kDa, approximately 10 kDa to approximately 20 kDa, approximately 0.5 kDa to approximately 50 kDa, approximately 1 kDa to approximately 50 kDa, approximately 5 kDa to approximately 50 kDa, approximately 10 kDa to approximately 50 kDa, approximately 0.5 kDa to approximately 100 kDa, approximately 1 kDa to approximately 100 kDa, approximately 5 kDa to approximately 100 kDa, or approximately 10 kDa to approximately 100 kDa.

[0195] In some embodiments, the homopolymer or copolymer comprises acrylic acid or its esters and / or methacrylic acid or its esters. In some embodiments, the homopolymer or copolymer comprises poly(acrylic acid), polyacrylate, poly(methacrylic acid), and poly(methacrylic acid) polymers, for example, those sold under the trademark name Eudragit® (Rohm GmbH, Darmstadt, Germany), such as Eudragit® L, Eudragit® S, Eudragit® RL, Eudragit® RS coating materials and mixtures thereof.

[0196] In some embodiments, homopolymers or copolymers are bioadhesives or mucosal adhesives. Mucosal adhesive hydrogel-forming polymers are hydrophilic and swellable, containing numerous hydrogen bond-forming groups such as hydroxyl, thiol, carboxyl, or amine to promote adhesion. Upon contact with a mucosal surface, they can interact with portions on the biological interface that result in polymer / mucosal interactions (adhesion) via hydrogen bonding, electrostatic, hydrophobic, or van der Waals interactions. Furthermore, when used in a dry form, they can absorb moisture from the mucosal surface and swell. Exemplary hydrogel-forming excipients include PEG and other polymers having an ethylene glycol (EG) backbone (e.g., EG homopolymers or their crosslinked heteropolymers), block copolymers of EG units (e.g., PEG homopolymers (Polyox N10 / MW=100,000, Polyox-80 / MW=200,000; Polyox-1105 / MW=900,000; Polyox-301 / MW=4,000,000; Polyox-303 / MW=7,000,000, Polyox WSR-N-60K, all of which are trademark names of Union Carbide)), hydroxypropyl methylcellulose (HPMC) of all molecular weights and grades, or polyoxomers as combinations thereof (Lutrol F-68, Lutrol F-127, F-105, etc., all BASF) The materials are selected from biodegradable polymers such as polyacrylic acid (trademark name of Chemicals), genapol, PEG (e.g., PEG-1500, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000, etc.), natural gums (xanthan gum, locust bean gum, etc.), and cellulose derivatives (HC, HMC, HMPC, HPC, CP, CMC), free or crosslinked polyacrylic acid polymers and combinations thereof, physical blends or crosslinked polylactic acid, polyglycolic acid, and combinations thereof. In some embodiments, the hydrogel component is crosslinked.

[0197] In some embodiments, one or more co-excipients include polymers selected from Eudragit E PO (EPO), Eudragit RL 100 (RL100), poly(ethylene glycol) 1kDa (PEG-1kDa), branched poly(ethyleneimine) 800Da (PEI:b0.8), Kollidon SR (KOLSR), poly(methacrylic acid) 5kDa (PMA:5), poly(aspartic acid) 2kDa (POLD:2), poly(2-ethyl oxazoline) 25kDa (POXZ:25), poly(glutamic acid) 50kDa (POLE:50), branched poly(ethyleneimine)-copoly(ethylene glycol) 500Da (bPEIPPEG:0.5), Vivacoat (VIVA), and combinations thereof.

[0198] In some embodiments, one or more co-excipients include Eudragit E PO (EPO). In some embodiments, one or more co-excipients include Eudragit RL100 (RL100). In some embodiments, one or more co-excipients include poly(ethylene glycol) 1kDa (PEG-1kDa). In some embodiments, one or more co-excipients include branched poly(ethyleneimine) 800Da (PEI:b0.8). In some embodiments, one or more co-excipients include Kollidon SR (KOLSR). In some embodiments, one or more co-excipients include poly(methacrylic acid) 5kDa (PMA:5). In some embodiments, one or more co-excipients include poly(aspartic acid) 2kDa (POLD:2). In some embodiments, one or more co-excipients include poly(2-ethyl oxazoline) 25kDa (POXZ:25). In some embodiments, one or more co-excipients include poly(glutamic acid) 50 kDa (POLE: 50). In some embodiments, one or more co-excipients include branched poly(ethyleneimine)-co-poly(ethylene glycol) 500 Da (bPEIPPEG: 0.5). In some embodiments, one or more co-excipients include Vivacoat (VIVA).

[0199] Dendrimer In some embodiments, the present disclosure provides a therapeutic agent and a composition comprising at least one bile acid or a salt thereof as described herein and one or more dendrimers.

[0200] Dendrimers are iteratively branched polymers containing a central core surrounded by peripheral groups. Dendrimers are typically synthesized stepwise around a core. During synthesis, each sequential reaction step adds a generation of branching. The number of repeated steps corresponds to the dendrimer generation. For example, a single reaction step yields a first-generation (G1) dendrimer.

[0201] In some embodiments, the co-excipients of the present disclosure comprise one or more dendrimers. In some embodiments, the dendrimer comprises a poly(amidoamine), poly(propyleneimine), polyamide, polyether, polyester, or phosphorus-based architecture.

[0202] In some embodiments, the dendrimer contains propyleneimine units. In some embodiments, the dendrimer contains ethylene oxide units. In some embodiments, the dendrimer contains polybenzyl ether units. In some embodiments, the dendrimer contains peptidyl units. In some embodiments, the dendrimer contains sugar units. In some embodiments, the dendrimer contains polyester units. In some embodiments, the polymer contains amidoamine units. In some embodiments, the dendrimer contains ether units. In some embodiments, the dendrimer contains polyester units. In some embodiments, the dendrimer is phosphorus-based.

[0203] In some embodiments, the dendrimer is a G1-G11 dendrimer. In some embodiments, the dendrimer is a G1 dendrimer. In some embodiments, the dendrimer is a G1.5 dendrimer. In some embodiments, the dendrimer is a G2 dendrimer. In some embodiments, the dendrimer is a G2.5 dendrimer. In some embodiments, the dendrimer is a G3 dendrimer. In some embodiments, the dendrimer is a G3.5 dendrimer. In some embodiments, the dendrimer is a G4 dendrimer. In some embodiments, the dendrimer is a G4.5 dendrimer. In some embodiments, the dendrimer is a G5 dendrimer. In some embodiments, the dendrimer is a G5.5 dendrimer. In some embodiments, the dendrimer is a G6 dendrimer. In some embodiments, the dendrimer is a G6.5 dendrimer. In some embodiments, the dendrimer is a G7 dendrimer. In some embodiments, the dendrimer is a G7.5 dendrimer. In some embodiments, the dendrimer is a G8 dendrimer. In some embodiments, the dendrimer is a G8.5 dendrimer. In some embodiments, the dendrimer is a G9.5 dendrimer. In some embodiments, the dendrimer is a G10 dendrimer.

[0204] In some embodiments, the dendrimer contains a terminal carboxylate. In some embodiments, the dendrimer contains a terminal amine. In some embodiments, the dendrimer contains a terminal malonate. In some embodiments, the dendrimer contains a terminal hydroxyl group. In some embodiments, the dendrimer contains a terminal amino group. In some embodiments, the dendrimer contains a terminal aliphatic group (e.g., a C2-C20 branched or unbranched alkyl chain).

[0205] In some embodiments, the dendrimer is a poly(amidoamine)(PAMAM) dendrimer. In some embodiments, the PAMAM dendrimer is G1 to G10. In some embodiments, the PAMAM dendrimer is G1, G1.5, G2, G2.5, G3, G3.5, G4, G4.5, G5, G5.5, G6, G6.5, G7, G7.5, G8, G8.5, G9, G9.5, or G10. In some embodiments, the PAMAM dendrimer contains a terminal carboxylate (carboxylate-terminated PAMAM). In some embodiments, the PAMAM dendrimer contains a terminal amine (amine-terminated PAMAM). In some embodiments, the PAMAM dendrimer contains a terminal hydroxyl group (PAMAM-OH). In some embodiments, the PAMAM dendrimer contains a terminal amino group (PAMAM-NH2).

[0206] In some embodiments, the dendrimer is a 3.5th generation PAMAM dendrimer. In some embodiments, the dendrimer is a 3.5th generation carboxylate-terminated poly(amidoamine) dendrimer (DENDAC3.5). In some embodiments, the dendrimer is a 4th generation PAMAM dendrimer. In some embodiments, the dendrimer is a 4th generation amine-terminated poly(amidoamine) dendrimer (DENDAM4).

[0207] microscopic particles In some embodiments, the Disclosure provides a composition comprising a therapeutic agent, at least one bile acid or a salt thereof as described herein, and one or more microparticles. In some embodiments, the microparticles include nanoparticles, fine particles, or combinations thereof.

[0208] As used herein, the term “microparticles” refers to microparticles having an average size of less than approximately 1000 microns. In some embodiments, microparticles include microparticles. As used herein, the term “microparticles” refers to substantially spherical colloidal structures having a size of at least approximately 0.5 microns to a maximum of approximately 1000 microns. In some embodiments, size is the number-average particle diameter measured using any method of particle analysis known in the art. In some embodiments, size is the volume-average particle diameter measured using any method of particle analysis known in the art. Methods of particle analysis include, but are not limited to, optical microscopy, scanning electron microscopy, transmission electron microscopy, laser diffraction, light scattering, or time of flight.

[0209] In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) are microcapsules. As used herein, the term “microcapsule” refers to a particle (e.g., nanoparticles, fine particles, or combinations thereof) having an outer shell surrounding a core of another material. The core may be a gas, liquid, gel, solid, or combination thereof.

[0210] As used herein, the term “nanoparticles” refers to microscopic particles having an average dimension of less than approximately 1000 nanometers. In some embodiments, nanoparticles are substantially spherical particles having an average diameter of approximately 500, 200, 100, 50, or 10 nm.

[0211] In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) are solid. In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) are porous. In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) contain pores or voids embedded in a matrix material or shell. In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) contain a therapeutic agent. In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) contain a core containing the therapeutic agent, which is encapsulated in a shell or polymer matrix. In some embodiments, the therapeutic agent is scattered within the shell or polymer matrix. In some embodiments, the therapeutic agent is uniformly mixed with the material forming the shell or polymer matrix.

[0212] In some embodiments, the particles (e.g., nanoparticles, microparticles, or combinations thereof) are spherical. In some embodiments, the particles (e.g., nanoparticles, microparticles, or combinations thereof) are non-spherical, for example, rod-shaped, spherical, acieular (elongated needle-shaped particles of the same width and thickness), columnar (long, thin particles with greater width and thickness than those of needle-shaped particles), flake (thin, flat particles of the same length and width), plate (flat particles of the same length and width but with greater thickness than flakes), lath (long, thin, blade-shaped particles), equant (particles of the same length, width, and thickness, which include both cubic and spherical particles), layered (stacked plates), or disc-shaped.

[0213] In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) comprise one or more polymers. In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) comprise one or more polymers described herein (e.g., polylactic acid, polyglycolic acid, and copolymers thereof, polyanhydrides, polyorthoesters, and poly(hydroxy acids) comprising certain types of protein and polysaccharide polymers). In some embodiments, the particles (e.g., nanoparticles, fine particles, or combinations thereof) are biodegradable.

[0214] Suitable methods for producing fine particles or nanoparticles include spray drying, other spray-type manufacturing processes, and solvent removal. One method for producing formulations is described in detail in WO2004 / 098570. Another method is described in U.S. Patent No. 6,143,211 granted to Mathiowitz et al.

[0215] In some embodiments, the particles contain sodium bicarbonate. In some embodiments, the particles contain calcium phosphate (e.g., tribasic calcium phosphate or dibasic calcium phosphate). In some embodiments, the particles contain hydroxyapatite. In some embodiments, the particles contain zinc oxide.

[0216] In some embodiments, the particle diameter (e.g., the longest diameter if the particle is non-spherical) is approximately 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 15 microns, 20 microns, 25 microns, 30 microns, 35 microns, 35 microns, 40 microns, 45 microns, or 50 microns in length. In some embodiments, the particle diameter (e.g., the longest diameter if the particle is non-spherical) is approximately 50 nanometers, 100 nanometers, 150 nanometers, 200 nanometers, 250 nanometers, 300 nanometers, 350 nanometers, 400 nanometers, 450 nanometers, or 500 nanometers in length.

[0217] Medication and dosage forms In some embodiments, compositions of the Disclosure comprising one or more doses of a therapeutic agent described herein, a certain amount of at least one bile acid or a salt thereof as described herein, and optionally one or more co-excipients as described herein, are formulated as dosage forms for in vivo delivery to a subject (e.g., a human subject).

[0218] In some embodiments, the Disclosure provides a dosage form comprising a composition comprising a therapeutic agent as described herein and at least one bile acid or a salt thereof as described herein. In some embodiments, the Disclosure provides a dosage form comprising a composition comprising a therapeutic agent as described herein, at least one bile acid or a salt thereof as described herein and one or more co-excipients as described herein.

[0219] In some embodiments, the dosage form is for enteral administration. In some embodiments, the composition is formulated as a dosage form for enteral administration. In some embodiments, the dosage form is for oral administration. In some embodiments, the composition is formulated as a dosage form for oral administration. In some embodiments, the composition is effective in distributing a substantial portion (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) of one or more doses of a therapeutic agent to an absorption site, for example, after enteral administration to a subject. In some embodiments, the absorption site includes one or more sections of a GI tubule (e.g., the upper GI tubule). In some embodiments, the absorption site includes the stomach. In some embodiments, the absorption site includes the small intestine. In some embodiments, the absorption site includes one or a combination of the duodenum, jejunum, and ileum. In some embodiments, the absorption site includes the duodenum and / or jejunum.

[0220] It will be understood that the compositions described herein are converted into dosage forms for delivery to a subject (e.g., via enteral administration) using procedures routinely used by those skilled in the art. For example, in some embodiments, the compositions of this disclosure include therapeutic agents in dosage forms that are administered and dispensed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, the schedule of administration, and other factors known to the physician. In human therapy, it is important to provide dosage forms that deliver an effective amount of drug in vivo and make the drug bioavailable in a timely manner.

[0221] In some embodiments, the composition is formulated as a solid dosage form. In some embodiments, the solid dosage form is effective for distributing a substantial portion of one or more doses of the therapeutic agent (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) to an absorption site, for example, after enteral administration to a subject. In some embodiments, the absorption site is the stomach. In some embodiments, the site of the embodiment is the small intestine. In some embodiments, the solid dosage form is effective for releasing a substantial portion of one or more doses of the therapeutic agent (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) into the liquid volume of the stomach. In some embodiments, solid dosage forms are effective for releasing a substantial portion of one or more doses of the therapeutic agent (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) into the fluid volume of the small intestine. In some embodiments, solid dosage forms are effective for releasing a substantial portion of one or more doses of the therapeutic agent (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) into the combined fluid volume of the stomach and small intestine. In some embodiments, the solid dosage form contains a certain amount of at least one bile acid or salt thereof, such that when diluted in the liquid volume of the stomach, the liquid volume of the small intestine, or a combination of both, it achieves an effective concentration of at least one bile acid or salt thereof at an absorption site shown to enhance GI permeability according to any assay described herein (e.g., GI-ORIS). In some embodiments, the amount of at least one bile acid or salt thereof is substantially equal to the effective concentration multiplied by a dilution factor, the dilution factor being substantially equal to the liquid volume of the GI tube or a portion thereof (e.g., the liquid volume of the stomach, the liquid volume of the small intestine, or a combination of both).

