Apical sodium-dependent transporter inhibitor compositions

Abstract

Provided herein are pharmaceutical compositions comprising an apical sodium-dependent transporter inhibitor (ASBTI) and methods of using the same for the treatment of cholestatic liver disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 271,857, filed October 26, 2021, the disclosure of which is incorporated by reference in its entirety into this application. [Technical Field]

[0002] The present invention relates to pharmaceutical compositions comprising apical sodium-dependent transporter inhibitors (ASBTIs) and methods of using same for the treatment of cholestatic liver disease. [Background technology]

[0003] Hypercholesterolemia and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis), which are often secondary to and often associated with the intracellular accumulation of bile acids / bile salts in hepatocytes. Hypercholesterolemia is characterized by elevated serum concentrations of bile acids or bile salts. Clinicopathologically, cholestasis can be divided into two major categories: biliary obstructive, often extrahepatic, cholestasis, and non-biliary obstructive or intrahepatic cholestasis. Non-biliary obstructive intrahepatic cholestasis can be further divided into two major subgroups: primary intrahepatic cholestasis, which is caused by a constitutive defect in bile secretion, and secondary intrahepatic cholestasis, which is caused by hepatocellular damage. Primary intrahepatic cholestasis includes benign recurrent intrahepatic cholestasis, an adult form with primarily similar clinical manifestations, and progressive familial intrahepatic cholestasis types 1, 2, and 3, which affect children. Neonatal respiratory distress syndrome and pneumonia are often associated with intrahepatic cholestasis during pregnancy. Aggressive treatment and prevention are limited. Effective treatments for hypercholic acidemia and cholestatic liver disease to date include surgery, liver transplantation, and, rarely, ursodiol administration.

[0004] Although pediatric cholestatic liver disease affects a small percentage of children, its treatment incurs significant medical costs each year. Currently, many cases of pediatric cholestatic liver disease require invasive and expensive treatments such as liver transplantation and surgery.

[0005] It is well understood and accepted that the therapeutic needs of children differ from those of adults, requiring unique research into pediatric drug therapy. For example, while oral administration of solid dosage forms of drugs is painless and easy for most adult patients, swallowing oral solid dosage forms manufactured for adult use can be problematic for the pediatric patient population. Furthermore, the taste of drugs used in solid dosage forms is often unpleasant. More importantly, oral administration of adult drugs targeting cholestatic liver disease can result in side effects such as diarrhea and intestinal discomfort. These issues pose safety risks and affect compliance. Effective and tolerable forms of pediatric drugs for pediatric cholestatic liver disease are needed.

[0006] The apical sodium-dependent transporter (ASBT) protein in the terminal ileum plays a key physiological role in the enterohepatic circulation of bile acids and is therefore essential for bile acid homeostasis. To this end, pharmacological inhibition of ASBT is rapidly emerging as an attractive target.

[0007] Some ASBT inhibitors (ASBTIs) are designed to limit systemic absorption by an individual. In this regard, it can sometimes be difficult to formulate these compounds into stable and effective compositions. Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there is an unmet need for safe and effective formulations and compositions containing ASBTI. [Means for solving the problem]

[0009] Various non-limiting aspects and embodiments of the present invention are described below.

[0010] In one aspect, the present invention provides a pharmaceutical composition comprising an ASBTI, a preservative, and an antioxidant.

[0011] In one embodiment, the preservative is an antimicrobial preservative, hi one embodiment, the preservative is propylene glycol.

[0012] In one embodiment, the preservative is present in an amount of at least 30% of the composition. In one embodiment, the preservative is present in an amount of about 30% to about 40% of the composition. In one embodiment, the preservative is present in an amount of about 32% to about 37% of the composition. In one embodiment, the preservative is present in an amount of about 33% to about 36% of the composition. In one embodiment, the preservative is present in an amount of about 33% of the composition. In one embodiment, the preservative is present in an amount of about 34% of the composition. In one embodiment, the preservative is present in an amount of about 35% of the composition.

[0013] In one embodiment, the antioxidant is an aminocarboxylic acid or aminopolycarboxylic acid selected from EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), NTA (nitrilotriacetic acid), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), NOTA (2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid), DOTA (tetracarboxylic acid), and EDDHA (ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid). In one embodiment, the antioxidant is EDTA.

[0014] In one embodiment, the ASBTI is [ka] or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the ASBTI is [ka] is.

[0016] In one embodiment, the ASBTI is vorixibat or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the ASBTI is odevixibat or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment, the ASBTI is elobixibat or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, the ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0020] In one embodiment, ASBTI is present in an amount of about 0.1 mg / mL to about 500 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 1 mg / mL to about 250 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 2 mg / mL to about 100 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 5 mg / mL to about 50 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 8 mg / mL to about 20 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 9 mg / mL to about 10 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 10 mg / mL of the composition. In one embodiment, ASBTI is present in an amount of about 9.5 mg / mL of the composition.

[0021] In one embodiment, the preservative is an antimicrobial preservative.

[0022] In one embodiment, the antimicrobial preservative is selected from the group consisting of propylene glycol, ethyl alcohol, glycerin, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimide (cetyltrimethylammonium bromide), cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof.

[0023] In one embodiment, the preservative is propylene glycol.

[0024] In one embodiment, the preservative is present in an amount of at least about 30% w / w of the composition. In one embodiment, the preservative is present in an amount of about 30% to about 40% of the composition. In one embodiment, the preservative is present in an amount of about 32% to about 37% of the composition. In one embodiment, the preservative is present in an amount of about 33% to about 36% of the composition. In one embodiment, the preservative is present in an amount of about 33% of the composition. In one embodiment, the preservative is present in an amount of about 34% of the composition. In one embodiment, the preservative is present in an amount of about 35% of the composition.

[0025] In one embodiment, the antioxidant is selected from the group consisting of aminocarboxylic acids, aminopolycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, and combinations thereof.

[0026] In one embodiment, the antioxidant is an aminopolycarboxylic acid selected from EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), NTA (nitrilotriacetic acid), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), NOTA (2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid), DOTA (tetracarboxylic acid), and EDDHA (ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid).

[0027] In one embodiment, the antioxidant is EDTA.

[0028] In one embodiment, the antioxidant is present in an amount of about 0.001% to about 1% w / w of the composition. In one embodiment, the antioxidant is present in an amount of about 0.005% to about 0.75% w / w of the composition. In one embodiment, the antioxidant is present in an amount of about 0.01% to about 0.5% w / w of the composition. In one embodiment, the antioxidant is present in an amount of about 0.05% to about 0.25% w / w of the composition. In one embodiment, the antioxidant is present in an amount of about 0.075% to about 0.2% w / w of the composition. In one embodiment, the antioxidant is present in an amount of about 0.1% w / w of the composition.

[0029] In one embodiment, the composition is stable at room temperature for at least 1 month. In one embodiment, the composition is stable at room temperature for at least 2 months. In one embodiment, the composition is stable at room temperature for at least 3 months. In one embodiment, the composition is stable at room temperature for at least 6 months. In one embodiment, the composition is stable at room temperature for at least 1 year. In one embodiment, the composition is stable at room temperature for at least 2 years.

[0030] In one embodiment, the composition is a liquid composition for oral administration, hi one embodiment, the composition is an aqueous solution.

[0031] In one embodiment, the composition further comprises a sweetener, a taste-masking ingredient, or a combination thereof.

[0032] In another aspect, the present invention provides a method for producing a method of manufacturing a semiconductor device comprising: a. About 5 mg / mL to about 50 mg / mL of maralixibat; b. about 300 mg / mL to about 400 mg / mL propylene glycol; c. approximately 1 mg / mL disodium EDTA; d. sweeteners, taste-masking ingredients, or combinations thereof; and e.Water The present invention provides a pharmaceutical composition comprising:

[0033] In one embodiment, the pharmaceutical composition comprises: a. About 8 mg / mL to about 20 mg / mL of maralixibat; b. about 330 mg / mL to about 380 mg / mL propylene glycol; c. approximately 1 mg / mL disodium EDTA; d. sweeteners, taste-masking ingredients, or combinations thereof; and e.Water Includes.

[0034] In one embodiment, maralixibat is present as maralixibat chloride.

[0035] In one embodiment, the pharmaceutical composition further comprises a second therapeutic agent.

[0036] In one embodiment, the second therapeutic agent is ursodeoxycholic acid (UDCA), rifampicin, an antihistamine, or an FXR-targeted drug.

[0037] In another aspect, the present invention provides a pharmaceutical dosage form for oral administration comprising the pharmaceutical composition of any of the above embodiments.

[0038] In another aspect, the invention provides a method of treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of any of the above embodiments.

[0039] In one embodiment, the pediatric cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome (ALGS), biliary atresia (BA), post-Kasai operation biliary atresia, post-liver transplant biliary atresia, Dubin-Johnson syndrome, post-liver transplant cholestasis, post-liver transplant-associated liver disease, intestinal failure-associated liver disease, bile acid-mediated liver injury, or pediatric primary sclerosing cholangitis. (PSC), MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric biliary obstructive cholestasis, pediatric non-biliary obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis.

[0040] In one embodiment, the pediatric cholestatic liver disease is PFIC, ALGS, BA, or pediatric PSC.

[0041] In one embodiment, the pediatric cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, elevated serum concentrations of bile acids, elevated intrahepatic concentrations of bile acids, elevated serum concentrations of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, characteristic odor, dark urine, light stools, steatorrhea, failure to thrive, and renal failure.

[0042] In another aspect, the invention provides a method of treating or ameliorating pruritus, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of any of the above-described embodiments.

[0043] In another aspect, the invention provides a method of treating or ameliorating hyperbiliary acidemia, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of any of the above-described embodiments.

[0044] In another aspect, the present invention provides a method of treating or ameliorating xanthomas, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition or pharmaceutical dosage form of any of the above-described embodiments.

[0045] In another aspect, the invention provides a method of reducing serum or intrahepatic bile levels in a subject, comprising administering to the pediatric subject a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of any of the above embodiments.

[0046] In one embodiment of any of the above methods, the pediatric subject is between 6 months and 18 years of age.

[0047] In one embodiment of any of the above methods, the method further comprises administering a second therapeutic agent.

[0048] In one embodiment, the second therapeutic agent is UDCA, rifampicin, an antihistamine, an FXR targeted drug, or a combination thereof.

[0049] In one embodiment, the second therapeutic agent is administered in a subclinical therapeutically effective amount.

[0050] In yet another aspect, the present invention provides a method of treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of the pharmaceutical composition or pharmaceutical dosage form of any of the above embodiments in combination with a subclinical therapeutically effective amount of a second therapeutic agent selected from the group consisting of UDCA, rifampicin, an antihistamine, and an FXR targeted drug.

[0051] In one embodiment, the subclinical therapeutically effective amount of the second therapeutic agent is at least 10% less than the amount of the second therapeutic agent administered as monotherapy, hi one embodiment, the subclinical therapeutically effective amount of the second therapeutic agent is at least 20% less than the amount of the second therapeutic agent administered as monotherapy.

[0052] In one embodiment, the second therapeutic agent is a PPAR agonist, hi one embodiment, the PPAR agonist is selected from bezafibrate, seladelpar (MBX-8025), GW501516 (cardarine), fenofibrate, elafibranor, REN001, KD3010, ASP0367, and CER-002.

[0053] In one embodiment, the PPAR agonist is a PPARδ agonist. In one embodiment, the PPARδ agonist is selected from seladelpar (MBX-8025), REN001, KD3010, ASP0367, and CER-002.

[0054] In yet another aspect, the present invention provides a method of treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of maralixibat in combination with a therapeutically effective amount of a PPAR agonist.

[0055] In one embodiment, the PPAR agonist is selected from bezafibrate, seladelpar (MBX-8025), GW501516 (cardarine), fenofibrate, elafibranor, REN001, KD3010, ASP0367, and CER-002.

[0056] In one embodiment, the PPAR agonist is a PPARδ agonist. In one embodiment, the PPARδ agonist is selected from seladelpar (MBX-8025), REN001, KD3010, ASP0367, and CER-002.

[0057] In one embodiment, the pediatric cholestatic liver disease is sclerosing cholangitis.

[0058] In one embodiment, said pediatric cholestatic liver disease is selected from PSC and PBC.

[0059] These and other aspects of the present invention will become apparent to those skilled in the art upon reading the following detailed description of the invention, including the appended claims.

[0060] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with one or more color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0061] [Figure 1] FIG. 1 is a plot of the stability of maralixibat oral solution at 25° C. and 60% relative humidity (RH). [Figure 2] FIG. 2 is a plot of the effect of disodium EDTA dihydrate concentration on the level of the oxidative impurity desmethylmaralixibat chloride in maralixibat oral solution at 25° C. and 40° C. [Figure 3A] Figures 3A-3E are plots of ItchRO versus dose of maralixibat (MRX) and selected antipruritic agents for five exemplary PFIC patients enrolled in the LUM001-501 study. Figure 3A shows that patients maintained excellent pruritus control even after discontinuing rifampicin (Rif) and UDCA (Urso). [Figure 3B]FIG. 3B shows that the patient maintained excellent pruritus control even after discontinuing rifampicin (Rif). [Figure 3C] FIG. 3C shows that the patient maintained excellent pruritus control even after discontinuing rifampicin (Rif). [Figure 3D] FIG. 3D shows that the patient maintained control of pruritus even after discontinuing UDCA (Urso). [Figure 3E] FIG. 3E shows that the patient maintained control of pruritus even after discontinuing UDCA (Urso). [Figure 4] Figure 4 shows the mean hepatic and serum bile acid, ALT, total bilirubin, and ALP concentrations relative to the mean in vehicle-treated MDR2- / - mice. One-way ANOVA was applied to determine differences between treatment groups and the "vehicle control"; ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05. DETAILED DESCRIPTION OF THE INVENTION

[0062] Although detailed embodiments of the present invention are disclosed herein, it should be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Furthermore, the examples given in connection with various embodiments of the present invention are intended to be illustrative, not limiting. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but rather as a representative basis for teaching those skilled in the art how the present invention may be variously used.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0064] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods and / or steps of the type described herein and / or which will become apparent to those skilled in the art upon reading this disclosure.

[0065] The terms "treat" or "treatment" with respect to a condition, disorder, or condition: (1) preventing, delaying, or reducing the incidence of at least one clinical or subclinical symptom of said condition, disorder, or condition in a subject who may be suffering from said condition, disorder, or condition, and / or the likelihood of at least one clinical or subclinical symptom of said condition, disorder, or condition in a subject who may be predisposed to said condition, disorder, or condition but who has not yet experienced or developed a clinical or subclinical symptom of said condition, disorder, or condition; or (2) arresting said condition, disorder, or condition, i.e., preventing, reducing, or delaying the onset or recurrence of the disease or at least one clinical or subclinical symptom thereof; or (3) ameliorating the disease, i.e., regressing said condition, disorder, or condition, or at least one clinical or subclinical symptom thereof. The benefit to the subject being treated is statistically significant or at least discernible by the patient or physician.

[0066] As used herein, "subject," or "patient," or "individual," or "animal" refers to humans, domestic animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of disease (e.g., mice, rats). In a preferred embodiment, the subject is a human.

[0067] As used herein, the term "effective" as applied to dose or amount refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity when administered to a subject in need thereof. It should be noted that when a combination of multiple active ingredients is administered, the effective amount of the combination may or may not include the amount of each ingredient that was effective when administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular agent(s) employed, the mode of administration, etc.

[0068] The phrase "pharmaceutically acceptable," when used in connection with a composition of the present invention, refers to molecular entities and other components of the composition that are physiologically tolerable and do not normally produce adverse reactions upon administration to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, more particularly humans.

[0069] Ranges may be expressed herein as "about" or "approximately" from one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. As used herein, the terms "about" or "approximately" in connection with any numerical value or range indicate an appropriate tolerance that allows the portion or collection of components to function for its desired purpose as described herein. More specifically, "about" or "approximately" may refer to a range of values ​​±20% of the stated value; for example, "about 90%" may refer to a range of values ​​from 71% to 99%.

[0070] "Comprising" or "containing" or "including" means that the composition or article or method has at least the recited compound, element, particle, or method step present, but does not exclude the presence of other compounds, materials, particles, or method steps, even if such other compounds, materials, particles, or method steps have the same function as the recited one.

[0071] The compounds of the present invention include those described throughout the present specification and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75th Ed.). Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the contents of which are incorporated herein by reference in their entirety.

[0072] It should also be understood that a reference to one or more method steps does not exclude the presence of additional or intervening method steps between the steps explicitly identified. Similarly, it should also be understood that a reference to one or more components of a device or system does not exclude the presence of additional or intervening components between the components explicitly identified.

[0073] Unless otherwise specified, all crystalline forms of the compounds of the present invention and their salts are also within the scope of the present invention. The compounds of the present invention can be isolated in various amorphous and crystalline forms, including, but not limited to, anhydrous, hydrated, non-solvated, or solvated forms. Exemplary hydrates include hemihydrates, monohydrates, dihydrates, and the like. In some embodiments, the compounds of the present invention are anhydrous and unsolvated. "Anhydrous" means that the crystalline form of the compound is substantially free of bound water within the crystal lattice structure, i.e., the compound does not form crystalline hydrates.

[0074] As used herein, "crystalline form" is intended to refer to a particular lattice structure of a crystalline material. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) due to the different physical properties characteristic of each crystalline form. In some cases, the different lattice structures have different water or solvent contents. These different crystal lattices can be identified by solid-state characterization methods such as powder X-ray diffraction (PXRD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state NMR, etc., can further help identify crystalline forms and also determine stability and solvent / water content.

[0075] Crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that contain water within the crystal lattice. Hydrated forms may be stoichiometric hydrates, in which water is present in the lattice at a specific water / molecule ratio, such as for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms may also be non-stoichiometric, in which the water content is variable and dependent on external conditions such as humidity.

[0076] In some embodiments, the compounds of the present invention are substantially isolated. "Substantially isolated" means that a particular compound is at least partially isolated from impurities. For example, in some embodiments, the compounds of the present invention contain less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include anything that is not a substantially isolated compound, such as other crystalline forms and other substances.

