Classifications

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  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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Definitions

• compositions and methods for treating or ameliorating a pediatric cholestatic liver disease or pediatric cholestasis comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a composition comprising an Apical Sodium- dependent Bile Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating a pediatric cholestatic liver disease comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a pediatric dosage form comprising an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof.
• ASBTI Apical Sodium-dependent Bile Transporter Inhibitor
• methods for treating or ameliorating a pediatric cholestatic liver disease comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• pediatric dosage forms comprising a pediatric dosage of a non-systemically absorbed Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof.
• ASBTI Apical Sodium-dependent Bile Acid Transporter Inhibitor
• pediatric dosage forms comprising any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof described herein.
• pediatric dosage forms comprising any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof and a second agent described herein.
• compositions and methods for treating or ameliorating pruritis comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating pruritis comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for treating or ameliorating pruritis comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating pruritis comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• compositions and methods for treating or ameliorating pediatric hypercholemia comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating pediatric hypercholemia comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for treating or ameliorating pediatric hypercholemia comprising non-systemically administering to a pediatric patient a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are methods for treating or ameliorating pediatric hypercholemia comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non- systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• compositions and methods for lowering serum bile acid are provided herein.
• provided herein are methods for decreasing serum bile acid levels or concentrations or hepatic bile acid levels or concentrations comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for decreasing serum bile acids or hepatic bile acids comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for decreasing serum bile acid levels or concentrations or hepatic bile acid levels or concentrations comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for decreasing serum bile acids or hepatic bile acids comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non- systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• compositions and methods provided herein decrease serum or hepatic bile acid levels by at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, as compared to the levels prior to administration of the compositions provided herein or as compared to control subjects.
• methods provided herein decrease serum or hepatic bile acid levels by at least 30%.
• methods provided herein decrease serum or hepatic bile acid levels by at least 25%.
• methods provided herein decrease serum or hepatic bile acid levels by at least 20%.
• methods provided herein decrease serum or hepatic bile acid levels by at least 15%.
• compositions and methods for treating or ameliorating xanthoma are provided herein.
• methods for treating or ameliorating xanthoma comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating xanthoma comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for treating or ameliorating xanthoma comprising non-systemically administering to a pediatric patient suffering from a pediatric cholestatic liver disease a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for treating or ameliorating xanthoma comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• compositions and methods decreasing serum lipoprotein X levels or concentrations comprising non-systemically administering to a pediatric patient suffering from xanthoma a therapeutically effective amount of a composition comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for decreasing serum lipoprotein X comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• provided herein are methods for decreasing serum lipoprotein X levels or concentrations comprising non-systemically administering to a pediatric patient suffering from xanthoma a therapeutically effective amount of a pediatric dosage form comprising an ASBTI or a pharmaceutically acceptable salt thereof.
• methods for decreasing serum lipoprotein X comprising administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• compositions and methods for reducing serum levels of bilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase (GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, in an individual in need thereof comprising non-systemically administering a therapeutically effective amount of a composition of an ASBTI or a pharmaceutically acceptable salt thereof.
• methods comprise administering a therapeutically effective amount of a composition comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• methods for reducing serum levels of bilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase (GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, in an individual in need thereof comprising non-systemically administering a therapeutically effective amount of a pediatric dosage form of an ASBTI or a pharmaceutically acceptable salt thereof.
• methods comprise administering a therapeutically effective amount of a pediatric dosage form comprising a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
• methods provided herein comprise administering compounds that inhibit the ASBT or any recuperative bile salt transporter.
• use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract.
• the methods provided herein reduce intraenterocyte bile acids/salts or reduce necrosis and/or damage to intestinal or hepatocellular architecture.
• the methods described herein treat or ameliorate a pediatric cholestatic liver disease by increasing intraluminal concentrations of bile acids/salts, which are then excreted in the feces, thereby reducing overall bile acid and serum bile acid or hepatic bile acid load in an individual in need thereof.
• increasing intraluminal bile acid concentrations according to methods described herein provide protection and/or control of the integrity of an individual's liver and/or intestine that has been injured by cholestasis and/or cholestatic liver disease.
• the methods described herein treat or ameliorate pruritis by increasing intraluminal concentrations, and/or reducing serum concentrations, or hepatic concentrations of bile acids/salts in an individual in need thereof.
• increasing intraluminal bile acid concentrations according to methods described herein provide protection and/or control of the integrity of an individual's liver and/or intestine that has been injured by a cholestatic liver disease.
• the methods described herein lower serum bile acid concentrations or hepatic bile acid concentrations by increasing intraluminal concentrations of bile acids/salts in an individual in need thereof.
• increasing intraluminal bile acid concentrations according to methods described herein provide protection and/or control of the integrity of an individual's liver and/or intestine that has been injured by a cholestatic liver disease.
• an ASBTI or a pharmaceutically acceptable salt thereof for use in the treatment of a pediatric cholestatic liver disease wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed.
• a pharmaceutical composition for use in the treatment of a pediatric cholestatic liver disease wherein the composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed.
• a composition provided herein is suitable for non-systemically administering to the distal ileum, colon, and/or rectum.
• an ASBTI or a pharmaceutically acceptable salt thereof for use in the treatment of pruritis in a pediatric patient suffering from a pediatric cholestatic liver disease, wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed.
• a pharmaceutical composition for use in the treatment of pruritis wherein the composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed.
• a composition provided herein is suitable for non-systemically administering to the distal ileum, colon, and/or rectum.
• an ASBTI or a pharmaceutically acceptable salt thereof for use in lowering serum bile acid concentrations or hepatic bile acid concentrations in a pediatric patient suffering from a pediatric cholestatic liver disease, wherein the ASBTI is a non-systemically absorbed or is formulated to be non-systemically absorbed.
• a pharmaceutical composition for use in lowering serum bile acid concentrations or hepatic bile acid concentrations wherein the composition comprises a pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient, wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed.
• a composition provided herein is suitable for non-systemically administering to the distal ileum, colon, and/or rectum.
• an ASBTI provided herein is minimally absorbed or formulated to be minimally absorbed.
• a pediatric dosage form of an ASBTI is non-systemically administered to the distal ileum, colon, and/or rectum of an individual in need thereof.
• an ASBTI is non-systemically administered to the ileum, colon or rectum of an individual in need thereof.
• less than 50%, less than 40%, less than 30%, less than 20%, less than 10%), less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is systemically absorbed.
• less than 10% of the ASBTl is systemically absorbed.
• less than 5% of the ASBTl is systemically absorbed.
• less than 1% of the ASBTl is systemically absorbed.
• provided herein is a method for treating a pediatric cholestatic liver disease in an individual in need thereof comprising non-systemically administering to the distal gastrointestinal tract of the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl or a pharmaceutically acceptable salt thereof.
• a method for treating pruritis in an individual in need thereof comprising non-systemically administering to the distal gastrointestinal tract of the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations in an individual in need thereof comprising non-systemically administering to the distal gastrointestinal tract of the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl or a pharmaceutically acceptable salt thereof.
• the distal gastrointestinal tract is jejunum, ileum, colon, or rectum.
• the distal gastrointestinal tract is ileum, colon, or the rectum.
• the distal gastrointestinal tract is jejunum.
• the distal gastrointestinal tract is ileum.
• the pediatric 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 biliary atresia, post-liver transplantation biliary atresia, post-liver transplantation cholestasis, post-liver transplantation associated liver disease, intestinal failure associated liver disease, bile acid mediated liver injury, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, a pediatric obstructive cholestasis, a pediatric non-obstructive cholestasis, a pediatric extrahepatic cholestasis, a pediatric intrahepatic cholestasis, a pediatric primary intrahepatic cholestasis, a pediatric primary intrahepatic
• a pediatric cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, lung pneumonia, increased serum concentration of bile acids, increased hepatic concentration of bile acids, increased serum concentration 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, peculiar smell, dark urine, light stools, steatorrhea, failure to thrive, and/or renal failure.
• the pediatric patient is a new born, a pre-term new born, an infant, a toddler, a pre-schooler, a school-age child, a pre-pubescent child, post-pubescent child, an adolescent, or a teenager under the age of eighteen.
• the pediatric patient is a new born, a pre-term new born, an infant, a toddler, a pre-schooler, or a school-age child.
• the pediatric patient is a new born, a pre-term new born, an infant, a toddler, or a pre-schooler.
• the pediatric patient is a new born, a pre-term new born, an infant, or a toddler.
• the pediatric patient is a new born, a pre-term new born, or an infant. In some embodiments, the pediatric patient is a new born. In some embodiments, the pediatric patient is an infant. In some embodiments, the pediatric patient is a toddler.
• the individual is an infant less than 2 years of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 0 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 1 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 2 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 3 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 4 to 18 months of age.
• the individual is an infant between 6 to 18 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 18 to 24 months of age. In some cases, for any of the methods and/or compositions described herein, the individual is an infant between 6 to 12 months of age. In some instances, for any of the methods and/or compositions described herein, the individual is a child of between about 2 to about 10 years of age. In some instances, the individual is less than about 10 years old. In some instances, the individual is between about 10 to about 17 years old.
• the individual is a child between 6 months to 12 years of age.
• compositions using compounds that inhibit the Apical Sodium-dependent Bile Transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recuperative bile salt transporter for treatment of a pediatric cholestatic liver disease or pruritis or for lowering serum bile acid concentrations.
• ASBT Apical Sodium-dependent Bile Transporter
• use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract.
• the methods provided herein reduce intraenterocyte bile acids/salts and/or damage to ileal or hepatocellular architecture caused by a pediatric cholestatic liver disease and/or allow for regeneration of the intestinal lining or liver.
• the bile transport inhibitors are non-systemic compounds. In other embodiments, the bile acid transporter inhibitors are systemic compounds delivered non-systemically. In other embodiments, the bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein enhance enteroendocrine peptide secretion by intestinal L-cells. [0028] In some embodiments of the methods described above, the ASBTl is a compound of Formula I or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, the ASBTl is a compound of Formula II or a pharmaceutically acceptable salt thereof, as described herein.
• the ASBTl is a compound of Formula III or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, the ASBTl is a compound of Formula IV or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, the ASBTl is a compound of Formula V or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, the ASBTl is a compound of Formula VI or Formula VID or a pharmaceutically acceptable salt thereof, as described herein.
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula I or a pharmaceutically acceptable salt thereof.
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula I or a pharmaceutically acceptable salt thereof.
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula I or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula I or a pharmaceutically acceptable salt thereof.
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula II or a pharmaceutically acceptable salt thereof.
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula II or a pharmaceutically acceptable salt thereof.
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTl of Formula II or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula II or a pharmaceutically acceptable salt thereof.
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula III or a
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula III or a
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula III or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula III or a pharmaceutically acceptable salt thereof.
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula TV or a
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula TV or a
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula IV or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula IV or a pharmaceutically acceptable salt thereof.
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula V or a
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula V or a
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula V or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula V or a
• provided herein is a method for treating or ameliorating a pediatric cholestatic liver disease comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula VI or a
• a method for treating or ameliorating pruritis comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula VI or a
• provided herein is a method for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a pediatric cholestatic liver disease comprising non-systemically administering to the individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula VI or a pharmaceutically acceptable salt thereof.
• a method for lowering serum bile acid concentrations or hepatic bile acid concentration comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric dosage form of an ASBTI of Formula VI or a pharmaceutically acceptable salt thereof.
• an ASBTI is any compound described herein that inhibits recycling of bile acids/salts in the gastrointestinal tract of an individual.
• an ASBTI is (-)-(3R, 5R)- trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,4-benzothiazepinel ,l -dioxide;
• an ASBTI is l -[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- l ,l -dioxido-l -benzothiepin-5-yl]phenoxy]butyl]4-aza-l -azoniabicyclo[2.2.2]octane methane sulfonate salt ("Compound 100B”) or any other salt or analog thereof.
• an ASBTI is N, N- dimethylimido-dicarbonimidic diamide (“Compound lOOC”) or any salt or analog thereof.
• an ASBTI is any commercially available ASBTI including but not limited to SD-5613, A- 3309, 264W94, S-8921 , SAR-548304, BARI-1741 , HMR-1453, TA-7552, R-146224, or SC-435.