[0222] In some embodiments, the composition is formulated as a liquid dosage form. In some embodiments, the liquid dosage form is effective for distributing a substantial portion of one or more doses of the therapeutic agent (e.g., at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100%) to the absorption site, for example, after enteral administration to a subject.

[0223] In some embodiments, a dosage form comprising the compositions of the present disclosure comprises one or more doses of the therapeutic agent described herein. In some embodiments, one or more doses of the therapeutic agent constitute an effective dose of the therapeutic agent. As used herein, “effective dose” refers to the amount of the therapeutic agent that elicits a response to treat a pre-existing disease or disorder and / or prevents or delays the onset of the disease or disorder in a subject (e.g., a human subject). In some embodiments, the effective therapeutic dose is provided in a single dose. In some embodiments, the effective therapeutic dose is distributed over multiple doses. As will be understood by those skilled in the art, studies in animal models are generally used for guidance regarding effective therapeutic doses for treating disorders or diseases in subjects. With respect to treatment protocols, it should be understood that the dose administered depends on several factors, including the specific therapeutic agent being administered, the route of administration selected, the age of the subject, and the condition of the particular subject. In some embodiments, the dose of the therapeutic agent is selected from a range of about 0.5 μg to about 1000 mg.

[0224] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral, transduodenal, or transrectal delivery), and the composition comprises a certain amount of at least one bile acid or a salt thereof as described herein. In some embodiments, the amount is sufficient to provide an effective concentration of at least one bile acid or a salt thereof at an absorption site (e.g., one or more regions of a GI tube). In some embodiments, the effective concentration is higher than the CMC of at least one bile acid or a salt thereof. In some embodiments, the effective concentration is at least about 2 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 greater than the CMC of at least one bile acid or a salt thereof. In some embodiments, the effective concentration is approximately 2 to 10 times, 2 to 20 times, 2 to 30 times, 2 to 40 times, 2 to 50 times, 2 to 100 times, 2 to 150 times, 2 to 200 times, 3 to 10 times, 3 to 20 times, 3 to 30 times, 3 to 40 times, 3 to 50 times, 3 to 100 times, and 3 to 30 times. It is approximately 2 to 150 times larger, approximately 3 to 200 times larger, approximately 3 to 10 times larger, approximately 3 to 20 times larger, approximately 3 to 30 times larger, approximately 3 to 40 times larger, approximately 3 to 50 times larger, approximately 3 to 100 times larger, approximately 3 to 150 times larger, approximately 3 to 200 times larger, approximately 4 to 10 times larger, approximately 4 to 20 times larger, approximately 4 to 30 times larger, approximately 4 to 40 times larger, approximately 4 to 50 times larger, approximately 4 to 100 times larger, approximately 4 to 150 times larger, or approximately 4 to 200 times larger. In some embodiments, the effective concentration is about 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, or 200 times greater than the CMC of at least one bile acid or its salt.

[0225] In some embodiments, the amount of at least one bile acid or salt thereof is selected to provide an effective concentration of at least one bile acid or salt thereof at an absorption site (e.g., one or more regions of the GI tubule), and the effective concentration is determined using an assay of a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of at least one bile acid or salt thereof that results in an increased GI of the therapeutic agent (e.g., intestine and / or stomach) compared to a control composition containing a therapeutic agent (e.g., a composition containing a therapeutic agent that does not contain at least one bile acid or salt thereof) as measured using a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS).

[0226] In some embodiments, the effective concentration (for example, when measured using the intestinal permeability assay described herein) is at least about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL. In some embodiments, the effective concentration (for example, when measured using the intestinal permeability assay described herein) is approximately 10 mg / mL to approximately 20 mg / mL, approximately 10 mg / mL to approximately 30 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 60 mg / mL, approximately 20 mg / mL to approximately 70 mg / mL, approximately 20 mg / mL to approximately 80 mg / mL, approximately 20 mg / mL to approximately 90 mg / mL, approximately 30 mg / mL to approximately 100 mg / mL, approximately 30 mg / mL to approximately 110 mg / mL, approximately 30 mg / mL to approximately 120 mg / mL, and approximately The effective concentrations are approximately 30 mg / mL to 130 mg / mL, approximately 30 mg / mL to 170 mg / mL, approximately 30 mg / mL to 180 mg / mL, approximately 40 mg / mL to 160 mg / mL, approximately 40 mg / mL to 170 mg / mL, approximately 40 mg / mL to 180 mg / mL, approximately 40 mg / mL to 190 mg / mL, approximately 40 mg / mL to 200 mg / mL, approximately 50 mg / mL to 150 mg / mL, approximately 50 mg / mL to 160 mg / mL, approximately 50 mg / mL to 170 mg / mL, approximately 50 mg / mL to 180 mg / mL, approximately 50 mg / mL to 190 mg / mL, or approximately 50 mg / mL to 200 mg / mL. In some embodiments, the effective concentration (for example, when measured using the permeabilization assay described herein) is approximately 30 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is approximately 50 mg / mL.In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 70 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 90 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 110 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 130 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 150 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 175 mg / mL. In some embodiments, the effective concentration (measured, for example, using the permeabilization assay described herein) is about 200 mg / mL.

[0227] In some embodiments, the amount of at least one bile acid or its salt is substantially equal to the effective concentration (e.g., weight percentage per volume (e.g., ml / mL)) multiplied by a dilution factor. In some embodiments, the amount of at least one bile acid or its salt is substantially equal to the effective concentration as weight percentage per volume (e.g., ml / mL) multiplied by a dilution factor. As used herein, the term “substantially equal” refers to a value that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of a reference value.

[0228] In some embodiments, the dilution factor is approximately 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the liquid volume of the GI tube (e.g., the liquid volume of a human GI tube). In some embodiments, the dilution factor is approximately 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the liquid volume of the stomach (e.g., the liquid volume of a human stomach). In some embodiments, the dilution factor is approximately 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the liquid volume of the small intestine (e.g., the liquid volume of a human small intestine). In some embodiments, the dilution factor is about 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times greater or less than the liquid volume of the GI tube (e.g., the liquid volume of a human GI tube). In some embodiments, the weight percentage per volume is mg / mL, and the dilution factor is about 2 mL to about 30 mL. In some embodiments, the dilution factor is about 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 27 mL, 28 mL, or 30 mL. In some embodiments, the composition is formulated for immediate release, with dilution factors of less than about 30 mL, less than about 25 mL, less than about 20 mL, or less than about 15 mL. In some embodiments, the composition is formulated for immediate release, with dilution factors of about 10 mL to about 20 mL. In some embodiments, the composition is formulated for immediate release, with dilution factors of about 5 mL to about 15 mL. In some embodiments, the composition is formulated for delayed release, with dilution factors of less than about 15 mL, less than about 10 mL, or less than about 5 mL. In some embodiments, the composition is formulated for immediate release, with dilution factors of about 2 mL to about 15 mL. In some embodiments, the composition is formulated for immediate release, with dilution factors of about 2 mL to about 10 mL.

[0229] In some embodiments, the amount of at least one bile acid or its salt is about 60 mg to about 2,000 mg. In some embodiments, the amount of at least one bile acid or its salt is about 60 mg to about 1,000 mg. In some embodiments, the amount of at least one bile acid or its salt is about 60 mg to about 600 mg. In some embodiments, the amount of at least one bile acid or its salt is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg.

[0230] In some embodiments, the composition comprises a certain amount of one bile acid or salt selected to provide one bile acid or salt at an effective concentration to an absorption site (e.g., one or more regions of a GI tube), the effective concentration being determined using a GI permeabilization assay described herein (e.g., a permeabilization assay using GI-ORIS). In some embodiments, the amount of one bile acid or salt is substantially equal to the effective concentration (e.g., weight percent per volume (e.g., ml / mL)) obtained by multiplying it by a dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the amount of one bile acid or salt is about 60 mg to about 2,000 mg. In some embodiments, the amount of one bile acid or salt is about 60 mg to about 1,000 mg. In some embodiments, the amount of one bile acid or salt is about 60 mg to about 600 mg. In some embodiments, the amount of one bile acid or its salt is approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1,000 mg.

[0231] In some embodiments, the composition comprises a certain amount of two or more bile acids or salts thereof (e.g., bile acids 2, 3, 4, 5, 6, 7, 8, 9, or 10) selected to provide an effective concentration of two or more bile acids or salts thereof at an absorption site (e.g., one or more regions of a GI tube), and the effective concentration is determined using an assay of a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS). In some embodiments, the amount of two or more bile acids or salts thereof is substantially equal to the effective concentration (e.g., weight percent per volume (e.g., ml / mL)) obtained by multiplying it by a dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the amount of two or more bile acids or salts thereof is independently about 60 mg to about 2,000 mg each. In some embodiments, the amount of two or more bile acids or salts thereof is independently about 60 mg to about 1,000 mg each. In some embodiments, the amounts of two or more bile acids or their salts are independently about 60 mg to about 600 mg each. In some embodiments, the amounts of two or more bile acids or their salts are independently about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg each.

[0232] In some embodiments, the bile acid or salt comprises at least two bile acids or salts thereof, a first bile acid or salt thereof, and a second bile acid or salt thereof, with the molar ratio of the first bile acid or salt thereof to the second bile acid or salt thereof being about 1:1, about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. In some embodiments, the bile acid or salt comprises at least two bile acids or salts thereof, a first bile acid or salt thereof, a second bile acid or salt thereof, and a third bile acid or salt thereof, and the composition comprises equimolar amounts of the first, second, and third bile acids or salts thereof. In some embodiments, the bile acid or salt thereof comprises at least two or more bile acids or salts thereof, a first bile acid or salt thereof, a second bile acid or salt thereof, a third bile acid or salt thereof, and a fourth bile acid or salt thereof, and the composition comprises equimolar amounts of the first, second, third, and fourth bile acids or salts thereof. In some embodiments, the dosage form comprises the composition described herein, comprising a certain amount of the therapeutic agent and a certain amount of at least one bile acid or salt thereof, and the composition comprises a molar ratio of the amount of at least one bile acid or salt thereof to the therapeutic agent, which is about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 100:1, about 150:1, about 200:1, about 300:1, about 400:1, or about 500:1.

[0233] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral, transduodenal, or transrectal delivery), and the composition comprises a certain amount of one or more co-excipients selected from chelating agents, polymers, dendrimers, nanoparticles, lipids, alkyl acids, and combinations thereof. In some embodiments, the amount is sufficient to provide an effective concentration of one or more co-excipients at an absorption site (e.g., one or more regions of the GI tube). In some embodiments, the effective concentration is determined using a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more co-excipients that results in increased GI permeation of the therapeutic agent compared to a control composition comprising the therapeutic agent (e.g., a composition comprising a therapeutic agent without at least one bile acid or a salt thereof and one or more co-excipients) when measured using a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more co-excipients that results in increased intestinal permeability of the therapeutic agent compared to a control composition containing the therapeutic agent (e.g., a composition comprising a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more co-excipients) when measured using the GI permeability assay described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the amount of one or more co-excipients is substantially equal to the effective concentration (e.g., weight percent per volume (e.g., ml / mL)) obtained by multiplying it by the dilution factor described herein (e.g., about 2 mL to about 30 mL).

[0234] In some embodiments, the amount of one or more co-excipients is about 20 mg to about 2,000 mg. In some embodiments, the amount of one or more co-excipients is about 20 mg to about 1,000 mg. In some embodiments, the amount of one or more co-excipients is about 20 mg to about 600 mg. In some embodiments, the amount of one or more co-excipients is approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1,000 mg.

[0235] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral, transduodenal, or transrectal delivery), and the composition comprises a certain amount of one or more chelating agents as described herein (e.g., ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetic acid or a salt thereof, ethylene dinitrilotetraacetic acid or a salt thereof, glutamic acid or a salt thereof). In some embodiments, the amount is sufficient to provide an effective concentration of one or more chelating agents at an absorption site (e.g., one or more regions of the GI tube). In some embodiments, the effective concentration is the concentration of one or more chelating agents that results in increased GI permeability of the therapeutic agent compared to a control composition comprising the therapeutic agent (e.g., a composition comprising a therapeutic agent without at least one bile acid or a salt thereof and one or more chelating agents) as measured using a GI permeability assay as described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more chelating agents that results in increased GI permeability of the therapeutic agent compared to a control composition containing the therapeutic agent (e.g., a composition containing a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more chelating agents), as measured using the GI permeability assay described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration of one or more chelating agents (measured, for example, using a GI permeation assay described herein, e.g., GI-ORIS) is at least about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL.

[0236] In some embodiments, the effective concentration of one or more chelating agents (measured, for example, using the GI permeation assay described herein, e.g., GI-ORIS) is approximately 5 mg / mL to 20 mg / mL, approximately 5 mg / mL to 30 mg / mL, approximately 10 mg / mL to 40 mg / mL, approximately 10 mg / mL to 50 mg / mL, approximately 20 mg / mL to 50 mg / mL, approximately 20 mg / mL to 60 mg / mL, and approximately 20 mg / mL / m³. The recommended dosages are approximately 70 mg / mL for L, 80 mg / mL for L, 90 mg / mL for L, 100 mg / mL for L, 110 mg / mL for L, 120 mg / mL for L, 130 mg / mL for L, 170 mg / mL for L, 180 mg / mL for L, or 150 mg / mL for L. In some embodiments, the amount of one or more chelating agents is substantially equal to the effective concentration (e.g., weight percentage per volume (e.g., ml / mL)) obtained by multiplying by the dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the amount of chelating agent is about 10 mg to about 1,500 mg. In some embodiments, the amount of chelating agent is about 10 mg to about 1,000 mg. In some embodiments, the amount of chelating agent is about 10 mg to about 500 mg. In some embodiments, the amount of chelating agent is about 10 mg to about 250 mg. In some embodiments, the amount of chelating agent is about 10 mg to about 100 mg.

[0237] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral, transduodenal, or transrectal delivery), and the composition contains a certain amount of one or more polymers as described herein. In some embodiments, the amount is sufficient to provide an effective concentration of one or more polymers at an absorption site (e.g., one or more regions of the GI tube). In some embodiments, the effective concentration is the concentration of one or more polymers that results in increased GI permeability of the therapeutic agent compared to a control composition containing the therapeutic agent (e.g., a composition containing a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more polymers) as measured using a GI permeability assay as described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more polymers that results in increased intestinal permeability of the therapeutic agent compared to a control composition containing the therapeutic agent (e.g., a composition containing a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more polymers) as measured using a GI permeability assay as described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration of one or more polymers (measured, for example, using a GI permeation assay described herein, e.g., a permeation assay using GI-ORIS) is at least about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL.In some embodiments, the effective concentration of one or more polymers (measured, for example, using a GI permeation assay described herein, e.g., a permeation assay using GI-ORIS) is approximately 5 mg / mL to approximately 20 mg / mL, approximately 5 mg / mL to approximately 30 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 60 mg / mL, and approximately 20 The concentrations are approximately mg / mL to about 70 mg / mL, approximately 20 mg / mL to about 80 mg / mL, approximately 20 mg / mL to about 90 mg / mL, approximately 30 mg / mL to about 100 mg / mL, approximately 30 mg / mL to about 110 mg / mL, approximately 30 mg / mL to about 120 mg / mL, approximately 30 mg / mL to about 130 mg / mL, approximately 30 mg / mL to about 170 mg / mL, approximately 30 mg / mL to about 180 mg / mL, or approximately 40 mg / mL to about 150 mg / mL. In some embodiments, the amount of one or more polymers is substantially equal to the effective concentration (e.g., weight percentage per volume (e.g., ml / mL)) obtained by multiplying it by the dilution factor described herein (e.g., approximately 2 mL to about 30 mL).