[0077] The term "baseline" or "pre-administration baseline," as used herein, refers to information collected at the beginning of a study or a known value used to compare subsequent data. A baseline is an initial measurement of a measurable condition obtained at an early time point and used for comparison over time to look for changes in the measurable condition. For example, a patient's serum bile acid concentration before administration of a drug (baseline) and after administration of the drug. A baseline is an observation or value representing the normal or initial level of a measurable quality, which is used for comparison with values ​​representing a response to an intervention or environmental stimulus. A baseline is a "zero" time point before study participants receive an experimental agent or intervention, or a negative control. For example, "baseline" can refer, in some instances, to: 1) the state of the measurable quality immediately prior to the start of a clinical study; or 2) the state of the measurable quality immediately prior to changing the dosage level or composition administered to a patient from a first dosage level or composition to a second dosage level or composition.

[0078] The terms "level" and "concentration" are used interchangeably herein. For example, "high serum level of bilirubin" can be rephrased as "high serum concentration of bilirubin."

[0079] The terms "normalized" or "normal range," as used herein, refer to age-specific values ​​(i.e., normal or normalized values) that fall within a range corresponding to a healthy individual. For example, the phrase "serum bilirubin concentration normalized within 3 weeks" means that the serum bilirubin concentration fell within a range known in the art to correspond to that of a healthy individual (i.e., a normal, e.g., not elevated, range) within 3 weeks. In various embodiments, a normalized serum bilirubin concentration is between about 0.1 mg / dL and about 1.2 mg / dL. In various embodiments, a normalized serum bile acid concentration is between about 0 μmol / L and about 25 μmol / L.

[0080] As used herein, the terms "ITCHRO(OBS)" and "ITCHRO" (or "ItchRO(Pt)") are used interchangeably, provided that the ITCHRO(OBS) scale is used to measure the severity of itch in children under 18 years of age, and the ITCHRO scale is used to measure the severity of itch in adults at least 18 years of age. Thus, when the ITCHRO(OBS) scale is referred to in relation to adult patients, the scale referred to is the ITCHRO scale. Similarly, when the ITCHRO scale is referred to in relation to pediatric patients, the scale referred to is often the ITCHRO(OBS) scale (although some older children have been permitted to report their scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[0081] As used herein, the term "bile acid" or "bile acids" includes steroid acids (and / or their carboxylate anions) and salts thereof found in animal (e.g., human) bile, including, but not limited to, cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid (UDCA), ursodiol, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-β-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and / or taurocholate are referred to herein as TCAs. As used herein, any reference to a bile acid includes a reference to a bile acid, a single bile acid, one or more bile acids, or at least one bile acid. Thus, the terms "bile acid," "bile salt," and "bile acid / bile salt" are used interchangeably herein unless otherwise indicated. Any reference to a bile acid as used herein includes a reference to a bile acid or its salt. Additionally, the term "bile acid" as used herein optionally refers to a pharmaceutically acceptable bile acid ester, such as a bile acid / bile salt conjugated with an amino acid (e.g., glycine or taurine). Other bile acid esters include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, or substituted or unsubstituted heteroaryl esters. For example, the term "bile acid" includes cholic acid conjugated with glycine or taurine: glycocholate and taurocholate (and salts thereof), respectively. Any reference to a bile acid as used herein includes a reference to the same compound, whether naturally occurring or synthetically prepared. Furthermore, it should be understood that any singular reference to a component (bile acid or otherwise) as used herein includes a reference to only one, more than one, or at least one such component.Similarly, any plural reference to an ingredient as used herein includes a reference to only one, one or more, or at least one such ingredient unless otherwise noted.

[0082] As used herein, the term "composition" includes disclosure of both a composition and a composition administered in a manner described herein. Furthermore, in some embodiments, a composition of the invention is or comprises a "formulation," an oral dosage form, or a rectal dosage form described herein.

[0083] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of at least one agent (e.g., a therapeutically active agent) administered that is sufficient to achieve a desired result in a subject or individual, e.g., relieve to some extent one or more symptoms of the disease or condition being treated. In certain instances, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or some other desired alteration of a biological system. In certain instances, an "effective amount" for therapeutic use is the amount of a composition comprising an agent described herein that is necessary to provide a clinically significant reduction in the disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" or "effective amount" of ASBTI refers to an amount of ASBTI sufficient to treat cholestasis or cholestatic liver disease in a subject or individual.

[0084] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of an agent or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Administration techniques optionally employed with the agents and methods described herein are identified in sources such as Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa., all of which are incorporated by reference in their entirety into this application for all purposes. In certain embodiments, the agents and compositions described herein are administered orally.

[0085] The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile acid transport or any restorable bile salt transport. The term "apical sodium-dependent bile acid transporter (ASBT)" is used interchangeably with the term "ileal bile acid transporter (IBAT)."

[0086] bile acids Bile contains water, electrolytes, and numerous organic molecules, including bile acids, cholesterol, phospholipids, and bilirubin. It is secreted from the liver and stored in the gallbladder. When the gallbladder contracts due to the ingestion of a fatty meal, bile enters the intestine through the bile duct. Bile acids / bile salts are important for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400–800 mL of bile per day. Bile secretion can be thought of as occurring in two stages. First, hepatocytes secrete bile into the canaliculi, which then flow into the bile ducts. This hepatic bile contains large amounts of bile acids, cholesterol, and other organic molecules. Second, as bile flows through the bile ducts, it is modified by the addition of aqueous, bicarbonate-rich secretions from bile duct epithelial cells. Bile typically becomes fivefold concentrated during storage in the gallbladder.

[0087] Bile flow is lowest during fasting, with most of it being diverted to the gallbladder for concentration. When chyme from a ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, which are important for bile secretion and flow. Cholecystokinin (cholecysto = gallbladder, kinin = movement) is a hormone that stimulates contraction of the gallbladder and common bile duct, causing bile to be delivered into the intestine. The most potent stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Selectin is a hormone secreted in response to acid in the duodenum, stimulating cholangiocytes to secrete bicarbonate and water, increasing bile volume and increasing bile flow into the intestine.

[0088] Bile acids / bile salts are derivatives of cholesterol. Cholesterol ingested as part of the diet or derived from liver synthesis is converted into bile acids / bile salts in liver cells. Examples of such bile acids / bile salts include cholic acid and chenodeoxycholic acid, which are then conjugated with amino acids (such as glycine or taurine) to form conjugated forms that are actively secreted into the canaliculi. The most abundant bile salts in the human body are cholate and deoxycholate, which are usually conjugated with glycine or taurine to form glycocholate or taurocholate, respectively.

[0089] Free cholesterol is virtually insoluble in aqueous solutions, but becomes soluble in bile due to the presence of bile acids / bile salts and lipids. Hepatic synthesis of bile acids / bile salts accounts for the majority of cholesterol degradation in the body. In humans, approximately 500 mg of cholesterol is converted into bile acids / bile salts daily and excreted in bile. Therefore, secretion into bile is the primary route of cholesterol excretion. Although a large amount of bile acids / bile salts is secreted into the intestine every day, only a relatively small amount is lost from the body. This is because approximately 95% of bile acids / bile salts delivered to the duodenum are reabsorbed into the blood in the ileum by a process known as "enterohepatic recirculation."

[0090] Venous blood from the ileum enters the portal vein directly and passes through the hepatic sinusoids. Hepatocytes extract bile acids / bile salts from sinusoidal blood very efficiently, with little spillage into the systemic circulation from a healthy liver. Bile acids / bile salts are then transported through hepatocytes and re-secreted into the canaliculi. The net effect of this enterohepatic recycling is that each bile salt molecule is reused approximately 20 times during a single digestive process, often two or three times. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for over half of the approximately 800 mg / day of cholesterol consumed by the average adult for metabolic processes. In comparison, steroid hormone biosynthesis consumes only approximately 50 mg of cholesterol per day. Much more than 400 mg of bile salts are required and secreted into the intestine daily, achieved through bile salt recycling. Most bile salts secreted into the upper region of the small intestine are absorbed with emulsified dietary lipids at the lower end of the small intestine. These are separated from dietary lipids and returned to the liver for reuse, thus recycling 20-30 g of bile salts into the small intestine each day.

[0091] Bile acids / bile salts are amphiphilic; the cholesterol-derived moiety contains both hydrophobic (lipid-soluble) and polar (hydrophilic) moieties, while amino acid conjugates are generally polar and hydrophilic. This amphiphilicity allows bile acids / bile salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids in aqueous environments. Bile acids / bile salts have a detergent effect on dietary lipid particles, causing the disruption or emulsification of lipid droplets. Emulsification is important because it significantly increases the surface area of ​​fat available for digestion by lipases that cannot access the interior of lipid droplets. Furthermore, bile acids / bile salts are lipid carriers and can solubilize many lipids by forming micelles, which are important for the transport and absorption of fat-soluble vitamins.

[0092] As used herein, the terms "non-systemic" or "minimally absorbed" refer to low systemic bioavailability and / or absorption of an administered compound. In some embodiments, a non-systemic compound is a compound that is not substantially systemically absorbed. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the distal ileum, large intestine, and / or rectum rather than systemically (e.g., a substantial portion of ASBTI is not systemically absorbed). In some embodiments, the systemic absorption of the non-systemic compound is less than 0.1%, less than 0.3%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1%, less than 1.5%, less than 2%, less than 3%, or less than 5% (wt % or mol %) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 10% of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 15% of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 25% of the administered dose. In an alternative approach, the non-systemic ASBTI is a compound that has a low systemic bioavailability relative to the systemic bioavailability of a systemic ASBTI (e.g., Compounds 100A, 100C). In some embodiments, the systemic bioavailability of the non-systemic ASBTI described herein is less than 30%, less than 40%, less than 50%, less than 60%, or less than 70% of the systemic bioavailability of a systemic ASBTI (e.g., Compounds 100A, 100C).

[0093] In another alternative approach, the compositions described herein are formulated to systemically deliver less than 10% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 20% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 30% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 40% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 50% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 60% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 70% of the administered dose of ASBTI. In some embodiments, systemic absorption is determined by any suitable method, including total circulating amount or amount cleared after administration, etc.

[0094] ASBTI In one embodiment, the compositions of the present invention include ASBTI as the active agent. A variety of ASBTIs are suitable for use in combination with the compositions of the present disclosure.

[0095] In some embodiments, the ASBTI is: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is maralixibat or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is maralixibat chloride or another pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is vorixibat or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is odebixibat or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is elobixibat or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0096] In various embodiments, the ASBTI can be the free base or a pharmaceutically acceptable salt of a compound disclosed herein.

[0097] In some embodiments, the ASBTI is [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the ASBTI is [ka] (maralixibat chloride, LUM-001, SHP625, lopixibat chloride), or another pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the ASBTI is [ka] (vorixibat, (2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate), or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the ASBTI is [ka] (LUM-002; SHP626; SAR548304; vorixibat potassium), or another pharmaceutically acceptable salt thereof.

[0101] In various embodiments, the ASBTI is: [ka] (odevixibat; AZD8294; WHO10706; AR-H064974; SCHEMBL946468; A4250; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine), or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the ASBTI is [ka] (elobixibat; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,5-benzothiazepin-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid), or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the ASBTI is [ka] (GSK2330672; Linelixibat; 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid), or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the ASBTI described herein is synthesized as described, for example, in WO 96 / 05188, U.S. Pat. No. 5,994,391, U.S. Pat. No. 7,238,684, U.S. Pat. No. 6,906,058, U.S. Pat. No. 6,020,330, and U.S. Pat. No. 6,114,322.

[0105] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat (SHP625), vorixibat (SHP626), or odevixibat (A4250), or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat chloride.

[0107] In some embodiments, the ASBTI used in the methods or compositions of the invention is vorixibat, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the ASBTI used in the methods or compositions of the present invention is odevixibat, or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the ASBTI used in the methods or compositions of the invention is elobixibat, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the ASBTI used in the methods or compositions of the invention is GSK2330672, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the ASBTI may comprise a mixture of different ASBTIs, for example, the ASBTI may be a composition comprising maralixibat (e.g., maralixibat chloride), vorixibat, odebixibat, GSK2330672, elobixibat, or various combinations thereof.

[0112] Pediatric dosage formulations and compositions Provided herein, in certain embodiments, are pediatric dosage formulations or compositions comprising a therapeutically effective amount of any of the compounds described herein. In certain examples, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any of the ASBTIs described herein), a preservative, and an antioxidant.

[0113] preservatives In certain embodiments, the compositions of the present invention comprise a preservative, hi certain embodiments, the preservative is an antimicrobial preservative.

[0114] In certain embodiments, the antimicrobial preservative is selected from the group consisting of propylene glycol, ethyl alcohol, glycerin, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimide (cetyltrimethylammonium bromide), cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof.

[0115] In certain embodiments, the preservative is propylene glycol.

[0116] In certain embodiments, the preservative is present in an amount of at least about 10% by weight of the composition. In certain embodiments, the preservative is present in an amount of at least about 20% by weight of the composition. In certain embodiments, the preservative is present in an amount of at least about 25% by weight of the composition. In certain embodiments, the preservative is present in an amount of at least about 30% by weight of the composition.

[0117] In certain embodiments, the preservative is present in an amount of about 30% to about 40% of the composition.

[0118] In certain embodiments, the preservative is present in an amount of about 32% to about 37% of the composition, hi certain embodiments, the preservative is present in an amount of about 33% to about 36% of the composition.

[0119] In certain embodiments, the preservative is present in an amount of about 33% of the composition, in certain embodiments, about 34% of the composition, and in certain embodiments, about 35% of the composition.

[0120] antioxidants In certain embodiments, the compositions of the present invention comprise an antioxidant selected from the group consisting of aminocarboxylic acids, aminopolycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, and combinations thereof.

[0121] In certain embodiments, the antioxidant is an aminopolycarboxylic acid selected from EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), NTA (nitrilotriacetic acid), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), NOTA (2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid), DOTA (tetracarboxylic acid), and EDDHA (ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid).

[0122] In certain embodiments, the antioxidant is EDTA.

[0123] In certain embodiments, the antioxidant is present in an amount of about 0.001% to about 1% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.005% to about 0.75% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.01% to about 0.5% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.05% to about 0.25% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.075% to about 0.2% w / w of the composition. In certain embodiments, the antioxidant is present in an amount of about 0.1% w / w of the composition.

[0124] In certain embodiments, dosage forms suitable for pediatric dosage formulations or compositions include liquid dosage forms. Non-limiting examples of liquid dosage forms include: aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, and solutions; controlled-release formulations; sustained-release formulations; and immediate-release formulations. In some embodiments, provided herein are pharmaceutical compositions wherein the pediatric dosage form is selected from a solution, syrup, suspension, and elixir.

[0125] In another aspect, provided herein is a composition comprising a composition comprising at least one excipient fragrance or sweeteners. In some embodiments, provided herein are coatings. In some embodiments, provided herein are taste-masking techniques selected from: coating drug particles with bland-tasting polymers by spray drying, wet granulation, fluidized bed, and microencapsulation; coating a mixture of molten wax and other pharmaceutical adjuvants with molten wax; entrapment of drug particles by complexation, coagulation, or solidification of aqueous polymer dispersions; adsorption of drug particles onto resins and inorganic supports; and solid dispersions in which a drug and one or more bland-tasting compounds are melted and cooled or co-precipitated by solvent evaporation. In some embodiments, provided herein are delayed- or sustained-release formulations comprising drug particles or granules in a rate-controlling polymer or matrix.

[0126] Suitable sweeteners include sucrose, glucose, fructose, or high-intensity sweeteners, i.e., agents with a sweetness greater than that of sucrose (e.g., at least 10 times sweeter than sucrose). Suitable high-intensity sweeteners include aspartame, saccharin, sodium, potassium, or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neotame, neohesperidin dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, and Magnasweet®. The total concentration of the sweetener may range from substantially 0 mg / mL to about 300 mg / mL based on the liquid composition.

[0127] To enhance the palatability of the liquid composition upon reconstitution with an aqueous medium, one or more taste-masking agents may be added to the composition to mask the taste of the ASBT inhibitor. Taste-masking agents include sweeteners, fragrance or a combination thereof. The taste-masking agent is typically about 0.1% or 5% by weight of the total pharmaceutical composition. In certain preferred embodiments of the present invention, the composition comprises one or more sweeteners and one or more fragrance Contains both.

[0128] In this specification fragrance is a substance capable of enhancing the taste or aroma of the composition. Suitable natural or synthetic fragrance can be selected from standard reference books, such as Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). fragranceAnd / or sweeteners, non-limiting examples include acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid salt, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime , lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, ciritol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any of these flavors. Fee Any combination of ingredients may be used, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. fragrance In some embodiments, the composition comprises a sweetener or a saccharide in a concentration of about 0.001% to about 5.0% by volume of the composition. fragranceIn one embodiment, the composition comprises a sweetener or a mixture thereof at a concentration of about 0.001% to about 1.0% by volume of the aqueous dispersion. fragrance In another embodiment, the composition comprises a sweetener or a syrup at a concentration of about 0.002% to about 0.5% by volume of the composition. fragrance In yet another embodiment, the composition comprises a sweetener or fragrance In yet another embodiment, the composition comprises a sweetener or a syrup at a concentration of about 0.005% to about 0.1% by volume of the composition. fragrance Includes.

[0129] In certain embodiments, pediatric pharmaceutical compositions described herein comprise one or more compounds described herein as the active ingredient, in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are utilized as N-oxides or in crystalline or amorphous form (i.e., polymorphs). In some situations, the compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in unsolvated or solvated form, where solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be presented herein.

[0130] "Carriers" for pediatric pharmaceutical compositions, in some embodiments, include pharmaceutically acceptable excipients, selected based on compatibility with the compounds described herein, such as ASBTI, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference in their entireties for all purposes.

[0131] Additionally, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated as dosage forms. Thus, in some embodiments, provided herein are dosage forms suitable for administration to an individual, comprising a compound described herein. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, liquid oral dosage forms, controlled release formulations, immediate release formulations, delayed release formulations, extended release formulations, sustained release formulations, pulsed release formulations, and mixtures of immediate release and controlled release formulations.

[0132] In some embodiments, ASBTI or other compounds described herein are administered orally in association with a carrier suitable for delivery to the distal gastrointestinal tract (eg, the distal ileum, colon, and / or rectum).