• an ASBTI is l ,l -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)-a-[N-((R)-l -carboxy-2- methylthio-ethyl)carbamoyl]-4-hydroxybenzyl ⁇ carbamoylmethoxy)-2,3,4,5-tetrahydro-l ,2,5- benzothiadiazepine; 1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)- a-[N-((S)-l -carboxy-2-(R)- hydroxypropyl)carbamoyl] -4-hydroxybenzyl ⁇ carbamoylmethoxy)-2,3 ,4,5 -tetrahydro- 1 ,2,5 - benzothiadiazepine; l ,l -
• an ASBTI is 264W94 (Glaxo), SC-435 (Pfizer), SD-5613 (Pfizer), or A3309 (Astra-Zeneca).
• methods provided herein further comprise administration of a second agent selected from ursodiol, UDCA, cholestyramine/resins, antihistamine agents (e.g., hydroxyzine,
• methods provided herein further comprise administration of a second agent selected from a bile acid or salt with reduced toxicity or a hydrophilic bile acid such as ursodiol, norursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid, or tauroursodeoxycholic acid.
• a second agent selected from a bile acid or salt with reduced toxicity or a hydrophilic bile acid such as ursodiol, norursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid, or tau
• pediatric dosage forms such as a solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, gummy candy, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, sachet, soft gelatin capsule, and sprinkle oral powder or granules.
• the pediatric dosage of an ASBTI is between about 1 ⁇ g/kg/day and about 10 mg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 5 ⁇ g/kg/day and about 1 mg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 300 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is any dosage from about 14 ⁇ g/kg/day and about 280 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is any dosage from about 14 ⁇ g/kg/day and about 140 ⁇ g/kg/day.
• the pediatric dosage of an ASBTI is between about 5 ⁇ g/kg/day and about 200 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 200 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 175 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 150 ⁇ g/kg/day. In some
• the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 140 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 25 ⁇ g/kg/day and about 140 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 50 ⁇ g/kg/day and about 140 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 70 ⁇ g/kg/day and about 140 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 10 ⁇ g/kg/day and about 100 ⁇ g/kg/day.
• the pediatric dosage of an ASBTI is 10 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 20 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 30 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 35 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 40 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 50 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 60 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 70 ⁇ g/kg/day.
• the pediatric dosage of an ASBTI is 80 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 90 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 100 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 110 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 120 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 130 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 140 ⁇ g/kg/day. In some embodiments, the pediatric dosage of an ASBTI is 150 ⁇ g/kg/day. In some
• the pediatric dosage of an ASBTI is 175 ⁇ g/kg/day.
• pediatric dosages of anASBTI between 14 ⁇ g/kg/day and 140 ⁇ g/kg/day, or between 14 ⁇ g/kg/day and 280 ⁇ g/kg/day.
• the pediatric dosage of an ASBTI is between about 0.5 mg/day and about 40 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 0.5 mg/day and about 30 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg/day and about 20 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg/day and about 10 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between about 1 mg/day and about 5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 1 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 5 mg/day.
• the pediatric dosage of an ASBTI is 10 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 20 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 4.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 4 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 3.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 3 mg/day.
• the pediatric dosage of an ASBTI is between 0.5 mg/day and 2.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 2 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 1.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and 1 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg/day and 4.5 mg/day. In some
• the pediatric dosage of an ASBTI is between 1 mg/day and 4 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg/day and 3.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg/day and 3 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg/day and 2.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is between 1 mg/day and 2 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 0.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 1 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 1.5 mg/day.
• the pediatric dosage of an ASBTI is 2 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 2.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 3 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 3.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 4 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 4.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 5 mg/day. In some embodiments, the pediatric dosage described herein is the dosage of the total composition
• the pediatric dosage form comprises 0.5 mg of the ASBTI. In some embodiments, the pediatric dosage form comprises 1 mg of the ASBTI. In some embodiments, the pediatric dosage form comprises 2.5 mg of the ASBTI. In some embodiments, the pediatric dosage form comprises 5 mg of the ASBTI. In some embodiments, the pediatric dosage form comprises 10 mg of the ASBTI. In some embodiments, the pediatric dosage form comprises 20 mg of the ASBTI.
• the pediatric dosage of an ASBTI is given once a day.
• the pediatric dosage of an ASBTI is given q.d. In some embodiments, the pediatric dosage of an ASBTI is given once a day in the morning. In some embodiments, the pediatric dosage of an ASBTI is given once a day at noon. In some embodiments, the pediatric dosage of an ASBTI is given once a day in the evening or night. In some embodiments, the pediatric dosage of an ASBTI is given twice a day. In some embodiments, the pediatric dosage of an ASBTI is given b.i.d. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, in the morning and noon. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, in the morning and evening.
• the pediatric dosage of an ASBTI is given twice a day, in the morning and night. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, at noon and in the evening. In some embodiments, the pediatric dosage of an ASBTI is given twice a day, at noon and in the night. In some embodiments, the pediatric dosage of an ASBTI is given three times a day. In some embodiments, the pediatric dosage of an ASBTI is given t.i.d. In some embodiments, the pediatric dosage of an ASBTI is given four times a day. In some embodiments, the pediatric dosage of an ASBTI is given q.i.d. In some embodiments, the pediatric dosage of an ASBTI is given every four hours.
• the pediatric dosage of an ASBTI is given q.q.h. In some embodiments, the pediatric dosage of an ASBTI is given every other day. In some embodiments, the pediatric dosage of an ASBTI is given q.o.d. In some embodiments, the pediatric dosage of an ASBTI is given three times a week. In some embodiments, the pediatric dosage of an ASBTI is given t.i.w.
• kits for use in the treatment of a pediatric cholestatic liver disease or pruritis, or lowering serum bile acid concentrations comprising a therapeutically effective amount of an ASBTI, or a pharmaceutically acceptable salt thereof, and a carrier.
• a method for treating cholestasis and/or a cholestatic liver disease comprising orally administering a therapeutically effective amount of a minimally absorbed ASBTI , or a pharmaceutically acceptable salt thereof, to an individual in need thereof.
• a method for treating cholestasis and/or a cholestatic liver disease comprising orally administering a therapeutically effective amount of a minimally absorbed ASBTI, or a pharmaceutically acceptable salt thereof, to an individual in need thereof.
• ASBTI, or salt thereof is a minimally absorbed ASBTI.
• the dosage form is an enteric formulation, an ileal-pH sensitive release formulation, or a suppository or other suitable form.
• a composition for use in the treatment of a pediatric cholestatic liver disease or pruritis, or lowering serum bile acid concentrations comprises at least one of a spreading agent or a wetting agent.
• the composition comprises an absorption inhibitor.
• an absorption inhibitor is a mucoadhesive agent (e.g., a mucoadhesive polymer).
• the mucoadhesive agent is selected from methyl cellulose, polycarbophil, polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinations thereof.
• the enteroendocrine peptide secretion enhancing agent is covalently linked to the absorption inhibitor.
• the pharmaceutical composition comprises an enteric coating.
• a composition for use in treatment of cholestasis, a cholestatic liver disease or pruritis described above comprises a carrier.
• the carrier is a rectally suitable carrier.
• any pharmaceutical composition described herein is formulated as a suppository, an enema solution, a rectal foam, or a rectal gel.
• any pharmaceutical composition described herein comprises an orally suitable carrier.
• a pediatric dosage form comprising an ASBTI is administered orally.
• the ASBTI is administered as an ileal-pH sensitive release formulation that delivers the ASBTI to the distal ileum, colon and/or rectum of an individual.
• the ASBTI is administered as an enterically coated formulation.
• oral delivery of an ASBTI provided herein can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.
• enteric -coated and enteric -coated controlled release formulations are within the scope of the present invention.
• Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
• the methods and compositions provided herein further comprise administration of a bile acid sequestrant or binder for reducing gastrointestinal side effects.
• methods comprise administering a labile bile acid sequestrant, wherein the labile bile acid sequestrant has a low affinity in the colon or rectum of the individual for at least one bile acid.
• a labile bile acid sequestrant provided herein releases a bile acid in the colon or the rectum of a human.
• a labile bile acid sequestrant provided herein does not sequester a bile acid for excretion or elimination in feces.
• a labile bile acid sequestrant provided herein is a non-systemic labile bile acid sequestrant.
• non-systemic labile bile acid sequestrant is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% absorbed systemically.
• the labile bile acid sequestrant is lignin or a modified lignin.
• the labile bile acid sequestrant is a polycationic polymer or copolymer.
• the labile bile acid sequestrant is a polymer or copolymer comprising one or more 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; cholestyramine, cholestipol, or cholesevelamor a combination thereof.
• a pediatric dosage form comprising an ASBTl is administered before ingestion of food. In some embodiments of the methods described above, a pediatric dosage form comprising an ASBTl is administered with or after ingestion of food.
• the methods provided herein further comprise administration of vitamin supplements to compensate for reduced digestion of vitamins, in particular fat-soluble vitamins, in an individual with a pediatric cholestatic liver disease, pruritis, or elevated serum bile acid levels or concentrations.
• the vitamin supplements comprise fat-soluble vitamins.
• the fat-soluble vitamins are vitamin A, D, E, or K.
• administering reduces intraenterocyte bile acids/salts in an individual in need thereof.
• the methods described herein reduce accumulation of bile acids/salts in ileal enterocytes of an individual in need thereof.
• administration of an ASBTl inhibits transport of bile acids/salts from ileal lumen into enterocytes of an individual in need thereof.
• administration of an ASBTl increases ileal luminal bile acids/salts in an individual in need thereof.
• administration of an ASBTl reduces damage to intestinal (e.g., ileal cells) or hepatocellular (e.g., liver cells) architecture associated with a pediatric cholestatic liver disease or elevated serum or hepatic bile acid concentrations in an individual in need thereof.
• administration of an ASBTl regenerates intestinal lining or liver cells that have been injured by cholestasis and/or by a cholestatic liver disease in an individual suffering from a cholestatic liver disease.
• kits for the treatment of a pediatric cholestatic liver disease comprising administration of a therapeutically effective amount of a pediatric dosage form comprising a combination of an ASBTl and ursodiol to an individual in need thereof.
• methods for the treatment of a pediatric cholestatic liver disease comprising
• an ASBTl is administered in combination with one or more agent selected from the group consisting of ursodiol, UDCA,
• ursodeoxycholic acid ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid,
• tauroursodeoxycholic acid tauroursodeoxycholic acid
• cholestyramine/resins cholestyramine/resins
• antihistamine agents e.g., hydroxyzine
• the methods provided herein further comprise partial external biliary diversion (PEBD) therapy.
• PEBD partial external biliary diversion
• kits comprising any composition described herein (e.g., a pharmaceutical composition formulated for rectal administration) and a device for localized delivery within the rectum or colon.
• the device is a syringe, bag, or a pressurized container.
• FIGURE 1 Oral administration of 264W94 dose-dependently increased bile acids in the feces. Fecal bile acid concentrations were elevated up to 6.5 fold with an ED 50 of 0.17 mg/kg, when compared to vehicle treated rats. Fecal NEFA also slightly increased in 264W94 treated rats. Plasma bile acid concentrations were decreased dose-dependently in 264W94 treated rats.
• FIGURE 2 Plasma bile acid levels of ZDF rats after administration of ascending doses of SC-435 and LUM002.
• Plasma bile acid levels were determined at the end of the second week. Data are expressed as mean values ⁇ SEM.
• FIGURE 4 Fecal bile acid analysis of healthy subjects after administration of ascending multiple oral doses of LUMOOl a randomized, double-blind, placebo-controlled study. Fecal samples were collected for all panels except the dose-titration panel, 2.5 (2) and 5 mg (2), on Days 9 through 14 and 23 through 28.
• FIGURE 5 Fasting serum bile acid levels and morning post-prandial peak in children under the age of 12.
• LUMOOl was administered once-a-day (QD) in the morning for fourteen days.
• the placebo patients had an average fasting serum bile acid level of 8.6 ⁇ /L and a post-prandial peak serum bile acid level of 11.9 ⁇ /L.
• the values were 6.5 ⁇ /L and 9.2, respectively, representing a 24% and 23% decrease.
• Bile acids/salts play a critical role in activating digestive enzymes and solubilizing fats and fat- soluble vitamins and are involved in liver, biliary, and intestinal disease.
• Bile acids are synthesized in the liver by a multistep, multiorganelle pathway. Hydroxyl groups are added to specific sites on the steroid structure, the double bond of the cholesterol B ring is reduced and the hydrocarbon chain is shortened by three carbon atoms resulting in a carboxyl group at the end of the chain.