[0238] In some embodiments, the amount of polymer is about 10 mg to about 1,500 mg. In some embodiments, the amount of polymer is about 10 mg to about 1,000 mg. In some embodiments, the amount of polymer is about 10 mg to about 500 mg. In some embodiments, the amount of polymer is about 10 mg to about 250 mg. In some embodiments, the amount of polymer is about 10 mg to about 100 mg.

[0239] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral delivery, transduodenal delivery, or transrectal delivery), and the composition comprises one or more dendrimers (e.g., G1-G10 PAMAM dendrimers) in a certain amount as described herein. In some embodiments, the amount is sufficient to provide an effective concentration of one or more dendrimers at an absorption site (e.g., one or more regions of the GI tube). In some embodiments, the effective concentration is the concentration of one or more dendrimers that results in increased GI permeability of the therapeutic agent compared to a control composition comprising the therapeutic agent (e.g., a composition comprising a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more dendrimers) when measured using a GI permeability assay as described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more polymers that results in increased intestinal permeability of the therapeutic agent compared to a control composition comprising the therapeutic agent (e.g., a composition comprising a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more dendrimers) when measured using a GI permeability assay as described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration of one or more dendrimers (measured, for example, using a GI permeabilization assay described herein, e.g., GI-ORIS) is at least about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.In some embodiments, the effective concentration of one or more dendrimers (measured, for example, using the GI permeabilization assay described herein, e.g., a permeabilization assay using GI-ORIS) is approximately 0.01 mg / mL to approximately 1 mg / mL, approximately 0.05 mg / mL to approximately 1 mg / mL, approximately 0.5 mg / mL to approximately 2 mg / mL, approximately 1 mg / mL to approximately 5 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL, approximately 1 mg / mL to approximately 15 mg / mL, and approximately 1 mg / mL to approximately 20 mg / mL. The concentrations are approximately 1 mg / mL to 30 mg / mL, approximately 5 mg / mL to 20 mg / mL, approximately 5 mg / mL to 30 mg / mL, approximately 10 mg / mL to 40 mg / mL, approximately 10 mg / mL to 50 mg / mL, approximately 20 mg / mL to 50 mg / mL, approximately 20 mg / mL to 60 mg / mL, approximately 20 mg / mL to 70 mg / mL, approximately 20 mg / mL to 80 mg / mL, approximately 20 mg / mL to 90 mg / mL, or approximately 30 mg / mL to 100 mg / mL. In some embodiments, the amount of one or more dendrimers is substantially equal to the effective concentration (e.g., weight percentage per volume (e.g., ml / mL)) obtained by multiplying by the dilution factor described herein (e.g., approximately 2 mL to approximately 30 mL).

[0240] In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 1,500 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 1,000 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 500 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 250 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 100 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 50 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 20 mg. In some embodiments, the amount of one or more dendrimers is about 0.1 mg to about 10 mg. In some embodiments, the amount of one or more dendrimers is about 1 mg to about 10 mg.

[0241] In some embodiments, the composition is formulated as a dosage form for enteral delivery (e.g., oral, transduodenal, or transrectal delivery), and the composition comprises a certain amount of one or more microparticles described herein (e.g., metal oxides, metal salts, mineral colloids, inorganic salts, or carbon-based nanoparticles or fine particles). In some embodiments, the amount is sufficient to provide an effective concentration of one or more microparticles at an absorption site (e.g., one or more regions of a GI tube). In some embodiments, the effective concentration is the concentration of one or more microparticles that results in increased GI permeation of the therapeutic agent compared to a control composition comprising the therapeutic agent (e.g., a composition comprising a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more microparticles), as measured using a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS). In some embodiments, the effective concentration is the concentration of one or more polymers that result in increased intestinal permeability of the therapeutic agent, compared to a control composition containing the therapeutic agent (e.g., a composition containing a therapeutic agent that does not contain at least one bile acid or a salt thereof and one or more microscopic particles), as measured using the GI permeability assay described herein (e.g., a permeability assay using GI-ORIS). In some embodiments, the effective concentration of one or more microscopic particles (measured, for example, using a GI permeation assay described herein, e.g., a permeation assay using GI-ORIS) is at least about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.In some embodiments, the effective concentration of one or more microparticles (measured, for example, using a GI permeation assay described herein, e.g., a permeation assay using GI-ORIS) is approximately 0.01 mg / mL to approximately 1 mg / mL, approximately 0.05 mg / mL to approximately 1 mg / mL, approximately 0.5 mg / mL to approximately 2 mg / mL, approximately 1 mg / mL to approximately 5 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL, approximately 1 mg / mL to approximately 15 mg / mL, and approximately 1 mg / mL to approximately 20 mg / mL. L, approximately 1 mg / mL to approximately 30 mg / mL, approximately 5 mg / mL to approximately 20 mg / mL, approximately 5 mg / mL to approximately 30 mg / mL, approximately 10 mg / mL to approximately 40 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 50 mg / mL, approximately 20 mg / mL to approximately 60 mg / mL, approximately 20 mg / mL to approximately 70 mg / mL, approximately 20 mg / mL to approximately 80 mg / mL, approximately 20 mg / mL to approximately 90 mg / mL, or approximately 30 mg / mL to approximately 100 mg / mL. In some embodiments, the amount of one or more microscopic particles is substantially equal to the effective concentration (e.g., weight percentage per volume (e.g., ml / mL)) obtained by multiplying by the dilution factor described herein (e.g., approximately 2 mL to approximately 30 mL).

[0242] In some embodiments, the amount of microparticles is about 0.2 mg to about 1,500 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 1,000 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 500 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 250 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 100 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 50 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 20 mg. In some embodiments, the amount of microparticles is about 0.2 mg to about 10 mg. In some embodiments, the amount of microparticles is about 1 mg to about 10 mg.

[0243] Method for preparing dosage forms Methods for preparing dosage forms comprising the compositions of the Disclosure are provided herein. In some embodiments, the method comprises obtaining a certain amount of each component of the composition (e.g., one or more doses of the therapeutic agent, an amount of at least one bile acid or a salt thereof, and an amount of one or more co-excipients, optionally) and formulating the amount into a dosage form described herein (e.g., a solid dosage form, a semi-solid dosage form, or a liquid dosage form). Methods and processes for formulating dosage forms described herein that are known in the Art.

[0244] In some embodiments, formulation into liquid dosage forms involves combining amounts of the components of the composition with a liquid vehicle (e.g., aqueous solvent or buffer, alcohol solvent, glycerin, propylene glycol, oil, or a combination thereof), a surfactant, a co-solvent, a preservative, a viscosity modifier, or a suspending agent, for example, any of those described herein. In some embodiments, the formulation involves the preparation of a syrup (a viscous liquid containing the components of the composition in a solution), a suspension (a liquid containing one or more components of the composition in a suspension in a liquid carrier), a solution (a liquid containing the components of the composition solubilized in a liquid carrier), a droplet (a liquid prepared in small quantities for administration using a measuring device such as an injector), an emulsion (an oil-in-water dispersion liquid containing the components of the composition in one or both phases of a mixture), a mixture (a liquid containing one or more components of the composition suspended or dispersed in a liquid carrier), a linkus (a viscous liquid containing one or more components of the composition dissolved in a liquid carrier containing a high concentration of sucrose or other sugars), or an elixir (a liquid containing one or more components of the composition dissolved in a carrier containing a high proportion of sucrose and optionally an alcohol).

[0245] In some embodiments, formulation into a solid dosage form involves powder grinding, dry powder mixing, and tableting by direct compression. In some embodiments, formulation into a solid dosage form involves a wet granulation process. Such a method (e.g., a high-shear granulation process) involves mixing the components of the composition and, optionally, a combination of one or more factors in a mixer. A binder is added to the dry mixture or dissolved in the fluid used for granulation. The granulation solution or suspension is added to the dry powder in a mixer and mixed until the desired properties are achieved. This typically produces granules of suitable properties for producing a dosage form having appropriate dissolution time, uniformity of content, and other physical properties. After the wet granulation step, the product is dried and / or ground after drying to obtain the majority of the product within the desired size range. As will be understood by those skilled in the art, the product may be dried after being made wet-sized using a suitable apparatus such as a vibrating granulator or mill. The dry granulated mixture may then be processed to obtain an acceptable size range by first screening it with a sieving apparatus and then grinding the oversized particles. In some embodiments, a suitable lubricant is added to improve the flow properties of the granules.

[0246] In some embodiments, formulation into solid dosage forms includes alternative granulation processes known in the art, such as spray fluidized bed granulation, extrusion and spheroidization, or fluidized bed rolling granulation.

[0247] In some embodiments, the solid dosage form includes a coating. In some embodiments, the coating is selected to protect the core against damage (e.g., due to transport and storage) and / or for aesthetic purposes (e.g., by providing a desired color and / or taste). In some embodiments, the coating is carried out by methods known in the art, such as Wuerster coating, dry coating, film coating, fluidized bed coating, pan coating, etc. In some embodiments, the coating material is selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate copolymer (PVPVA), polyvinyl alcohol (PVA), polyvinyl alcohol / polyethylene glycol copolymer (PVA / PEG), cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, methacrylate, methylcellulose, hydroxypropyl methylcellulose, and carraeeenan.

[0248] In some embodiments, the coating comprises a bioadhesive material. In some embodiments, the coating improves the bioadhesion of the tablet in the sublingual space. In some embodiments, the solid dosage form is prepared for rapid disintegration, and the solid dosage form is a tablet comprising an erosion or hydrogel core coated with a bioadhesive material, where upon contact with saliva, the hydrogel core swells, applying force to the coating, resulting in its disintegration and rapid erosion. In some embodiments, the core comprises a disintegrant to facilitate erosion.

[0249] In some embodiments, the coating comprises a moisture-resistant material (e.g., a hydrophobic polymer) to create a barrier against moisture intrusion, thereby protecting the moisture-sensitive therapeutic agent present in the tablet core (e.g., during storage and transport). Several coating materials, such as EUDRAGIT® E PO and Opadry® AMB5 starch acetate, can be used to improve the moisture resistance of tablets.

[0250] Example formulation This disclosure provides compositions for enhancing the delivery of therapeutic agents to the GI duct. In some embodiments, the compositions are formulated as dosage forms for enteral delivery (e.g., oral, transduodenal, or transrectal delivery). In some embodiments, the compositions are formulated as dosage forms for oral delivery. In some embodiments, the compositions are effective in increasing the GI permeability of a therapeutic agent compared to the GI permeability of a control composition containing the therapeutic agent alone. In some embodiments, GI permeability is measured using a permeability assay described herein, for example, a permeability assay using GI-ORIS.

[0251] In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients. In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients. In some embodiments, the one or more co-excipients are selected from chelating agents, polymers, microparticles, nanoparticles, dendrimers, and combinations thereof.

[0252] In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of a compound of formula (I) as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt is a compound of formula (I) as described herein, at an effective concentration higher than the critical micelle concentration (CMC) of the bile acid or salt thereof.

[0253] In some embodiments, the composition comprises one or more doses of a therapeutic agent, a certain amount of a compound of formula (I) as described herein, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, and a certain amount of at least one bile acid or salt of a co-excipient, wherein at least one bile acid or salt is a compound of formula (I) as described herein, at an effective concentration higher than the CMC of the bile acid or salt.

[0254] In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A. In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, at an effective concentration higher than the CMC of the bile acid or salt thereof.

[0255] In some embodiments, the composition comprises one or more doses of a therapeutic agent, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, at an effective concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients. In some embodiments, the composition comprises one or more doses of a therapeutic agent, a certain amount of at least one bile acid or salt thereof at a concentration substantially equal to a higher concentration (weight per volume) of the bile acid or salt than the CMC of the bile acid or salt, multiplied by the dilution factors specified herein (e.g., about 2 mL to about 30 mL), wherein the at least one bile acid or salt thereof is a compound selected from Table A, and a certain amount of one or more co-excipients as specified herein.

[0256] In some embodiments, the composition comprises one or more doses of a therapeutic agent and a certain amount of at least one bile acid or salt thereof, at an effective concentration higher than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholate, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof, and a certain amount of at least one bile acid or salt thereof. In some embodiments, at least one bile acid. In some embodiments, the composition comprises one or more doses of a therapeutic agent, a certain amount of at least one bile acid or salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof, and a certain amount of one or more co-excipients, wherein the one or more co-excipients are selected from chelating agents, polymers, microparticles, nanoparticles, dendrimers, and combinations thereof. In some embodiments, the therapeutic agent is characterized by poor GI permeability. In some embodiments, the therapeutic agent is a Class III compound according to BCS. In some embodiments, the therapeutic agent is a Class IV compound according to BCS.

[0257] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS, and a certain amount of at least one bile acid or a salt thereof as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS, and a certain amount of at least one bile acid or a salt thereof, wherein the concentration of at least one bile acid or a salt thereof is higher than the CMC of the bile acid or salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS, and a certain amount of at least one bile acid or a salt thereof, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS; a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or a salt thereof; and a certain amount of one or more co-excipients as described herein.

[0258] In some embodiments, the composition comprises one or more doses of a therapeutic agent, which is a Class III or Class IV compound according to BCS, and a certain amount of a compound of formula (I) as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, which is a Class III or Class IV compound according to BCS, and a certain amount of at least one bile acid or salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of a compound of formula (I) as described herein.

[0259] In some embodiments, the composition comprises one or more doses of a therapeutic agent, which is a Class III or Class IV compound according to BCS; a certain amount of a compound of formula (I) as described herein; and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, which is a Class III or Class IV compound according to BCS; a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound of formula (I) as described herein, at a concentration higher than the CMC of the bile acid or salt thereof; and a certain amount of one or more co-excipients as described herein.

[0260] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to the BCS, and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to the BCS, and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, at a concentration higher than the CMC of the bile acid or salt thereof.

[0261] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS; a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A; and one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a Class III or Class IV compound according to BCS; a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, at a concentration higher than the CMC of the bile acid or salt thereof; and one or more co-excipients as described herein.

[0262] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is Class III or Class IV according to the BCS, and a certain amount of at least one bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof, at a concentration greater than the CMC of the bile acid or salt thereof, and a certain amount of at least one bile acid or salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is Class III or Class IV according to the BCS; a certain amount of at least one bile acid or salt thereof, at a concentration greater than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof; and a certain amount of one or more co-excipients, wherein the co-excipients are selected from chelating agents, polymers, microparticles, dendrimers, and combinations thereof.

[0263] In some embodiments, the therapeutic agent is selected from polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, and combinations thereof. In some embodiments, the therapeutic agent has a molecular weight greater than about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or about 30 kDa. In some embodiments, the therapeutic agent has a molecular weight of about 0.1 to about 1 kDa.

[0264] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a polypeptide having a molecular weight of about 1 kDa to 250 kDa; and a certain amount of at least one bile acid or a salt thereof, at an effective concentration higher than the critical micelle concentration (CMC) of the bile acid or a salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a polypeptide having a molecular weight of about 1 kDa to 250 kDa; and a certain amount of at least one bile acid or a salt thereof, at a concentration exceeding the critical micelle concentration (CMC) of the bile acid or a salt thereof; and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a polypeptide having a molecular weight of about 1 kDa to 250 kDa; a certain amount of at least one bile acid or a salt thereof, at a concentration exceeding the critical micelle concentration (CMC) of the bile acid or a salt thereof; and a certain amount of one or more co-excipients as described herein, wherein one or more co-excipients are selected from chelating agents, polymers, fine particles, nanoparticles, dendrimers, and combinations thereof.

[0265] In some embodiments, the composition comprises one or more doses of a polypeptide having a molecular weight of about 1 kDa to 250 kDa and a certain amount of a compound of formula (I) as described herein. In some embodiments, the composition comprises one or more doses of a polypeptide having a molecular weight of about 1 kDa to 250 kDa and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt is a compound of formula (I) as described herein at a concentration exceeding the CMC of the bile acid or salt.