[0133] In certain embodiments, pediatric compositions described herein comprise an ASBTI or other compound described herein associated with a matrix (e.g., a matrix comprising hypromellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or colon. In some embodiments, the composition comprises a pH-sensitive polymer (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain acidic groups (e.g., —COOH, —SO3H) and swell at basic pHs in the intestine (e.g., a pH of about 7 to about 8). In some embodiments, compositions suitable for controlled release in the distal ileum comprise a microparticulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable poly(dl-lactide-co-glycoside) (PLGA) core is suitable for delivery of enteroendocrine peptide secretagogues to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretagogues are coated with an enteric polymer (e.g., Eudragit® S-100; cellulose acetate phthalate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; anionic polymers such as methacrylic acid or methacrylic acid esters) for site-specific delivery to the distal ileum and / or colon. In some embodiments, bacterially activated systems are suitable for targeted delivery to the distal portion of the ileum. Examples of bacterial flora-activated systems include dosage forms containing pectin, galactomannan, and / or azohydrogel and / or glycoside conjugates (e.g., D-galactosides or β-D-xylopyranosides) of active agents. Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, or β-D-xylopyranosidase.

[0134] The pediatric pharmaceutical compositions described herein optionally contain an additional therapeutic compound described herein, and one or more pharmaceutically acceptable excipients, such as compatible carriers, binders, fillers, suspending agents, fragrance , sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof.

[0135] Liquid dosage form The pharmaceutical liquid dosage forms of the present invention can be prepared according to techniques known in the pharmaceutical art.

[0136] "Solution" refers to a liquid pharmaceutical preparation in which the active ingredient is dissolved in a liquid. Pharmaceutical solutions of the present invention include syrups and elixirs. "Suspension" refers to a liquid pharmaceutical preparation in which the active ingredient is a precipitate in a liquid.

[0137] It is desirable for a liquid dosage form to have a certain pH and / or to be maintained within a certain pH range. A suitable buffer system can be used to control the pH. Furthermore, the buffer system must have sufficient capacity to maintain the desired pH range. Examples of buffer systems that can be used in the present invention include, but are not limited to, citrate buffer, phosphate buffer, or any other suitable buffer known in the art. Preferably, the buffer system includes sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. The concentration of the buffer system in the final suspension will vary depending on factors such as the strength and pH range of the buffer system required for the liquid dosage form. In one embodiment, the concentration is within the range of 0.005-0.5 w / v% of the final liquid dosage form.

[0138] The pharmaceutical compositions comprising the liquid dosage forms of the present invention may also contain suspending / stabilizing agents to prevent settling of the active ingredients. Over time, settling can cause the active ingredients to stick to the inner walls of the product pack, making redispersion and accurate dispensing difficult. Suitable stabilizers include, but are not limited to, polysaccharide stabilizers such as xanthan gum, guar gum, and tragacanth gum, as well as cellulose derivatives HPMC (hydroxypropylmethylcellulose), methylcellulose, and Avicel RC-591 (microcrystalline cellulose / sodium carboxymethylcellulose). In another embodiment, polyvinylpyrrolidone (PVP) can also be used as a stabilizer.

[0139] In addition to the components described above, the ASBTI oral composition may optionally contain other excipients commonly found in pharmaceutical compositions, such as additional solvents, taste-masking agents, antioxidants, bulking agents, acidifying agents, enzyme inhibitors, and other ingredients described in Handbook of Pharmaceutical Excipients, Rowe et al., Eds., 4th Edition, Pharmaceutical Press (2003), which is incorporated herein by reference in its entirety for all purposes.

[0140] The addition of another solvent can help improve the solubility of the active ingredient in the liquid dosage form, and therefore its absorption and bioavailability in the subject's body. Preferably, the other solvent includes methanol, ethanol, or propylene glycol.

[0141] In another aspect, the present invention provides a process for preparing a liquid dosage form. The process comprises mixing ASBTI or a pharmaceutically acceptable salt thereof with ingredients including glycerol or syrup or a mixture thereof, preservatives, a buffer system, and suspending / stabilizing agents in a liquid medium. Generally, the liquid dosage form is prepared by uniformly and thoroughly mixing these various ingredients in the liquid medium. For example, ingredients such as glycerol or syrup or a mixture thereof, preservatives, a buffer system, and suspending / stabilizing agents can be dissolved in water to form an aqueous solution, and the active ingredient can then be dispersed in the aqueous solution to form a suspension.

[0142] In some embodiments, the volume of the liquid dosage forms provided herein can be from about 0.001 ml to about 50 ml. In some embodiments, the volume of the liquid dosage forms provided herein can be from about 0.01 ml to about 20 ml. In some embodiments, the volume of the liquid dosage forms provided herein can be from about 0.05 ml to about 10 ml. In some embodiments, the volume of the liquid dosage forms provided herein can be from about 0.1 ml to about 5 ml. In some embodiments, the volume of the liquid dosage forms provided herein can be from about 0.1 ml to about 3 ml.

[0143] In some embodiments, the volume of the liquid dosage forms provided herein can be about 0.1 ml, or about 0.15 ml, or about 0.2 ml, or about 0.25 ml, or about 0.3 ml, or about 0.35 ml, or about 0.4 ml, or about 0.45 ml, or about 0.5 ml, or about 0.55 ml, or about 0.6 ml, or about 0.65 ml, or about 0.7 ml, or about 0.75 ml, or about 0.8 ml, or about 0.85 ml, or about 0.9 ml, or about 0.95 ml, or about 1.00 ml, or about 1.05 ml, or about 1.1 ml, or about 1.2 ml, or about 1.25 ml, or about 1.5 ml, or about 1.75 ml, or about 2.00 ml, or about 2.25 ml, or about 2.5 ml, or about 2.75 ml, or about 3.00 ml.

[0144] In some embodiments, the amount of ASBTI can be in the range of about 0.001% to about 90% of the total volume. In some embodiments, the amount of ASBTI can be in the range of about 0.01% to about 80% of the total volume. In some embodiments, the amount of ASBTI can be in the range of about 0.1% to about 50% of the total volume. In some embodiments, the amount of ASBTI can be in the range of about 0.2% to about 25% of the total volume. In some embodiments, the amount of ASBTI can be in the range of about 0.5% to about 10% of the total volume. In some embodiments, the amount of ASBTI can be in the range of about 0.5% to about 5% of the total volume.

[0145] In one embodiment, the liquid volume of the compositions described herein can be from about 0.01 ml to about 50 ml, or from about 0.1 ml to about 5 ml, and the amount of active ingredient (e.g., maralixibat) can be from about 0.001 mg / ml to about 500 mg / ml, or from about 0.5 mg / ml to about 100 mg / ml, or from about 1 mg / ml to about 80 mg / ml, or from about 5 mg / ml to about 50 mg / ml, or about 5 mg / ml, or about 9.5 mg / ml, or about 10 mg / ml, or about 15 mg / ml, or about 20 mg / ml, or about 25 mg / ml, or about 30 mg / ml, or about 35 mg / ml, or about 40 mg / ml, or about 50 mg / ml.

[0146] In one non-limiting embodiment, the concentration of maralixibat in the composition is 10 mg / ml based on maralixibat chloride.

[0147] In one non-limiting embodiment, the concentration of maralixibat in the composition is 9.5 mg / ml based on maralixibat free base.

[0148] In certain embodiments, the compositions described herein are stable at room temperature for at least one month. In certain embodiments, the compositions described herein are stable at room temperature for at least two months. In certain embodiments, the compositions described herein are stable at room temperature for at least three months. In certain embodiments, the compositions described herein are stable at room temperature for at least six months. In one embodiment, the compositions are stable at room temperature for at least one year. In one embodiment, the compositions are stable at room temperature for at least 18 months. In one embodiment, the compositions are stable at room temperature for at least two years.

[0149] In certain embodiments, the compositions described herein are liquid compositions for oral administration.

[0150] Route of Administration, Dosage Forms, and Dosage Regimen In some embodiments, the compositions described herein and compositions administered in the methods described herein are formulated to inhibit bile acid reuptake or reduce serum or hepatic bile acid levels. In certain embodiments, the compositions described herein are formulated for oral administration. In some embodiments, the formulations are administered orally. In some embodiments, the compositions described herein are formulated for oral administration and enteral delivery to the colon.

[0151] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, but not systemically (e.g., the majority of the enteroendocrine peptide secretagogue is not absorbed systemically). In some embodiments, the oral compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, but not systemically (e.g., the majority of the enteroendocrine peptide secretagogue is not absorbed systemically).

[0152] In certain embodiments, the non-systemic compositions described herein deliver less than 90 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 80 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 70 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 60 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 50 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 40 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 30 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 25 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 20 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 15 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 10 wt% of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 5 wt% of ASBTI systemically. In some embodiments, systemic absorption is determined by any suitable method, including total circulating amount or amount cleared after administration, etc.

[0153] In certain embodiments, the compositions and / or formulations described herein are administered at least once daily. In certain embodiments, the formulations containing ASBTI are administered at least twice daily, while in other embodiments, the formulations containing ASBTI are administered at least three times daily. In certain embodiments, the formulations containing ASBTI are administered up to five times daily. It should be understood that in certain embodiments, the dosing regimen for the compositions containing ASBTI described herein will be determined taking into account various factors, such as the patient's age, sex, and diet.

[0154] The concentration of ASBTI administered in the formulations described herein is about 0.1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 1 mM to about 250 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 5 mM to about 100 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 7 mM to about 70 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is about 7 mM, or about 10 mM, or about 15 mM, or about 20 mM, or about 25 mM, or about 30 mM, or about 40 mM, or about 50 mM, or about 60 mM, or about 70 mM.

[0155] In certain embodiments, by targeting the distal gastrointestinal tract (e.g., the distal ileum, colon, and / or rectum), the compositions and methods described herein provide efficacy (e.g., in reducing microbial growth and / or alleviating symptoms of cholestasis or cholestatic liver disease) at lower doses of enteroendocrine peptide secretagogues (e.g., compared to oral doses that do not target the distal gastrointestinal tract).

[0156] In certain embodiments of the present disclosure, the effective amount of a given agent will vary depending on one or more of a number of factors, such as the particular compound, the disease or condition and its severity, the individual characteristics of the subject or host requiring treatment (e.g., weight), and will be determined depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In some embodiments, the administered dose includes a dose up to the maximum tolerated dose. In some embodiments, the administered dose includes a dose up to the maximum tolerated dose for a newborn or infant.

[0157] In various embodiments of the present disclosure, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously (or closely spaced) or at appropriate intervals, for example, two, three, four, or more sub-doses per day. In various embodiments, a single dose of ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or once a week. In some embodiments, the total single dose of ASBTI is within the ranges described below.

[0158] In various embodiments of the present disclosure, if the patient's condition improves, optionally at the physician's discretion, the ASBTI may be continued or the dose of the administered drug may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year, and may include, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The duration of the drug holiday may vary from 2 days to 1 year, and may be, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Agent reductions include 10% to 100% of the original dose, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the original dose. In some embodiments, the total single dose of ASBTI is within the ranges set forth below.

[0159] After improvement in the patient's condition has occurred, maintenance doses are administered as needed. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, upon any recurrence of symptoms, the patient will require intermittent treatment on a long-term basis.

[0160] In certain instances, there are many variables regarding individual treatment regimens, and significant deviations from these recommendations are contemplated within the ranges set forth herein. The dosages set forth herein are subject to change depending upon many variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0161] The toxicity and efficacy of such treatment regimens are 50 (lethal dose for 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the dose therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a range of dosages for human use. In specific embodiments, the dosage of the compounds described herein is such that ED is achieved with minimal toxicity. 50 The dosage may optionally vary within this range depending upon the dosage form employed and the route of administration utilized.

[0162] Dosage In various embodiments, the patient is a pediatric patient under the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years of age. In certain embodiments, the pediatric subject is a newborn, a premature newborn, an infant, a toddler, a preschooler, a school-age child, a prepubertal child, a postpubertal child, an adolescent, or a teenager under 18 years of age. In some embodiments, the pediatric subject is a newborn, a premature newborn, an infant, a toddler, a preschooler, or a school-age child ... or a preschooler. In some embodiments, the pediatric subject is a newborn, a premature newborn, an infant, a toddler, or a preschooler. In some embodiments, the pediatric subject is a newborn, a premature newborn, an infant, or a toddler. In some embodiments, the pediatric subject is a newborn, a premature newborn, an infant, or a toddler. In some embodiments, the pediatric subject is a newborn, a premature newborn, an infant, or a toddler. In some embodiments, the pediatric subject is a newborn. In some embodiments, the pediatric subject is an infant. In some embodiments, the pediatric subject is a toddler.

[0163] In various embodiments, the ASBTI is maralixibat or vorixibat, or a pharmaceutically acceptable salt thereof.

[0164] In various embodiments, the efficacy and safety of ASBTI administration to patients is monitored by measuring serum levels of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum total cholesterol concentration, serum LDL-C cholesterol concentration, serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the efficacy of ASBTI administration is measured by monitoring observer-reported itch reported outcome (ITCHRO (OBS)) score, HRQoL (e.g., PedsQL) score, CSS score, xanthomas score, height Z score, weight Z score, or various combinations thereof. In various embodiments, the method includes monitoring serum levels of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum total cholesterol concentration, serum LDL-C cholesterol concentration, serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the method includes monitoring an observer-reported pruritus outcome (ITCHRO(OBS)) score, an HRQoL (e.g., PedsQL) score, a CSS score, a xanthomas score, a height Z-score, a weight Z-score, or various combinations thereof.

[0165] The dosage of ASBTI can be calculated based on the molecular weight of ASBTI as the compound free base or as a pharmaceutically acceptable salt. In one embodiment, the dosage of ASBTI is based on the compound as a pharmaceutically acceptable salt. In one embodiment, the dosage of ASBTI is based on the compound free base.

[0166] In some embodiments, ASBTI is about or at least about 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 100 μg / kg, 140 μg / kg, 150 μg / kg kg, 200μg / kg, 240μg / kg, 280μg / kg, 300μg / kg, 250μg / kg, 280μg / kg, 300μg / kg, 400μg / kg, 500μg / kg, 560μg / kg, 600μg / kg, 700μg / kg, 800μg / kg, 900μg / kg, 1 Administered at doses of ,000μg / kg, 1,100μg / kg, 1,200μg / kg, 1,300μg / kg, 1,400μg / kg, 1500μg / kg, 1,600μg / kg, 1,700μg / kg, 1,800μg / kg, 1,900μg / kg, or 2,000μg / kg.In various embodiments, ASBTI is about 1 μg / kg or less, 2 μg / kg or less, 3 μg / kg or less, 4 μg / kg or less, 5 μg / kg or less, 6 μg / kg or less, 7 μg / kg or less, 8 μg / kg or less, 9 μg / kg or less, 10 μg / kg or less, 15 μg / kg or less, 20 μg / kg or less, 25 μg / kg or less, 30 μg / kg or less, 35 μg / kg or less, 40 μg / kg or less, 45 μg / kg or less, 50 μg / kg or less, 55 μg / kg or less, 60 μg / kg or less, 65 μg / kg or less, 70 μg / kg or less, 75 μg / kg or less, 80 μg / kg or less, 85 μg / kg or less, 90 μg / kg or less, 100 μg / kg or less, 140 μg / kg or less, 150 μg / kg or less, 200 μg / kg or less Below, 240μg / kg or less, 280μg / kg or less, 300μg / kg or less, 250μg / kg or less, 280μg / kg or less, 300μg / kg or less, 400μg / kg or less Lower, 500μg / kg or less, 560μg / kg or less, 600μg / kg or less, 700μg / kg or less, 800μg / kg or less, 900μg / kg or less, 1,000μg / kg It is administered at a dose of 1,100 μg / kg or less, 1,200 μg / kg or less, 1,300 μg / kg or less, 1,400 μg / kg or less, 1,500 μg / kg or less, 1,600 μg / kg or less, 1,700 μg / kg or less, 1,800 μg / kg or less, 1,900 μg / kg or less, 2,000 μg / kg or less, or 2,100 μg / kg or less.

[0167] In various embodiments, ASBTI is administered at a dose of about or at least about 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, It is administered in doses of 19 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, and 1000 mg / day. In various embodiments, ASBTI is about 1 mg / day or less, 2 mg / day or less, 3 mg / day or less, 4 mg / day or less, 5 mg / day or less, 6 mg / day or less, 7 mg / day or less, 8 mg / day or less, 9 mg / day or less, 10 mg / day or less, 11 mg / day or less, 12 mg / day or less, 13 mg / day or less, 14 mg / day or less, 15 mg / day or less, 16 mg / day or less, 17 mg / day or less, 18 mg / day or less, 19 mg / day or less, 20 mg / day or less The doses are as follows: 30mg / day or less, 40mg / day or less, 50mg / day or less, 60mg / day or less, 70mg / day or less, 80mg / day or less, 90mg / day or less, 100mg / day or less, 150mg / day or less, 200mg / day or less, 300mg / day or less, 500mg / day or less, 600mg / day or less, 700mg / day or less, 800mg / day or less, 900mg / day or less, 1,000mg / day or less, 1,100mg / day or less.