• the most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before exiting the hepatocytes and forming bile, the bile acids are conjugated to either glycine (to produce glycocholic acid or
• bile salts are found in bile.
• Bile salts are excreted by the hepatocytes into the canaliculi to form bile.
• the canaliculi drain into the right and left hepatic ducts and the bile flows to the gallbladder.
• Bile is released from the gallbladder and travels to the duodenum, where it contributes to the metabolism and degradation of fat.
• the bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted via feces. A small percentage of bile salts may be reabsorbed in the proximal intestine by either passive or carrier-mediated transport processes.
• ASBT sodium-dependent apically located bile acid transporter
• ASBT sodium-dependent apically located bile acid transporter
• a truncated version of ASBT is involved in vectorial transfer of bile acids/salts into the portal circulation.
• Completion of the enterohepatic circulation occurs at the basolateral surface of the hepatocyte by a transport process that is primarily mediated by a sodium-dependent bile acid transporter.
• Intestinal bile acid transport plays a key role in the enterohepatic circulation of bile salts. Molecular analysis of this process has recently led to important advances in our understanding of the biology, physiology and pathophysiology of intestinal bile acid transport.
• Bile acid concentrations vary, with the bulk of the reuptake occurring in the distal intestine. Bile acids/salts alter the growth of bacterial flora in the gut. Described herein are certain compositions and methods that control bile acid concentrations in the intestinal lumen, thereby controlling the hepatocellular damage caused by bile acid accumulation in the liver.
• compositions and methods provided herein increase bile acid concentrations in the gut.
• the increased concentrations of bile acids/salts stimulate subsequent secretion of factors that protect and control integrity of the intestine when it is injured by pediatric cholestasis and/or a pediatric cholestatic liver disease (e.g., a pediatric cholestatic liver disease associated with pruritis, or a pediatric cholestatic liver disease associated with elevated serum bile acid concentrations or hepatic bile acid concentrations).
• compositions and methods described herein have an advantage over systemically absorbed agents.
• the compositions and methods described herein utilize ASBT inhibitors that are not systemically absorbed.
• ASBT inhibitors that are not systemically absorbed.
• the pediatric formulations described herein have an advantage over existing adult dosage forms and dosages to reduce harmful side effects and increase compliance.
• compositions and methods described herein stimulate the release of enteroendocrine hormones GLP-2 and PYY. Increased secretion of GLP-2 or PYY allows for prevention or treatment of pediatric cholestasis and/or a pediatric cholestatic liver disease by controlling the adaptive process, attenuating intestinal injury, reducing bacterial translocation, inhibiting the release of free radical oxygen, inhibiting production of proinflammatory cytokines, or any combination thereof.
• Described herein is the use of inhibitors of the ASBT or any recuperative bile salt transporter that are active in the gastrointestinal (GI) tract for treating or preventing pediatric cholestasis and/or a pediatric cholestatic liver disease in an individual in need thereof.
• GI gastrointestinal
• described herein is the use of inhibitors of the ASBT or any recuperative bile salt transporter that are active in the gastrointestinal (GI) tract for treating or preventing pruritis in an individual in need thereof.
• described herein is the use of inhibitors of the ASBT or any recuperative bile salt transporter that are active in the gastrointestinal (GI) tract for lowering serum bile acid concentrations or hepatic bile acid concentrations in an individual in need thereof.
• the methods provided herein comprise administering a therapeutically effective amount of an ASBTI to an individual in need thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed.
• such bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• ASBT inhibitors are systemically absorbed.
• the ASBTI provided herein are formulated for non-systemic delivery to the distal ileum.
• an ASBTI is minimally absorbed.
• an ASBTI is non- systemically administered to the colon or the rectum of an individual in need thereof.
• such ASBT inhibitors are not systemically absorbed.
• such bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• such ASBT inhibitors are systemically absorbed.
• the ASBTI are formulated for non-systemic delivery to the distal ileum.
• an ASBTI is minimally absorbed.
• an ASBTI is non-systemically administered to the colon or the rectum of an individual in need thereof.
• ASBTIs described herein inhibit scavenging of bile salts by recuperative bile acid salt transporters in the distal gastrointestinal tract (e.g., the distal ileum, the colon and/or the rectum).
• the inhibition of bile salt recycling results in higher concentrations of bile salts in the lumen of the distal gastrointestinal tract or portions thereof (e.g., the distal small bowel and/or colon and/or rectum).
• the distal gastrointestinal tract includes the region from the distal ileum to the anus.
• the compounds described herein reduce intraenterocyte bile acids/salts or accumulation thereof.
• the compounds described herein reduce damage to hepatocellular or intestinal architecture associated with cholestasis and/or a cholestatic liver disease.
• Mammalian microbiome, bile acid pools and metabolic interactions [0068] The integrated metabolism of the bile acid pools in the intestinal lumen lends itself to complex biochemical interactions between host and microbiome symbionts.
• Bile acids/salts are synthesized from cholesterol in the liver by a multi-enzyme coordinated process and are crucial for the absorption of dietary fats and lipid-soluble vitamins in the intestine. Bile acids/salts play a role in maintaining the intestinal barrier function to prevent intestinal bacterial overgrowth and translocation, as well as invasion of underlying tissues by enteric bacteria.
• symbiotic gut microorganisms interact closely with the host's metabolism and are important determinants of health. Many bacterial species in the gut are capable of modifying and metabolizing bile acids/salts and the gut flora affects systemic processes such as metabolism and inflammation.
• Bile acids/salts have strong antimicrobial and antiviral effects - deficiency leads to bacterial overgrowth and increased deconjugation, leading to less ileal resorption. In animals, conjugated bile acid feeding abolishes bacterial overgrowth, decreases bacterial translocation to lymph nodes and reduces endotoxemia.
• the methods and compositions described herein allow for replacement, displacement, and/or redirection of bile acids/salts to different areas of the gastrointestinal tract thereby affecting (e.g., inhibiting or slowing) growth of microorganisms that may cause infection-associated cholestasis and/or a cholestatic liver disease.
• cholestasis means the disease or symptoms comprising impairment of bile formation and/or bile flow.
• cholestatic liver disease means a liver disease associated with cholestasis. Cholestatic liver diseases are often associated with jaundice, fatigue, and pruritis. Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyltranspeptidease, elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.
• AP serum alkaline phosphatase
• Cholestatic liver disease can be sorted clinicopathologically between two principal categories of obstructive, often extrahepatic, cholestasis, and nonobstructive, or intrahepatic, cholestasis. In the former, cholestasis results when bile flow is mechanically blocked, as by gallstones or tumor, or as in extrahepatic biliary atresia.
• cholestasis results when processes of bile secretion and modification, or of synthesis of constituents of bile, are caught up secondarily in hepatocellular injury so severe that nonspecific impairment of many functions can be expected, including those subserving bile formation.
• the second subgroup no presumed cause of hepatocellular injury can be identified. Cholestasis in such patients appears to result when one of the steps in bile secretion or modification, or of synthesis of constituents of bile, is constitutively damages. Such cholestasis is considered primary.
• kits for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with cholestasis and/or a cholestatic liver disease comprise increasing bile acid concentrations and/or GLP-2 concentrations in the intestinal lumen.
• Hypercholemia, and elevated levels of AP alkaline phosphatase
• LAP leukocyte alkaline phosphatase
• gamma GT gamma-glutamyl transpeptidase
• 5 '-nucleotidase are biochemical hallmarks of cholestasis and cholestatic liver disease.
• the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• compositions for reducing hypercholemia, and elevated levels of AP alkaline phosphatase
• LAP leukocyte alkaline phosphatase
• gamma GT gamma-glutamyl transpeptidase
• 5 '-nucleotidase comprising reducing overall bile acid load by excreting bile acid in the feces.
• Pruritus is often associated with pediatric cholestasis and pediatric cholestatic liver diseases. It has been suggested that pruritus results from bile salts acting on peripheral pain afferent nerves. The degree of pruritus varies with the individual (i.e., some individuals are more sensitive to elevated levels of bile acids/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 regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with pruritus. In some of such embodiments, the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen. Further provided herein, are methods and compositions for treating pruritus comprising reducing overall bile acid load by excreting bile acid in the feces.
• Another symptom of pediatric cholestasis and pediatric cholestatic liver disease is the increase in serum concentration of conjugated bilirubin. Elevated serum concentrations of conjugated bilirubin result in jaundice and dark urine. The magnitude of elevation is not diagnostically important as no relationship has been established between serum levels of conjugated bilirubin and the severity of cholestasis and cholestatic liver disease. Conjugated bilirubin concentration rarely exceeds 30 mg/dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with elevated serum
• the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• methods and compositions for treating elevated serum concentrations of conjugated bilirubin comprising reducing overall bile acid load by excreting bile acid in the feces.
• Increased serum concentration of nonconjugated bilirubin is also considered diagnostic of cholestasis and cholestatic liver disease. Portions of serum bilirubin and covalently bound to albumin (delta bilirubin or biliprotein). This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice.
• delta bilirubin indicates long-standing cholestasis.
• Delta bilirubin in cord blood or the blood of a newborn is indicative of pediatric cholestasis/cholestatic liver disease that antedates birth.
• methods and compositions for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with elevated serum concentrations of nonconjugated bilirubin or delta bilirubin comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• methods and compositions for treating elevated serum concentrations of nonconjugated bilirubinand delta bilirubin comprising reducing overall bile acid load by excreting bile acid in the feces.
• the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• methods and compositions for treating hypercholemia comprising reducing overall bile acid load by excreting bile acid in the feces.
• Hyperlipidemia is characteristic of some but not all cholestatic diseases. Serum cholesterol is elevated in cholestasis due to the decrease in circulating bile salts which contribute to the metabolism and degradation of cholesterol. Cholesterol retention is associated with an increase in membrane cholesterol content and a reduction in membrane fluidity and membrane function. Furthermore, as bile salts are the metabolic products of cholesterol, the reduction in cholesterol metabolism results in a decrease in bile acid/salt synthesis. Serum cholesterol observed in children with cholestasis ranges between about 1,000 mg/dL and about 4,000 mg/dL.
• kits for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with hyperlipidemia comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• methods and compositions for treating hyperlipidemia comprising reducing overall bile acid load by excreting bile acid in the feces.
• xanthomas develop from the deposition of excess circulating cholesterol into the dermis.
• the development of xanthomas is more characteristic of obstructive cholestasis than of hepatocellular cholestasis.
• Planar xanthomas first occur around the eyes and then in the creases of the palms and soles, followed by the neck.
• Tuberous xanthomas are associated with chronic and long-term cholestasis. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals with xanthomas.
• the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen.
• methods and compositions for treating xanthomas comprising reducing overall bile acid load by excreting bile acid in the feces.
• Ursodeoxycholic acid which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of intestinal lining and/or enhancement of the adaptive processes in the intestine in individuals (e.g., children) with failure to thrive. In some of such embodiments, the methods comprise increasing bile acid concentrations concentrations in the intestinal lumen. Further provided herein, are methods and compositions for treating failure to thrive comprising reducing overall bile acid load by excreting bile acid in the feces.
• Symptoms of pediatric cholestasis and pediatric cholestatic liver disease have been treated with choleretic agents (e.g., ursodiol), phenobarbitols, corticosteroids (e.g., prednisone and budesonide), immunosuppressive agents (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and
• choleretic agents e.g., ursodiol
• corticosteroids e.g., prednisone and budesonide
• immunosuppressive agents e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and
• any of the methods disclosed herein further comprise administration of an additional active agent selected from: choleretic agents (e.g., ursodiol), phenobarbitols, corticosteroids (e.g., prednisone and budesonide), immunosuppressive agents (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and
• the methods are used to treat individuals that are non-responsive to treatment with choleretic agents (e.g., ursodiol), phenobarbitols, corticosteroids (e.g., prednisone and budesonide),
• choleretic agents e.g., ursodiol
• phenobarbitols e.g., corticosteroids
• corticosteroids e.g., prednisone and budesonide
• immunosuppressive agents e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and
• the methods are used to treat individuals that are non-responsive to treatment with choleretic agents. In some embodiments, the methods are used to treat individuals that are non-responsive to treatment with ursodiol.
• PFIC 1 also known as, Byler disease or FICl deficiency
• ATP8B1 gene also designated as FICl
• This gene which encodes a P-type ATPase, is located on human chromosome 18 and is also mutated in the milder phenotype, benign recurrent intrahepatic cholestasis type 1 (BRIO) and in Greenland familial cholestasis.