[0266] In some embodiments, the composition comprises one or more doses of polypeptides having a molecular weight of about 1 kDa to 250 kDa, a certain amount of a compound of formula (I) as described herein, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of polypeptides having a molecular weight of about 1 kDa to 250 kDa, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt is a compound of formula (I) as described herein at a concentration exceeding the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients as described herein.

[0267] In some embodiments, the composition comprises one or more doses of polypeptides having a molecular weight of about 1 kDa to 250 kDa, and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A.

[0268] In some embodiments, the composition comprises one or more doses of polypeptides having a molecular weight of about 1 kDa to 250 kDa, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of polypeptides having a molecular weight of about 1 kDa to 250 kDa, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound selected from Table A, at an effective concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients as described herein.

[0269] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a polypeptide having a molecular weight of about 1 kDa to 250 kDa, and a certain amount of at least one bile acid or salt thereof at a concentration greater than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof, and a certain amount of at least one bile acid or salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a polypeptide having a molecular weight of about 1 kDa to 250 kDa; a certain amount of at least one bile acid or salt thereof, at a concentration greater than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, and combinations thereof; and a certain amount of one or more co-excipients as described herein, wherein the co-excipients are selected from chelating agents, polymers, fine particles, nanoparticles, dendrimers, and combinations thereof.

[0270] In some embodiments, the polypeptide is a Class III compound according to BCS. In some embodiments, the polypeptide is a Class IV compound according to BCS. In some embodiments, the polypeptide is selected from enzymes, antibodies or their antigen-binding fragments, antibacterial agents, hormones, growth factors, chemokines, and cytokines. In some embodiments, the polypeptide is a recombinant protein. In some embodiments, the polypeptide is a therapeutic peptide.

[0271] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a nucleic acid or a nucleic acid-containing vector; and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a nucleic acid or a nucleic acid-containing vector; and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof; and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a nucleic acid or a nucleic acid-containing vector; a certain amount of at least one bile acid or a salt thereof, wherein the concentration of the bile acid or salt thereof is higher than the CMC of the bile acid or salt thereof; and a certain amount of one or more co-excipients as described herein, wherein the one or more co-excipients are selected from chelating agents, polymers, microparticles, nanoparticles, dendrimers, and combinations thereof.

[0272] In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids and a certain amount of a compound of formula (I) as described herein. In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids and a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound of formula (I) as described herein at a concentration higher than the CMC of the bile acid or salt thereof.

[0273] In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, a certain amount of a compound of formula (I) as described herein, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, a certain amount of at least one bile acid or salt thereof, wherein at least one bile acid or salt thereof is a compound of formula (I) as described herein at a concentration higher than the CMC of the bile acid or salt thereof, and a certain amount of one or more co-excipients as described herein.

[0274] In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, and a certain amount of at least one bile acid or a salt thereof, wherein at least one bile acid or a salt thereof is a compound selected from Table A. In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, and a certain amount of at least one bile acid or a salt thereof, wherein at least one bile acid or a salt thereof is a compound selected from Table A, at a concentration higher than the CMC of the bile acid or a salt thereof.

[0275] In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, a certain amount of at least one bile acid or a salt thereof, wherein at least one bile acid or a salt thereof is a compound selected from Table A, and a certain amount of one or more co-excipients as described herein. In some embodiments, the composition comprises one or more doses of nucleic acids or a vector containing nucleic acids, a certain amount of at least one bile acid or a salt thereof, wherein at least one bile acid or a salt thereof is a compound selected from Table A, at a concentration higher than the CMC of the bile acid or a salt thereof, and a certain amount of one or more co-excipients as described herein.

[0276] In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a nucleic acid or a nucleic acid-containing vector, and a certain amount of at least one bile acid or a salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and chenodeoxycholic acid. In some embodiments, the composition comprises one or more doses of a therapeutic agent, wherein the therapeutic agent is a nucleic acid or a nucleic acid-containing vector; a certain amount of at least one bile acid or salt thereof, at a concentration higher than the CMC of the bile acid or salt thereof, wherein the bile acid is selected from taurocholic acid, glycocholic acid, cholic acid, 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and chenodeoxycholic acid; and a certain amount of one or more co-excipients as described herein, wherein the one or more co-excipients are selected from chelating agents, polymers, microparticles, nanoparticles, dendrimers, and combinations thereof.

[0277] In some embodiments, the nucleic acid or vector is a Class III compound according to BCS. In some embodiments, the nucleic acid or vector is a Class IV compound according to BCS. In some embodiments, the nucleic acid comprises RNA, DNA, or a combination thereof. In some embodiments, the vector is a viral vector containing nucleic acid (e.g., an adenovirus vector or retrovirus vector containing nucleic acid). In some embodiments, the vector is a non-viral vector containing nucleic acid (e.g., a plasmid containing nucleic acid). In some embodiments, the nucleic acid is selected from immunostimulatory oligonucleotides, mRNA, plasmid DNA, and RNA interference (RNAi) oligonucleotides. In some embodiments, the RNAi oligonucleotide is selected from siRNA, shRNA, miRNA, and antisense oligonucleotides (ASOs). In some embodiments, the ASO is a gapmer. In some embodiments, the nucleic acid comprises one or more chemical modifications. In some embodiments, the chemical modifications are selected from modified sugar moieties, modified nucleoside bonds, modified nucleic acid bases, and combinations thereof.

[0278] In some embodiments, the compound of formula (I) is the compound of formula (I-1-a). In some embodiments, the compound of formula (I) is the compound of formula (I-1-b). In some embodiments, the compound of formula (I) is the compound of formula (I-1-c). In some embodiments, the compound of formula (I) is the compound of formula (I-1-d). In some embodiments, the compound of formula (I) is the compound of formula (I-1-e). In some embodiments, the compound of formula (I) is the compound of formula (I-1-f). In some embodiments, the compound of formula (I) is the compound of formula (I-2-a). In some embodiments, the compound of formula (I) is the compound of formula (I-2-b). In some embodiments, the compound of formula (I) is the compound of formula (I-2-c). In some embodiments, the compound of formula (I) is the compound of formula (I-2-d). In some embodiments, the compound of formula (I) is the compound of formula (I-2-e). In some embodiments, the compound of formula (I) is the compound of formula (I-2-f). In some embodiments, the compound of formula (I) is the compound of formula (I-1-a'). In some embodiments, the compound of formula (I) is the compound of formula (I-1-b'). In some embodiments, the compound of formula (I) is the compound of formula (I-1-c'). In some embodiments, the compound of formula (I) is the compound of formula (I-1-d'). In some embodiments, the compound of formula (I) is the compound of formula (I-1-e'). In some embodiments, the compound of formula (I) is the compound of formula (I-1-f'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-a'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-b'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-c'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-d'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-e'). In some embodiments, the compound of formula (I) is the compound of formula (I-2-f').

[0279] In some embodiments, one or more co-excipients include a chelating agent. In some embodiments, the chelating agent is selected from ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetate sodium (EGTA), ethylene dinitrilotetraacetate sodium (EDTA), sodium glutamate (AAE), and combinations thereof.

[0280] In some embodiments, one or more co-excipients include polymers, such as naturally occurring polymers, semi-synthetic polymers, or synthetic polymers. In some embodiments, the polymers include poly(methacrylate), poly(ethyl acrylate), poly(ethylene glycol), hyaluronic acid, polysaccharides, chitosan, arginine, poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(ethyleneimine), poly(N-(2-hydroxypropyl)methacrylamide), poly(glycolic acid), poly(lactic acid), poly(lactic acid-coglycolic acid), poly(caprolactone), poly(orthoester), poly(anhydride), poly(amide), poly(esteramide), poly(phosphoester), poly(alkyanoacrylate), or combinations thereof. In some embodiments, the polymer is selected from Eudragit E PO (EPO), Eudragit RL100 (RL100), poly(ethylene glycol) 1kDa (PEG-1kDa), branched poly(ethyleneimine) 800Da (PEI:b0.8), Kollidon SR (KOLSR), poly(methacrylic acid) 5kDa (PMA:5), poly(aspartic acid) 2kDa (POLD:2), poly(2-ethyl oxazoline) 25kDa (POXZ:25), poly(glutamic acid) 50kDa (POLE:50), branched poly(ethyleneimine)-co-poly(ethylene glycol) 500Da (bPEIPPEG:0.5), and Vivacoat (VIVA).

[0281] In some embodiments, one or more co-excipients include a dendrimer. In some embodiments, the dendrimer includes poly(amidoamine) (PAMAM), poly(propyleneimine), polyamide, polyether, polyester, or phosphorus-based architectures. In some embodiments, the dendrimer is G1, G2, G3, G4, G5, G6, G7, G8, G9, G10, or G11. In some embodiments, the dendrimer includes a carboxylate terminus, an amino terminus, a hydroxyl terminus, a succinic acid terminus, a hydrophobic surface, or a combination thereof. In some embodiments, the dendrimer includes a G1-G10 PAMAM architecture. In some embodiments, the dendrimer is selected from 3.5th generation carboxylate-terminated poly(amidoamine) dendrimers (DENDAC3.5) and 4th generation amine-terminated poly(amidoamine) dendrimers (DENDAM4).

[0282] In some embodiments, one or more co-excipients include microscopic particles (e.g., fine particles or nanoparticles). In some embodiments, the particles are inorganic, carbon-based, ceramic, metallic, polymer, lipid-based, or a combination thereof. In some embodiments, the particles include metal oxides, metal salts, mineral colloids, inorganic salts, or a combination thereof. In some embodiments, the particles are carbon nanoparticles. In some embodiments, the particles are selected from calcium tribasic fine particles (CaPO4), calcium dibasic fine particles (CaHPO4), 5 μm spherical hydroxyapatite fine particles (HAP:5U), 2.5 μm spherical hydroxyapatite fine particles (HAP:2.5U), zinc oxide fine particles (ZNO:r10n), hydroxyapatite rod-shaped nanoparticles with a diameter of 40 nm (HAP:r40n), and carbon black nanoparticles with a diameter of 13 nm (CB:13n).

[0283] In some embodiments, the disclosure provides a dosage form of any one of the aforementioned compositions, which is formulated for enteral delivery (e.g., oral, duodenal, or rectal delivery). In some embodiments, the dosage form is a solid dosage form comprising a composition. In some embodiments, the solid dosage form is formulated for immediate release. In some embodiments, the solid dosage form is formulated for sustained release. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the dosage form is a liquid dosage form comprising a composition.

[0284] In some embodiments, the dosage form comprises one or more doses of the therapeutic agent. In some embodiments, the dosage form comprises an effective amount of the therapeutic agent.

[0285] In some embodiments, the dosage form contains an amount sufficient to achieve an effective concentration at the absorption site (e.g., GI tube) of at least one bile acid or a salt thereof. In some embodiments, the effective concentration is higher than the CMC of at least one bile acid or a salt thereof. In some embodiments, the CMC is measured by a method selected from potentiometric, spectroscopic, light scattering, and combinations thereof. In some embodiments, the effective concentration is at least about 2 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 greater than the CMC. In some embodiments, the effective concentration is about 2 to about 200 times, about 3 to about 200 times, about 4 to about 200 times, about 5 to about 200 times, about 6 to about 200 times, about 7 to about 200 times, about 8 to about 200 times, about 9 to about 200 times, or about 10 to about 200 times greater than the CMC. In some embodiments, the effective concentration is determined using a GI permeation assay described herein (e.g., a permeation assay using GI-ORIS), and the effective concentration results in increased GI permeation of the therapeutic agent (e.g., intestinal and / or gastric permeation) compared to the GI permeation of the therapeutic agent formulated as a control composition (e.g., a control composition lacking at least one bile acid or a salt thereof or one or more co-excipients). In some embodiments, the effective concentration results in GI permeation (e.g., intestinal and / or gastric permeation) that is increased by about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 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 compared to GI permeation of the therapeutic agent formulated as a control composition.In some embodiments, the effective concentration of at least one bile acid or its salt is about 30 mg / mL to 200 mg / mL, about 40 mg / mL to 200 mg / mL, about 50 mg / mL to 200 mg / mL, about 60 mg / mL to 200 mg / mL, about 70 mg / mL to 200 mg / mL, about 80 mg / mL to 200 mg / mL, about 90 mg / mL to 200 mg / mL, or about 100 mg / mL to 200 mg / mL. In some embodiments, the amount of at least one bile acid or its salt is substantially equal to the effective concentration (weight per volume) obtained by multiplying it by the dilution factor described herein (e.g., about 2 mL to about 30 mL).

[0286] In some embodiments, the dosage form contains at least one bile acid or a salt thereof in an amount of about 60 mg to about 2,000 mg. In some embodiments, the amount of at least one bile acid or a salt thereof is about 60 mg to about 1,000 mg. In some embodiments, the amount of at least one bile acid or a salt thereof is about 60 mg to about 600 mg. In some embodiments, the amount of at least one bile acid or its salt is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg.

[0287] In some embodiments, the dosage form contains a certain amount of one or more co-excipients. In some embodiments, the amount is sufficient to achieve an effective concentration at the absorption site (e.g., GI tube). In some embodiments, the effective concentration is determined using a GI permeabilization assay as described herein (e.g., a permeabilization assay using GI-ORIS), and the effective concentration results in increased GI permeability of the therapeutic agent compared to the GI permeability of the therapeutic agent formulated as a control composition (e.g., a control composition lacking at least one bile acid or its salt or one or more co-excipients). In some embodiments, the amount of one or more co-excipients is substantially equal to the effective concentration (weight per volume) multiplied by a dilution factor as described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the dosage form contains one or more co-excipients in an amount of about 60 mg to about 2,000 mg. In some embodiments, the amount of one or more co-excipients is about 60 mg to about 1,000 mg. In some embodiments, the amount of one or more co-excipients is about 60 mg to about 600 mg. In some embodiments, the amount of one or more co-excipients is approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, or approximately 1,000 mg.

[0288] In some embodiments, the dosage form contains a sufficient amount of chelating agent to achieve an effective concentration at an absorption site of about 5 mg / mL to about 100 mg / mL. In some embodiments, the amount of chelating agent is substantially equal to the effective concentration (weight per volume) obtained by multiplying it by the dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the dosage form contains chelating agent in an amount of about 10 mg to about 1,500 mg. In some embodiments, the dosage form contains chelating agent in an amount of about 10 mg to about 1,000 mg. In some embodiments, the dosage form contains chelating agent in an amount of about 10 mg to about 500 mg. In some embodiments, the dosage form contains chelating agent in an amount of about 10 mg to about 250 mg. In some embodiments, the dosage form contains chelating agent in an amount of about 10 mg to about 100 mg.

[0289] In some embodiments, the dosage form contains an amount of polymer sufficient to achieve an effective concentration at an absorption site of about 5 mg / mL to about 150 mg / mL. In some embodiments, the amount of polymer is substantially equal to the effective concentration (weight per volume) obtained by multiplying it by the dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the dosage form contains an amount of polymer from about 10 mg to about 1,500 mg. In some embodiments, the dosage form contains an amount of polymer from about 10 mg to about 1,000 mg. In some embodiments, the dosage form contains an amount of polymer from about 10 mg to about 500 mg. In some embodiments, the dosage form contains an amount of polymer from about 10 mg to about 250 mg. In some embodiments, the dosage form contains an amount of polymer from about 10 mg to about 100 mg.