[0168] In some embodiments, ASBTI is administered at a dose of about 140 μg / kg / day to about 1400 μg / kg / day. In various embodiments, ASBTI is administered at a dose of about or at least about 0.5 μg / kg / day, 1 μg / kg / day, 2 μg / kg / day, 3 μg / kg / day, 4 μg / kg / day, 5 μg / kg / day, 6 μg / kg / day, 7 μg / kg / day, 8 μg / kg / day, 9 μg / kg / day, 10 μg / kg / day, 15 μg / kg / day, 20 μg / kg / day, 25 μg / kg / day, 30 μg / kg / day, 35 μg / kg / day, 40 μg / kg / day, 45 μg / kg / day, 50 μg / kg / day, 100 μg / kg / day, 140 μg / kg / day, The drug is administered at doses of 150 μg / kg / day, 200 μg / kg / day, 240 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 250 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 400 μg / kg / day, 500 μg / kg / day, 560 μg / kg / day, 600 μg / kg / day, 700 μg / kg / day, 800 μg / kg / day, 900 μg / kg / day, 1,000 μg / kg / day, 1,100 μg / kg / day, 1,200 μg / kg / day, or 1,300 μg / kg / day.In various embodiments, ASBTI is about 1 μg / kg / day or less, 2 μg / kg / day or less, 3 μg / kg / day or less, 4 μg / kg / day or less, 5 μg / kg / day or less, 6 μg / kg / day or less, 7 μg / kg / day or less, 8 μg / kg / day or less, 9 μg / kg / day or less, 10 μg / kg / day or less, 15 μg / kg / day or less, 20 μg / kg / day or less, 25 μg / kg / day or less, 30 μg / kg / day or less, 35 μg / kg / day or less, 40 μg / kg / day or less, 45 μg / kg / day or less, 50 μg / kg / day or less, 100 μg / kg / day or less, 140 μg / kg / day or less, 150 μg / kg / day or less, 200 μg / kg / day or less, 240 μg / kg / day or less g / day or less, 280 μg / kg / day or less, 300 μg / kg / day or less, 250 μg / kg / day or less, 280 μg / kg / day or less, 300 μg / kg / day or less, 360 μg / kg / day or less, 380 μg / kg / day or less, 400 μg / kg / day or less, 500 μg / kg / day or less, 560 μg / kg / day or less, 600 μg / kg / day or less, 700 μg / kg / day or less, 800 μg / kg / day or less, 880 μg / kg / day or less, 900 μg / kg / day or less, 1,000 μg / kg / day or less, 1,100 μg / kg / day or less, 1,200 μg / kg / day or less, 1,300 μg / kg / day or less, or 1,400 μg / kg / day or less.In various embodiments, ASBTI is administered at a dose of from about 0.5 μg / kg / day to about 500 μg / kg / day, from about 0.5 μg / kg / day to about 250 μg / kg / day, from about 1 μg / kg / day to about 100 μg / kg / day, from about 10 μg / kg / day to about 50 μg / kg / day, from about 10 μg / kg / day to about 100 μg / kg / day, from about 0.5 μg / kg / day to about 2000 μg / kg / day, from about 280 μg / kg / day to about 1400 μg / kg / day, from about 420 μg / kg / day to about 14 00μg / kg / day, about 250 to about 550μg / kg / day, about 560μg / kg / day to about 1400μg / kg / day, 700μg / kg / day to about 1400μg / kg / day, about 560μg / kg / day to about 1200μg / kg / day , about 700μg / kg / day to about 1200μg / kg / day, about 560μg / kg / day to about 1000μg / kg / day, about 700μg / kg / day to about 1000μg / kg / day, about 800μg / kg / day to about 1000μg / kg / day , about 200μg / kg / day to about 600μg / kg / day, about 300μg / kg / day to about 600μg / kg / day, about 360μg / kg / day to about 880μg / kg / day, about 400μg / kg / day to about 500μg / kg / day, about 40 0 μg / kg / day ~ approx. 600 μg / kg / day, approx. 400 μg / kg / day ~ approx. 700 μg / kg / day, approx. 400 μg / kg / day ~ approx. 800 μg / kg / day, approx. 500 μg / kg / day ~ approx. 800 μg / kg / day, approx. The dose is administered at a dose of about 600 μg / kg / day to about 900 μg / kg / day, about 700 μg / kg / day to about 900 μg / kg / day, about 200 μg / kg / day to about 600 μg / kg / day, about 800 μg / kg / day to about 900 μg / kg / day, about 100 μg / kg / day to about 1500 μg / kg / day, about 300 μg / kg / day to about 2,000 μg / kg / day, or about 400 μg / kg / day to about 2000 μg / kg / day.

[0169] In some embodiments, ASBTI is administered at a dose of about 30 μg / kg to about 1400 μg / kg per dose. In some embodiments, ASBTI is administered at a dose of about 0.5 μg / kg to about 2000 μg / kg per dose, about 0.5 μg / kg to about 1500 μg / kg per dose, about 100 μg / kg to about 700 μg / kg per dose, about 5 μg / kg to about 100 μg / kg per dose, about 10 μg / kg to about 500 μg / kg per dose, about 50 μg / kg to about 1400 μg / kg per dose, about 300 μg / kg to about 2000 μg / kg per dose, about 60 μg / kg to about 1200 μg / kg per dose, about 70 μg / kg to about 1000 μg / kg per dose, or about 10 μg / kg to about 2000 μg / kg per dose. The dose is administered at a dose of about 70 μg / kg to about 700 μg / kg per dose, 80 μg / kg to about 1000 μg / kg per dose, 80 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 600 μg / kg per dose, 150 μg / kg to about 700 μg / kg per dose, 150 μg / kg to about 500 μg / kg per dose, 200 μg / kg to about 400 μg / kg per dose, 200 μg / kg to about 300 μg / kg per dose, or 300 μg / kg to about 400 μg / kg per dose.

[0170] In some embodiments, ASBTI is administered at a dose of about 0.5 mg / day to about 550 mg / day. In various embodiments, ASBTI is administered at a dose of about 1 mg / day to about 500 mg / day, about 1 mg / day to about 300 mg / day, about 1 mg / day to about 200 mg / day, about 2 mg / day to about 300 mg / day, about 2 mg / day to about 200 mg / day, about 4 mg / day to about 300 mg / day, about 4 mg / day to about 200 mg / day, about 4 mg / day to about 150 mg / day, about 5 mg / day to about 150 mg / day, about 5 mg / day to about 100 mg / day, about 5 mg / day to about 80 mg / day, about 5 mg / day to about 50 mg / day, or about 5 mg / day to about 40 mg / day. It is administered at a dose of about 5 mg / day to about 30 mg / day, about 5 mg / day to about 20 mg / day, about 5 mg / day to about 15 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 80 mg / day, about 10 mg / day to about 50 mg / day, about 10 mg / day to about 40 mg / day, about 10 mg / day to about 20 mg / day, about 20 mg / day to about 100 mg / day, about 20 mg / day to about 80 mg / day, about 20 mg / day to about 50 mg / day, or about 20 mg / day to about 40 mg / day, or about 20 mg / day to about 30 mg / day.

[0171] In some embodiments, ASBTI is administered twice daily (BID) in an amount of about 200 μg / kg to about 400 μg / kg per dose. In some embodiments, ASBTI is administered in an amount of about 280 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 360 μg / kg / day to about 880 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 20 mg / kg / day to about 50 mg / kg / day. In some embodiments, ASBTI is administered in an amount of about 5 mg / kg / day to about 15 mg / kg / day. In some embodiments, ASBTI is administered in an amount of about 560 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 700 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 700 μg / kg / day to about 900 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 560 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 700 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 200 μg / kg / day to about 600 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 600 μg / kg / day.

[0172] In various embodiments, the dose of ASBTI is a first dose level. In various embodiments, the dose of ASBTI is a second dose level. In some embodiments, the second dose level is higher than the first dose level. In some embodiments, the second dose level is about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times higher than the first dose level. In some embodiments, the second dose level is not more than about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times higher than the first dose level.

[0173] In various embodiments, ASBTI is administered once daily (QD) at one of the doses or within one of the dose ranges described above. In various embodiments, ASBTI is administered twice daily (BID) at one of the doses or within one of the dose ranges described above. In various embodiments, one ASBTI dose is administered daily, every other day, twice weekly, or weekly.

[0174] In various embodiments, ASBTI is administered periodically for a period of about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, or 800 weeks. In various embodiments, ASBTI is administered for no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, or 1000 weeks. In various embodiments, ASBTI is administered periodically for a period of about or at least about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In various embodiments, ASBTI is administered periodically for a period of about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years or less.

[0175] Oral administration for delivery to the terminal ileum or colon In certain aspects, compositions or formulations containing one or more compounds described herein are orally administered for ASBTI, i.e., localized delivery of the compounds described herein to the terminal ileum, colon, and / or rectum. The unit dosage form of the composition includes a liquid dosage form formulated for enteral delivery to the terminal ileum and / or colon. In certain embodiments, the liquid dosage form, e.g., a solution, suspension, or elixir, contains a composition described herein encapsulated or embedded within microspheres. In some embodiments, microspheres include, but are not limited to, chitosan microcores, HPMC capsules, and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known to those skilled in the art of pharmaceutical formulation.

[0176] In some embodiments, the ASBTIs described herein are administered orally in association with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal and / or terminal ileum, colon, and / or rectum).

[0177] In certain embodiments, the compositions described herein comprise an ASBTI or other compound described herein associated with a matrix (e.g., a matrix comprising hypromellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or the colon. In some embodiments, the compositions comprise a pH-sensitive polymer (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain acidic groups (e.g., —COOH, —SO3H) and swell at basic pHs in the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the compositions suitable for controlled release in the distal ileum comprise a microparticulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable poly(dl-lactide-co-glycoside) (PLGA) core is suitable for delivery of enteroendocrine peptide secretagogues to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretagogues are coated with an enteric polymer (e.g., Eudragit® S-100; cellulose acetate phthalate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; anionic polymers such as methacrylic acid or methacrylic acid esters) for site-specific delivery to the distal ileum and / or colon. In some embodiments, bacterially activated systems are suitable for targeted delivery to the distal portion of the ileum. Examples of bacterial flora-activated systems include dosage forms containing pectin, galactomannan, and / or azohydrogel and / or glycoside conjugates (e.g., D-galactosides or β-D-xylopyranosides) of active agents. Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, or β-D-xylopyranosidase.

[0178] The pharmaceutical compositions described herein optionally contain an additional therapeutic compound described herein, and one or more pharmaceutically acceptable excipients, such as compatible carriers, binders, fillers, suspending agents, fragrance , sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof.

[0179] Bile acid sequestrants In certain embodiments, the compositions described herein are, for example, ASBTIs associated with labile bile acid sequestrants. Labile bile acid sequestrants are bile acid sequestrants that have an unstable affinity for bile acids. In certain embodiments, the bile acid sequestrants described herein are agents that sequester (e.g., absorb or charge) bile acids and / or their salts.

[0180] In specific embodiments, the labile bile acid sequestrant is an agent that sequester (e.g., absorbs or charges) bile acids and / or their salts and releases at least a portion of the absorbed or charged bile acids and / or their salts in the distal gastrointestinal tract (e.g., the colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof). In certain embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In specific embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in higher concentrations in the colon or rectum than in the human small intestine. Examples of systems activated by the microflora include dosage forms comprising pectin, galactomannan, and / or azohydrogel and / or glycoside conjugates of the active agent (e.g., D-galactosides or β-D-xylopyranosides, etc.). Examples of gut microbiota enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, or β-D-xylopyranosidase. In some embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant (i.e., the bile acid sequestrant sequesters bile acids and / or salts thereof and releases at least a portion of the bile acids and / or salts thereof after a period of time). In some embodiments, a time-dependent bile acid sequestrant is an agent that degrades over time in an aqueous environment. In certain embodiments, the labile bile acid sequestrants described herein have a low affinity for bile acids and / or their salts, such that the bile acid sequestrant sequesters bile acids and / or their salts in environments where bile acids / bile salts and / or their salts are present at high concentrations and can release them in environments where bile acids / bile salts and / or their salts are present at low relative concentrations. In some embodiments, the labile bile acid sequestrant has a high affinity for primary bile acids and a low affinity for secondary bile acids, such that the bile acid sequestrant sequesters primary bile acids or their salts and can subsequently release the secondary bile acids or their salts upon conversion (e.g., metabolism) of the primary bile acids or their salts to the secondary bile acids or their salts. In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant.In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6 or less and a low affinity for bile acids at a pH above 6. In certain embodiments, the pH-dependent bile acid sequestrant is degraded at a pH above 6.

[0181] In some embodiments, the labile bile acid sequestrants described herein include any compound, e.g., macrostructure compounds, capable of sequestering bile acids / bile salts and / or salts thereof by any suitable mechanism. For example, in certain embodiments, the bile acid sequestrant sequesters bile acids / bile salts and / or salts thereof by ionic, polar, electrostatic, hydrophobic, lipophilic, hydrophilic, or conformational interactions, etc. In certain embodiments, the macrostructure compounds sequester bile acids / bile salts and / or salts thereof by trapping them within a pocket of the macrostructure compound, and optionally by other interactions, such as those described above. In some embodiments, bile acid sequestrants (e.g., labile bile acid sequestrants) include, by way of non-limiting example, lignin; modified lignin; polymers; polycationic polymers and copolymers; polymers and / or copolymers comprising any one or more of N-alkenyl-N-alkylamine residues, one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkyl-azanium residues, one or more N,N,N-trialkyl-N-alkenyl-azanium residues, one or more alkenyl-amine residues, or combinations thereof; or any combinations thereof.

[0182] Covalent binding of drug to carrier In some embodiments, strategies used for colon-targeted delivery include, by way of non-limiting example, covalently linking ASBTI or other compounds described herein to a carrier; coating the dosage form with a pH-sensitive polymer for delivery upon reaching the pH environment of the colon; use of redox-sensitive polymers; use of sustained-release formulations; utilization of coatings that are specifically degraded by colonic bacteria; use of bioadhesive systems; and use of osmotically controlled drug delivery systems.

[0183] Certain embodiments of the oral administration of compositions containing ASBTI or other compounds described herein include covalent attachment to a carrier, which remains intact in the stomach and small intestine upon oral administration. Upon entry into the colon, the covalent attachment is disrupted by changes in pH, enzymes, and / or intestinal flora. In certain embodiments, the covalent attachment between ASBTI and the carrier includes, but is not limited to, azo bonds, glycosidic conjugation, glucuronidation, cyclodextrin conjugation, dextran conjugation, and amino acid conjugation (due to the high hydrophilicity and long chain length of the carrier amino acid).

[0184] Coating with polymers: pH-sensitive polymers In some embodiments, the oral dosage forms described herein are coated with an enteric coating to facilitate delivery of the ASBTI or other compounds described herein to the colon and / or rectum. In certain embodiments, the enteric coating remains intact in the low pH environment of the stomach, but is readily dissolved once the optimum dissolution pH for the particular coating is reached, depending on the chemical composition of the enteric coating. The thickness of the coating depends on the solubility characteristics of the coating material. In certain embodiments, the coating thickness used in the formulations described herein is from about 25 μm to about 200 μm.

[0185] In certain embodiments, coating a composition or formulation described herein delivers the ASBTI or other compounds described herein in the composition or formulation to the colon and / or rectum without absorption in the upper intestine. In a specific embodiment, specific delivery to the colon and / or rectum is achieved by coating the dosage form with a polymer that degrades only in the pH environment of the colon. In an alternative embodiment, the composition is coated with an enteric coating that dissolves at intestinal pH and an outer matrix that slowly erodes in the intestine. In some such embodiments, the matrix slowly erodes until only the core composition comprising the enteroendocrine peptide secretagogue (and, in some embodiments, an agent absorption inhibitor) remains, and the core is delivered to the colon and / or rectum.

[0186] In certain embodiments, the pH-dependent system takes advantage of the gradual increase in pH along the human gastrointestinal tract (GIT), from the stomach (pH 1-2, rising to 4 during digestion) through the digestive portion of the small intestine (pH 6-7) and into the distal ileum (pH 7-8). In certain embodiments, dosage forms for oral administration of the compositions described herein are coated with one or more pH-sensitive polymers to provide delayed release and protect the enteroendocrine peptide secretagogue from gastric fluids. In certain embodiments, the dosage forms can withstand the relatively low pH values ​​of the stomach and proximal small intestine, but disintegrate at the neutral or slightly alkaline pH of the terminal ileum and / or ileocecal region. Thus, in certain embodiments, provided herein are oral dosage forms with a coating, wherein the coating comprises a pH-sensitive polymer. In some embodiments, polymers used for colon and / or rectal targeting include, by way of non-limiting example, methacrylic acid copolymer, methacrylic acid and methyl methacrylate copolymer, Eudragit L100, Eudragit S100, Eudragit L-30D, Eudragit FS-30D, Eudragit L100-55, polyvinyl acetate phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate 50, hydroxypropyl methyl cellulose phthalate 55, cellulose acetate trimellitate, cellulose acetate phthalate, and combinations thereof.

[0187] In certain embodiments, oral dosage forms suitable for delivery to the colon and / or rectum comprise a coating comprising a biodegradable and / or bacterially degradable polymer, or a polymer that is degraded by the colonic flora (bacteria). In such biodegradable systems, suitable polymers include, by non-limiting example, azopolymers, linear segmented polyurethanes containing azo groups, polygalactomannans, pectin, glutaraldehyde-crosslinked dextran, polysaccharides, amylose, guar gum, pectin, chitosan, inulin, cyclodextrin, chondroitin sulfate, dextran, locust bean gum, chondroitin sulfate, chitosan, poly(-caprolactone), polylactic acid, and poly(lactic-co-glycolic acid).

[0188] In certain embodiments of oral administration of compositions containing one or more ASBTIs or other compounds described herein, the compositions are delivered to the colon without being absorbed in the upper intestine by coating the dosage form with a redox-sensitive polymer that is degraded by the colonic flora (bacteria). In such biodegradable systems, the polymers include, but are not limited to, redox-sensitive polymers containing azo and / or disulfide bonds in the backbone.

[0189] In some embodiments, compositions formulated for delivery to the colon and / or rectum are formulated for sustained release, ie, sustained release formulations that withstand the acidic environment of the stomach, thereby delaying release of the enteroendocrine peptide secretagogue until the dosage form enters the colon and / or rectum.

[0190] Combination therapy In clinical practice, the majority of patients with ALGS are treated with off-label agents, most commonly UDCA and rifampin, to control or reduce pruritus symptoms. These drugs are usually only partially or temporarily effective in relieving pruritus associated with cholestatic liver diseases such as ALGS or PFIC.

[0191] In some embodiments, the compositions described herein are administered in combination with one or more additional agents. In some embodiments, the present invention also provides compositions comprising a compound (e.g., ASBTI) and one or more additional agents. In some embodiments, a reduction in the amount / dosage of ASBTI and / or the second therapeutic agent is achieved compared to the amount / dosage of ASBTI and / or the second therapeutic agent administered as monotherapy.

[0192] In some embodiments, a reduction in the amount / dosage of the second therapeutic agent is achieved, ie, a reduction in the amount / dosage of the second therapeutic agent of at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 90% compared to the amount / dosage of the second therapeutic agent administered as monotherapy.

[0193] In some embodiments, the subject can discontinue treatment with the second therapeutic agent, i.e., a 100% reduction in the amount / dosage of the second therapeutic agent is achieved.

[0194] In some embodiments, the compositions described herein comprise a combination of an ASBTI (e.g., maralixibat) and a subclinically therapeutically effective amount of a second therapeutic agent selected from the group consisting of UDCA, rifampicin, an antihistamine, and an FXR-targeted drug.

[0195] In some embodiments, the ASBTI compositions described herein are administered in combination with a subclinical therapeutically effective amount of a second therapeutic agent selected from the group consisting of UDCA, rifampicin, an antihistamine, and an FXR-targeted drug.