• FICl protein is located on the canalicular membrane of the hepatocyte but within the liver it is mainly expressed in cholangiocytes.
• P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phophatidylethanolamme on the inner leaflet of the plasma membrane in comparison of the outer leaflet.
• the asymmetric distribution of lipids in the membrane bilayer plays a protective role against high bile salt concentrations in the canalicular lumen.
• the abnormal protein function may indirectly disturb the biliary secretion of bile acids.
• the anomalous secretion of bile acids/salts leads to hepatocyte bile acid overload.
• PFIC-1 typically presents in infants (e.g., age 6-18 months). The infants may show signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and shortened stature. Biochemically, individuals with PFIC-1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low levels of gammaGT. The individual may also have liver fibrosis. Individuals with PFIC-1 typically do not have bile duct proliferation. Most individuals with PFIC-1 will develop end-stage liver disease by 10 years of age. No medical treatments have proven beneficial for the long term treatment of PFIC-1. In order 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 demonstrated as effective in individuals with PFIC-1.
• ASBTTI Apical Sodium-dependent Bile Acid Transporter Inhibitor
• bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• ASBT inhibitors are systemically absorbed.
• the ASBTI are formulated for non-systemic delivery to the distal ileum.
• an ASBTI is minimally absorbed.
• an ASBTI is non-systemically administered to the colon or the rectum of an individual in need thereof.
• the methods further comprise administering a therapeutically-effective amount of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g., prednisone and budesonide), an immunosuppressive agent (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof.
• a secondary bile acid e.g., ursodiol
• a corticosteroid e.g., prednisone and budesonide
• an immunosuppressive agent e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate
• sulindac e.g., bezafibrate, tamoxifen, lam
• PFIC 2 (also known as, Byler Syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also designated BSEP).
• the ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) of human liver and is located on human chromosome 2.
• BSEP protein expressed at the hepatocyte canalicular membrane, is the major exporter of primary bile acids/salts against extreme concentration gradients. Mutations in this protein are responsible for the decreased biliary bile salt secretion described in affected patients, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte with ongoing severe hepatocellular damage.
• PFIC-2 typically presents in infants (e.g., age 6-18 months). The infants may show signs of pruritus. Biochemically, individuals with PFIC-2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low levels of gammaGT. The individual may also have portal inflammation and giant cell hepatitis. Further, individuals often develop hepatocellular carcinoma. No medical treatments have proven beneficial for the long term treatment of PFIC- 1. In order 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 demonstrated as effective in individuals with PFIC-2.
• ASBTTI Apical Sodium-dependent Bile Acid Transporter Inhibitor
• bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• ASBT inhibitors are systemically absorbed.
• the ASBTI are formulated for non-systemic delivery to the distal ileum.
• an ASBTI is minimally absorbed.
• an ASBTI is non-systemically administered to the colon or the rectum of an individual in need thereof.
• the methods further comprise administering a therapeutically-effective amount of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g., prednisone and budesonide), an immunosuppressive agent (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof.
• a secondary bile acid e.g., ursodiol
• a corticosteroid e.g., prednisone and budesonide
• an immunosuppressive agent e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate
• sulindac e.g., bezafibrate, tamoxifen, lam
• PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also designated MDR3) located on chromosome 7.
• MDR3 Class III Multidrug Resistance
• P- gp P-glycoprotein
• PFIC3 results from the toxicity of bile in which detergent bile salts are not inactivated by phospholipids, leading to bile canaliculi and biliary epithelium injuries.
• PFIC-3 also presents in early childhood. As opposed to PFIC-1 and PFIC-2, individuals have elevated gammaGT levels. Individuals also have portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic gallstone disease. Ursodiol has been effective in treating or ameliorating PFIC-3.
• ASBT inhibitors are not systemically absorbed.
• bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• ASBT inhibitors are systemically absorbed.
• the ASBTI are formulated for non-systemic delivery to the distal ileum.
• an ASBTI is minimally absorbed.
• an ASBTI is non-systemically administered to the colon or the rectum of an individual in need thereof.
• the methods further comprise administering a therapeutically-effective amount of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g., prednisone and budesonide), an immunosuppressive agent (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof.
• a secondary bile acid e.g., ursodiol
• a corticosteroid e.g., prednisone and budesonide
• an immunosuppressive agent e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate
• sulindac e.g., bezafibrate, tamoxifen, lam
• BRIC1 is caused by a genetic defect of the FICl protein in the canalicular membrane of hepatocytes.
• BRIC1 is typically associated with normal serum cholesterol and ⁇ -glutamyltranspeptidase levels, but elevated serum bile salts. Residual FICl expression and function is associated with BRICl .
• cholestasis or cholestatic liver disease there is no progression to chronic liver disease in a majority of patients. During the attacks, the patients are severely jaundiced and have pruritis, steatorrhea, and weight loss. Some patients also have renal stones, pancreatitis, and diabetes.
• BRIC2 is caused by mutations in ABCB11, leading to defective BSEP expression and/or function in the canalicular membrane of hepatocytes.
• BRIC3 is related to the defective expression and/or function of MDR3 in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency usually display elevated serum ⁇ -glutamyltranspeptidase levels in the presence of normal or slightly elevated bile acid levels.
• DJS is characterized by conjugated hyperbilirubinemia due to inherited dysfunction of MRP2.
• Hepatic function is preserved in affected patients.
• Several different mutations have been associated with this condition, resulting either in the complete absence of immunohistochemically detectable MRP2 in affected patients or impaired protein maturation and sorting.
• Pediatric PSC is a chronic inflammatory hepatic disorder slowly progressing to end stage liver failure in most of the affected patients. In pediatric PSC inflammation, fibrosis and obstruction of large and medium sized intra- and extrahepatic ductuli is predominant.
• Gallstone disease is one of the most common and costly of all digestive diseases with a prevalence of up to 17% in Caucasian women. Cholesterol containing gallstones are the major form of gallstones and supersaturation of bile with cholesterol is therefore a prerequisite for gallstone formation. ABCB4 mutations may be involved in the pathogenesis of cholesterol gallstone disease.
• Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis, leading to the hepatic accumulation of bile salts and subsequent liver cell damage.
• drugs have been implicated in BSEP inhibition.
• Most of these drugs such as rifampicin, cyclosporine, glibenclamide, or troglitazone directly cis-inhibit ATP-dependent taurocholate transport in a competitive manner, while estrogen and progesterone metabolites indirectly trans-inhibits Bsep after secretion into the bile canaliculus by Mrp2.
• drug-mediated stimulation of MRP2 can promote cholestasis or cholestatic liver disease by changing bile composition.
• TPNAC is one of the most serious clinical scenarios where cholestasis or cholestatic liver disease occurs rapidly and is highly linked with early death. Infants, who are usually premature and who have had gut resections are dependent upon TPN for growth and frequently develop cholestasis or cholestatic liver disease that rapidly progresses to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of life. The degree of cholestasis or cholestatic liver disease and chance of survival in these infants have been linked to the number of septic episodes, likely initiated by recurrent bacterial translocation across their gut mucosa. Although there are also cholestatic effects from the intravenous formulation in these infants, septic mediators likely contribute the most to altered hepatic function.
• Alagille syndrome is a genetic disorder that affects the liver and other organs. It often presents during infancy (e.g., age 6-18 months) through early childhood (e.g., age 3-5 years) and may stabilize after the age of 10. Symptoms may include chronic progressive cholestasis, ductopenia, jaundice, pruritus, xanthomas, congenital heart problems, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, cardiac murmur, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and Tetralogy of Fallot.
• ASBT inhibitors are not systemically absorbed.
• such bile salt transport inhibitors include a moiety or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo.
• a charged moiety or group on the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption.
• ASBT inhibitors are systemically absorbed.
• the ASBTI are formulated for non-systemic delivery to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some embodiments, an ASBTI is non-systemically administered to the colon or the rectum of an individual in need thereof.
• the methods further comprise administering a therapeutically-effective amount of a secondary bile acid (e.g., ursodiol), a corticosteroid (e.g., prednisone and budesonide), an immunosuppressive agent (e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination thereof.
• a secondary bile acid e.g., ursodiol
• a corticosteroid e.g., prednisone and budesonide
• an immunosuppressive agent e.g., azathioprine, cyclosporin A, methotrexate, chlorambucil and mycophenolate
• sulindac e.g., bezafibrate, tamoxifen, lam
• Biliary atresia is a life -threatening condition in infants in which the bile ducts inside or outside the liver do not have normal openings. With biliary atresia, bile becomes trapped, builds up, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver eventually fails and the infant needs a liver transplant to stay alive.
• the two types of biliary atresia are fetal and perinatal. Fetal biliary atresia appears while the baby is in the womb. Perinatal biliary atresia is much more common and does not become evident until 2 to 4 weeks after birth.
• Biliary atresia is treated with surgery called the Kasai procedure or a liver transplant.
• the Kasai procedure is usually the first treatment for biliary atresia.
• the pediatric surgeon removes the infant's damaged bile ducts and brings up a loop of intestine to replace them.
• the Kasai procedure can restore bile flow and correct many problems caused by biliary atresia, the surgery doesn't cure biliary atresia. If the Kasai procedure is not successful, infants usually need a liver transplant within 1 to 2 years.
• liver transplantation is the only option. Although liver transplantation is generally successful at treating biliary atresia, liver transplantation may have complications such as organ rejection. Also, a donor liver may not become available. Further, in some patients, liver transplantation may not be successful at curing biliary atresia. Xanthoma
• Xanthoma is a skin condition associated cholestatic liver diseases, in which certain fats build up under the surface of the skin. Cholestasis results in several disturbances of lipid metabolism resulting in formation of an abnormal lipid particle in the blood called lipoprotein X. Lipoprotein X is formed by regurgitation of bile lipids into the blood from the liver and does not bind to the LDL receptor to deliver cholesterol to cells throughout the body as does normal LDL. Lipoprotein X increases liver cholesterol production by five fold and blocks normal removal of lipoprotein particles from the blood by the liver.
• ASBT inhibitors that reduce or inhibit bile acid recycling in the distal gastrointestinal (GI) tract, including the distal ileum, the colon and/or the rectum.
• the ASBTIs are systemically absorbed.
• the ASBTIs are not systemically absorbed.
• ASBTIs described herein are modified or substituted (e.g., with a -L-K group) to be non-systemic.
• any ASBT inhibitor is modified or substituted with one or more charged groups (e.g., K) and optionally, one or more linker (e.g., L), wherein L and K are as defined herein.
• an ASBTI suitable for the methods described herein is a compound of Formula I:
• R 1 is a straight chained Ci_ 6 alkyl group
• R 2 is a straight chained Ci_ 6 alkyl group
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_ 6 alkyl or a Ci_ 6 alkylcarbonyl group;
• R 4 is pyridyl or optionally substituted phenyl or -L z -K z ; wherein z is 1 , 2 or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption;
• R 5 , R 6 , R 7 and R 8 are the same or different and each is selected from hydrogen, halogen, cyano, R 5 -acetylide,
• R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen and optionally substituted Ci_6 alkyl; or
• R 6 and R 7 are linked to form a group
• R 12 and R 13 are as hereinbefore defined and m is 1 or 2;
• R 9 and R 10 are the same or different and each is selected from hydrogen or Ci_6 alkyl
• the compound of Formula I is a compound
• R 1 is a straight chained Ci_ 6 alkyl group
• R 2 is a straight chained Ci_ 6 alkyl group
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_ 6 alkyl or a Ci_ 6 alkylcarbonyl group;
• R 4 is optionally substituted phenyl
• R 5 , R 6 and R 8 are independently selected from hydrogen, Ci_ 4 alkyl optionally substituted by fluorine, C1.4 alkoxy, halogen, or hydroxy;
• n, p and R 12 to R 15 are as hereinbefore defined;
• salts solvates and physiologically functional derivatives thereof.