[0290] In some embodiments, the dosage form contains a sufficient amount of microparticles (e.g., fine particles or nanoparticles) to achieve an effective concentration at an absorption site of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the amount of microparticles is substantially equal to the effective concentration (weight per volume) obtained by multiplying it by the dilution factor described herein (e.g., about 2 mL to about 30 mL). In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 1,500 mg. In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 1,000 mg. In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 500 mg. In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 250 mg. In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 100 mg. In some embodiments, the dosage form contains an amount of microparticles from about 0.2 mg to about 50 mg. In some embodiments, the dosage form contains about 0.2 mg to about 20 mg of microparticles. In some embodiments, the dosage form contains about 0.2 mg to about 10 mg of microparticles. In some embodiments, the dosage form contains about 1 mg to about 10 mg of microparticles.

[0291] Enhanced delivery methods to GI tissue This disclosure provides a method for enhancing the delivery of a therapeutic agent described herein to a subject, the method comprising administering to the subject a composition of this disclosure comprising the therapeutic agent, at least one bile acid or a salt thereof as described herein, and optionally one or more co-excipients as described herein. In some embodiments, the composition has one or more properties for enhancing delivery to a subject compared to the therapeutic agent alone or a control composition comprising the therapeutic agent, but lacks at least one bile acid or a salt thereof or one or more co-excipients of choice. In some embodiments, the enhanced delivery is due to improved GI permeability of the therapeutic agent (e.g., intestine and / or stomach) compared to GI permeability of the therapeutic agent alone or a control composition comprising the therapeutic agent. In some embodiments, the enhanced delivery is due to increased water solubility of the therapeutic agent compared to the therapeutic agent alone or a control composition comprising the therapeutic agent.

[0292] Most orally administered compounds are absorbed primarily by the duodenum and jejunum in the upper part of the gastric duct (GI). Absorption of compounds from the lumen of the GI duct requires passing through multiple layers, including gastric juice, the pericellular matrix, and the mucosal rich layer, to reach the epithelium, mucosa, and capillary walls of the blood or lymph. The epithelial cells lining the luminal side of the GI duct are a substantial barrier to drug delivery by oral administration. Epithelial cells are arranged in a single column layer and intercalated with intestinal cells. Several transport pathways traverse the intestinal epithelium, including transcellular, paracellular, carrier-mediated, and transcytotic transport pathways. Compounds delivered by carrier-mediated pathways rely on nutrient transport systems located on the apical cell membrane. Transcytotic pathways enable the active transport of compounds between cells. Passive diffusion between cells constitutes transcellular and paracellular pathways, respectively. Barriers exist in transport; for example, tight junctions limit intercellular permeability by creating seals between adjacent cells. Additional barriers to intestinal epithelial permeability include the presence of hydrolytic enzymes at the apical surface of the epithelial membrane, the presence of an aqueous boundary layer on the surface of the epithelial membrane which can provide an additional diffusion barrier, a mucous layer associated with the aqueous boundary layer, and an acidic microenvironment which generates a proton gradient across the apical membrane. Drug absorption, and ultimately bioavailability, may also be reduced by other processes regulated by P-glycoprotein, such as the return transport of drugs into the die gut lumen and cytochrome P450 metabolism. The presence of food and / or beverages can also interfere with absorption and bioavailability. Without being constrained by theory, compositions that increase the passage of therapeutic agents through one or more of these pathways result in enhanced delivery of therapeutic agents from the GI duct to the systemic circulation.

[0293] In some embodiments, the present disclosure provides a method for enhancing the delivery of a therapeutic agent to a target, the method comprising: formulating the therapeutic agent in a dosage form (e.g., a solid or liquid dosage form) comprising the composition of the present disclosure; and administering the dosage form to a GI tubule of a target (e.g., via enteral administration), wherein the composition comprises (i) one or more doses of the therapeutic agent; (ii) a certain amount of at least one bile acid or salt thereof as described herein, the amount being sufficient to achieve an effective concentration of at least one bile acid or salt thereof at an absorption site in the GI tubule (e.g., the effective concentration is determined using a GI permeabilization assay as described herein, e.g., a permeabilization assay using GI-ORIS); and optionally (iii) a certain amount of one or more co-excipients as described herein, thereby providing a method for enhancing the delivery of the therapeutic agent described herein to a target.

[0294] In some embodiments, the GI permeability of the therapeutic agent is increased compared to the GI permeability of the therapeutic agent alone or a control composition containing the therapeutic agent (e.g., a composition lacking (ii) or (iii)). Methods for determining the GI permeability of a therapeutic agent in a subject are known in the art and are described herein (e.g., in vivo pharmacokinetic mass balance in humans, non-human primates, or other non-human animals; perfusion assays in humans, non-human primates, or other non-human animals; or in vitro using GI-ORIS, Transwell permeability assays, or Ussing chamber assays).

[0295] In some embodiments, the GI permeation of the therapeutic agent is increased by at least about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 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 compared to the GI permeation of the therapeutic agent alone or a control composition containing the therapeutic agent (e.g., a composition lacking (ii) or (iii)). In some embodiments, the GI permeation of the therapeutic agent is increased by about 1.1 to about 2 times, about 1.1 to about 3 times, about 1.5 to about 2 times, about 1.5 to about 3 times, about 1.5 to about 5 times, about 1.5 to about 5 times, about 2 to about 5 times, about 2 to about 10 times, about 5 to about 10 times, about 5 to about 15 times, about 5 to about 15 times, about 5 to about 20 times, about 5 to about 30 times, about 5 to about 50 times, about 10 to about 100 times, about 10 to about 150 times, or about 10 to about 200 times compared to the GI permeation of the therapeutic agent alone or a control composition containing the therapeutic agent (e.g., a composition lacking (ii) or (iii)).

[0296] In some embodiments, the GI permeation of the compound is increased compared to the GI permeation of the control composition, and optionally, the control composition contains the compound alone.

[0297] In some embodiments, enteral administration is oral. In some embodiments, enteral administration is via an enteral feeding tube. In some embodiments, enteral administration is via the buccal mucosa. In some embodiments, enteral administration is transrectal.

[0298] Enhanced Bioavailability Methods This disclosure provides a method for increasing the bioavailability of a therapeutic agent in a subject, the method comprising administering to the subject a composition of this disclosure comprising one or more doses of the therapeutic agent (e.g., an effective amount of the therapeutic agent), a certain amount of at least one bile acid or salt thereof as described herein (e.g., an amount sufficient to achieve an effective concentration of at least one bile acid or salt thereof at one or more absorption sites in a GI tube), and optionally one or more co-excipients as described herein. In some embodiments, the administration is enteral (e.g., orally, transduodenal, or transrectal). In some embodiments, the administration is transdermal. In some embodiments, the administration is sublingual or buccal mucosa. In some embodiments, the administration is transnasal (e.g., via inhalation). In some embodiments, the administration is ophthalmic.

[0299] As used herein, the term “bioavailability” refers to fractions of one or more doses of the therapeutic agent to be administered to a target that are available at the site of action after administration. The term “site of action” refers to one or more body compartments and / or tissue sites containing the biological target(s) of the therapeutic agent, and modification of the biological target(s) is effective in achieving the desired biological outcome (e.g., the desired therapeutic effect). In some embodiments, the amount of the therapeutic agent available at the site of action is considered to be equivalent to the amount in the systemic circulation after administration.

[0300] In some embodiments, the Disclosure provides a method for increasing the bioavailability of a therapeutic agent in a subject, the method comprising administering to the subject a composition of the Disclosure comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt thereof as described herein, and optionally one or more co-excipients as described herein. In some embodiments, the Disclosure provides a method for increasing the oral bioavailability of a therapeutic agent in a subject, the method comprising administering to the subject a composition of the Disclosure comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt thereof as described herein, and optionally one or more co-excipients as described herein. As used herein, the term “oral bioavailability” refers to the proportion of one or more doses of a therapeutic agent orally administered to a subject that are available at the site of action after administration. In some embodiments, oral bioavailability is the proportion of one or more doses of a therapeutic agent orally administered to a subject that is in systemic circulation after administration.

[0301] Methods for measuring bioavailability (e.g., oral bioavailability) are known in the art (see, for example, Olivares-Morales A, et al. Pharm Res. 2014 31:720-30; Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018 Sep;46(3):221-230; Herkenne C, et al. Pharm Res. 2008 Jan;25(1):87-103; Chow SC. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312). In some embodiments, bioavailability is determined by measuring the percentage of one or more doses of the therapeutic agent present at the site of action after administration to a subject. In some embodiments, the measurement includes obtaining a tissue sample from the subject and quantifying the amount of the therapeutic agent in the tissue sample. In some embodiments, the measurement involves obtaining a fluid sample (e.g., blood sample, urine sample) from the subject and quantifying the amount of therapeutic agent in the fluid sample. In some embodiments, bioavailability is calculated as the percentage of the dose of therapeutic agent administered to the subject that reaches systemic circulation in an unaltered form. In some embodiments, this definition assumes that all or most of the dose administered to the subject entering systemic circulation reaches the site of action.

[0302] In some embodiments, administration (e.g., enteral administration) of a composition of the Disclosure comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt as described herein, and optionally one or more co-excipients via a route of administration as described herein results in an increased bioavailability of the therapeutic agent compared to a control composition comprising one or more doses of the therapeutic agent but lacking at least one bile acid or salt thereof and optionally one or more co-excipients. In some embodiments, the bioavailability of the therapeutic agent (e.g., oral bioavailability) is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99% of the bioavailability of the therapeutic agent when administered systemically, for example, by intravenous injection or infusion. In some embodiments, the bioavailability of the therapeutic agent (e.g., oral bioavailability) is substantially equal to the bioavailability of the therapeutic agent when administered systemically, for example, by intravenous injection or infusion.

[0303] In some embodiments, the amount of the therapeutic agent measured in systemic circulation after administration of the compositions of this disclosure to a subject via the route described herein (e.g., enteral administration) is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99% of the total amount of the therapeutic agent in the composition.

[0304] In some embodiments, the amount of the therapeutic agent measured in the systemic circulation after oral administration (e.g., single oral administration) of the composition of the present disclosure to a subject is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0305] In some embodiments, the amount of the therapeutic agent measured in the systemic circulation after administration of a dosage form (e.g., solid or liquid dosage form) containing the composition of the present disclosure to a subject according to the route described herein (e.g., enteral administration) is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0306] In some embodiments, the amount of the therapeutic agent measured in the systemic circulation after oral administration (e.g., single oral administration) of a dosage form (e.g., solid or liquid dosage form) containing the composition of the present disclosure to a subject is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0307] In some embodiments, the bioavailability of the compositions of this disclosure after administration according to the specified routes (e.g., enteral administration) is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0308] In some embodiments, the bioavailability of the therapeutic agent after administration (e.g., single oral administration) of the compositions of the present disclosure is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0309] In some embodiments, the bioavailability of the therapeutic agent after administration (e.g., enteral administration) of a dosage form (e.g., solid or liquid dosage form) containing the compositions of this disclosure according to the specified route is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0310] In some embodiments, the bioavailability of the therapeutic agent after oral administration (e.g., single oral administration) of a dosage form (e.g., solid or liquid dosage form) containing the composition of the present disclosure is at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%.

[0311] In some embodiments, administration (e.g., enteral administration) of a composition of this disclosure comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt as described herein, and optionally one or more co-excipients via a route of administration as described herein results in an increased Cmax of the therapeutic agent compared to administration of a control composition comprising one or more doses of the therapeutic agent but lacking at least one bile acid or salt thereof and optionally one or more co-excipients. As used herein, the term "Cmax" refers to the maximum plasma concentration of the therapeutic agent observed after administration. In some embodiments, administration of a dosage form (e.g., solid or liquid dosage form) containing the composition via a route of administration as described herein (e.g., enteral administration) results in an increased Cmax of the therapeutic agent compared to a dosage form containing a control composition. In some embodiments, the Cmax of the therapeutic agent is increased by at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times compared to administration of a control composition or a dosage form containing a control composition.

[0312] In some embodiments, administration (e.g., enteral administration) of a composition of this disclosure comprising one or more doses of the therapeutic agent, a certain amount of at least one bile acid or salt as described herein, and optionally one or more co-excipients via a route of administration as described herein results in an increased Tmax of the therapeutic agent compared to administration of a control composition comprising one or more doses of the therapeutic agent but lacking at least one bile acid or salt thereof and optionally one or more co-excipients. As used herein, the term "Tmax" refers to the time of the maximum plasma concentration observed after administration. In some embodiments, administration of a dosage form (e.g., solid or liquid dosage form) containing the composition via a route of administration as described herein (e.g., enteral administration) results in an increased Tmax of the therapeutic agent compared to a dosage form containing a control composition. In some embodiments, the Tmax of the therapeutic agent is increased by at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times compared to administration of a control composition or a dosage form containing a control composition.

[0313] In some embodiments, administration of a composition of the Disclosure comprising one or more doses of a therapeutic agent, a certain amount of at least one bile acid or salt as described herein, and one or more co-excipients via an optional route of administration as described herein (e.g., enteral administration) results in an increased mean AUC of the therapeutic agent compared to the mean AUC of a control composition administered systemically via the same route (e.g., intravenous injection) of a control composition comprising one or more doses of the therapeutic agent but lacking at least one bile acid or salt thereof and optionally one or more co-excipients. As used herein, the term “AUC” refers to the “area under the curve” versus time of a plot of the concentration of the therapeutic agent present in a tissue sample (e.g., blood sample) obtained from a subject after administration of the therapeutic agent. As will be understood by those skilled in the art, AUC is determined using a mathematical approach that calculates the concentration from 0 to infinity over a time interval ("total AUC") or a given time point (e.g., the calculation of the concentration over a time interval of 0 to 7 days provides “AUC0 to 7”). In some embodiments, administration of a dosage form (e.g., solid or liquid dosage form) containing the composition of this disclosure via the route of administration described herein (e.g., enteral administration) results in an increased mean AUC of the therapeutic agent compared to the mean AUC after systemic administration of the composition (e.g., intravenous injection) or administration of a dosage form containing a control composition via the same route.

[0314] In some embodiments, the AUC of the composition of this disclosure after administration via the route of administration described herein (e.g., enteral administration) is at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times the AUC of the composition after systemic administration of the composition (e.g., intravenous injection). In some embodiments, the AUC of the composition of this disclosure after administration via the route of administration described herein (e.g., enteral administration) is at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times the AUC of the control composition after administration via the same route. In some embodiments, the AUC of a dosage form (e.g., solid, semi-solid, or liquid dosage form) containing the composition of this disclosure after administration via the route of administration described herein (e.g., enteral administration) is at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times the AUC of the composition after systemic administration of the composition (e.g., intravenous injection). In some embodiments, the AUC of a dosage form (e.g., solid, semi-solid, or liquid dosage form) containing the composition of this disclosure after administration via the route of administration described herein (e.g., enteral administration) is at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times the AUC of administration of a control composition via the same route.

[0315] In some embodiments, the percentage bioavailability of the therapeutic agent is increased when administered as a composition of the present disclosure compared to a control composition lacking at least one bile acid or its salt and optionally one or more co-excipients. As used herein, “percent bioavailability” (also referred to as “F”) represents the percentage of the amount of therapeutic agent measured in circulation when administered intravenously (e.g., as an oral dose) compared to the amount of therapeutic agent measured in circulation when administered systemically (e.g., by intravenous injection). F is calculated by measuring the AUC (e.g., total AUC) of the therapeutic agent when administered intravenously (“test route”) compared to the AUC (“systemic route”) when administered systemically. For example, in some embodiments, the following formula is used to calculate the percentage bioavailability: F(%) = AUCtotal (Test Route) / AUC total (Systemic pathway). This is a key term that establishes the relative proportion of the therapeutic agent entering circulation via the test pathway compared to the maximum possible amount entering circulation via the systemic pathway. In some embodiments, the percentage bioavailability of the therapeutic agent administered as a composition of the present disclosure is increased by at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times compared to the percentage bioavailability of the therapeutic agent administered as a control composition (e.g., a composition lacking at least one bile acid or a salt thereof, and one or more optional co-excipients). In some embodiments, the percentage bioavailability of a therapeutic agent administered as a dosage form containing the compositions of the present disclosure (e.g., a solid, semi-solid, or liquid dosage form) is increased by at least about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, about 15 times, or about 20 times compared to the percentage bioavailability of a therapeutic agent administered as a dosage form containing a control composition (e.g., a composition lacking at least one bile acid or a salt thereof, and any one or more co-excipients).