[0196] Fat-soluble vitamins In some embodiments, the compositions provided herein further comprise one or more vitamins, in some embodiments, vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, β-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, phylloquinone, and menaquinone.

[0197] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamins A, D, E, K, retinol, β-carotene, cholecalciferol, tocopherol, phylloquinone, etc. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0198] Partial External Biliary Diversion (PEBD) In some embodiments, methods of using the compositions provided herein include using partial external biliary diversion as a treatment for patients who have not yet developed cirrhosis. This treatment helps reduce the circulation of bile acids / bile salts within the liver, thereby reducing complications and avoiding the need for early transplantation in many patients.

[0199] This surgical technique involves separating a 10-cm-long segment of intestine from the rest of the intestine to serve as a bile conduit (a channel through which bile can pass). One end of the conduit is attached to the gallbladder, and the other end is brought out through the skin to form a stoma (a surgically constructed opening that allows waste products to pass). Partial external biliary diversion can be used in patients who do not respond to any medical therapy, especially older and larger patients. This procedure may not be helpful in younger patients, such as infants. Partial external biliary diversion can reduce the intensity of pruritus and abnormally low blood cholesterol levels.

[0200] ASBTI and PPAR agonists In various embodiments, the present disclosure provides a combination of ASBTI and a PPAR (peroxisome proliferator-activated receptor) agonist. In various embodiments, the PPAR agonist is a fibrate. In some embodiments, the fibrate is clofibrate, gemfibrozil, ciprofibrate, benzafibrate, fenofibrate, or various combinations thereof. In various embodiments, the PPAR agonist is aleglitazar, muraglitazar, tesaglitazar, saroglitazar, GW501516, GW-9662, a thiazolidinedione (TZD), an NSAID (e.g., ibuprofen), an indole, or various combinations thereof. In some embodiments, the PPAR agonist is bezafibrate, seradelpar (MBX-8025), GW501516 (cardarine), fenofibrate, elafibranor, REN001, KD3010, ASP0367, or CER-002.

[0201] In various embodiments, the PPAR agonist used in combination with an ASBTI of the present disclosure is a pan-PPAR agonist, or a PPARα, PPARγ, PPARβ, or PPARδ agonist.

[0202] In one non-limiting embodiment, the PPAR agonist is a PPARδ agonist. In one embodiment, the PPARδ agonist is seladelpar (MBX-8025), GW501516 (cardarine), REN001, KD3010, ASP0367, or CER-002.

[0203] ASBTI and FXR medications In various embodiments, the present disclosure provides a combination of an ASBTI and a farnesoid X receptor (FXR)-targeted drug. In various embodiments, the FXR-targeted drug is avermectin B1a, bepridil, fluticasone propionate, GW4064, gliquidone, nicardipine, triclosan, CDCA, ivermectin, chlorotrianisene, tribenoside, mometasone furoate, miconazole, amiodarone, butoconazole, bromocriptine mesylate, pizotifen malate, or various combinations thereof. In some embodiments, a reduction in the amount / dosage of the ASBTI and / or FXR-targeted drug is achieved compared to the amount / dosage of the ASBTI and / or FXR-targeted drug administered as monotherapy.

[0204] ASBTI and antihistamines In various embodiments, the present disclosure provides a combination of an ASBTI and an antihistamine. In various embodiments, the antihistamine is azelastine, carbinoxamine, cyproheptadine, desloratadine, emedastine, hydroxyzine, levocabastine, levocetirizine, brompheniramine, cetirizine, chlorpheniramine, clemastine, diphenhydramine, fexofenadine, loratadine, or various combinations thereof. In some embodiments, a reduction in the amount / dosage of the ASBTI and / or antihistamine is achieved compared to the amount / dosage of the ASBTI and / or antihistamine administered as monotherapy.

[0205] ASBTI and ursodiol / UDCA In some embodiments, compositions of the present disclosure are administered in combination with ursodiol, or ursodeoxycholic acid (UDCA), chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid, or tauroursodeoxycholic acid. In some embodiments, increasing bile acid / salt concentrations in the distal gut induces intestinal regeneration, reduces intestinal damage, reduces bacterial translocation, inhibits the release of free radical oxygen, inhibits the production of inflammatory cytokines, or any combination thereof.

[0206] In certain embodiments, a patient receives about or at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg Ursodiol is administered at daily doses of 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, or 3,000 mg. In certain embodiments, the patient receives about 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, 35 mg or less, 36 mg or less, 40 mg or less, 45 mg or less, 50 mg or less, 55 mg or less, 60 mg or less, 65 mg or less, 70 mg or less, 75 mg or less, 80 mg or less, 85 mg or less, 90 mg or less, 95 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, Ursodiol is administered at a daily dose of 0.1 mg or less, 500 mg or less, 550 mg or less, 600 mg or less, 650 mg or less, 700 mg or less, 750 mg or less, 800 mg or less, 850 mg or less, 900 mg or less, 950 mg or less, 1,000 mg or less, 1,250 mg or less, 1,500 mg or less, 1,750 mg or less, 2,000 mg or less, 2,250 mg or less, 2,500 mg or less, 2,750 mg or less, 3,000 mg or less, or 3,500 mg or less. In various embodiments, patients are administered ursodiol at a daily dose of about or at least about 3 mg to about 300 mg, about 30 mg to about 250 mg, about 36 mg to about 200 mg, about 10 mg to about 3000 mg, about 1000 mg to about 2000 mg, or about 1500 to about 1900 mg.

[0207] In various embodiments, ursodiol is administered as a tablet. In various embodiments, ursodiol is administered as a suspension. In various embodiments, the concentration of ursodiol in the suspension is about 10 mg / mL to about 200 mg / mL, about 50 mg / mL to about 150 mg / mL, about 10 mg / mL to about 500 mg / mL, or about 40 mg / mL to about 60 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about or at least about 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, or 80 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about 25 mg / mL or less, 30 mg / mL or less, 35 mg / mL or less, 40 mg / mL or less, 45 mg / mL or less, 50 mg / mL or less, 55 mg / mL or less, 60 mg / mL or less, 65 mg / mL or less, 70 mg / mL or less, 75 mg / mL or less, 80 mg / mL or less, or 85 mg / mL or less.

[0208] In certain embodiments, a patient receives a dose of about or at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 40 mg, 450 ...0 mg, 60 mg, 650 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 40 mg, 450 mg, 500 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 mg, 550 UDCA is administered at a daily dose of 0 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, or 3,000 mg. In certain embodiments, the patient receives a dose of about 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, 35 mg or less, 36 mg or less, 40 mg or less, 45 mg or less, 50 mg or less, 55 mg or less, 60 mg or less, 65 mg or less, 70 mg or less, 75 mg or less, 80 mg or less, 85 mg or less, 90 mg or less, 95 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 500 mg or less, 550 mg or less, 600 mg or less, 650 mg or less, 700 mg or less, 750 mg or less, 800 mg or less, 850 mg or less, 90 mg or less, 95 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 5 ... UDCA is administered at a daily dose of 50 mg or less, 500 mg or less, 550 mg or less, 600 mg or less, 650 mg or less, 700 mg or less, 750 mg or less, 800 mg or less, 850 mg or less, 900 mg or less, 950 mg or less, 1,000 mg or less, 1,250 mg or less, 1,500 mg or less, 1,750 mg or less, 2,000 mg or less, 2,250 mg or less, 2,500 mg or less, 2,750 mg or less, 3,000 mg or less, or 3,500 mg or less. In various embodiments, the patient is administered UDCA at a daily dose of about or at least about 3 mg to about 300 mg, about 30 mg to about 250 mg, about 36 mg to about 200 mg, about 10 mg to about 3000 mg, about 1000 mg to about 2000 mg, or about 1500 to about 1900 mg.

[0209] In various embodiments, UDCA is administered as a tablet. In various embodiments, UDCA is administered as a suspension. In various embodiments, the concentration of UDCA in the suspension is about 10 mg / mL to about 200 mg / mL, about 50 mg / mL to about 150 mg / mL, about 10 mg / mL to about 500 mg / mL, or about 40 mg / mL to about 60 mg / mL. In various embodiments, the concentration of UDCA in the suspension is about or at least about 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, or 80 mg / mL. In various embodiments, the concentration of UDCA in the suspension is about 25 mg / mL or less, 30 mg / mL or less, 35 mg / mL or less, 40 mg / mL or less, 45 mg / mL or less, 50 mg / mL or less, 55 mg / mL or less, 60 mg / mL or less, 65 mg / mL or less, 70 mg / mL or less, 75 mg / mL or less, 80 mg / mL or less, or 85 mg / mL or less.

[0210] The ASBTI and the second active ingredient are used such that the combination is present in a therapeutically effective amount. This therapeutically effective amount results from the use of ASBTI in combination with another active ingredient (e.g., ursodiol or UDCA), each of which is used in a therapeutically effective amount, or each of which may be used in a subclinical therapeutically effective amount, i.e., an amount that would be less effective for the therapeutic purposes described herein if used alone, due to additive or synergistic effects resulting from the combination, provided that the combination is therapeutically effective. In some embodiments, the use of ASBTI in combination with any other active ingredient described herein includes combinations in which ASBTI or the other active ingredient is present in a therapeutically effective amount and the other is present in a subclinical therapeutically effective amount, provided that the additive or synergistic effects render the combination therapeutically effective. As used herein, the term "additive effect" describes a combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effects of each agent administered alone. A synergistic effect is a combined effect of two (or more) pharmaceutically active agents that is greater than the sum of the effects of each agent administered alone. Any suitable combination of an ASBTI with one or more of the other active ingredients described above, and optionally one or more other pharmacologically active substances, is contemplated as being within the scope of the methods described herein.

[0211] In some embodiments, a reduced amount / dosage of ASBTI and / or UDCA is achieved compared to the amount / dosage of ASBTI and / or UDCA administered as monotherapy.

[0212] In some embodiments, the particular choice of compounds will depend on the attending physician's diagnosis and judgment regarding the individual's condition and the appropriate treatment protocol. Compounds are optionally administered concurrently (e.g., simultaneously, approximately simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the individual's condition, and the actual choice of compounds used. In certain instances, the determination of the order of administration and number of administration repetitions of each therapeutic agent during a treatment protocol is based on an evaluation of the disease being treated and the individual's condition.

[0213] In some embodiments, therapeutically effective dosages vary when agents are used in therapeutic combinations. Methods for experimentally determining therapeutically effective dosages of agents and other agents for use in combination therapy regimens are described in the literature.

[0214] In some embodiments of the combination therapies described herein, the dosage of the co-administered compound varies depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. Additionally, when co-administered with one or more bioactive agents, the compounds provided herein are optionally administered simultaneously or sequentially with the one or more bioactive agents. In certain instances, in the case of sequential administration, the attending physician will determine the appropriate sequence of the therapeutic compounds described herein and the additional therapeutic agent.

[0215] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or simultaneously. If administered simultaneously, the multiple therapeutic agents are optionally provided in a combined form or in multiple forms (by way of example only, as a single pill or as two separate pills). In certain examples, one of the therapeutic agents is optionally administered in multiple doses. In other examples, both are optionally administered in multiple doses. If not administered simultaneously, the timing between the multiple doses can be any appropriate time, for example, more than 0 weeks and less than 4 weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations (including two or more compounds described herein) is also contemplated.

[0216] In certain embodiments, the dosage regimen for treating, preventing, or ameliorating one or more conditions for which relief is sought is modified depending on various factors. These factors include the disorder from which the subject suffers, as well as the subject's age, weight, sex, diet, and medical condition. Thus, in various embodiments, the dosage regimen actually adopted will vary and deviate from the dosage regimen described herein.

[0217] In some embodiments, the pharmaceutical agents comprising the combination therapy described herein are provided in a single combined dosage form or in separate dosage forms intended for approximately simultaneous administration. In certain embodiments, the pharmaceutical agents comprising the combination therapy are administered sequentially, and the therapeutic compound is administered according to a regimen requiring two-step administration. In some embodiments, the two-step administration regimen requires sequential administration of the active agents or spaced-apart administration of the separate active agents. In certain embodiments, the period between multiple administration steps can vary, for example, but not limited to, from minutes to hours, depending on the properties of each pharmaceutical agent, such as the potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

[0218] In certain embodiments, provided herein are combination therapies. In certain embodiments, the compositions described herein comprise an additional therapeutic agent. In some embodiments, the methods described herein comprise administering a second dosage form comprising the additional therapeutic agent. In certain embodiments, the compositions described herein are administered as part of a regimen. Thus, the additional therapeutic agent and / or additional pharmaceutical dosage form can be administered to a patient directly or indirectly, along with or sequentially with the compositions and formulations described herein.

[0219] kit In another aspect, provided herein is an administration device pre-filled with the pharmaceutical composition described herein. include In certain embodiments, the kit comprises an oral administration device and a pharmaceutical composition described herein. include In certain embodiments, the kit includes a pre-filled sachet or bottle for oral administration, while in other embodiments, the kit includes a pre-filled bag for administration of a gel. In certain embodiments, the kit includes a pre-filled syringe for administration of an oral enema.

[0220] In some embodiments, the kit includes a bottle with a pre-installed adapter and a child-resistant cap. In some embodiments, the bottle may have a volume of 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 60 mL, 80 mL, 100 mL, 200 mL, or 250 mL.

[0221] In some embodiments, the kit includes one or more oral medication dispensers, such as oral syringes, which may have a volume of 0.1 mL, or 0.2 mL, or 0.25 mL, or 0.5 mL, or 1 mL, or 2 mL, or 3 mL, or 5 mL, or 10 mL.

[0222] In one non-limiting embodiment, the kit includes a 30 mL bottle and three oral syringes with capacities of 0.5 mL, 1 mL, and 3 mL, packaged together in a secondary container closure system.

[0223] Release in the distal ileum and / or colon In certain embodiments, the composition and / or dosage form comprises a matrix (e.g., a matrix comprising hypromellose) that allows for controlled release of the active agent in the distal jejunum, proximal ileum, distal ileum, and / or colon. In some embodiments, the composition and / or dosage form comprises a pH-sensitive polymer (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the ileum and / or colon. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, such as Carbopol® polymers) that contain acidic groups (e.g., —COOH, —SO3H) and swell at basic pHs in the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the composition and / or dosage form suitable for controlled release in the distal ileum comprises a microparticulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable poly(dl-lactide-co-glycoside) (PLGA) core is suitable for delivery of ASBTI to the distal ileum. In some embodiments, dosage forms containing ASBTI are coated with an enteric polymer (e.g., Eudragit® S-100; cellulose acetate phthalate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose phthalate; anionic polymers such as methacrylic acid or methacrylic acid esters) for site-specific delivery to the ileum and / or colon. In some embodiments, bacterially activated systems are suitable for targeted delivery to the ileum. Examples of bacterial flora-activated systems include dosage forms containing pectin, galactomannan, and / or azohydrogel and / or glycoside conjugates of the active agent (e.g., D-galactosides or β-D-xylopyranosides, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, or β-D-xylopyranosidase.

[0224] The pharmaceutical compositions and / or dosage forms described herein optionally comprise an additional therapeutic compound described herein, and one or more pharmaceutically acceptable excipients, such as compatible carriers, binders, fillers, suspending agents, fragrance , sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In some aspects, a film coating is applied around the ASBTI formulation using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compounds described herein are in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated or coated.

[0225] ASBT inhibitors can be used in the preparation of medicaments for the prophylactic and / or therapeutic treatment of cholestasis or cholestatic liver disease. Methods for treating any of the diseases or conditions described herein in an individual in need of such treatment can include administering to the individual a pharmaceutical composition containing a therapeutically effective amount of at least one ASBT inhibitor described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0226] Classification of pediatric cholestatic liver disease In one aspect of the present disclosure, the compositions and dosage forms comprising ASBTI described herein are suitable for treating or ameliorating pediatric cholestatic liver disease. In some embodiments, the compositions and dosage forms comprising ASBTI described herein are suitable for treating or ameliorating pruritus. In some embodiments, the compositions and dosage forms comprising ASBTI described herein are suitable for treating or ameliorating hyperbiliary acidemia. In some embodiments, the compositions and dosage forms comprising ASBTI described herein are suitable for treating or ameliorating xanthomas.

[0227] In certain embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai surgery biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant-related liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal cirrhosis, In some embodiments, the cholestatic liver disease is a pediatric form of liver disease.

[0228] In certain embodiments, the cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, elevated serum concentrations of bile acids, elevated intrahepatic concentrations of bile acids, elevated serum concentrations of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, characteristic odor, dark urine, light stools, steatorrhea, failure to thrive, and / or renal failure.

[0229] In certain embodiments, the methods of the invention involve non-systemic administration of a therapeutically effective amount of ASBTI. In certain embodiments, the methods involve contacting the gastrointestinal tract, including the distal ileum and / or colon and / or rectum, of an individual in need thereof with ASBTI. In various embodiments, the methods of the invention result in a reduction of bile acids in absorptive epithelial cells or a reduction in damage to hepatocytes or intestinal structures caused by cholestasis or cholestatic liver disease.

[0230] In various embodiments, the subject has a condition associated with, caused by, or partially caused by BSEP deficiency. In certain embodiments, the condition associated with, caused by, or partially caused by BSEP deficiency is neonatal hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC2, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary atresia, or a combination thereof.

[0231] In various embodiments, the methods of the present invention comprise delivering a therapeutically effective amount of any ASBTI described herein to the ileum or colon of an individual.

[0232] As used herein, "cholestasis" refers to a disease or condition involving impaired bile formation and / or bile flow. As used herein, "cholestatic liver disease" refers to a liver disease associated with cholestasis. Cholestatic liver disease is often accompanied by jaundice, fatigue, and pruritus. Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated γ-glutamyl transpeptidase, elevated conjugated bilirubin, and elevated serum cholesterol.

[0233] Cholestatic liver disease can be divided clinicopathologically into two major categories: biliary obstructive, often extrahepatic, cholestasis, and non-biliary obstructive or intrahepatic cholestasis. In the former, cholestasis occurs when bile flow is mechanically obstructed, as occurs by gallstones or tumors, or in extrahepatic biliary atresia.