• the compound of Formula I is a compound wherein
• R 1 is a straight chained Ci_ 6 alkyl group
• R 2 is a straight chained Ci_ 6 alkyl group
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_ 6 alkyl or a Ci_ 6 alkylcarbonyl group;
• R 4 is un-substituted phenyl
• R 5 is hydrogen or halogen
• R 6 and R 8 are independently selected from hydrogen, C 1 .4 alkyl optionally substituted by fluorine, C 1 .4 alkoxy, halogen, or hydroxy;
• R 9 and R 10 are the same or different and each is selected from hydrogen or Ci_6 alkyl
• R 1 is methyl, ethyl or n-propyl
• R 2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_6 alkyl or a Ci_6 alkylcarbonyl group;
• R 4 is un-substituted phenyl
• R 5 is hydrogen
• R 6 and R 8 are independently selected from hydrogen, C M alkyl optionally substituted by fluorine, CM alkoxy, halogen, or hydroxy;
• R 9 and R 10 are the same or different and each is selected from hydrogen or Ci_6 alkyl
• the compound of Formula I is a compound
• R 1 is methyl, ethyl or n-propyl
• R 2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_ 6 alkyl or a Ci_ 6 alkylcarbonyl group;
• R 4 is un-substituted phenyl
• R 5 is hydrogen
• R 6 is C 1.4 alkoxy, halogen, or hydroxy
• R 7 is OR 15 , wherein R 15 is hydrogen or optionally substituted Ci_ 6 alkyl
• R 8 is hydrogen or halogen
• R 9 and R 10 are the same or different and each is selected from hydrogen or alkyl
• the compound of Formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
• the compound of Formula I is not a structure shown as:
• m represents an integer of 1 or 2
• R 3 and R 4 which may be mutually different, each represents an alkyl group having 1 to 5 carbon atoms.
• an ASBTI suitable for the methods described herein is a compound of Formula II
• q is an integer from 1 to 4.
• n is an integer from 0 to 2;
• R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,
• alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 , NR 9 R 10 , N + R 9 R 10 R W A ⁇ SR 9 , S + R 9 R 10 A-,
• alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (poly alkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 , N + R 9 R 10 A " , S, SO, S0 2 , S + R 9 A " , P + R 9 R 10 A-, or phenylene,
• R 9 , R 10 , and R w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or
• R 1 and R 2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl
• R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 , S0 2 R 9 , and S0 3 R 9 , wherein R 9 and R 10 are as defined above; or
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carb oalkoxyalkyl, cyclo alkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , C0 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9 and R 10 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 , and SH, or
• R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• R 5 and R 6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quarternary heteroaryl, OR 9 , SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , and -L z -K z ; wherein z is 1, 2 or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl
• alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S0 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)N R 1 3 R 1 4 , C ( 0 ) O
• a " is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 , NR 7 R 8 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , C0 2 R 7 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A " , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R 7 R 8 , P + R 7 R 8 R 9 A ⁇ , and P(0)(OR 7 ) OR 8 and
• alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 , N + R 7 R 8 A " , S, SO, S0 2 , S + R 7 A " , PR 7 , P(0)R 7 , P + R 7 R 8 A " , or phenylene
• R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V-W, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl
• G, T and V are each independently a bond, -0-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, - N(H)-alkyl, -C(0)N(H)-, -N(H)C(0)-, -N(H)C(0)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl
• W is quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, N + R 9 R 1 ⁇ 12 ⁇ " , P + R 9 R 10 R 11 A " , OS(0) 2 OM, or S + R 9 R 10 A-, and
• R 13 , R 14 and R 15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R U R 12 A " , SR 9 , S(O) R 9 , S0 2 R 9 , S0 3 R 9 , oxo, C0 2 R 9 , CN, halogen, CONR 9 R 10 , S0 2 OM, S0 2 NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R U A-, S + R 9 R 10 A-, and C(0)OM,
• R 16 and R 17 are independently selected from the substituents constituting R 9 and M; or
• alkyl is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;
• R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl
• R x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S(0) 2 R 13 , S0 3 R 13 , S + R 13 R 14 A " , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , NR 14 C(0)R 13 , C(0)NR 13 R 14 , NR 14 C(0)R 13 , C(0)OM, COR 13 , OR 18 , S(0) n NR 18 , NR 13 R 18 , NR 18 R 14 , S(0)
• alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 , NR 9 R 10 , ⁇ 3 ⁇ 43 ⁇ 43 ⁇ 4 12 ⁇ ⁇ , SR 9 , S(0)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, C0 2 R 9 , CN, halogen, CONR 9 R 1 0 , S 0 2 OM, S0 2 NR 9 R 10 , PO(OR 1 6 )OR 17 , P + R 9 R n R 12 A ⁇ S + R 9 R 10 A " , or C(0)M, and
• R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
• acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 , NR 9 R 10 , 3 ⁇ 43 ⁇ 4 U R 12 A SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , oxo, C0 3 R 9 , CN, halogen,
• R x one or more carbons are optionally replaced by O, NR 13 , N + R 13 R 14 A " , S, SO, S0 2 , S + R 13 A ⁇ , PR 13 , P(0)R 13 , P + R 13 R 14 A ⁇ , phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,
• quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S 0 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)NR 13 R 14 ,
• R 5 or R 6 is phenyl, only one of R 1 or R 2 is H;
• the compound of Formula II is a compound wherein q is an integer from 1 to 4;
• n 2;
• R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino, and alkylthio,
• alkyl, alkoxy, dialkylamino, and alkylthio are optionally substituted with one or more substituents selected from the group consisting of OR 9 , NR 9 R 10 , SR 9 , S0 2 R 9 , C0 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 ;
• each R 9 and R 10 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle, and arylalkyl;
• R 3 and R 4 are independently selected from the group consisting of H, alkyl, acyloxy, OR 9 , NR 9 R 10 , SR 9 , and S0 2 R 9 , wherein R 9 and R 10 are as defined above;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carb oxyalkyl , c arb o alko xyalkyl , cyc lo alkyl , cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , C0 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9 and R 10 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 , and SH, or
• R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• R 5 and R 6 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle, and -L z -K z ;
• each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted
• each K is a moiety that prevents systemic absorption
• alkyl, aryl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S0 2 R 13 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, and CR 13 ,
• a " is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation
• R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein R 13 , R 14 and R 15 are optionally substituted with one or more groups selected from the group consisting of quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 ,
• R 14 and R 15 together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R x are independently selected from the group consisting of H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR 13 , NR 13 R 14 , SR 13 , S(0) 2 R 13 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, S0 2 NR 13 R 14 , NR 14 C(0)R 13 , C(0)NR 13 R 14 , NR
• R 5 or R 6 is phenyl, only one of R 1 or R 2 is H;
• R x is styryl, anilido, or anilinocarbonyl, only one of R 5 or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• the compound of Formula II is a compound wherein
• n 2;
• R x is N(CH 3 ) 2 ;
• R 7 and R 8 are independently H;
• R 1 and R 2 is alkyl
• R 3 is H, and R 4 is OH;
• R 5 is H
• R 6 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quarternary heteroaryl, OR 9 , SR 9 , S(0)R 9 , S0 2 R 9 , SO 3 R 9 , and -L z -K z ;
• each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption;
• alkyl alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and
• quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S0 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)N R 1 3 R 1 4 , C ( 0 ) O M , C R 1 3 ,
• a " is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation
• said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 , NR 7 R 8 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , C0 2 R 7 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A " , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R 7 R 8 , P + R 7 R 8 R 9 A " , and P(0)(OR 7 ) OR 8 and wherein said alkyl, alkenyl, alkynyl, polyal
• G, T and V are each independently a bond, -0-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(0)N(H)-, -N(H)C(0)-, -N(H)C(0)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl
• W is quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, N + R 9 R 1 ⁇ 12 ⁇ " , P + R 9 R 10 R 11 A "
• R 9 and R 10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carb oxyalkyl , c arb o alko xyalkyl , cyc lo alkyl , cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , C0 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9 and R 10 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 , and SH, or
• R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• R 13 , R 14 and R 15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R U R 12 A " , SR 9 , S(0)
• R 16 and R 17 are independently selected from the substituents constituting R 9 and M; or
• R 14 and R 15 together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;
• the compound of Formula II is a compound wherein
• n 2;
• R x is N(CH 3 ) 2 ; R 7 and R 8 are independently H;
• R 1 and R 2 is independently C 1 -C4 alkyl
• R 3 is H, and R 4 is OH;
• R 5 is H
• R 6 is arylsubstituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S0 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)NR 1 3 R 1 4 , C ( 0 ) O M , C R 1 3 , P ( 0 ) R 1 3 R 1 4 , P + R 13 R 14 R 1 5 A
• a " is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation
• said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 , NR 7 R 8 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , C0 2 R 7 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A ⁇ , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R 7 R 8 , P + R 7 R 8 R 9 A " , and P(0)(OR 7 ) OR 8 and
• alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 , N + R 7 R 8 A " , S, SO, S0 2 , S + R 7 A " , PR 7 , P(0)R 7 , P + R 7 R 8 A " , or phenylene
• R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -G-T-V-W, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optional
• G, T and V are each independently a bond, -0-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(0)N(H)-, -N(H)C(0)-, -N(H)C(0)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl
• R 9 and R 10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 , S0 2 R 9 , S0 3 R 9 , C0 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9 and R 10 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 , and SH, or
• R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• R 13 , R 14 and R 15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R U R 12 A ⁇ , SR 9 , S(O)
• R 16 and R 17 are independently selected from the substituents constituting R 9 and M; or
• R 14 and R 15 together with the nitrogen atom to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;
• the compound of Formula II is a compound
• R 5 and R 6 are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quarternary heteroaryl
• aryl, heteroaryl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S O 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)NR 13 R 14 , C(0)OM, COR 13 , P(0)R 13 R 14 P + R 13 R 14 R 15 A ,P(OR 13 )OR 14 , S + R 13 R 14 A " ,
• the compound of Formula II is a compound
• R 5 or R 6 is -Ar-(R y ) t
• t is an integer from 0 to 5;
• Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and
• R y are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, halo alkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , OR 13 R 14 , NR 13 R 14 , SR 13 , S(0)R 13 , S 0 2 R 13 , S O 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, OM, S0 2 OM, S0 2 NR 13 R 14 , C(0)NR 13 R 14 , C(0)OM, COR 13 , P(0)R 13 R 14 P + R 13 R 14 R 15 A ,P(OR 13 )OR 14 ,
• alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S0 2 R 13 , S0 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N0 2 , C0 2 R 13 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A ⁇ , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R 7 R 8 , P + R 7 R 8 A " , and P(0)(OR 7 )OR 8 , and or phenylene; wherein said alkyl, alkyl
• the compound of Formula II is a compound wherein
• R 5 or R 6 is
• the compound of Formula II is a compound wherein n is 1 or 2. In some embodiments of the methods, the compound of Formula II is a compound wherein R 1 and R 2 are independently H or Ci_ 7 alkyl. In some embodiments of the methods, the compound of Formula II is a compound wherein each Ci_ 7 alkyl is independently ethyl, n-propyl, n-butyl, or isobutyl. In some embodiments of the methods, the compound of Formula II is a compound wherein R 3 and R 4 are
• compound of Formula II is a compound wherein R 9 is H
• the compound of Formula II is a compound wherein one or more R x are in the 7-, 8- or 9- position of the benzo ring of Formula II. In some embodiments of the methods, the compound of Formula II is a compound wherein R x is in the 7- position of the benzo ring of Formula II. In some embodiments of the methods, the compound of Formula II is a compound wherein one or more R x are independently selected from OR 13 and NR 13 R 14 .
• the compound of Formula II is a compound
• q 1 or 2;
• n 2;
• R 1 and R 2 are each alkyl
• R is hydroxy
• R 4 and R 6 are hydrogen
• R 5 has the formula
• t is an integer from 0 to 5;
• R F are OR 13 or OR 13 R 14 ;
• R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl;
• alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons replaced by O, NR 9 , N + R 9 R 10 A " , S, SO, S0 2 , S + R 9 A " , PR 9 , P + R 9 R 10 A-, P(0)R 9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide;
• R 13 and R 14 are optionally substituted with one or more groups independently selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R U R 12 A " , SR 9 ,
• A is a pharmaceutically acceptable anion
• M is a pharmaceutically acceptable cation
• R 9 and R 10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxy alkyl, cycloalkyl, cyanoalkyl, OR 9 ,
• R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and R 16 and R 17 are independently selected from the substituents constituting R 9 and M;
• R 7 and R 8 are hydrogen
• R x are independently selected from the group consisting of alkoxy, alkylamino and
• the compound of Formula II is N-(00130] in some embodiments of the methods.
• ASBTIs suitable for the methods described herein are non-systemic analogs of Compound 1 OOC.
• Certain compounds provided herein are Compound 1 OOC analogues modified or substituted to comprise a charged group.