[0316] Pharmaceutical composition This disclosure provides a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable carrier.

[0317] In some embodiments, the pharmaceutical composition is formulated as a dosage form suitable for administration according to the routes of administration described herein. In some embodiments, the routes of administration include enteral administration (e.g., oral, duodenal, or transrectal administration). In some embodiments, the pharmaceutical composition is formulated as a dosage form suitable for administration across the skin or mucosal barrier of the subject (e.g., nasal, ophthalmic, or transdermal administration). In some embodiments, the pharmaceutical composition is formulated as a solid dosage form for enteral administration to the subject (e.g., oral, duodenal, or transrectal administration). In some embodiments, the pharmaceutical composition is formulated as a solid dosage form for administration across the skin or mucosal barrier of the subject (e.g., nasal, ophthalmic, or transdermal administration). In some embodiments, the pharmaceutical composition is formulated as a suspension for enteral administration to the subject (e.g., oral, duodenal, or transrectal administration). In some embodiments, the pharmaceutical composition is formulated as a suspension for administration across the skin or mucosal barrier of the subject (e.g., nasal, ophthalmic, or transdermal administration). In some embodiments, the pharmaceutical composition is formulated as a liquid dosage form for enteral administration to a subject (e.g., oral, duodenal, or rectal administration). In some embodiments, the pharmaceutical composition is formulated in a dosage form that is convenient for storage, and when the composition is reconstituted in an aqueous solution, the dosage form dissolves, resulting in a suspension suitable for enteral administration to a subject (e.g., oral, duodenal, or rectal administration). For example, in some embodiments, the pharmaceutical composition is manufactured in a concentrated form (e.g., a tablet, suspension tablet, or effervescent tablet or powder) and reconstituted with water or another diluent to produce an aqueous form for enteral administration to a subject (e.g., oral, duodenal, or rectal administration). In some embodiments, the concentrated form is suitable for enteral administration to a subject (e.g., oral, duodenal, or rectal administration). In some embodiments, the pharmaceutical composition is formulated in a dosage form for inhalation.

[0318] Pharmaceutically acceptable carriers for use in the pharmaceutical compositions described herein are known in the art; see, for example, Remington's Pharmaceutical Sciences, 17th Edition, 1985. In some embodiments, the pharmaceutically acceptable carrier is a liquid for dissolving or dispersing the compositions of this disclosure. In some embodiments, the liquid is aqueous, non-aqueous, or a combination thereof. Non-aqueous solvents / co-solvents may be added to increase the solubility of less solubility substances and enhance the chemical stability of the therapeutic agent. Suitable solvents / co-solvents, solubilizers or vehicles include, but are not limited to, dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, water, glycerin, coconut fatty acid diethanolamide, medium-chain and / or long-chain fatty acids or glycers, monoglycerides, diglycerides, triglycerides, structured triglycerides, soybean oil, peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproyl macroglycerides, caproyl 90, propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutyl ketone, and methyl ethyl ketone.

[0319] In some embodiments, the pharmaceutical composition includes a buffer. As used herein, the term “buffer” refers to a pharmaceutically acceptable weak or strong base (and mixtures thereof) that, when formulated or delivered together with the composition (e.g., before, during, and / or after), substantially prevents or inhibits the acid-mediated degradation of the therapeutic agent by gastric acid, thereby maintaining the bioavailability of the therapeutic agent after oral administration. In some embodiments, the buffer is administered in an amount sufficient to render the gastric pH to improve the bioavailability of the therapeutic agent after oral administration. In some embodiments, the buffer includes any one or any combination selected from sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitation, mixtures of amino acids and buffers, mixtures of aluminum glycinate and buffers, mixtures of amino acids and buffer salts, and mixtures of amino acids and buffer alkali salts. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium coridocalcium, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0320] In some embodiments, the pharmaceutical composition includes additives to enhance stability, sterility, and / or isotonicity. For example, in some embodiments, the pharmaceutical composition includes antimicrobial preservatives and / or antioxidants. Antimicrobial and antifungal agents are known in the art. Non-limiting examples include parabens, chlorobutanol, phenol, and sorbic acid. In some embodiments, the pharmaceutical composition includes isotonic agents (e.g., sugars or sodium chloride). In some embodiments, the pharmaceutical composition includes thickeners (e.g., methylcellulose) to promote the stability of the therapeutic agent in solution. In some embodiments, the pharmaceutical composition further includes flavoring agents. In some embodiments, the pharmaceutical composition includes antifoaming agents (e.g., simethicone 80 mg, Mylicon®).

[0321] solid dosage form In some embodiments, the pharmaceutical compositions described herein are formulated as solid dosage forms (e.g., capsules or tablets) for administration according to the routes of administration described herein. In some embodiments, the routes of administration include enteral administration (e.g., oral, duodenal, or rectal administration). In some embodiments, the pharmaceutical compositions described herein are formulated as solid dosage forms (e.g., capsules or tablets) for administration across the skin or mucous membrane barrier (e.g., nasal, ophthalmic, or transdermal administration).

[0322] As used herein, the term “solid dosage form” refers to a dosage form that is solid under ambient conditions. In some embodiments, the solid dosage form includes a therapeutic agent in a substantially amorphous form. In some embodiments, the solid dosage form includes a therapeutic agent in a substantially crystalline form. In some embodiments, the solid dosage form includes a therapeutic agent as a mixture of amorphous and crystalline forms.

[0323] In some embodiments, the pharmaceutical composition is formulated as an enteric-coated solid dosage form (either as a delayed-release capsule or a tablet). In some embodiments, the pharmaceutical composition is formulated as a semi-solid dosage form for enteral administration (e.g., oral, duodenal, or rectal administration).

[0324] In some embodiments, the pharmaceutical composition is formulated as a solid dosage form for controlled drug delivery. As used herein, “controlled drug delivery” refers to the controlled release or administration of a therapeutic agent from a solid dosage form to achieve a desired pharmacokinetic profile in vivo. One aspect of “controlled release” drug delivery is the ability to manipulate the dosage form to establish a desired kinetics of drug release. In some embodiments, the pharmaceutical composition is formulated as a solid dosage form for sustained drug delivery, and the release of the therapeutic agent from the formulation lasts for a period of time, e.g., minutes, hours, days, weeks, or months. In some embodiments, the release of the therapeutic agent provides a consistent level of the therapeutic agent over a period ranging from minutes to a day. In some embodiments, the release profile is characterized by the absence of an immediate release phase, such as that obtained from intravenous administration.

[0325] In some embodiments, the solid dosage form is formulated for immediate release. As used herein, the term “immediate release” with respect to the solid dosage forms of this disclosure means that the solid dosage form dissolves without substantially prolonging the release of the therapeutic agent contained therein (e.g., upon exposure to gastrointestinal lysis conditions or after oral administration). As used herein, the term “gastrointestinal lysis conditions” refers to the dissolution test as defined by the USP (see, for example, The United States Pharmocopeial Convention, 2011, world wide web:ftp.uspbpep.com / v29240 / usp29nf24s0_c711.html). In some embodiments, the dissolution test involves exposing the solid dosage form to a release medium (e.g., 900 mL of 0.1 M HCl in a USP apparatus 1 (basket) or apparatus 2 (paddle) at about 37°C and about 100 rpm). In some embodiments, a solid dosage form formulated for immediate release is characterized by releasing at least about 85% of the therapeutic agent contained therein in less than about 60 minutes under gastrointestinal solubility conditions. In some embodiments, a solid dosage form formulated for immediate release dissolves rapidly after oral administration, releasing the therapeutic agent contained therein for gastrointestinal absorption. In some embodiments, a solid dosage form formulated for immediate release is characterized by the release of at least about 70%, about 75%, about 80%, or higher of the active ingredient contained therein within about 30 minutes, about 45 minutes, about 60 minutes, or about 90 minutes after oral administration.

[0326] In some embodiments, solid dosage forms are formulated for sustained or delayed release. As used herein, the term “sustained-release” in relation to solid dosage forms of this disclosure means that a solid dosage form releases the therapeutic agent contained therein over a period of time (e.g., when exposed to gastrointestinal conditions or after oral administration). In some embodiments, a solid dosage form formulated for sustained release is characterized by releasing the therapeutic agent contained therein at a predetermined rate after oral administration. In some embodiments, a solid dosage form formulated for sustained release is characterized by the release of the therapeutic agent contained therein at a predetermined location in the gastrointestinal tract after oral administration (e.g., in the stomach or small intestine). In some embodiments, a solid dosage form formulated for sustained release is characterized by the release of at least about 85% of the active ingredient contained therein over about 60, 90, 120, or 180 minutes under gastrointestinal conditions. In some embodiments, the sustained release is pulsating. In some embodiments, the solid dosage form includes an enteric coating that provides sustained release.

[0327] In some embodiments, the solid oral dosage form is a tablet, multiply particle, or capsule. In some embodiments, the solid oral dosage form is a delayed-release dosage form, in which the release of the therapeutic agent, one or more bile acids or salts thereof, and one or more optional co-excipient drugs in the GI tubule is sustained over a period of time. In some embodiments, the solid oral dosage form is selected to provide a release profile that minimizes the dilution of one or more bile acids or salts thereof in the GI tubule. In some embodiments, the solid oral dosage form is a delayed-release rapid-acting dosage form. Such a dosage form minimizes the release of the composition components (i.e., the therapeutic agent, one or more bile acids or salts thereof, and one or more optional co-excipients) in the stomach, but rapidly releases the components in the intestines, thereby maximizing the concentration of the components at the absorption site.

[0328] In some embodiments, the solid dosage form includes a disintegrant to increase solubility after reconstitution. In some embodiments, the solid dosage form includes one or more additives (e.g., microcrystalline cellulose) to increase compressibility. In some embodiments, the solid dosage form includes any one or any combination selected from flavoring agents, sweeteners, flow aids, lubricants, colorants, diluents, buffers, humectants, preservatives, pharmaceutically acceptable carriers, and disintegrants. In some embodiments, the solid dosage form is a powder, tablet, capsule, pellet dosage form, lozenge, troche, or effervescent tablet.

[0329] As used herein, the term “tablet” includes, but is not limited to, immediate-release (IR) tablets, sustained-release (SR) tablets, matrix tablets, multilayer tablets, multilayer matrix tablets, sustained-release tablets, delayed-release tablets, and pulse-release tablets. In some embodiments, a tablet includes one or more coating materials, such as polymer coating materials, including enteric coatings, rate-controlled coatings, and semipermeable coatings.

[0330] As used herein, the term “capsule” includes immediate-release capsules, sustained-release capsules, coated immediate-release capsules, coated sustained-release capsules, delayed-release capsules, and coated delayed-release capsules. In some embodiments, the solid dosage form is an enteric-coated capsule dosage form. In some embodiments, the solid dosage form is an enteric-coated rapid-start capsule dosage form.

[0331] In some embodiments, the solid dosage form is multiplying. As used herein, the term “multiplying” means multiple distinct particles, pellets, minitablets, and mixtures thereof, or combinations thereof. In some embodiments, the solid dosage form includes a rigid or flexible gelatin capsule enclosing the multiplying. In some embodiments, the solid dosage form includes a sachet containing the multiplying. In some embodiments, the solid dosage form includes multiplying coated with a layer containing a rate-controlled polymer material. In some embodiments, the solid dosage form includes multiplying containing at least two types of particles having different release properties. For example, in some embodiments, the multiplying dosage form includes a blend of an immediate-release component and a delayed-release component contained in a capsule. In some embodiments, the multiplying dosage form includes a capsule containing a delayed-release immediate-acting minitablet. In some embodiments, the multiplying dosage form includes a delayed-release capsule containing an immediate-release minitablet. In some embodiments, the multiplying dosage form includes a capsule containing delayed-release granules. In some embodiments, the multiplying dosage form includes a delayed-release capsule containing immediate-release granules.

[0332] In some embodiments, the solid dosage form is compressed or comprises a compressed tablet. The term “compressed tablet” generally refers to a flat, uncoated, plain tablet for oral administration, prepared by a single compression or by tapping before compression followed by a final compression. In some embodiments, the solid dosage form comprises a coating. For example, in some embodiments, the solid dosage form comprises a coating that dissolves upon ingestion or in contact with a diluent.

[0333] Methods for producing solid dosage forms are known in the art. The manufacturing process may use one or a combination of four established methods: (1) dry mixing, (2) direct compression, (3) grinding, and (4) non-aqueous granulation. (Lachman et al., The Theory and Practice of Industrial Pharmacy (1986)).

[0334] In some embodiments, the solid dosage form includes a controlled-release modifier. A “controlled-release modifier” refers to a substance that, upon hydration of the dosage form, preferentially interacts with the therapeutic agent to reduce its diffusion rate from the dosage form. Such excipients may also reduce the rate of water uptake by the formulation, thus enabling longer-lasting dissolution and release of the therapeutic agent. In some embodiments, the controlled-release modifier can molecularly bind to the therapeutic agent via physical (and therefore reversible) interactions, thereby increasing the effective molecular weight of the therapeutic agent and thus further modifying its permeability (diffusion) properties through the sublingual mucosa epithelium and basement membrane. Such binding is inherently reversible and does not involve chemical modification of the therapeutic agent. In some embodiments, the controlled-release modifier upon hydration forms a three-dimensional structure that captures the therapeutic agent and prolongs its release from the dosage form. Exemplary controlled-release modifiers are selected from lipids, phospholipids, sterols, surfactants, polymers, and salts.

[0335] In some embodiments, the solid dosage form includes a filler or extender. Exemplary extenders include, but are not limited to, lactose USP, starch 1500, mannitol, sorbitol, malitol or other non-reducing sugars, microcrystalline cellulose (e.g., Avicel), calcium dibasic phosphate dihydrate, sucrose, and mixtures thereof.

[0336] In some embodiments, the solid dosage form includes a solubilizer. In some embodiments, the solubilizer improves the solubility of the therapeutic agent while facilitating ease of handling and manufacture. Exemplary solubilizers include, but are not limited to, cyclodextrins, pH adjusters, salts and buffers, surfactants, fatty acids, phospholipids, and fatty acid metals. Exemplary surfactants include, but are not limited to, ionic (e.g., sodium lauryl sulfate), nonionic, e.g., polysorbates (Tween® and Span surfactant series, poloxamer, etc.), bile salts (e.g., sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium glycocholate), various alkyl glycosides, fatty acids, phosphatidylcholine, triglycerides, sphingolipids, glycosylated lipids, PEGylated lipids, and mixtures thereof. Examples of metal salts and buffers include, but are not limited to, organic (e.g., acetates, citrates, tartrates) or inorganic (e.g., phosphates, carbonates, bicarbonates, borates, sulfates, sulfites, bisulfites, metabisulfites, chlorides) metal salts of metals (e.g., sodium, potassium, calcium, magnesium).

[0337] In some embodiments, the solid dosage form includes additives to stabilize the therapeutic agent from chemicals of physical degradation. Such degradation reactions may include oxidation, hydrolysis, agglutination, deamidation, and the like. Suitable excipients that can stabilize the drug include antioxidants (e.g., BHT, BHA, vitamins, citrate, EDTA, sodium bisulfite, sodium metadisulfite, thiourea, methionine), anti-hydrolysis agents, and anti-aggregation agents (e.g., surfactants, amino acids such as arginine, glycine, histidine, and methionine).