[0234] The latter group, including non-biliary obstructive intrahepatic cholestasis, is further divided into two subgroups. In the first subgroup, cholestasis occurs when the processes of bile secretion and modification, or the synthesis of bile components, are secondarily involved in hepatocellular injury so severe that nonspecific impairment of many functions, including those supporting bile formation, can be expected. In the second subgroup, the likely cause of hepatocellular injury cannot be identified. Cholestasis in such patients appears to occur when one of the steps of bile secretion or modification, or the step of synthesis of bile components, is constitutively damaged. Such cholestasis is considered primary.

[0235] Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with cholestasis and / or cholestatic liver disease. In some such embodiments, the methods include increasing bile acid and / or GLP-2 concentrations in the intestinal lumen.

[0236] Hyperbile acidemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γ-GT (γ-glutamyl transpeptidase), and 5'-nucleotidase are biochemical evidence of cholestasis and cholestatic liver disease. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with hyperbile acidemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γ-GT (γ-glutamyl transpeptidase, or GGT), and 5'-nucleotidase. In some such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen. Further provided herein are methods and compositions for reducing hypercholic acidemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γ-GT (γ-glutamyl transpeptidase), and 5'-nucleotidase, comprising the step of reducing overall serum bile acid load by excreting bile acids in the feces.

[0237] Pruritus is often associated with pediatric cholestasis and pediatric cholestatic liver disease. It has been suggested that pruritus is caused by the action of bile salts on peripheral pain afferents. The severity of pruritus varies among individuals (i.e., some individuals are sensitive to elevated levels of bile acids / bile salts). Administration of agents that reduce serum bile acid concentrations has been shown to reduce pruritus in certain individuals. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with pruritus. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating pruritus, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0238] Another symptom of pediatric cholestasis and pediatric cholestatic liver disease is elevated serum levels of conjugated bilirubin. Elevated serum levels of conjugated bilirubin result in jaundice and dark urine. The magnitude of the elevation is not diagnostically significant, as the relationship between serum levels of conjugated bilirubin and the severity of cholestasis and cholestatic liver disease has not been established. Conjugated bilirubin concentrations rarely exceed 30 mg / dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with elevated serum levels of conjugated bilirubin. In some such embodiments, the method includes increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating elevated serum concentrations of conjugated bilirubin, comprising reducing overall serum bile acid load by excreting bile acids in the feces.

[0239] Elevated serum concentrations of unconjugated bilirubin are also considered diagnostic of cholestasis and cholestatic liver disease. A portion of serum bilirubin is covalently bound to albumin (delta bilirubin or biliproteins). This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of delta bilirubin indicates long-standing cholestasis. Delta bilirubin in umbilical cord blood or neonatal blood is an indicator of pediatric cholestasis / cholestatic liver disease from prenatal onset. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with elevated serum concentrations of unconjugated bilirubin or delta bilirubin. In some such embodiments, the method comprises increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating elevated serum levels of unconjugated bilirubin or delta bilirubin, comprising reducing overall serum bile acid load by excreting bile acids in the feces.

[0240] Pediatric cholestasis and cholestatic liver disease result in hypercholic acidemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts reflux from hepatocytes into the serum, thereby increasing the concentration of bile salts in the peripheral circulation. Furthermore, inefficient uptake of bile salts entering the liver into the portal vein results in spillover of bile salts into the peripheral circulation. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with hypercholic acidemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating hypercholic acidemia, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0241] Hyperlipidemia is a hallmark of some, but not all, cholestatic disorders. In cholestasis, serum cholesterol increases due to a decrease in circulating bile salts, which contribute to cholesterol metabolism and degradation. Cholesterol retention is associated with increased membrane cholesterol content and decreased membrane fluidity and function. Furthermore, because bile salts are metabolic products of cholesterol, decreased cholesterol metabolism reduces bile acid / bile salt synthesis. Serum cholesterol levels observed in children with cholestasis range from about 1,000 mg / dL to about 4,000 mg / dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with hyperlipidemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating hyperlipidemia, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0242] In individuals with pediatric cholestasis and pediatric cholestatic liver disease, xanthomas develop from the deposition of excess circulating cholesterol in the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Flat xanthomas first develop around the eyes, followed by the creases of the palms and soles, and then on the neck. Nodular xanthomas are associated with chronic and long-term cholestasis. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals with xanthomas. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating xanthomas, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0243] In children with chronic cholestasis, one of the major consequences of pediatric cholestasis and pediatric cholestatic liver disease is failure to thrive. Failure to thrive is the result of reduced delivery of bile salts to the intestine, leading to inefficient digestion and absorption of fat and reduced vitamin uptake (vitamins E, D, K, and A all suffer from malabsorption in cholestasis). Furthermore, delivery of fat to the colon can lead to colonic secretions and diarrhea. Treatments for failure to thrive include dietary replacement and supplementation with long-chain triglycerides, medium-chain triglycerides, and vitamins. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals (e.g., children) with failure to thrive. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating failure to thrive, comprising reducing overall serum bile acid load by excreting bile acids in the feces.

[0244] In children with chronic cholestasis, a further consequence of pediatric cholestasis and pediatric cholestatic liver disease is reduced growth compared to children without pediatric cholestasis or pediatric cholestatic liver disease. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancing adaptive processes in the intestine of individuals (e.g., children) experiencing reduced growth. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating reduced growth, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0245] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a rare genetic disorder that typically causes progressive liver disease leading to liver failure. In patients with PFIC, liver cells are impaired in their ability to secrete bile. The resulting accumulation of bile leads to liver disease in affected individuals. Signs and symptoms of PFIC typically appear during infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increasing liver dysfunction (liver failure). The disease is estimated to affect 1 in 50,000 to 100,000 live births in the United States and Europe. Six genetically identified types of PFIC have been identified, all of which are similarly characterized by impaired bile flow and progressive liver disease.

[0246] PFIC1 PFIC1 (also known as Byler disease or FICl deficiency) is associated with mutations in the ATP8B1 gene (also called FICl). This gene, encoding a P-type ATPase, is located on human chromosome 18 and is also mutated in milder phenotypes such as benign recurrent intrahepatic cholestasis type 1 (BRIO) and Greenland familial cholestasis. The FICl protein is located on the canalicular membrane of hepatocytes, but is primarily expressed in cholangiocytes within the liver. P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining phosphatidylserine and phosphatidylethanolamine enrichment in the inner leaflet of the plasma membrane relative to the outer leaflet. Asymmetric lipid distribution in the membrane bilayer protects against high bile salt concentrations in the canalicular lumen. Abnormal protein function may indirectly interfere with biliary secretion of bile acids. Abnormal secretion of bile acids / bile salts leads to hepatocellular bile acid overload.

[0247] PFIC1 typically manifests in infants (e.g., 6-18 months of age). Infants may exhibit signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. These individuals may also have liver fibrosis. Individuals with PFIC1 typically lack bile duct proliferation. Most individuals with PFIC1 develop end-stage liver disease by the age of 10. No medical treatment has proven beneficial for the long-term treatment of PFIC1. To reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive), children are often administered medium-chain triglycerides and fat-soluble vitamins. Ursodiol has not been shown to be effective in individuals with PFIC1.

[0248] PFIC2 PFIC2 (also known as Byler syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt pump (BSEP) in the human liver and is located on human chromosome 2. The BSEP protein, expressed in the hepatocyte canalicular membrane, is the primary transporter of primary bile acids / bile salts against extreme concentration gradients. Mutations in this protein are responsible for the bile salt secretion described in affected patients, leading to reduced bile flow and intrahepatic bile salt accumulation, accompanied by progressive severe hepatocellular damage.

[0249] PFIC2 typically presents in infants (e.g., 6-18 months of age). Infants may exhibit signs of pruritus. Biochemically, individuals with PFIC2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. These individuals may also have portal vein inflammation and giant cell hepatitis. Additionally, individuals often develop hepatocellular carcinoma. No medical treatment has proven beneficial for the long-term treatment of PFIC2. To reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive), children are often administered medium-chain triglycerides and fat-soluble vitamins. PFIC2 patients account for approximately 60% of the PFIC population.

[0250] PFIC3 PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also called MDR3) located on chromosome 7. Class III multidrug resistance (MDR3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the export of bile phospholipids (phosphatidylcholine) from the canalicular membrane of hepatocytes. PFIC3 results from bile toxicity in which surfactant bile salts are not inactivated by phospholipids, leading to damage to the bile canaliculi and bile duct epithelium.

[0251] PFIC3 also appears in early childhood. In contrast to PFIC1 and PFIC2, the individual's γGT levels are elevated. The individual also has portal vein inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. The individual also develops intrahepatic cholelithiasis. Ursodiol is effective in treating or ameliorating PFIC3.

[0252] Benign recurrent intrahepatic cholestasis (BRIC) BRIC1 BRIC1 is caused by a genetic defect in the FIC1 protein in the bile canalicular membrane of hepatocytes. BRIC1 is typically associated with elevated serum bile salts while serum cholesterol and gamma-glutamyl transpeptidase levels are normal. Residual FIC1 expression and function are associated with BRIC1. Despite frequent attacks of cholestasis or cholestatic liver disease, most patients do not progress to chronic liver disease. During attacks, patients experience severe jaundice, pruritus, steatorrhea, and weight loss. Some patients also develop kidney stones, pancreatitis, and diabetes.

[0253] BRIC2 BRIC2 is caused by mutations in ABCB11, which leads to defective BSEP expression and / or function in the bile canalicular membrane of hepatocytes.

[0254] BRIC3 BRIC3 is associated with defective expression and / or function of MDR3 in the bile canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically exhibit elevated serum gamma-glutamyl transpeptidase levels with normal or slightly elevated bile acid levels.

[0255] Dubin-Johnson syndrome (DJS) DJS is characterized by elevated conjugated bilirubin due to inherited dysfunction of MRP2. Liver function is preserved in affected patients. Several different mutations have been associated with the condition, which result in either a complete absence of immunohistochemically detectable MRP2 or impaired protein maturation and sorting in affected patients.

[0256] Acquired cholestatic disorders Pediatric primary sclerosing cholangitis (PSC) Pediatric PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in the majority of affected patients. Pediatric PSC inflammation is characterized by fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic bile ducts.

[0257] cholelithiasis Cholelithiasis is one of the most common and costly of all gastrointestinal diseases, with a prevalence of up to 17% in Caucasian women. Cholesterol-containing gallstones are the predominant form of gallstones, and therefore supersaturation of bile with cholesterol is a prerequisite for gallstone formation. Mutations in ABCB4 may be involved in the pathogenesis of cholesterol cholelithiasis.

[0258] Drug-induced cholestasis Drug-induced inhibition of BSEP function is an important mechanism of drug-induced cholestasis, leading to the accumulation of bile salts in the liver and subsequent hepatocellular injury. Several drugs have been implicated in BSEP inhibition. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide, and troglitazone, directly inhibit ATP-dependent taurocholate transport in a competitive manner through cis-inhibition, whereas estrogen and progesterone metabolites indirectly inhibit BSEP through trans-inhibition after bile secretion into the bile canaliculi via MRP2. Alternatively, drug-mediated stimulation of MRP2 may promote cholestasis or cholestatic liver disease by altering bile composition.

[0259] Total Parenteral Nutrition-Associated Cholestasis TPNAC represents one of the most serious clinical scenarios, with rapid onset of cholestasis or cholestatic liver disease and a strong association with early mortality. Infants, usually premature and undergoing intestinal resection, rely on TPN for growth and frequently develop cholestasis or cholestatic liver disease, which rapidly progresses to fibrosis, cirrhosis, and portal hypertension, usually by 6 months of age. The extent of cholestasis or cholestatic liver disease in these infants and their chances of survival are related to the number of septic episodes that may be initiated by frequent bacterial translocation across the intestinal mucosa. Although cholestatic effects from intravenous preparations are also present in these infants, septic mediators appear to be the primary contributor to altered liver function.

[0260] Alagille Syndrome Alagille syndrome is a genetic disorder affecting the liver and other organs. It often manifests during infancy (e.g., 6–18 months) or early childhood (3–5 years) and may stabilize after age 10. Symptoms include chronic progressive cholestasis, bile duct cytopenia, jaundice, pruritus, xanthomas, congenital heart disease, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmur, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot. Individuals diagnosed with Alagille syndrome are treated with ursodiol, hydroxyzine, cholestyramine, rifampin, and phenobarbital. Due to a reduced ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are also given high-dose multivitamins.

[0261] biliary atresia Biliary atresia is a life-threatening condition in infants in which the bile ducts in or out of the liver do not have their normal opening. In biliary atresia, bile becomes trapped and builds up, damaging the liver. This damage leads to scarring, loss of liver tissue, and cirrhosis. If untreated, the liver eventually fails, and the infant requires a liver transplant to survive. There are two types of biliary atresia: fetal and perinatal. Fetal biliary atresia manifests while the fetus is in the womb. Perinatal biliary atresia is much more common and does not become apparent until 2-4 weeks after birth.

[0262] Biliary atresia after Kasai operation Biliary atresia is treated with a surgical procedure called the Kasai procedure or liver transplantation. The Kasai procedure is usually the first treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile duct and replaces it with a loop of intestine. While the Kasai procedure can restore bile flow and correct many problems caused by biliary atresia, it does not cure the disease. If the Kasai procedure fails, the infant usually requires a liver transplant within one to two years. Even after successful surgery, most infants with biliary atresia develop cirrhosis slowly over several years, requiring a liver transplant by adulthood. Potential complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

[0263] Biliary atresia after liver transplantation Once atresia becomes complete, liver transplantation becomes the only option. While liver transplantation is generally effective in treating biliary atresia, it can be associated with complications, such as organ rejection. Also, donor livers may not be available. Furthermore, in some patients, liver transplantation may not be effective in curing biliary atresia.

[0264] xanthomas Xanthomas are a skin condition associated with cholestatic liver disease, resulting in the accumulation of certain fats beneath the skin's surface. Cholestasis causes multiple disturbances in lipid metabolism, leading to the formation of abnormal lipid particles in the blood called lipoprotein X. Lipoprotein X is formed by the reflux of bile lipids from the liver into the blood and, like normal LDL, does not bind to the LDL receptor that delivers cholesterol to cells throughout the body. Lipoprotein X increases hepatic cholesterol production fivefold and blocks the liver's normal removal of lipoprotein particles from the blood.

[0265] All references cited anywhere in this specification are incorporated by reference into this application in their entirety for all purposes.

[0266] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that these embodiments are provided by way of example only.

[0267] The recitation of ranges of values ​​herein, unless otherwise indicated, is intended to serve as a shorthand method of referring individually to each individual value and each endpoint within the range, and each individual value and endpoint is incorporated herein as if each individual value and endpoint were individually set forth herein.

[0268] Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be embraced therein. [Example]

[0269] The following examples illustrate specific aspects of the present description and should not be construed as limiting, as they merely provide a more specific understanding and practice of the embodiments and various aspects thereof.

[0270] Example 1: Formulation of Maralixibat This example outlines various formulations of the ASBTI maralixibat according to embodiments of the present disclosure. The formulations are shown in Table 1.

[0271] [Table 1]

[0272] Example 2: Antipruritic Agents for the Treatment of ALGS Patients with ALGS are typically treated with UDCA and rifampin, along with other off-label agents, to control or reduce pruritus symptoms. These drugs are usually only partially or temporarily effective in reducing pruritus.

[0273] Eligibility for maralixibat studies required moderate to severe pruritus, as measured by a score of 2 or greater on the ItchRO(Obs) instrument, regardless of background antipruritic therapy. In study LUM001-304, participants were not permitted to make any changes to their antipruritic therapy until week 22. In studies LUM001-301 and LUM001-302, changes to concomitant antipruritic medications were permitted throughout the primary analysis period, up to week 13. Thus, in all studies, participants had to receive a stable dose of antipruritic medication (except for weight-based dose adjustments) throughout the randomized controlled period.

[0274] Participants in LUM001-301 received 70 μg / kg / day, 140 μg / kg / day, or 280 μg / kg / day of maralixibat (as maralixibat chloride). Participants in LUM001-302 received 140 μg / kg / day or 280 μg / kg / day of maralixibat (as maralixibat chloride). Dosing in long-term LUM001-303 was 280 μg / kg QD and 280 μg / kg BID. Dosing in long-term LUM001-305 was 280 μg / kg / day.

[0275] After these stable dose periods during the long-term extension study, changes to the antipruritic medication were permitted. Weight-based dose adjustments of the antipruritic medication were planned over the course of the 5-year study.

[0276] Table 2 shows the proportion of participants receiving one or more concomitant antipruritic medications at baseline.

[0277] [Table 2]

[0278] After week 22 of Study LUM001-304, 10 of the 29 participants in the long-term extension had their concomitant antipruritic medications reduced. Of these 10 participants, 3 discontinued UDCA; 3 discontinued rifampin and UDCA; 1 discontinued rifampin and reduced UDCA; and 3 discontinued rifampin. Two participants underwent a combined medication change: stopping rifampin and increasing UDCA. Additionally, three participants had their UDCA dose increased; 1 discontinued UDCA and started rifampin; and 1 increased rifampin. The remaining participants underwent no or minimal changes in concomitant antipruritic medications.

[0279] During the stable medication period of Study LUM001-303, of the 19 participants in the long-term extension, two participants reduced their concomitant antipruritic medications: one participant discontinued both UDCA and rifampin; one participant discontinued rifampin and reduced UDCA. Five participants increased their concomitant antipruritic medications: one participant increased the doses of UDCA and rifampin; one participant started rifampin; one participant increased UDCA; and two participants increased the dose of rifampin without changing UDCA. The remaining 12 participants made no or minimal changes to their concomitant antipruritic medications.

[0280] During the stable medication period of Study LUM001-305, of the 34 participants in the long-term extension, 10 participants reduced their concomitant antipruritic medications. Of these 10 participants, 1 discontinued UDCA; 1 discontinued UDCA and rifampin; 2 discontinued rifampin; 1 reduced UDCA and continued rifampin; 1 reduced rifampin and increased UDCA by a small amount; 1 discontinued UDCA and continued rifampin; 1 discontinued rifampin and continued UDCA; 2 discontinued rifampin and increased UDCA. Seven participants increased their concomitant antipruritic medications: 2 increased the doses of UDCA and rifampin; 1 started rifampin; 2 increased the dose of rifampin; and 2 increased UDCA. The remaining 17 participants had no or minimal changes in concomitant antipruritic medications.