• the Compound lOOC analogues are modified or substituted with a charged group that is an ammonium group (e.g., a cyclic ar acyclic ammonium group).
• the ammonium group is a non-protic ammonium group that contains a quarternary nitrogen.
• a compound of Formula II is l -[[5-[[3-[(3S,4R,5R)-3-butyl-7- (dimethylamino)-3-ethyl-2,3,4,5 etrah ⁇
• a compound of Formula II is potassium((2R,3R,4S,5R,6R)-4-benzyloxy-6- ⁇ 3-[3 -((3 S,4R,5R)-3 -butyl-7-dimethylamino-3-ethyl-4-hydroxy- 1 , 1 -dioxo-2,3 ,4,5-tetrahydro-lH- benzo[b]thiepin-5-yl)-phenyl]-ureido ⁇ -3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulphate ethanolate, hydrate or SAR548304B (a.k.a. SAR-548304).
• an ASBTI suitable for the methods described herein is a compound of Formula III: Formula III
• R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl- cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K;
• n 0-7;
• K is a moiety that prevents systemic absorption
• R 1 , R 2 , R 3 or R 4 is -L-K;
• R 1 and R 3 are -L-K. In some embodiments, R ⁇ and R 3 are -L-K.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is H.
• R 5 is H.
• R , R are H and R , R z , R J and R * are alkyl, aryl, alkyl-aryl, or heteroalkyl. In some embodiments, R and R are H. In some embodiments, R , R , R , R and R are H. In some embodiments, R and R together form a bond. In certain embodiments, R 5 ,R 6 and R 7 are H, alkyl or O-alkyl.
• R 1 and R 3 are -L-K. In some embodiments, R 1 , R 2 and R 3 are -L-K. In some embodiments, R 3 and R 4 are -L-K. In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached form a 3-8 membered ring and the ring is substituted with -L-K. In some embodiments, R 1 or R 2 or R 3 or R 4 are aryl optionally substituted with -L-K. In some embodiments, R 1 or R 2 or R 3 or R 4 are alkyl optionally substituted with -L-K.
• R 1 or R 2 or R 3 or R 4 are alky-aryl optionally substituted with -L-K. In some embodiments, R 1 or R 2 or R 3 or R 4 are heteroalkyl optionally substituted with -L-K.
• L is a Ci-C 7 alkyl. In some embodiments, L is heteroalkyl. In certain embodiments, L is Ci-C 7 alkyl-aryl. In some embodiments, L is Ci-C 7 alkyl-aryl- Ci-C 7 alkyl.
• K is a non-protic charged group. In some specific embodiments, each K is a ammonium group. In some embodiments, each K is a cyclic non-protic ammonium group. In some embodiments, each K is an acyclic non-protic ammonium group.
• each K is a cyclic non-protic ammonium group of structure:
• K is an acnch non-protic ammonium group of structure:
• p, q, R 9 , R 10 and Z are as defined above.
• p is 1.
• p is 2.
• p is 3.
• q is 0.
• q is 1.
• q is 2.
• the compounds further comprise 1, 2, 3 or 4 anionic counterions selected from CI “ , Br “ , ⁇ , R U S0 3 _ , wherein R 11 is as defined above.
• the counterion is CI " , Br “ , ⁇ , CH 2 C0 2 " , CH 3 S0 3 " , or C 6 H 5 S0 3 " or C0 2 " - (CH 2 ) 2 -C0 2 " .
• the compound of Formula III has one K group and one counterion.
• the compound of Formula III has one K group, and two molecules of the compound of Formula III have one counterion.
• the compound of Formula III has two K groups and two counterions.
• the compound of Formula III has one K group comprising two ammonium groups and two counterions.
• each R 1 , R 2 is independently H, substituted or unsubstituted alkyl, or -L-K; or R 1 and R 2 together with the nitrogen to which they are attached form a 3-8-membered ring that is optionally susbtituted with R 8 ;
• R 3 , R 4 , R 8 , L and K are as defined above.
• L is A n , wherein each A is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, and n is 0-7.
• R 1 is H.
• R 1 and R 2 together with the nitrogen to which they are attached form a 3-8-membered ring that is optionally susbtituted with -L-K.
• each R , R is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, or -L-K;
• R 1 , R 2 , L and K are as defined above.
• R 3 is H. In certain embodiments, R 3 and R 4 are each -L-K. In some embodiments, R 3 is H and R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl containing one or two - L-K groups.
• an ASBTI suitable for the methods described herein is a compound of Formula IIIC
• each X is independently NH, S, or O;
• each Y is independently NH, S, or O;
• R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl- cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K;
• each m is independently 0- 2;
• n 0-7;
• K is a moiety that prevents systemic absorption
• an ASBTI suitable for the methods described herein is a compound of
• R 1 is a straight chain Ci_ 6 alkyl group
• R 2 is a straight chain Ci_ 6 alkyl group
• R 3 is hydrogen or a group OR 11 in which R 11 is hydrogen, optionally substituted Ci_ 6 alkyl or a Ci_ 6 alkylcarbonyl group;
• R 4 is pyridyl or an optionally substituted phenyl
• R 5 , R 6 and R 8 are the same or different and each is selected from:
• p is an integer from 1-4
• n is an integer from 0-3 and
• R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen and optionally substituted C 1"6 alkyl;
• R 7 is a group of the formula
• hydroxyl groups may be substituted by acetyl, benzyl,
• alkyl group may be substituted with one or more hydroxyl groups
• R 16 is— COOH,— CH 2 — OH,— CH 2 — O-Acetyl,— COOMe or— COOEt;
• R 17 is H,—OH,— NH 2 ,—COOH or COOR 18 ;
• R 18 is (Q-C ⁇ -alkyl or— NH— (Ci-C 4 )-alkyl
• X is— NH— or—0—
• R 9 and R 10 are the same or different and each is hydrogen or C 1-C6 alkyl; and salts thereof.
• a compound of Formula IV has the structure of Formula IVA or Formula rVB:
• a compound of Formula IV has the structure of Formula IVC:
• X is O and R 7 is selected from
• a compound of Formula IV is:
• an ASBTI suitable for the methods described herein is a compound of Formula V: R v is selected from hydrogen or Ci_ 6 alkyl;
• R 1 and R 2 are selected from hydrogen or Ci_ 6 alkyl and the other is selected from Ci_ 6 alkyl;
• R x and R y are independently selected from hydrogen, hydroxy, amino, mercapto, Ci_ 6 alkyl, Q. 6 alkoxy, N— (Ci_ 6 alkyl)amino, N,N— (Ci_ 6 alkyl) 2 amino, Ci_ 6 alkylS(0) a wherein a is 0 to 2;
• R z is selected from halo, nitr, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, Ci_ 6 alkanoyl, Ci_ 6 alkanoyloxy, N— (Ci_ 6 alkyl)amino, N,N— (Ci. 6 alkyl) 2 amino, Ci_ 6 alkanoylamino, N— (Ci_ 6 alkyl)carbamoyl, N,N— (Ci_ 6 alkyl) 2 carbamoyl, Q_
• n 0-5;
• R 4 and R 5 are a group of formula (VA):
• R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci_ 6 alkoxy, Ci_ 6 alkanoyl, Ci_ 6 alkanoyloxy, N— (Ci_ 6 alkyl)amino, N,N— (Ci_ 6 alkyl) 2 amino, Ci_ 6 alkanoylamino, N— (Q.
• R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on carbon by one or more R 17 ;
• X is— O— ,— N(R a )— ,— S(0) b — or— CH(R a )— ;
• R a is hydrogen or and b is 0-2;
• Ring A is aryl or heteroaryl
• Ring A is optionally substituted on carbon by one or more substituents selected from R 18 ;
• R 7 is hydrogen, Ci_ 6 alkyl, carbocyclyl or heterocyclyl
• R 7 is optionally substituted on carbon by one or more substituents selected from R 19 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 20 ;
• R 8 is hydrogen or Ci_6-alkyl
• R 9 is hydrogen or
• R 10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci.ioalkyl, C 2 _ioalkynyl, C 2 _ioalkynyl, Ci.ioalkoxy, Ci.ioalkanoyl, Ci.ioalkanoyloxy, N— (Ci.ioalkyl)amino, N,N— (Ci_ioalkyl) 2 amino, ⁇ , ⁇ , ⁇ — (Ci_ioalkyl) 3 ammonio, Ci.ioalkanoylamino, N— (Ci.ioalkyl)carbamoyl, N,N— (Ci_ioalkyl) 2 carbamoyl, Ci_ioalkylS(0) a wherein a is 0 to 2, N— (Ci_ 10 alkyl)sulphamoyl
• R 11 is hydrogen or Ci_ 6 -alkyl
• R 12 and R 13 are independently selected from hydrogen, halo, carbamoyl, sulphamoyl, Ci.ioalkyl, C 2 _ i 0 alkynyl, C 2 -ioalkynyl, Ci.ioalkanoyl, N— (Ci.ioalkyl)carbamoyl, N,N— (Ci_ioalkyl) 2 carbamoyl, Q.
• a is 0 to 2, N— (Ci.ioalkyl)sulphamoyl, N,N— (Ci_ioalkyl) 2 sulphamoyl, N— (Ci_ i 0 alkyl)sulphamoylamino, N,N— (Ci.ioalkyl) 2 sulphamoylamino, carbocyclyl or heterocyclyl; wherein R 12 and R 13 may be independently optionally substituted on carbon by one or more substituents selected from R 25 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 26 ;
• R 14 is selected from hydrogen, halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, Ci.ioalkyl, C 2 _ i 0 alkenyl, C 2 _ioalkynyl, Ci.ioalkanoyl, N— (Ci.ioalkyl)carbamoyl, N,N— (Ci_ioalkyl) 2 carbamoyl, Ci_ i 0 alkylS(O) a wherein a is 0 to 2, N— (Ci_i 0 alkyl)sulphamoyl, N,N— (Ci_i 0 alkyl) 2 sulphamoyl, N— (d_ i 0 alkyl)sulphamoylamino, N,N— (Ci_i 0 alkyl) 2 sulphamoylamino, carbocyclyl, carbocyclylCi_i 0 alkyl,
• R 15 is hydrogen or Ci_ 6 alkyl
• R 16 is hydrogen or Ci_ 6 alkyl; wherein R 16 may be optionally substituted on carbon by one or more groups selected from R 31 ;
• R 15 and R 16 together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl may be optionally substituted on carbon by one or more R 37 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 38 ;
• R 7 may be the same or different;
• R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31 and R 37 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci.ioalkyl, C 2 .ioalkenyl, C 2 .ioalkynyl, Q.
• Ci_i 0 alkanoyl Ci_i 0 alkanoyloxy, N— (Ci_i 0 alkyl)amino, N,N— (Ci oalkyl) 2 amino, ⁇ , ⁇ , ⁇ — (Q.
• Ci_i 0 alkanoylamino N— (Ci_i 0 alkyi)carbamoyl, N,N— (Ci_ioalkyl) 2 carbamoyl, Q_ 10 alkylS(O) a wherein a is 0 to 2, N— (Ci_i 0 alkyl)sulphamoyl, N,N— (Ci_i 0 alkyl) 2 sulphamoyl, N— (Q.
• R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31 and R 37 may be independently optionally substituted on carbon by one or more R 34 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 35 ;
• p, q, r and s are independently selected from 0-2;
• R 34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;
• R 20 , R 24 , R 26 , R 30 , R 35 and R 38 are independently selected from Ci_ 6 alkyl, Ci_ 6 alkanoyl, Ci_
• heteroaryl is a totally unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heteroaryl may, unless otherwise specified, be carbon or nitrogen linked;
• heterocyclyl is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heterocyclyl may, unless otherwise specified, be carbon or nitrogen linked, wherein a— CH 2 - group can optionally be replaced by a— C(O)— group, and a ring sulphur atom may be optionally oxidised to form an S-oxide; and
• a "carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a— CH 2 - group can optionally be replaced by a— C(O) group; or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide formed on an available carboxy or hydroxy group thereof.