[0338] In some embodiments, the solid dosage form includes an enteric coating, e.g., any enteric coating known in the art. In some embodiments, the enteric coating includes a polymer that is preferentially soluble in the less acidic environment of the intestines compared to the more acidic environment of the stomach (e.g., a polymer that is more soluble at a pH greater than about 5 or 6 than at a pH less than about 5). In some embodiments, the polymer is selected from cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or ethylcellulose), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), acrylates (e.g., polymethacrylate (e.g., Eudragit® E)), cyclodextrins (e.g., β-cyclodextrin), and their copolymers and derivatives.

[0339] Liquid oral formulations In some embodiments, the pharmaceutical composition is formulated as a liquid dosage form for administration according to the routes of administration described herein. In some embodiments, the routes of administration include enteral administration (e.g., oral, duodenal, or transrectal administration). In some embodiments, the pharmaceutical composition is formulated as a liquid dosage form for administration across the skin or mucous membrane barrier (e.g., nasal, ophthalmic, or transdermal administration). As used herein, the term “liquid dosage form” refers to a dosage form that can flow at ambient temperature and includes solutions, suspensions, and emulsions.

[0340] In some embodiments, the liquid dosage form includes a wetting agent. In some embodiments, the liquid dosage form includes a buffering agent. In some embodiments, the liquid dosage form includes a viscosity modifier. In some embodiments, the liquid dosage form includes an antifoaming agent. In some embodiments, the liquid dosage form includes a preservative. In some embodiments, the liquid dosage form includes a sweetener. In some embodiments, the liquid dosage form includes a sweetener and / or a flavoring agent.

[0341] In some embodiments, the liquid dosage form includes a liquid dispersion, suspension, solution, emulsion, spray, syrup, elixir, drop, concentrate, or a combination thereof. In some embodiments, the liquid dosage form includes a dry powder that is prepared as a liquid before administration to a patient. In some embodiments, the liquid dosage form includes one or more pharmaceutically acceptable excipients or additives selected from the group including a vehicle, a solvent / co-solvent and / or solubilizer, a pH adjuster and / or buffer or any combination thereof. In some embodiments, the liquid dosage form includes an antimicrobial agent or a preservative or antiseptic.

[0342] In some embodiments, the liquid dosage form is an immediate-release or controlled-release dosage form, such as sustained-release, controlled-release, prolonged-release, and delayed-release. In some embodiments, the liquid dosage form includes one or more suitable excipients or additives for the preparation of controlled-release dosage forms, such as rate-controlled polymers.

[0343] In some embodiments, the liquid dosage form includes a wetting agent, for example, to produce a uniform dispersion of solid particles in a liquid vehicle. In the case of aqueous vehicles, alcohol, glycerin, and PG are frequently used to facilitate the removal of adsorbed air from the surface of the particles. In the case of non-aqueous liquid vehicles, mineral oil is commonly used as a wetting agent. Non-exclusive examples of wetting agents include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium doxate, nonoxynol 9, octoxynol, poloxamer, poloxamer 124, poloxamer 188, 237, 338, 407, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetyl stearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyroxapol, and combinations thereof. In some embodiments, the liquid dosage form includes solubility enhancers, such as DL-methionine, caffeine, nicotinamide, vanillin, benzyl alcohol, ethanol, and diethylene glycol monoethyl ether, or combinations thereof. In some embodiments, the liquid dosage form includes stabilizers, such as sodium metasulfite, sodium bisulfite, ethylenediaminetetraacetic acid (EDTA) or its salts, ascorbic acid, or combinations thereof. In some embodiments, the liquid dosage form includes viscous adhesives, such as hydroxypropyl cellulose, gelatin, crosslinked polyacrylic acid, polymethacrylic acid, polyhydroxyethyl methacrylic acid, hydroxypropyl methylcellulose, polyethylene glycol, sodium carboxymethylcellulose, hyaluronic acid, chitosan, polycarbophil, pectin, xanthan gum, alginic acid, dextran copolymer, polyacrylamide, acacia, caprolactone and ethylene oxide copolymer, carbopol 934, tragacanth, eudoragit, and combinations thereof.In some embodiments, the liquid dosage form includes a viscosity modifier, for example, to improve the suspension, impart viscosity, and / or reduce particle sedimentation. Viscosity modifiers can be classified into cellulose derivatives, clays, natural rubbers, and synthetic rubbers. Non-limiting examples of viscosity modifiers include any combination of acacia, agar, alginic acid, carbomer, carmellose sodium, dextrin, gelatin, bee gum or gel white, gellan gum, sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl starch, hypromellose, maltodextrin, methylcellulose, modified starch, pectin, poloxamer, polycarbophil, polyethylene glycol, polyvinyl acetate, poly(vinyl alcohol), potassium alginate, polyvinylpyrrolidone, pregeratinized starch, propylene glycol alginate, sodium alginate, carboxymethylcellulose or its potassium metal alkaline salts, microcrystalline cellulose, gum arabic, karaya gum, stercuria gum, tragacanth, xanthan gum, bentonite, carrageenan, guar gum, colloidal silicon dioxide, etc.

[0344] In some embodiments, the liquid dosage form includes pH adjusters such as acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium chloride, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium chloride, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodium propionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, and combinations thereof.

[0345] kit This disclosure provides kits for carrying out the methods described herein. In some embodiments, the kit includes the compositions of the disclosure (e.g., compositions comprising one or more doses of a therapeutic agent, a certain amount of at least one bile acid or a salt thereof, and optionally one or more co-excipients) or the pharmaceutically active ingredients (e.g., formulated as a solid or liquid dosage form) and a package insert including instructions for administering the compositions or pharmaceutically active ingredients to a subject according to the routes of administration described herein for the prevention, improvement or treatment of a disease or disorder in the subject. In some embodiments, the routes of administration include enteral administration (e.g., oral administration).

[0346] In some embodiments, the kit includes the composition of the present disclosure (e.g., a composition comprising one or more doses of a therapeutic agent, a certain amount of at least one bile acid or a salt thereof, and optionally one or more co-excipients) or its pharmaceutical composition (e.g., formulated as a solid or liquid dosage form) and a package insert including instructions for administering the composition or pharmaceutical composition across the skin or mucous membrane barrier of a subject to prevent, improve or treat a disease or disorder of interest (e.g., intranasal, ophthalmic, or transdermal administration).

[0347] In some embodiments, the kit includes a container containing a composition or pharmaceutical composition. In some embodiments, the composition or pharmaceutical composition is contained in a pharmaceutically acceptable package, container, pump, bottle with spray pump, bottle with dripper assembly, bottle, collapsible tube, glass ampoule, vial with stopper, or pre-filled syringe.

[0348] In some embodiments, the kit includes a container containing the composition or pharmaceutical composition, means for administering the composition or pharmaceutical composition (e.g., a syringe), and a package insert including instructions for administering the composition or pharmaceutical composition according to the route of administration described herein for the prevention, improvement, or treatment of a disease or disorder. In some embodiments, the kit includes a drug containing the composition or pharmaceutical composition, means for administering the drug (e.g., a syringe), and a package insert including instructions for administering the drug according to the route of administration described herein for the prevention, improvement, or treatment of a disease or disorder.

[0349] In some embodiments, the kit includes a container containing the composition or pharmaceutical composition, means for enteral administration of the composition or pharmaceutical composition to a subject (e.g., a syringe), and a package insert including instructions for enteral administration of the composition or pharmaceutical composition to a subject for preventing, improving, or treat...

Claims

1. A composition, (i) A compound comprising a polypeptide having a molecular weight of approximately 1 kDa to approximately 250 kDa, (ii) A composition comprising at least one bile acid or a salt thereof in an effective concentration higher than the CMC of the bile salt.

2. The composition according to claim 1, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the polypeptide compared to the GI permeability of the polypeptide alone.

3. The composition according to claim 1 or 2, wherein the polypeptide has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or more than about 30 kDa.

4. The polypeptide is approximately 1 kDa to approximately 5 kDa, approximately 2 kDa to approximately 5 kDa, approximately 3 kDa to approximately 5 kDa, approximately 1 kDa to approximately 10 kDa, approximately 2 kDa to approximately 10 kDa, approximately 5 kDa to approximately 10 kDa, approximately 5 kDa to approximately 20 kDa, approximately 5 kDa to approximately 50 kDa, approximately 10 kDa to approximately 50 kDa, approximately 10 kDa to approximately 100 kDa, approximately 10 kDa to approximately A composition according to any one of claims 1 to 3, having a molecular weight of 150 kDa, about 50 kDa to about 150 kDa, about 100 kDa to about 150 kDa, about 50 kDa to about 200 kDa, about 100 kDa to about 200 kDa, about 100 kDa to about 250 kDa, about 150 kDa to about 250 kDa, or about 200 kDa to about 250 kDa.

5. The composition according to any one of claims 1 to 4, wherein the polypeptide is selected from enzymes, antibodies or their antigen-binding fragments, antibacterial agents, hormones, growth factors, chemokines, cell signaling factors, and cytokines.

6. The composition according to any one of claims 1 to 5, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.

7. The composition according to any one of claims 1 to 5, wherein the polypeptide is a peptide therapeutic agent.

8. The composition according to any one of claims 1 to 5, wherein the polypeptide is a recombinant protein.

9. A composition, (i) Compounds containing nucleic acids, (ii) A composition comprising at least one bile acid or a salt thereof in an effective concentration higher than the critical micelle concentration (CMC) of the bile salt.

10. The composition according to claim 9, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the nucleic acid compared to the GI permeability of the nucleic acid alone.

11. The composition according to claim 9 or 10, wherein the nucleic acid comprises a ribonucleoside, a deoxyribonucleoside, or a combination thereof.

12. The composition according to any one of claims 9 to 11, wherein the nucleic acid is selected from immunostimulatory oligonucleotides, mRNA, plasmid DNA, and RNA interfering oligonucleotides.

13. The composition according to claim 12, wherein the RNA interfering oligonucleotide is selected from siRNA, shRNA, miRNA, and antisense oligonucleotides.

14. The composition according to claim 13, wherein the antisense oligonucleotide is a gapmer.

15. The composition according to any one of claims 9 to 14, wherein the nucleic acid comprises one or more modified nucleosides.

16. The composition according to claim 15, wherein the modification is selected from a modified sugar moiety, a modified nucleoside bond, a modified nucleic acid base, and a combination thereof.

17. The composition according to any one of claims 9 to 13, comprising a viral vector containing the nucleic acid.

18. A composition, (i) A Class III or Class IV compound according to the Biopharmaceutical Classification System (BCS), (ii) A certain amount of at least one bile acid or its salt at an effective concentration higher than the critical micelle concentration (CMC) of the bile acid or its salt, A composition containing the following:

19. The composition according to claim 18, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the class III or class IV compound compared to the GI permeability of the compound alone.

20. The composition according to claim 18 or 19, comprising a class III compound by the aforementioned BCS.

21. The composition according to claim 18 or 19, comprising a class IV compound according to the BCS.

22. The composition according to any one of claims 18 to 21, wherein the compound has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or more than about 30 kDa.

23. The composition according to any one of claims 18 to 21, wherein the compound has a molecular weight of about 0.1 to about 1 kDa.

24. The composition according to any one of claims 18 to 23, wherein the compound is selected from polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, and combinations thereof.

25. The composition according to any one of claims 1 to 24, wherein the effective concentration of the at least one bile acid or its salt is at least 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 greater than the CMC.

26. The composition according to any one of claims 1 to 25, wherein the effective concentration of the at least one bile acid or its salt is about 2 to about 200 times greater than that of the CMC.

27. The composition according to any one of claims 1 to 26, wherein the effective concentration of the at least one bile acid or salt thereof is about 32 mg / mL to about 160 mg / mL.

28. The composition according to claim 27, wherein the effective concentration of the at least one bile acid or salt thereof is at least about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL.

29. The composition according to any one of claims 1 to 28, comprising a pharmaceutically acceptable salt of the aforementioned bile acid.

30. The composition according to any one of claims 1 to 29, wherein the bile acid or a salt thereof comprises three, four, or five ring structures.

31. The composition according to any one of claims 1 to 30, wherein the bile acid or a salt thereof comprises a steroid nucleus.

32. The composition according to claim 31, wherein the steroid nucleus comprises one, two, or three hydroxyl groups.

33. The composition according to claim 31 or 32, wherein the 3-position of the steroid nucleus contains a hydroxyl group.

34. The composition according to any one of claims 31 to 33, wherein the steroid nucleus comprises a hydroxyl group at position 7, position 12, or both.

35. The composition according to any one of claims 31 to 34, wherein the 17th position of the steroid nucleus includes a carboxylate side chain.

36. The composition according to any one of claims 31 to 34, wherein the 17th position of the steroid nucleus comprises an ester or an amino side chain.

37. The composition according to claim 36, wherein the amino side chain is selected from taurine and glycine.

38. The composition according to any one of claims 1 to 37, wherein the bile acid or its salt is selected from sodium taurocholate (STC), sodium glycocholate (GCA), sodium cholate (CHA), 3-[(3-coramidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), sodium taurodeoxycholate (TDCA), sodium glycodeoxycholate (GDCA), sodium deoxycholate (DCA), sodium taurochenodeoxycholate (TCDCA), sodium glycochenodeoxycholate (GCDCA), and sodium chenodeoxycholate (CDCA).

39. The composition according to any one of claims 1 to 38, wherein the bile acid or its salt has a CMC of about 30 mg / mL, about 20 mg / mL, about 15 mg / mL, or less than about 5 mg / mL.

40. The composition according to any one of claims 1 to 39, wherein the CMC is measured by a method selected from potentiometric measurement, spectroscopic measurement, and light scattering.

41. The composition according to any one of claims 1 to 39, wherein the amount (mg) of the at least one bile acid or a salt thereof is substantially equal to the effective concentration (mg / mL) obtained by multiplying it by a dilution factor (mL).

42. The composition according to claim 41, wherein the dilution coefficient (mL) is approximately 2 mL to approximately 30 mL.

43. The composition according to claim 41 or 42, wherein the dilution coefficient (mL) is approximately 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL.

44. The composition according to claim 41, wherein the dilution coefficient (mL) is less than approximately 15 mL.

45. The composition according to any one of claims 1 to 44, wherein the amount of the at least one bile acid or salt thereof is about 60 mg to about 1,200 mg.

46. A composition according to any one of claims 1 to 45, comprising an effective amount of the compound.

47. A composition, (i) A compound comprising a polypeptide having a molecular weight of approximately 1 kDa to approximately 250 kDa, (ii) an amount of at least one bile acid or salt thereof at an effective concentration higher than the CMC of the bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof, A composition containing the following:

48. The composition according to claim 47, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the polypeptide compared to the GI permeability of the polypeptide alone.

49. The composition according to claim 47 or 48, wherein the compound has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or more than about 30 kDa.

50. The polypeptide is approximately 1 kDa to 5 kDa, approximately 2 kDa to 5 kDa, approximately 3 kDa to 5 kDa, approximately 1 kDa to 10 kDa, approximately 2 kDa to 10 kDa, approximately 5 kDa to 10 kDa, approximately 5 kDa to 20 kDa, approximately 5 kDa to 50 kDa, approximately 10 kDa to 50 kDa, approximately 10 kDa to 100 kDa, and approximately 10 kDa to 1 A composition according to any one of claims 47 to 49, having a molecular weight of 50 kDa, about 50 kDa to about 150 kDa, about 100 kDa to about 150 kDa, about 50 kDa to about 200 kDa, about 100 kDa to about 200 kDa, about 100 kDa to about 250 kDa, about 150 kDa to about 250 kDa, or about 200 kDa to about 250 kDa.