[0281] Nearly all participants in ALGS studies used one to three antipruritic medications and still met the inclusion criterion of moderate to severe pruritus. Overall, pruritus scores consistently improved during treatment with maralixibat over long-term follow-up. Study LUM001-304 demonstrated that a maralixibat dose of 400 μg / kg resulted in the greatest reduction in pruritus and the highest proportion of participants reducing concomitant antipruritic medications. Adjunctive ALGS studies using lower doses demonstrated similar, albeit less pronounced, effects.

[0282] These studies demonstrate that many patients receiving maralixibat in combination with UDCA and / or rifampicin were able to reduce the amount of UDCA and / or rifampicin they were receiving, indicating that a reduction in the dosage of each drug was achieved with combination therapy compared to monotherapy with UDCA or rifampicin.

[0283] Example 3: Antipruritic Agents for the Treatment of PFIC Patients with PFIC are typically treated with UDCA and rifampicin, along with other off-label agents, to control or reduce pruritus symptoms. These drugs are usually only partially or temporarily effective in reducing pruritus.

[0284] Cholestatic liver disease In an open-label study (Study LUM001-501) to evaluate the efficacy and long-term safety of maralixibat (LUM001) in treating cholestatic liver disease in patients with progressive familial intrahepatic cholestasis (PFIC), participants were not allowed to make any changes to their antipruritic therapy during the 13-week treatment period. No new drugs used to treat pruritus were added during the 13-week treatment period. Therefore, participants had to receive a stable dose of antipruritic medication (except for weight-based dose adjustments) throughout the 13-week treatment period.

[0285] During the long-term exposure period, changes to antipruritic medication were permitted.

[0286] Table 3 shows the proportion of participants receiving one or more concomitant antipruritic medications at baseline, as reported as part of their PFIC disease history.

[0287] [Table 3]

[0288] Post hoc analysis of pre- and concomitant antipruritic medication data from study LUM001-501 in the maralixibat population (N=33) showed that 26 participants (83.9%) were receiving antipruritic medications at baseline.

[0289] During the study, five participants increased the dose of antipruritic medication, three participants increased rifampicin (ItchRO(Obs) = 1-3), one participant increased UDCA and rifampicin (ItchRO(Obs) = 1), and one participant increased UDCA (ItchRO(Obs) = 2-4).

[0290] During the study, five participants underwent modifications (increase, decrease, or discontinuation) of antipruritic medications: three participants discontinued rifampicin and increased UDCA (ItchRO(Obs) = 0–2), one participant increased rifampicin and decreased UDCA (ItchRO(Obs) = 3–4), and one participant decreased rifampicin and increased UDCA (ItchRO(Obs) = 3–4).

[0291] During the study, 13 participants reduced or discontinued their antipruritic medication dose, 3 participants discontinued rifampicin (ItchRO(Obs) = 0-2), 4 participants discontinued UDCA (ItchRO(Obs) = 0-3), 2 participants discontinued UDCA and rifampicin (ItchRO(Obs) = 0-3), 1 participant reduced rifampicin (ItchRO(Obs) = 1), 2 participants reduced UDCA (ItchRO(Obs) = 1), and 1 participant discontinued rifampicin and reduced UDCA (ItchRO(Obs) = 2).

[0292] Figures 3A-3E are plots of ItchRO versus doses of maralixibat and selected antipruritic agents for five exemplary PFIC patients enrolled in the LUM001-501 study. These figures demonstrate that patients were able to maintain pruritus control with maralixibat while not only reducing the dosage of but completely discontinuing one or more antipruritic agents. Specifically, Figure 3A shows that patients maintained excellent pruritus control even after discontinuing both rifampicin and UDCA. Figures 3B and 3C show that patients maintained excellent pruritus control even after discontinuing rifampicin. Figures 3D and 3E show that patients maintained pruritus control even after discontinuing UDCA.

[0293] Overall, more participants experienced an overall improvement in pruritus as demonstrated by a decrease in ItchRO(Obs) scores over the sustained follow-up period while reducing and / or discontinuing antipruritic medications, indicating that medication dosage reductions were achieved with combination therapy.

[0294] Example 4: Development of Maralixibat Oral Solution Because the proposed target patient population for cholestatic disease is pediatric patients, an oral solution formulation was chosen due to the flexibility of dose adjustment based on patient weight and the preference of young children for this type of formulation. Maralixibat chloride is highly water-soluble, with a solubility in water of greater than 100 mg / mL, making it an excellent candidate for a solution formulation.

[0295] Therefore, oral solutions (fixed dosage volume, or "FDV," and fixed drug substance concentration, or "FDSC," formulations) using maralixibat chloride were developed to support the formulation of the final marketed drug product. The development of these oral solution formulations is described below.

[0296] Example 4: Fixed Dose Volume (FDV) Formulations soluble For early pediatric clinical trials, the desired maralixibat solution concentration was 0.02 to 20 mg / mL (based on maralixibat chloride). Initial formulation studies were conducted to determine the solubility and stability of the MRX drug substance in three liquid oral dosing vehicles: water, Pedialyte® (oral rehydration agent), and Ora-Sweet® SF (a sugar- and alcohol-free syrup vehicle for oral preparations). Using these three vehicles, samples were prepared at three different concentrations of the MRX drug substance (0.02 mg / mL, 2.0 mg / mL, and 4.0 mg / mL based on maralixibat chloride). After dispersing the drug in the liquid vehicle using a vortex mixer, the drug dissolution was visually inspected and recorded as shown in Table 4.

[0297] [Table 4]

[0298] As presented in Table 4, the results showed that of the three vehicles, only water was the solvent that provided acceptable solubility for the maralixibat drug substance. To take advantage of the taste-masking properties of Ora-Sweet®, the vehicle was mixed with a portion of a 4.0 mg / mL MRX solution in water. Upon addition, gel formation and phase separation of the material were observed. Heating the mixture in a water bath did not result in any improvement in the appearance of the formulation.

[0299] Solvent System It was found that commercially available oral vehicles alone could not provide sufficient solubility for the MRX drug substance at the desired concentration. Different solvents and their combinations were investigated to find the optimal vehicle for the MRX substance. Polyethylene glycol (PEG) 300, propylene glycol, glycerin, water, and ethanol were evaluated. The visual observations of the solubility of the MRX drug substance at a concentration of 4 mg / mL using various solvents are provided in Table 5.

[0300] [Table 5]

[0301] Based on the results presented in Table 5, the combination of propylene glycol, water, and ethanol provided the most preferred option for the development of a solution formulation of maralixibat. However, because the formulation is intended for pediatric use, ethanol was omitted from the solvent system. fragrance ( Grape Flavor F-9924 PFC) was added as a sweetener and a taste-masking agent, respectively.

[0302] Five prototype solvent systems were investigated for the maralixibat drug substance, as presented in Table 6.

[0303] [Table 6]

[0304] The prototype solvent system was prepared by mixing multiple solvents to form a solvent mixture, followed by sucralose and Grape Flavor To produce an active solution, an aliquot of the prototype solvent system was added with a specific amount of MRX drug substance (to achieve the desired dose). includeThe mixture was added to a vial and mixed manually. A concentration of 4.0 mg / mL (maralixibat chloride) was initially targeted as the highest dose for development. Prototype 5 was selected as the diluent for further drug product formulation development.

[0305] Diluent A bulk diluent of Prototype 5 was prepared and used to manufacture two MRX oral solution formulations at 0.02 mg / mL and 4.0 mg / mL (concentrations expressed as maralixibat chloride). As suggested by the short-term stability results (Tables 7 and 8 below), no changes in assay, pH, or impurity profile were observed for both solutions stored at 2°C-8°C and 25°C / 60% RH for up to 14 days. As clinical development progressed, larger quantities of MRX drug substance were required to account for proposed changes in dosing regimens. Grape Flavor The content of was also reduced from 0.75 w / w% to 0.5 w / w% in the formulation. The final composition of the diluent that can be used with the MRX drug substance for the MRX oral solution is presented in Table 9.

[0306] [Table 7]

[0307] [Table 8]

[0308] [Table 9]

[0309] soluble Additional studies were conducted to evaluate a wider concentration range of maralixibat solutions. MRX oral solutions were prepared and evaluated at concentrations ranging from 10 mg / mL to 50 mg / mL (based on maralixibat chloride) using the diluents listed in Table 9. All solutions became clear after mixing at room temperature for several hours. These prepared solutions are referred to as fixed dose volume (FDV) formulations.

[0310] Representative long-term stability of diluents for MRX oral solution at 25° C. / 60% RH is presented below in Table 10A.

[0311] [Table 10A]

[0312] The results of this stability study met the acceptance criteria applicable at the time of the study, and therefore indicate that all quality attributes of the diluent for MRX Oral Solution are stable for up to 24 months when stored at 25°C / 60% RH.

[0313] These FDV formulations were stable for up to 24 months at 2°C-8°C and 25°C / 60% RH. Table 10B provides the stability design for the FDV formulations. Table 11 provides a summary of the solution, container closure, and stability storage conditions for the manufactured batches. The stability data met applicable acceptance criteria at the time of testing and therefore supported the use of the FDV formulations at concentrations up to 50 mg / mL (shown as maralixibat chloride) for applicable clinical studies at this time.

[0314] [Table 10B]

[0315] [Table 11]

[0316] [Table 12]

[0317] [Table 13]

[0318] [Table 14]

[0319] [Table 15]

[0320] [Table 16]

[0321] [Table 17]

[0322] [Table 18]

[0323] Freeze-thaw research A freeze-thaw study was conducted using a 10 mg / mL (malalixibat chloride-based) FDV formulation. The solution was cycled from -20°C for 24 hours to room temperature for 5 hours, with samples tested at the end of the fifth cycle. The results are provided in Table 19 and demonstrate that the FDV formulation is stable for up to five freeze-thaw cycles.

[0324] [Table 19]

[0325] Conclusions regarding the development of FDV formulations Based on the above results, the FDV formulation was established and used in the clinical study as presented in Table 20. MRX oral solution was originally prepared for each patient at Quotient Sciences based on the patient's weight and target dose. The required amount of maralixibat chloride was added to 30 mL of grape-flavored diluent (Table 9). include The solution was added to a clear borosilicate glass vial and mixed to form a clear solution. Each vial was visually inspected for a clear solution prior to administration. include Vials were shipped refrigerated (2°C to 8°C) to the clinical site for administration according to the applicable study dosing instructions.

[0326] The FDV formulation was used in a phase 2 clinical study, including clinical studies of the proposed indication. The diluent for the phase 2 clinical supply was manufactured by Formex (San Diego, CA), and the drug was prepared by Quotient Sciences (UK).

[0327] [Table 20]

[0328] Example 5: Fixed Drug Substance Concentration (FDSC) Formulation For the ongoing clinical study and in preparation for the registration campaign (primary stability), multiple strengths (5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 40 mg / mL, and 50 mg / mL; maralixibat chloride-based concentrations) of ready-to-use MRX oral solution were developed and manufactured at Unither; four (5 mg / mL, 10 mg / mL, 15 mg / mL, and 20 mg / mL; maralixibat chloride-based concentrations) were manufactured on a larger scale at Halo. This ready-to-use MRX oral solution is a fixed drug substance concentration (FDSC) formulation developed based on the FDV formulation (Example 4).

[0329] Because maralixibat is minimally absorbed and the volume of the administered liquid formulation is small (≤3.0 mL per dose), excipient modifications between the FDV and FDSC formulations are not expected to affect bioavailability or efficacy. The commercial formulation was developed by making minor adjustments to the component quantities of the FDSC formulation to compensate for slight bias to the above-target assay and to normalize excipient levels across multiple formulation strengths during development.

[0330] Propylene Glycol Level Adjustment Propylene glycol is recognized as an effective antibacterial and antifungal agent in liquid and semisolid preparations. As in the FDV formulation (Example 4), this excipient serves the following dual function in the MRX oral solution: cosolvent and preservative. To evaluate the antimicrobial effectiveness (AET) of the FDV formulation, MRX oral solutions at 5 mg / mL (concentration based on maralixibat chloride) were prepared at propylene glycol levels of 25 w / w%, 30 w / w%, and 35 w / w%. This AET study was conducted in accordance with the United States Pharmacopoeia (USP). <51> and was carried out in accordance with European Pharmacopoeia 5.1.3.

[0331] The results, shown in Table 21, demonstrate that formulations containing up to 30 wt% propylene glycol met the USP acceptability criteria for the oral solution AET test but did not meet the European Pharmacopoeia acceptability criteria (Table 22). Both the USP and European Pharmacopoeia acceptability criteria were met only when the propylene glycol level was increased to 35 wt%. Therefore, the amount of propylene glycol in the MRX oral solution was adjusted from 25% in the FDV formulation to 35 wt%.

[0332] [Table 21]

[0333] [Table 22]

[0334] Although the stability results summarized in Example 4 indicated that the FDV formulation had acceptable stability for clinical use, levels of the oxidative degradant impurity desmethylmalalixibat chloride increased over time in the FDV formulation. Desmethylmalalixibat chloride is an oxidative degradant consistently observed in drug substance synthesis, drug product stability, and forced degradation studies.

[0335] During the initial development process, two types of mixing vessels for solution compounding, glass and stainless steel, were used and compared for their potential impact on product stability. Elevated levels of desmethylmalalixibat chloride were observed when MRX Oral Solution (50 mg / mL) was compounded in either glass or stainless steel containers and stored at room temperature for up to 14 days. However, solutions stored in stainless steel containers were found to have higher desmethylmalalixibat chloride levels compared to those stored in glass jars (Table 23). This suggests that metal containers may accelerate oxidative degradation.

[0336] [Table 23]

[0337] Two replicate measurements were performed at each time point.

[0338] To prevent drug oxidation, disodium ethylenediaminetetraacetic acid (EDTA) dihydrate was evaluated as a potential antioxidant in MRX oral solution. A laboratory-scale stability study was conducted in which disodium EDTA dihydrate was added to MRX oral solution (50 mg / mL, based on maralixibat chloride) at levels of 0 w / w%, 0.01 w / w%, and 0.05 w / w%, and the level of the oxidized impurity (desmethylmalalixibat chloride) was monitored at 25°C and 40°C for up to 1 month. The results of this study (Figure 2) showed that the level of desmethylmalalixibat chloride in MRX oral solution decreased with increasing concentrations of disodium EDTA dihydrate. At a disodium EDTA dihydrate concentration of 0.05 w / w%, no significant increase in desmethylmalalixibat chloride was observed after storage of the solution for 4 weeks at 25°C, and a slight increase was observed after storage for 2 weeks at 40°C. To further ensure the stability of the MRX oral solution, 0.1 w / w% disodium EDTA dihydrate was selected for inclusion in the drug product.

[0339] To confirm that edetate disodium dihydrate is effective in preventing the oxidative degradation of maralixibat chloride when the solutions are formulated in stainless steel containers, a study was conducted to compare the levels of desmethylmalalixibat chloride degradation products in MRX oral solutions with and without edetate disodium dihydrate. Briefly, MRX oral solutions with and without edetate were formulated in stainless steel containers and stirred for at least 2 hours at 30°C (worst-case scenario). The MRX oral solutions were packaged in 30 mL polyethylene terephthalate (PET) bottles with child-resistant caps and induction seals. The levels of desmethylmalalixibat chloride in the packaged drug product were monitored over time at 40°C / 75% RH. The compositions of the two solutions are provided in Table 24, and the results of the study are summarized in Table 25.

[0340] [Table 24]

[0341] [Table 25]

[0342] The results of this study show that at time zero, solutions containing edetate disodium dihydrate have much lower levels of the desmethylmalalixibat chloride oxidation impurity compared to solutions without this excipient (0.07% vs. 0.69%). When stored under accelerated aging conditions, the level of desmethylmalalixibat chloride in solutions containing edetate disodium dihydrate increased slowly from 0.07% to 1.52% over 5 months. However, in solutions without edetate disodium dihydrate, the level of desmethylmalalixibat chloride increased significantly from 0.69% to 23.15% over 5 months. In conclusion, the addition of 0.1 w / w% edetate disodium dihydrate effectively prevents the degradation of MRX in solution formulations, even when stainless steel vessels are used for compounding equipment.

[0343] Composition of FDSC formulation Based on the results of the study of the antimicrobial effect of propylene glycol and the antioxidant effect of disodium EDTA dihydrate, the MRX oral solution formulation was optimized and the composition was established as shown in Table 26. The MRX oral solution was manufactured as a directly usable, ready-to-use fixed drug substance concentration (FDSC) formulation.

[0344] In addition to increasing the propylene glycol level and adding disodium EDTA to the solution formulation, the level of sweetener (sucralose) in the FDSC formulation was increased slightly (from 0.75 w / w% to 1.0 w / w%).

[0345] [Table 26]

[0346] [Table 27]

[0347] Conclusions regarding the development of FDSC formulations In conclusion, a ready-to-use FDSC formulation of MRX oral solution was developed based on the composition of the FDV formulation used in early pediatric clinical studies, including a Phase 2 study for the proposed indication. Three formulation changes were made during development: 1. The propylene glycol level was increased from 25 w / w% to 35 w / w%, which effectively improved the antibacterial effect of the formulation. 2. Addition of edetate disodium dihydrate at a level of 0.1 w / w% as an antioxidant effectively inhibited the growth of the decomposition product desmethylmalalixibat chloride. 3. The level of sucralose, a common sweetener, was increased from 0.75 w / w% to 1 w / w%.

[0348] The resulting FDSC formulations have been demonstrated to be stable over a wide concentration range and upon storage at 2°C-8°C and 25°C / 60% RH. Bottle orientation and freeze-thaw cycling did not significantly affect the solution stability and overall performance of the drug product.

[0349] Example 6: Evaluation of the efficacy of combination therapy with an ASBT inhibitor and a PPAR agonist in a preclinical model of sclerosing cholangitis Both inhibition of ileal bile acid transporters (IBATs), which interrupt the enterohepatic circulation of bile acids (BAs), and activation of peroxisome proliferator-activated receptors (PPARs), which regulate BA synthesis, conjugation, and transport, have emerged as potential treatments for sclerosing cholangitis (SC), including PSC and PBC. Here, we test the hypothesis that combining these therapeutic modalities would improve efficacy over monotherapy in an MDR2- / - mouse model of SC.

[0350] Methods: Thirty-day-old female MDR2- / - mice (FVB background) were treated daily by oral gavage for 14 days with vehicle control (corifol and CMC), 100 mg / kg / day bezafibrate (pan-PPAR agonist), 100 mg / kg / day fenofibrate (PPARα agonist), 10 mg / kg / day seradelpar (PPARδ agonist), 0.008% SC-435 (a non-absorbable IBAT inhibitor) mixed in the feed, or a combination of SC-435 and a PPAR agonist.

[0351] Results: Compared with wild-type (WT) mice, the liver-to-body weight ratio was nearly doubled in MDR2- / - mice, which was not reduced by PPAR agonist monotherapy but was attenuated by IBATi and combination therapy. Liver and serum BA and biochemistry were significantly elevated in vehicle-treated MDR2- / - mice compared with WT mice (mean ± SE: liver BA: 930 ± 84 nmol / g, serum BA: 336 ± 40 μM, ALT: 1275 ± 47 IU / L, total bilirubin [TB]: 2.0 ± 0.4 mg / dL, ALP: 296 ± 17 IU / L) (Figure 4). PPAR agonists and IBATi significantly reduced BA retention in the liver, but only fenofibrate and IBATi, alone or in combination with PPAR agonists, reduced serum BA concentrations. All treatments except fenofibrate reduced serum ALT levels. IBATi treatment reduced serum TB concentrations, whereas monotherapy with a PPAR agonist did not. In contrast to studies in mice of other backgrounds, serum ALP was elevated by IBATi treatment alone and further elevated by combination with a fibrate in this FVB background mouse. ALP was not elevated by the combination of IBATi and a PPARδ agonist. Serum ALP levels correlated with bile volume and bile duct proliferation, as assessed by CK19 immunohistochemistry.

[0352] Conclusions: IBATi are more potent than PPAR agonists in reducing serum total BA and TB levels, markers of cholestasis. Combination therapy with IBATi and a PPARδ agonist shows synergistic effects in the above-mentioned mouse model of SC. Further preclinical investigations may help to better understand the mechanisms underlying this synergy and potential side effects and guide their use in clinical trials.

[0353] Since various changes can be made in the above-described subject matter without departing from the scope and spirit of the invention, it is intended that all subject matter contained in the above description or defined in the appended claims be interpreted as illustrative and exemplary of the invention. Numerous modifications and variations of the present invention are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variations that are within the scope of the appended claims.

[0354] All patents, patent applications, publications, test methods, literature, and other materials cited herein are incorporated by reference in their entirety into this application as if physically present herein. Finally, preferred embodiments of the present invention are described in sections. [Embodiment 1] A pharmaceutical composition comprising an ASBTI, a preservative, and an antioxidant. [Embodiment 2] The ASBTI is [ka] or a pharmaceutically acceptable salt thereof. [Embodiment 3] The ASBTI is [ka] 3. The pharmaceutical composition of embodiment 1 or 2, wherein [Embodiment 4] 3. The pharmaceutical composition of any one of claims 1 to 2, wherein the ASBTI is vorixibat or a pharmaceutically acceptable salt thereof. [Embodiment 5] 3. The pharmaceutical composition of any one of embodiments 1 to 2, wherein the ASBTI is odevixibat or a pharmaceutically acceptable salt thereof. [Embodiment 6] 3. The pharmaceutical composition of any one of embodiments 1 to 2, wherein the ASBTI is elobixibat or a pharmaceutically acceptable salt thereof. [Embodiment 7] 3. The pharmaceutical composition of embodiment 1 or 2, wherein the ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof. [Embodiment 8] 8. The pharmaceutical composition of any of embodiments 1-7, wherein the ASBTI is present in an amount of from about 0.1 mg / mL to about 500 mg / mL of the composition. [Embodiment 9] 9. The pharmaceutical composition of any of embodiments 1-8, wherein the ASBTI is present in an amount of from about 1 mg / mL to about 250 mg / mL of the composition. [Embodiment 10] 10. The pharmaceutical composition of any of embodiments 1-9, wherein the ASBTI is present in an amount of about 2 mg / mL to about 100 mg / mL of the composition. [Embodiment 11] 11. The pharmaceutical composition of any of embodiments 1-10, wherein the ASBTI is present in an amount of about 5 mg / mL to about 50 mg / mL of the composition. [Embodiment 12] 12. The pharmaceutical composition of any of embodiments 1-11, wherein the ASBTI is present in an amount of about 8 mg / mL to about 20 mg / mL of the composition. [Embodiment 13] 13. The pharmaceutical composition of any of embodiments 1-12, wherein the ASBTI is present in an amount of about 9 mg / mL to about 10 mg / mL of the composition. [Embodiment 14] 14. The pharmaceutical composition according to any one of embodiments 1 to 13, wherein the preservative is an antimicrobial preservative. [Embodiment 15] 15. The pharmaceutical composition of embodiment 14, wherein the antimicrobial preservative is selected from the group consisting of propylene glycol, ethyl alcohol, glycerin, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimide (cetyltrimethylammonium bromide), cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, potassium sorbate, thimerosal, thymol, and combinations thereof. [Embodiment 16] 16. The pharmaceutical composition of any of embodiments 1-15, wherein the preservative is propylene glycol. [Embodiment 17] 17. The pharmaceutical composition of any of embodiments 1-16, wherein the preservative is present in an amount of at least about 30 w / w% of the composition. [Embodiment 18] 18. The pharmaceutical composition of any of embodiments 1 to 17, wherein the preservative is present in an amount of about 30% to about 40% of the composition. [Embodiment 19] 19. The pharmaceutical composition of any of embodiments 1-18, wherein the preservative is present in an amount of about 32% to about 37% of the composition. [Embodiment 20] 20. The pharmaceutical composition of any of embodiments 1-19, wherein the preservative is present in an amount of about 33% to about 36% of the composition. [Embodiment 21] 21. The pharmaceutical composition of any of embodiments 1-20, wherein the preservative is present in an amount of about 33% of the composition. [Embodiment 22] 21. The pharmaceutical composition of any of embodiments 1-20, wherein the preservative is present in an amount of about 34% of the composition. [Embodiment 23] 21. The pharmaceutical composition of any of embodiments 1-20, wherein the preservative is present in an amount of about 35% of the composition. [Embodiment 24] 24. The pharmaceutical composition of any of the preceding claims, wherein the antioxidant is selected from the group consisting of aminocarboxylic acids, aminopolycarboxylic acids, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, and combinations thereof. [Embodiment 25] 25. The pharmaceutical composition of any one of embodiments 1 to 24, wherein the antioxidant is an aminopolycarboxylic acid selected from EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), NTA (nitrilotriacetic acid), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), NOTA (2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid), DOTA (tetracarboxylic acid), and EDDHA (ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid). [Embodiment 26] 26. The pharmaceutical composition of any one of embodiments 1 to 25, wherein the antioxidant is EDTA. [Embodiment 27] 27. The pharmaceutical composition of any of embodiments 1-26, wherein the antioxidant is present in an amount of about 0.001 w / w% to about 1 w / w% of the composition. [Embodiment 28] 28. The pharmaceutical composition of any of embodiments 1-27, wherein the antioxidant is present in an amount of about 0.005 w / w% to about 0.75 w / w% of the composition. [Embodiment 29] 29. The pharmaceutical composition of any of embodiments 1-28, wherein the antioxidant is present in an amount of about 0.01 w / w% to about 0.5 w / w% of the composition. [Embodiment 30] 30. The pharmaceutical composition of any of embodiments 1-29, wherein the antioxidant is present in an amount of about 0.05 w / w% to about 0.25 w / w% of the composition. [Embodiment 31] 31. The pharmaceutical composition of any of the preceding embodiments, wherein the antioxidant is present in an amount of about 0.075 w / w% to about 0.2 w / w% of the composition. [Embodiment 32] 32. The pharmaceutical composition of any of embodiments 1-31, wherein the antioxidant is present in an amount of about 0.1 w / w% of the composition. [Embodiment 33] 33. The pharmaceutical composition of any of embodiments 1-32, wherein the composition is stable at room temperature for at least one month. [Embodiment 34] 34. The pharmaceutical composition of any of embodiments 1-33, wherein the composition is stable at room temperature for at least 2 months. [Embodiment 35] 35. The pharmaceutical composition of any of embodiments 1-34, wherein the composition is stable at room temperature for at least 3 months. [Embodiment 36] 36. The pharmaceutical composition of any of embodiments 1-35, wherein the composition is stable at room temperature for at least 6 months. [Embodiment 37] 36. The pharmaceutical composition of any of embodiments 1-35, wherein the composition is stable at room temperature for at least 1 year. [Embodiment 38] 36. The pharmaceutical composition of any of embodiments 1-35, wherein the composition is stable at room temperature for at least 2 years. [Embodiment 39] 39. The pharmaceutical composition of any one of embodiments 1 to 38, wherein the composition is a liquid composition for oral administration. [Embodiment 40] 39. The pharmaceutical composition of embodiment 38, wherein the composition is an aqueous solution. [Embodiment 41] 41. The pharmaceutical composition of any one of embodiments 1-40, further comprising a sweetener, a taste-masking ingredient, or a combination thereof. [Embodiment 42] a. About 5 mg / mL to about 50 mg / mL of maralixibat; b. about 300 mg / mL to about 400 mg / mL propylene glycol; c. approximately 1 mg / mL disodium EDTA; d. sweeteners, taste-masking ingredients, or combinations thereof; and e.Water A pharmaceutical composition comprising: [Embodiment 43] a. About 8 mg / mL to about 20 mg / mL of maralixibat; b. about 330 mg / mL to about 380 mg / mL propylene glycol; c. approximately 1 mg / mL disodium EDTA; d. sweeteners, taste-masking ingredients, or combinations thereof; and e.Water 43. The pharmaceutical composition of embodiment 42, comprising: [Embodiment 44] 44. The pharmaceutical composition according to any of embodiments 1-43, wherein maralixibat is present as maralixibat chloride. [Embodiment 45] 44. The pharmaceutical composition according to any of embodiments 1 to 43, further comprising a second therapeutic agent. [Embodiment 46] 45. The pharmaceutical composition of embodiment 44, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), rifampicin, an antihistamine, or an FXR-targeted drug. [Embodiment 47] 47. A pharmaceutical dosage form for oral administration comprising the pharmaceutical composition according to any one of embodiments 1 to 46. [Embodiment 48] 47. A method for treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1 to 46, or a pharmaceutical dosage form according to embodiment 47. [Embodiment 49] The pediatric cholestatic liver diseases include progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai operation, biliary atresia after liver transplantation, Dubin-Johnson syndrome, post-liver transplant cholestasis, post-liver transplant-related liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis (PSC), MRP2 deficiency syndrome, and neonatal sclerosing cholangitis. 49. The method of embodiment 48, wherein the cholestasis is pediatric biliary obstructive cholestasis, pediatric non-biliary obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis. [Embodiment 50] 50. The method of embodiment 48 or 49, wherein the pediatric cholestatic liver disease is PFIC, ALGS, BA, or pediatric PSC. [Embodiment 51] 51. The method of any of embodiments 48-50, wherein the pediatric cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholic acidemia, neonatal respiratory distress syndrome, pneumonia, elevated serum levels of bile acids, elevated intrahepatic levels of bile acids, elevated serum levels of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, characteristic odor, dark urine, light stools, steatorrhea, failure to thrive, and renal failure. [Embodiment 52] A method for treating or ameliorating pruritus, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1 to 46, or a pharmaceutical dosage form according to embodiment 47. [Embodiment 53] A method for treating or ameliorating hypercholic acidemia, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1 to 46, or a pharmaceutical dosage form according to embodiment 47. [Embodiment 54] A method for treating or ameliorating xanthomas, comprising administering to a pediatric subject a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1 to 46, or a pharmaceutical dosage form according to embodiment 47. [Embodiment 55] A method for reducing serum or intrahepatic bile levels in a subject, comprising administering to the pediatric subject a therapeutically effective amount of a pharmaceutical composition according to any of embodiments 1 to 46, or a pharmaceutical dosage form according to embodiment 47. [Embodiment 56] A method according to any one of embodiments 48 to 55, wherein the pediatric subject is aged between 6 months and 18 years. [Embodiment 57] 57. The method of any of embodiments 48 to 56, further comprising administering a second therapeutic agent. [Embodiment 58] 58. The method of embodiment 57, wherein the second therapeutic agent is UDCA, rifampicin, an antihistamine, an FXR targeted drug, a PPAR agonist, or a combination thereof. [Embodiment 59] 59. The method of embodiment 57 or 58, wherein the second therapeutic agent is administered in a subclinical therapeutically effective amount. [Embodiment 60] 47. A method for treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of the pharmaceutical composition of any of embodiments 1 to 46, or the pharmaceutical dosage form of embodiment 47, in combination with a subclinically therapeutically effective amount of a second therapeutic agent selected from the group consisting of UDCA, rifampicin, an antihistamine, an FXR-targeted drug, and a PPAR agonist. [Embodiment 61] 61. The method of embodiment 60, wherein the subclinical therapeutically effective amount of the second therapeutic agent is at least 10% less than the amount of the second therapeutic agent administered as a monotherapy. [Embodiment 62] 61. The method of embodiment 60, wherein the subclinical therapeutically effective amount of the second therapeutic agent is at least 20% less than the amount of the second therapeutic agent administered as a monotherapy. [Embodiment 63] The method of embodiment 60, wherein the second therapeutic agent is UDCA or rifampicin. [Embodiment 64] The method of embodiment 60, wherein the subject discontinues administration of the second therapeutic agent without increasing pruritus. [Embodiment 65] The method of embodiment 60, wherein the second therapeutic agent is a PPAR agonist. [Embodiment 66] 66. The method of embodiment 65, wherein the PPAR agonist is selected from bezafibrate, seladelpar (MBX-8025), GW501516 (cardarine), fenofibrate, elafibranor, REN001, KD3010, ASP0367, and CER-002. [Embodiment 67] The method of embodiment 65, wherein the PPAR agonist is a PPARδ agonist. [Embodiment 68] 68. The method of embodiment 67, wherein the PPARδ agonist is selected from seladelpar (MBX-8025), REN001, KD3010, ASP0367, and CER-002. [Embodiment 69] A method of treating or ameliorating pediatric cholestatic liver disease, comprising administering to a pediatric subject a therapeutically effective amount of maralixibat in combination with a therapeutically effective amount of a PPAR agonist. [Embodiment 70] 70. The method of embodiment 69, wherein the PPAR agonist is selected from bezafibrate, seladelpar (MBX-8025), GW501516 (cardarine), fenofibrate, elafibranor, REN001, KD3010, ASP0367, and CER-002. [Embodiment 71] The method of embodiment 69, wherein the PPAR agonist is a PPARδ agonist. [Embodiment 72] 72. The method of embodiment 71, wherein the PPARδ agonist is selected from seladelpar (MBX-8025), REN001, KD3010, ASP0367, and CER-002. [Embodiment 73] 70. The method of embodiment 69, wherein the pediatric cholestatic liver disease is sclerosing cholangitis. [Embodiment 74] 70. The method of embodiment 69, wherein said pediatric cholestatic liver disease is selected from PSC and PBC. 。

Claims

1. a. about 5 mg / mL to about 50 mg / mL of maralixibat; b. about 300 mg / mL to about 400 mg / mL propylene glycol; c. about 1 mg / mL disodium EDTA; d. a sweetener, a taste-masking ingredient, or a combination thereof; and e. water A pharmaceutical composition comprising:

2. a. about 8 mg / mL to about 20 mg / mL of maralixibat; b. about 330 mg / mL to about 380 mg / mL propylene glycol; c. about 1 mg / mL disodium EDTA; d. a sweetener, a taste-masking ingredient, or a combination thereof; and e. water 2. The pharmaceutical composition of claim 1, comprising:

3. 10. The pharmaceutical composition of claim 1, wherein the maralixibat is present as maralixibat chloride.

4. The pharmaceutical composition of claim 1, wherein the sweetener, taste-masking ingredient, or combination thereof comprises grape flavor.

5. The pharmaceutical composition of claim 1, which is stable at room temperature for at least one year.

6. The pharmaceutical composition of claim 1, which is stable at room temperature for at least two years.

7. 10. The pharmaceutical composition of claim 1, further comprising a second therapeutic agent.

8. 8. The pharmaceutical composition of claim 7, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), rifampicin, an antihistamine, or an FXR-targeted drug.

9. A pharmaceutical dosage form for oral administration comprising the pharmaceutical composition of any one of claims 1 to 8.

10. A pharmaceutical composition described in any one of claims 1 to 8, for use in a method for treating or ameliorating pediatric cholestatic liver disease, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a pediatric subject.

11. The pediatric cholestatic liver diseases include progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome (ALGS), biliary atresia (BA), biliary atresia after Kasai operation, biliary atresia after liver transplantation, Dubin-Johnson syndrome, post-liver transplant cholestasis, post-liver transplant-related liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis (PSC), MRP2 deficiency syndrome, neonatal sclerosing cholangitis, 11. The pharmaceutical composition of claim 10, wherein the cholestasis is pediatric biliary obstructive cholestasis, pediatric non-biliary obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis.

12. 12. The pharmaceutical composition of claim 11, wherein the pediatric cholestatic liver disease is PFIC, ALGS, BA, or pediatric PSC.

13. 11. The pharmaceutical composition of claim 10, wherein the pediatric cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholic acidemia, neonatal respiratory distress syndrome, pneumonia, elevated serum levels of bile acids, elevated intrahepatic levels of bile acids, elevated serum levels of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, characteristic odor, dark urine, light-colored stools, steatorrhea, failure to thrive, and renal failure.

14. A pharmaceutical composition for use in a method for treating or ameliorating pruritus, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a pediatric subject, the pharmaceutical composition being described in any one of claims 1 to 8.

15. The pharmaceutical composition described in claim 14, wherein the pediatric subject has pediatric cholestatic liver disease.

16. A pharmaceutical composition for use in a method for treating or ameliorating pediatric cholestatic liver disease, the method comprising administering to a pediatric subject a therapeutically effective amount of the pharmaceutical composition in combination with a subclinically therapeutically effective amount of a second therapeutic agent, the second therapeutic agent being selected from the group consisting of UDCA, rifampicin, an antihistamine, an FXR targeted drug, and a PPAR agonist.

17. 17. The pharmaceutical composition of claim 16, wherein the subclinical therapeutically effective amount of the second therapeutic agent is at least 10% less than the amount of the second therapeutic agent administered as a monotherapy.

18. 11. The pharmaceutical composition of claim 10, wherein the pediatric subject is between 6 months and 18 years old.

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