51. The composition according to any one of claims 47 to 50, wherein the polypeptide is selected from enzymes, antibodies, antibacterial agents, hormones, growth factors, chemokines, and cytokines.

52. A composition, (i) Compounds containing nucleic acids, (ii) A composition comprising a certain amount of at least one bile acid or a salt thereof at an effective concentration higher than the critical micelle concentration (CMC) of a bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof, and the at least one bile acid or salt thereof is selected in a certain amount of at least one bile acid or salt thereof.

53. The composition according to claim 52, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the nucleic acid compared to the intestinal permeability of the nucleic acid alone.

54. The composition according to claim 52 or 53, wherein the nucleic acid comprises a ribonucleoside, a deoxyribonucleoside, or a combination thereof.

55. The composition according to any one of claims 52 to 54, wherein the nucleic acid is selected from immunostimulatory oligonucleotides, mRNA, plasmid DNA, and RNA interfering oligonucleotides.

56. The composition according to claim 55, wherein the RNA interfering oligonucleotide is selected from siRNA, shRNA, miRNA, and antisense oligonucleotides.

57. The composition according to claim 56, wherein the antisense oligonucleotide is a gapmer.

58. The composition according to any one of claims 52 to 57, wherein the nucleic acid comprises one or more modified nucleosides.

59. The composition according to claim 58, wherein the modification is selected from a modified sugar moiety, a modified nucleoside bond, a modified nucleic acid base, and a combination thereof.

60. The composition according to any one of claims 52 to 57, comprising a viral vector containing the nucleic acid.

61. A composition, (i) A Class III or Class IV compound according to the Biopharmaceutical Classification System (BCS), (ii) an amount of at least one bile acid or salt thereof at an effective concentration higher than the CMC of the bile salt, wherein the at least one bile acid or salt thereof is selected from glycocholic acid, taurocholic acid, and pharmaceutically acceptable salts thereof, A composition containing the following:

62. The composition according to claim 61, comprising a class III compound by the aforementioned BCS.

63. The composition according to claim 61, comprising a class IV compound by the BCS.

64. The composition according to any one of claims 61 to 63, wherein the compound has a molecular weight of about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, or more than about 30 kDa.

65. The composition according to any one of claims 61 to 63, wherein the compound has a molecular weight of about 0.1 to about 1 kDa.

66. The composition according to any one of claims 61 to 65, wherein the compound is selected from polypeptides, nucleic acids, oligosaccharides, small molecules, lipids, and combinations thereof.

67. The composition according to any one of claims 47 to 66, wherein the at least one bile acid or a salt thereof is sodium glycocholate (GCA).

68. The composition according to any one of claims 47 to 66, wherein the at least one bile acid or a salt thereof is sodium taurocholate (STC).

69. The composition according to any one of claims 47 to 68, wherein the effective concentration is about 2 to about 200 times greater than that of the CMC.

70. The composition according to claim 69, wherein the effective concentration is at least 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 greater than that of the CMC.

71. The composition according to claim 69, wherein the effective concentration is about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, about 110 times, about 120 times, about 130 times, about 140 times, about 150 times, about 160 times, about 170 times, about 180 times, about 190 times, or about 200 times greater than the CMC.

72. The composition according to any one of claims 47 to 71, wherein the effective concentration is approximately 32 mg / mL to approximately 160 mg / mL.

73. The composition according to claim 72, wherein the effective concentration is approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 50 mg / mL, approximately 55 mg / mL, approximately 60 mg / mL, approximately 65 mg / mL, approximately 70 mg / mL, approximately 75 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, approximately 95 mg / mL, approximately 100 mg / mL, approximately 110 mg / mL, approximately 120 mg / mL, approximately 130 mg / mL, approximately 140 mg / mL, approximately 150 mg / mL, or approximately 160 mg / mL.

74. The composition according to any one of claims 47 to 73, wherein the amount of the at least one bile acid or a salt thereof is effective in increasing the GI permeability of the compound compared to the GI permeability of the compound alone.

75. The composition according to any one of claims 47 to 74, wherein the amount (mg) of the at least one bile acid or a salt thereof is substantially equal to the effective concentration (mg / mL) obtained by multiplying it by a dilution factor (mL).

76. The composition according to claim 75, wherein the dilution coefficient (mL) is approximately 2 mL to approximately 30 mL.

77. The composition according to claim 75 or 76, wherein the dilution coefficient (mL) is approximately 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL.

78. The composition according to any one of claims 47 to 77, wherein the amount of the at least one bile acid or its salt is about 60 mg to about 600 mg.

79. A composition according to any one of claims 42 to 78, comprising an effective amount of the compound.

80. A composition according to any one of claims 1 to 79, comprising one, two, three, or four bile acids or a salt thereof.

81. The composition according to any one of claims 1 to 80, further comprising a certain amount of at least one co-excipient.

82. The composition according to claim 81, wherein the at least one co-excipient is selected from chelating agents, polymers, dendrimers, nanoparticles, lipids, alkyl acids, and combinations thereof.

83. The composition according to claim 81 or 82, wherein the amount of the at least one co-excipient is effective in increasing the permeability of the compound compared to the intestinal permeability of the control composition, and optionally the control composition is formulated without the at least one co-excipient.

84. The composition according to any one of claims 81 to 83, wherein the amount (mg) of the at least one co-excipient is substantially equal to the effective concentration (mg / mL) of the at least one co-excipient multiplied by a dilution factor (mL).

85. The composition according to claim 84, wherein the dilution coefficient (mL) is approximately 2 mL to approximately 30 mL.

86. The composition according to claim 84 or 85, wherein the dilution coefficient (mL) is approximately 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, or 20 mL.

87. The composition according to any one of claims 81 to 86, wherein the amount of the at least one co-excipient is about 0.1 mg to about 600 mg.

88. The composition according to any one of claims 81 to 87, wherein the at least one co-excipient is a chelating agent.

89. The composition according to claim 88, wherein the chelating agent is selected from ethylene glycol-bis(β-aminoethyl)-N,N,N',N'-tetraacetate sodium (EGTA), ethylene dinitrilotetraacetate sodium (EDTA), sodium glutamate (AAE), and combinations thereof.

90. The composition according to claim 88 or 89, comprising a certain amount of the chelating agent at a concentration of approximately 5 mg / mL to approximately 100 mg / mL.

91. The composition according to any one of claims 81 to 87, wherein the at least one co-excipient is a polymer.

92. The composition according to claim 91, wherein the polymer is a homopolymer or copolymer, and optionally the copolymer is selected from block copolymers, random copolymers, graft copolymers, and alternating copolymers.

93. The composition according to claim 91 or 92, wherein the polymer comprises poly(methacrylate), poly(ethyl acrylate), poly(ethylene glycol), hyaluronic acid, polysaccharide, chitosan, arginine, poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(ethyleneimine), poly(N-(2-hydroxypropyl)methacrylamide), poly(glycolic acid), poly(lactic acid), poly(lactic acid-coglycolic acid), poly(caprolactone), poly(orthoester), poly(anhydride), poly(amide), poly(esteramide), poly(phosphoester), poly(alkyanoacrylate), or a combination thereof.

94. The composition according to any one of claims 91 to 93, wherein the polymer has a molecular weight of about 0.5 kDa to about 100 kDa.

95. The composition according to any one of claims 91 to 94, wherein the polymer is branched, and optionally the polymer comprises a star-shaped, H-shaped, pom-pom-shaped, or comb-shaped architecture.

96. The composition according to claim 91, wherein the polymer is selected from Eudragit E PO (EPO), Eudragit RL100 (RL100), poly(ethylene glycol) 1 kDa (PEG-1 kDa), branched poly(ethyleneimine) 800 Da (PEI: b0.8), Kollidon SR (KOLSR), poly(methacrylic acid) 5 kDa (PMA: 5), poly(aspartic acid) 2 kDa (POLD: 2), poly(2-ethyl oxazoline) 25 kDa (POXZ: 25), poly(glutamic acid) 50 kDa (POLE: 50), branched poly(ethyleneimine)-co-poly(ethylene glycol) 500 Da (bPEIPPEG: 0.5), and Vivacoat (VIVA).

97. The composition according to any one of claims 91 to 96, comprising the polymer in an amount at a concentration of approximately 5 mg / mL to approximately 150 mg / mL.

98. The composition according to any one of claims 81 to 87, wherein the at least one co-excipient is a dendrimer.

99. The composition according to claim 98, wherein the dendrimer comprises a poly(amidoamine), poly(propyleneimine), polyamide, polyether, polyester, or a phosphorus-based architecture.

100. The composition according to claim 98 or 99, wherein the dendrimer is a first-generation (G1), G2, G3, G4, G5, G6, G7, G8, G9, G10, or G11 dendrimer.

101. The composition according to claim 98, wherein the dendrimer is selected from third- and fifth-generation carboxylate-terminated poly(amideamine)dendrimers (DENDAC3.5) and fourth-generation amine-terminated poly(amideamine)dendrimers (DENDAM4).

102. A composition according to any one of claims 98 to 101, comprising a certain amount of the dendrimer at a concentration of about 0.1 mg / mL to about 50 mg / mL.

103. The composition according to any one of claims 81 to 87, wherein the at least one co-excipient is microscopic particles.

104. The composition according to claim 103, wherein the microscopic particles are fine particles or nanoparticles.

105. The composition according to claim 103 or 104, wherein the microscopic particles are selected from inorganic particles, carbon particles, ceramic particles, metal particles, polymer particles, liposomes, lipid nanoparticles, and combinations thereof.

106. The composition according to any one of claims 103 to 105, wherein the microscopic particles include metal oxides, metal salts, mineral colloids, inorganic salts, and combinations thereof.

107. The composition according to any one of claims 103 to 105, wherein the microscopic particles are carbon particles, optionally fullerenes, or carbon nanotubes.

108. The aforementioned microscopic particles are calcium phosphate tribasic fine particles (CaPO ４ ), calcium phosphate dibasic particles (CaHPO ４ The composition according to claim 103, which is selected from 5 μm spherical hydroxyapatite nanoparticles (HAP: 5U), 2.5 μm spherical hydroxyapatite nanoparticles (HAP: 2.5U), zinc oxide nanoparticles (ZNO: r10n), hydroxyapatite rod-shaped nanoparticles with a diameter of 40 nm (HAP: r40n), and carbon black nanoparticles with a diameter of 13 nm (CB: 13n).

109. The composition according to any one of claims 103 to 108, wherein the amount of the microscopic particles is an effective concentration of about 0.1 mg / mL to about 100 mg / mL.

110. A dosage form comprising the composition according to any one of claims 1 to 109.

111. The dosage form according to claim 110, wherein the amount of the at least one bile acid or a salt thereof is sufficient to achieve the effective concentration at the absorption site in the GI tubule.

112. The dosage form according to claim 110 or 111, comprising a solid dosage form or a liquid dosage form.

113. A dosage form according to any one of claims 110 to 112, including a solid dosage form.

114. The dosage form according to claim 113, wherein the solid dosage form is formulated for immediate release.

115. The dosage form according to claim 113, wherein the solid dosage form is formulated for delayed release.

116. The dosage form according to claim 115, wherein the solid dosage form includes an enteric coating.

117. A pharmaceutical composition comprising the composition according to any one of claims 1 to 96 or the dosage form according to any one of claims 110 to 116, and a pharmaceutically acceptable carrier.

118. A pharmaceutical composition according to claim 117, formulated for enteral administration.

119. A pharmaceutical composition according to claim 117 or 118, formulated for transrectal administration.

120. A pharmaceutical composition according to claim 117 or 118, formulated for intraduodenal administration.

121. A pharmaceutical composition according to claim 117, formulated for oral administration.

122. The pharmaceutical composition according to claim 117, formulated for sublingual or buccal administration.

123. The pharmaceutical composition according to claim 117, formulated for ophthalmic or nasal administration.

124. A pharmaceutical composition according to claim 117, formulated for topical or transdermal administration.

125. A method for enhancing the GI permeability of a compound, wherein the method comprises administering to GI tissue the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124.

126. The method according to claim 125, wherein the GI tissue includes gastric tissue, intestinal tissue, rectal tissue, or a combination thereof.

127. The method according to claim 125 or 126, wherein the administration is in vivo.

128. The method according to claim 127, wherein the administration is enteral.

129. The method according to claim 128, wherein the administration is transrectal.

130. The method according to claim 128, wherein the administration is performed in the duodenum.

131. The method according to claim 128, wherein the administration is performed orally.

132. The method according to any one of claims 125 to 131, wherein the GI permeability of the compound is increased compared to the GI permeability of the control composition, and optionally the control composition comprises the compound alone.

133. The method according to claim 132, wherein the GI permeability of the compound is increased by at least about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 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 compared to the GI permeability of the control composition.

134. The method according to claim 132 or 133, wherein the GI permeability of the compound is increased by about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or 300 times compared to the GI permeability of the control composition.

135. The method according to any one of claims 125 to 134, wherein GI permeability is measured in vivo or in vitro using a Transwell permeability assay, a Ussing chamber assay, or a GI tube-organ robot interface system (GI-ORIS) based permeability assay.

136. A method for increasing the bioavailability of a compound in a target, the method comprising administering the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124 to the GI tube of the target, wherein the composition, the dosage form, or the pharmaceutical composition contains an effective dose of the compound.

137. The method according to claim 136, wherein the bioavailability of the compound is increased compared to the bioavailability of the control composition, and optionally the control composition comprises the compound alone.

138. The method according to claim 136 or 137, wherein the plasma maximum peak of the compound is increased compared to the plasma maximum peak of the control composition, and optionally the control composition comprises the compound alone.

139. A method for preventing or treating a disease or disorder in a subject, comprising administering to the subject a composition according to any one of claims 1 to 109, a dosage form according to any one of claims 110 to 116, or a pharmaceutical composition according to any one of claims 117 to 124, wherein the composition, dosage form, or pharmaceutical composition contains an effective dose of the compound.

140. The method according to any one of claims 136 to 139, wherein the administration is enteral.

141. The method according to any one of claims 136 to 140, wherein the administration is transrectal.

142. The method according to any one of claims 136 to 140, wherein the administration is performed in the duodenum.

143. The method according to any one of claims 136 to 140, wherein the administration is performed orally.

144. The method according to any one of claims 136 to 139, wherein the administration is sublingual or buccal mucosa.

145. The method according to claim 139, wherein the administration is by eye drops or by nasal infusion.

146. The method according to claim 139, wherein the administration is local or transdermal.

147. Use of the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124 for increasing the bioavailability of a compound in a target.

148. Use of the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124 in the manufacture of a drug for increasing the bioavailability of a compound in a target.

149. Use of the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124 for the prevention or treatment of a disease or disorder in a subject.

150. Use of a composition according to any one of claims 1 to 109, a dosage form according to any one of claims 110 to 116, or a pharmaceutical composition according to any one of claims 117 to 124 in the manufacture of a drug for preventing or treating a disease or disorder in a subject.

151. A kit comprising a container containing the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124, and an accompanying document containing instructions for administering the composition or pharmaceutical composition to increase the bioavailability of the compound in a target from the GI tube.

152. A kit comprising a container containing the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124, and an accompanying document containing instructions for orally administering the composition or pharmaceutical composition to increase the bioavailability of the compound in a subject.

153. A kit comprising a container containing the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124, and an accompanying document containing instructions for administering the composition or pharmaceutical composition for the prevention or treatment of a disease or disorder in a subject.

154. A kit comprising a container containing the composition according to any one of claims 1 to 109, the dosage form according to any one of claims 110 to 116, or the pharmaceutical composition according to any one of claims 117 to 124, and an accompanying document containing instructions for orally administering the composition or pharmaceutical composition for the prevention or treatment of a disease or disorder in a subject.

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