• compound of Formula V is l , l -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- ⁇ (R)-a-[N-((R)- 1 -carboxy-2-methylthio-ethyl)carbamoyl] -4-hydroxybenzyl ⁇ carbamoylmethoxy)- 2,3,4,5-tetrahydro-l ,2,5-benzothiadiazepine; 1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)- a-[N- ((S)-l-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl ⁇ carbamoylmethoxy)-2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine; l,l-di
• compound of Formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• an ASBTI suitable for the methods described herein is a compound of Formula VI:
• R v and R w are independently selected from hydrogen or
• R 1 and R 2 is selected from hydrogen or and the other is selected from
• R x and R y are independently selected from hydrogen or or one of R x and R y is hydrogen or Ci_ 6 alkyl and the other is hydroxy or
• R z is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, N— (Ci_ 6 alkyl)amino, N,N— (Ci_ 6 alkyl) 2 amino, N— (Ci_ 6 alkyl)carbamoyl, N,N— (Ci_ 6 alkyl) 2 carbamoyl, Ci_ 6 alkylS(0) a wherein a is 0 to 2, Ci_ 6 alkoxycarbonyl, N— (Ci_ 6 alkyl) sulphamoyl and N,N— (Q.
• n 0-5;
• R 4 and R 5 are a group of formula (VIA):
• R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl,
• Ci_ 6 alkanoyl N— (Ci_ 6 alkyl)amino, N,N— (Ci_ 6 alkyl) 2 amino, (Ci_ 6 alkyl)carbam oyl, N,N— (Ci_ 6 alkyl) 2 carbamoyl, Ci_ 6 alkylS(0) a wherein a is 0 t N— (Ci_ 6 alkyl)sulphamoyl and N,N— (Ci_ 6 alkyl) 2 sulphamoyl; wherein R 3 and R 6 and the other of R 4 and R 5 may be optionally substituted on carbon by one or more R 17 ;
• X is— O— ,— N(R a )— ,— S(0) b — or— CH(R a )— ; wherein R a is hydrogen or Ci_ 6 alkyl and b is 0-
• Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted on carbon by one or more substituents selected from R 18 ;
• R 7 is hydrogen, Ci_ 6 alkyl, carbocyclyl or heterocyclyl; wherein R 7 is optionally substituted on carbon by one or more substituents selected from R 19 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 20 ;
• R 8 is hydrogen or Ci_ 6 alkyl
• R 9 is hydrogen or Ci_ 6 alkyl
• R 10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci.ioalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci.ioalkoxy, Ci.ioalkanoyl, Ci.ioalkanoyloxy, N— (Ci.ioalkyl)amino, N,N— (Ci_ioalkyl) 2 amino, ⁇ , ⁇ , ⁇ — (Ci_ioalkyl) 3 ammonio, Ci.ioalkanoylamino, N— (Ci.ioalkyl)carbamoyl, N,N— (Ci_ioalkyl) 2 carbamoyl, Ci_ioalkylS(0) a wherein a is 0 to 2, N— (Ci_ i 0 alkyl)sulphamo
• R is hydrogen or
• R and R are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, Ci.ioalkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci.ioalkoxy, Ci.ioalkanoyl, Q_ 10 alkanoyloxy, N— (Ci 0 alkyl)amino, N,N— (Ci 0 alkyl) 2 amino, Ci 0 alkanoylamino, N— (d_ 10 alkyl)carbamoyl, N,N— (Ci_i 0 alkyl) 2 carbamoyl, Ci_i 0 alkylS(O) a wherein a is 0 to 2, N— (Ci_
• R 14 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci_i 0 alkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci_i 0 alkoxy, Ci_i 0 alkanoyl, d_ 10 alkanoyloxy, N— (Ci_i 0 alkyl)amino, N,N— (Ci_i 0 alkyl) 2 amino, ⁇ , ⁇ , ⁇ — (Ci.i 0 alkyl) 3 ammonio, Q_ 10 alkanoylamino, N— (Ci_i 0 alkyl)carbamoyl, N,N— (Ci_i 0 alkyl) 2 carbamoyl, Ci_i 0 alkylS(O) a wherein a is 0 to 2, N— (Ci_
• R 15 is hydrogen or
• R 16 is hydrogen or Ci_ 6 alkyl; wherein R 16 may be optionally substituted on carbon by one or more groups selected from R 31 ;
• n 1-3; wherein the values of R 7 may be the same or different;
• R , R , R , R , R , R or R are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, amidino, Ci_i 0 alkyl, C 2 _i 0 alkenyl, C 2 _i 0 alkynyl, Ci_i 0 alkoxy, Ci_i 0 alkanoyl, Ci_i 0 alkanoyloxy, (Ci_i 0 alkyl) 3 silyl, N— (Ci_i 0 alkyl)amino, N,N— (Q .
• Ci_i 0 alkanoylamino N— (Ci_i 0 alkyl)carbamoyl, N,N— (Ci_ i 0 alkyl) 2 carbamoyl, Ci_ioalkylS(0) a wherein a is 0 to 2, N— (Ci.ioalkyl)sulphamoyl, N,N— (Ci_
• R , R , R , R , R or R may be independently optionally substituted on carbon by one or more R 34 ; and wherein if said heterocyclyl contains an— NH— group, that nitrogen may be optionally substituted by a group selected from R 35 ;
• R 21 , R 22 , R 27 , R 28 , R 32 or R 33 are independently selected from— O— ,— NR 36 — ,— S(0) x — ,—
• R 36 is selected from hydrogen or Ci_ 6 alkyl, and x is 0-2; p, q, r and s are independently selected from 0-2;
• R 34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;
• R , R , R , R or R are independently selected from C i_ 6 alkyl, Ci_ 6 alkanoyl, Ci_ 6 alkylsulphonyl, Ci_ 6 alkoxycarbonyl, carbamoyl, N— (Ci_ 6 alkyl)carbamoyl, N,N— (Ci_ 6 alkyl)carbamoyl, benzyl,
• a compo nd of Formula VI has the structure of Formula VID:
• R 1 and R 2 are independently selected from one of R 4 and R 5 is a group of formula (VIE):
• R 3 and R 6 and the other of R 4 and R 5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl,
• R 7 is carboxy, sulpho, sulphino, phosphono,— P(0)(OR a )(OR b ), P(0)(OH)(OR a ),— P(0)(OH)(R a ) or P(0)(OR a )(R b ), wherein R a and R b are independently selected from C or R 7 is a group of formula (VIF): VIF R 8 and R 9 are independently hydrogen, Ci_ 4 alkyl or a saturated cyclic group, or R 8 and R 9 together form C 2 .
• R 8 and R 9 or R 8 and R 9 together may be independently optionally substituted on carbon by one or more substituents selected from R 15 ; and wherein if said saturated cyclic group contains an — NH— moiety, that nitrogen may be optionally substituted by one or more R 20 ;
• R 10 is hydrogen or Ci_ 4 alkyl; wherein R 10 is optionally substituted on carbon by one or more substituents selected from R 24 ;
• R 11 is hydrogen, C alkyl, carbocyclyl or heterocyclyl; wherein R 11 is optionally substituted on carbon by one or more substituents selected from R 16 ; and wherein if said heterocyclyl contains an— NH— moiety, that nitrogen may be optionally substituted by one or more R 21 ;
• R 12 is hydrogen or C M alkyl, carbocyclyl or heterocyclyl; wherein R 12 optionally substituted on carbon by one or more substituents selected from R 17 ; and wherein if said heterocyclyl contains an— NH— moiety, that nitrogen may be optionally substituted by one or more R 22 ;
• R 13 is carboxy, sulpho, sulphino, phosphono,— P(0)(OR c )(OR d ),— P(0)(OH)(OR c ),—
• n 1 -3 ; wherein the values of R 8 and R 9 may be the same or different;
• n 1-3; wherein the values of R 11 may be the same or different;
• R 12 is 1-3; wherein the values of R 12 may be the same or different;
• R 14 and R 16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, N-(Ci_ 4 alkyl)amino, N,N-(Ci_ 4 alkyl) 2 amino, N-(Ci_ 4 alkyl)carbamoyl, N,N-(Ci_
• Ci_ 4 alkylS(0) a wherein a is 0 to 2, N-(Ci_ 4 alkyl)sulphamoyl and N,N- (Ci_ 4 alkyl) 2 sulphamoyl; wherein R 14 and R 16 may be independently optionally substituted on carbon by one or more R 18 ;
• R 15 and R 17 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C M alkyl, C 2 _ 4 alkenyl, C 2 . 4 alkynyl, Ci_ 4 alkoxy, Ci_ 4 alkanoyl, Ci_ 4 alkanoyloxy, N-(Ci_ 4 alkyl)amino, N,N-(Ci_ 4 alkyl) 2 amino, Ci_ 4 alkanoylamino, N-(Ci_ 4 alkyl)carbamoyl, N,N-(Ci_
• R 24 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_ 4 alkyl, C 2 . 4 alkenyl, C 2 .
• Ci_ 4 alkynyl Ci_ 4 alkoxy, Ci_ 4 alkanoyl, Ci_ 4 alkanoyloxy, N-(Ci_ 4 alkyl)amino, N,N-(Ci_ 4 alkyl) 2 amino, Ci_ alkanoylamino, N-(Ci_ alkyl)carbamoyl, N,N-(Ci_ alkyl) 2 carbamoyl, Ci_ alkylS(0) a wherein a is 0 to 2, Ci_ 4 alkoxycarbonyl, N-(Ci_ 4 alkyl)sulphamoyl and N,N-(Ci_ 4 alkyl) 2 sulphamoyl, carbocyclyl, heterocyclyl; wherein R 24 may be independently optionally substituted on carbon by one or more R 25 ; and wherein if said heterocyclyl contains an— NH— moiety, that nitrogen may be optionally substituted by one or more R 26 ;
• any saturated cyclic group is a totally or partially saturated, mono or bicyclic ring containing 3-12 atoms of which 0-4 atoms are chosen from nitrogen, sulphur or oxygen, which may be carbon or nitrogen linked;
• any heterocyclyl is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may be carbon or nitrogen linked, wherein a— CH 2 — group can optionally be replaced by a— C(O)— or a ring sulphur atom may be optionally oxidised to form the S-oxides; and
• any carbocyclyl is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms, wherein a— CH 2 — group can optionally be replaced by a— C(O)— ;
• a compound of Formula IV is l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio- 8-(N- ⁇ (R)-l '-phenyl- l'-[N'-(carboxymethyl) carbamoyl] methyl ⁇ carbamoylmethoxy)-2,3,4,5-tetrahydro- 1,5-benzothiazepine; l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)-a-[N'-((S)-l - carboxypropyl)carbamoyl]-4-hydroxybenzyl ⁇ carbamoylmethoxy)-2,3,4,5-tetrahydro-l,5-benzothiazepine; l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- ⁇ (R)-
• any compound described herein is covalently conjugated to a bile acid using any suitable method.
• compounds described herein are covalently bonded to a cyclodextrin or a biodegradable polymer (e.g., a polysaccharide).
• compounds described herein are not systemically absorbed.
• compounds that inhibit bile salt recycling in the gastrointestinal tract of an individual may not be transported from the gut lumen and/or do not interact with ASBT.
• compounds described herein do not affect, or minimally affect, fat digestion and/or absorption.
• the administration of a therapeutically effective amount of any compound described herein does not result in gastrointestinal disturbance or lactic acidosis in an individual.
• compounds described herein are administered orally.
• an ASBTI is released in the distal ileum.
• An ASBTI compatible with the methods described herein may be a direct inhibitor, an allosteric inhibitor, or a partial inhibitor of the Apical Sodium-dependent Bile acid Transporter.
• compounds that inhibit ASBT or any recuperative bile acid transporters are compounds that are described in EP1810689, US Patent Nos. 6,458,851, 7413536, 7514421, US Appl. Publication Nos. 2002/0147184, 2003/0119809, 2003/0149010, 2004/0014806, 2004/0092500,
• compounds that inhibit ASBT or any recuperative bile acid transporters are compounds described in WO93/16055, W094/18183, W094/18184, WO96/05188, WO96/08484,
• compounds that inhibit ASBT or any recuperative bile acid transporter are benzothiepines, benzothiazepines (including 1,2-benzothiazepines; 1,4-benzothiazepines; 1,5- benzothiazepines; and/or 1,2,5-benzothiadiazepines).
• compounds that inhibit ASBT or any recuperative bile acid transporter include and are not limited to S-8921 (disclosed in EP597107, WO 93/08155), 264W94 (GSK) disclosed in WO 96/05188; SC-435 (l-[4-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- 1 , 1 -dioxido- 1 -benzothiepin-5-yl]phenoxy]butyl]4-aza- 1 - azoniabicyclo[2.2.2]octane methanesulfonate salt), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5- tetrahydro-5-phenyl-l,4-benzothiazepine 1,1-dioxide); BARI-1741 (Aventis SA), AZD
• compounds described herein have one or more chiral centers. As such, all stereoisomers are envisioned herein.
• compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds of the present invention encompasses racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieve in any suitable manner, including by way of non-limiting example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• mixtures of one or more isomer is utilized as the therapeutic compound described herein.
• compounds described herein contains one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and/or separation of a mixture of enantiomers and/or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.
• esters acyl halides alcohols/phenols
• Carboxamides carboxylic acids amines/anilines
• esters carboxylic acids Alcohols hydrazines Hydrazides carboxylic acids
• N-acylureas or Anhydrides carbodiimides carboxylic acids
• protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
• reducing conditions such as, for example, hydrogenolysis
• oxidative conditions such as, for example, hydrogenolysis
• Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
• Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.
• Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
• an allyl-blocked carboxylic acid is deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
• Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
• blocking/protecting groups are selected from:
• ASBTIs described herein are synthesized as described in, for example, WO 96/05188, U.S. Patent Nos. 5,994,391; 7,238,684; 6,906,058; 6,020,330; and 6,114,322.
• ASBTIs described herein are synthesized starting from compounds that are available from commercial sources or that are prepared using procedures outlined herein.
• compounds described herein are prepared according to the process set forth in Scheme 1 :
• the synthesis begins with a reaction of l,4-diazabicyclo[2.2.2]octane with 4-iodo-l -chloro butane to provide a compound of structure 1-1.
• Such compounds are prepared in any suitable manner, e.g., as set forth in Tremont, S. J. et. al, J. Med. Chem. 2005, 48, 5837-5852.
• the compound of structure 1-1 is then subjected to a reaction with phenethylamine to provide a compound of structure 1 -II.
• the compound of structure 1 -II is then allowed to react with dicyanodiamide to provide a compound of Formula I.
• a first compound of Formula III is subjected to a further reaction to provide a second compound of Formula III as shown in Scheme 2 below.
• a first compound of Formula III, 1-IA is alkylated with iodomethane to provide a second compound of Formula III, 1-IB. Alkylation of 1-IB with a compound of structure 2-II provides a further compound of Formula III, IC.
• a first compound of Formula III, 1-IA is alkylated with a compound of structure 2-1 to provide a second compound of Formula III, 1-IC
• bile acid includes steroid acids (and/or the carboxylate anion thereof), and salts thereof, found in the bile of an animal (e.g., a human), including, by way of non-limiting example, cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, a tauroursodeoxycholic acid, a glycoursodeoxycholic acid, a 7-B-methyl cholic acid, a methyl lithocholic acid, chenodeoxycholate, lithocholic acid, lithocolate, and the like.
• Taurocholic acid and/or taurocholate are referred to herein as TCA.
• Any reference to a bile acid used herein includes reference to a bile acid, one and only one bile acid, one or more bile acids, or to at least one bile acid. Therefore, the terms “bile acid,” “bile salt,” “bile acid/salt,” “bile acids,” “bile salts,” and “bile acids/salts” are, unless otherwise indicated, utilized interchangeably herein.
• Any reference to a bile acid used herein includes reference to a bile acid or a salt thereof.
• bile acids are optionally utilized as the "bile acids" described herein, e.g., bile acids/salts conjugated to an amino acid (e.g., glycine or taurine).
• Other bile acid esters include, e.g., substituted or unsubstituted alkyl ester, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, or the like.
• the term "bile acid” includes cholic acid conjugated with either glycine or taurine: glycocholate and taurocholate, respectively (and salts thereof).
• bile acid/salt mimics or mimetics described herein are compounds that mimic the agonist signaling properties of the bile acid/salt, especially at TGR5 (GPBAR1, BG37, Axorl09) receptors. Examples include those described in WO 2010/014836, which is incorporated herein for such disclosure.
• bile acid mimetics include triterpenoid, such as oleanoic acid, ursolic acid, or the like.
• the term "subject”, “patient” or “individual” are used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein.
• mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
• non-mammals include, but are not limited to, birds, fish and the like.
• the mammal is a human.
• composition includes the disclosure of both a composition and a composition administered in a method as described herein.
• composition of the present invention is or comprises a "formulation,” an oral dosage form or a rectal dosage form as described herein.
• the terms "treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, inhibiting or reducing symptoms, reducing or inhibiting severity of, reducing incidence of, reducing or inhibiting recurrence of, delaying onset of, delaying recurrence of, abating or ameliorating a disease or condition symptoms, ameliorating the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
• the terms further include achieving a therapeutic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated, and/or the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient.
• compositions include preventing additional symptoms, preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition and are intended to include prophylaxis.
• the terms further include achieving a prophylactic benefit.
• the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient reporting one or more of the physiological symptoms of a disease, or to a patient at risk of reoccurrence of the disease.
• the agents described herein be limited by the particular nature of the combination.
• the agents described herein are optionally administered in combination as simple mixtures as well as chemical hybrids.
• An example of the latter is where the agent is covalently linked to a targeting carrier or to an active pharmaceutical.
• Covalent binding can be accomplished in many ways, such as, though not limited to, the use of a commercially available cross-linking agent.
• combination treatments are optionally administered separately or concomitantly.
• the terms “pharmaceutical combination”, “administering an additional therapy”, “administering an additional therapeutic agent” and the like refer to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• the term “fixed combination” means that at least one of the agents described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that at least one of the agents described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more agents in the body of the patient.
• the co-agent is administered once or for a period of time, after which the agent is administered once or over a period of time.
• the co-agent is administered for a period of time, after which, a therapy involving the administration of both the co-agent and the agent are administered.
• the agent is administered once or over a period of time, after which, the co-agent is administered once or over a period of time.
• the terms “co-administration”, “administered in combination with” and their grammatical equivalents are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
• the agents described herein will be co-administered with other agents.
• These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
• the agents described herein and the other agent(s) are administered in a single composition.
• the agents described herein and the other agent(s) are admixed in the composition.
• an “effective amount” or “therapeutically effective amount” as used herein refer to a sufficient amount of at least one agent being administered which achieve a desired result, e.g., to relieve to some extent one or more symptoms of a 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 any other desired alteration of a biological system. In certain instances, an “effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
• administer refers to the methods that may be used to enable delivery of agents or compositions to the 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 that are optionally employed with the agents and methods described herein are found in sources e.g., Goodman and Gilman, The Pharmacological Basis of
• agents and compositions described herein are administered orally.
• pharmaceutically acceptable refers to a material that does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic (i.e., the toxicity of the material significantly outweighs the benefit of the material). In some instances, a
• pharmaceutically acceptable material may be administered to an individual without causing significant undesirable biological effects or significantly interacting in a deleterious manner with any of the components of the composition in which it is contained.
• carrier refers to relatively nontoxic chemical agents that, in certain instances, facilitate the incorporation of an agent into cells or tissues.
• non-systemic or “minimally absorbed” as used herein refers to low systemic bioavailability and/or absorption of an administered compound.
• a non-systemic compound is a compound that is substantially not absorbed systemically.
• ASBTI compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum and not systemically (e.g., a substantial portion of the ASBTI is not systemically absorbed.
• the systemic absorption of a non-systemic compound is ⁇ 0.1%, ⁇ 0.3%, ⁇ 0.5%, ⁇ 0.6%, ⁇ 0.7%, ⁇ 0.8%, ⁇ 0.9%, ⁇ 1%, ⁇ 1.5%, ⁇ 2%, ⁇ 3%, or ⁇ 5 % of the administered dose (wt. % or mol %).
• the systemic absorption of a non-systemic compound is ⁇ 10 % of the administered dose.
• the systemic absorption of a non-systemic compound is ⁇ 15 % of the administered dose.
• the systemic absorption of a non-systemic compound is ⁇ 25% of the administered dose.
• a non-systemic ASBTI is a compound that has lower systemic bioavailability relative to the systemic bioavailability of a systemic ASBTI (e.g., compound 100A, lOOC).
• the bioavailability of a non-systemic ASBTI described herein is ⁇ 30%, ⁇ 40%, ⁇ 50%, ⁇ 60%, or ⁇ 70% of the bioavailability of a systemic ASBTI (e.g., compound 100A, lOOC).
• compositions described herein are formulated to deliver ⁇ 10 % of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver ⁇ 20 % of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver ⁇ 30 % of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver ⁇ 40 % of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver ⁇ 50 % of the administered dose of the ASBTI systemically.
• compositions described herein are formulated to deliver ⁇ 60 % of the administered dose of the ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver ⁇ 70 % of the administered dose of the ASBTI systemically. In some embodiments, systemic absorption is determined in any suitable manner, including the total circulating amount, the amount cleared after administration, or the like.
• ASBT inhibitor refers to a compound that inhibits apical sodium-dependent bile transport or any recuperative bile salt transport.
• Apical Sodium-dependent Bile Transporter ASBT
• IBAT Ileal Bile Acid Transporter
• enhancing enteroendocrine peptide secretion refers to a sufficient increase in the level of the enteroendocrine peptide agent, for example, to treat any disease or disorder described herein.
• enhanced enteroendocrine peptide secretion reverses or alleviates symptoms of cholestasis or a cholestatic liver disease.
• pharmaceutically acceptable salts described herein include, by way of non- limiting example, a nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, subsalicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-tolunenesulfonate, mesylate and the like.
• pharmaceutically acceptable salts include, by way of non- limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), ammonium salts and the like.
• the term "optionally substituted” or “substituted” means that the referenced group substituted with one or more additional group(s).
• the one or more additional group(s) are individually and independently selected from amide, ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, ester, alkylsulfone, arylsulfone, cyano, halo, alkoyl, alkoyloxo, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino, alkyl-amino, dialkyl-amino, amido.
• alkyl group refers to an aliphatic hydrocarbon group. Reference to an alkyl group includes “saturated alkyl” and/or "unsaturated alkyl". The alkyl group, whether saturated or unsaturated, includes branched, straight chain, or cyclic groups. By way of example only, alkyl includes methyl, ethyl, propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, and hexyl. In some
• alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• a “lower alkyl” is a Ci-Ce alkyl.
• a "heteroalkyl” group substitutes any one of the carbons of the alkyl group with a heteroatom having the appropriate number of hydrogen atoms attached (e.g., a CH 2 group to an NH group or an O group).
• alkylene refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, an alkelene is a Ci-Ci 0 alkylene. In another apsect, an alkylene is a Ci-C 6 alkylene.
• Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and the like.
• alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
• An "amide” is a chemical moiety with formula -C(0)NHR or -NHC(0)R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings described herein include rings having five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl.
• aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are optionally substituted.
• aromatic includes both carbocyclic aryl ("aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
• aryl e.g., phenyl
• heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
• pyridine monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
• cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
• cycloalkyls are saturated, or partially unsaturated.
• cycloalkyls are fused with an aromatic ring.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
• Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• heterocyclo refers to heteroaromatic and heteroalicyclic groups containing one to four ring heteroatoms each selected from O, S and N. In certain instances, each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• Non-aromatic heterocyclic groups include groups having 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
• the heterocyclic groups include benzo-fused ring systems.
• An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridine).
• An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine).
• An example of a 5-membered heterocyclic group is thiazolyl.
• An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl.
• non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazol
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
• An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
• heteroaryl groups are monocyclic or polycyclic.
• heteroalicyclic group or heterocyclo refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur.
• the radicals are with an aryl or heteroaryl.
• heterocyclo groups also referred to as non- aromatic heterocycles, include:
• heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
• halo or, alternatively, "halogen” means fluoro, chloro, bromo and iodo.
• fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
• heteroalkyl include optionally substituted alkyl, alkenyl and alkynyl radicals which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
• the heteroatom(s) is placed at any interior position of the heteroalkyl group.
• up to two heteroatoms are consecutive, such as, by way of example, -CH 2 -CH 2
• a "cyano" group refers to a -CN group.
• An "isocyanato" group refers to a -NCO group.
• a "thiocyanato" group refers to a -CNS group.
• An "isothiocyanato" group refers to a -NCS group.
• modulate refers to having some affect on (e.g., increasing, enhancing or maintaining a certain level).
• the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from C i-Cealkyl, C 3 -Cgcycloalkyl, aryl, heteroaryl, C 2 -C 6 heteroalicyclic, hydroxy, Q-Cealkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, Ci-C 6 alkylthio, arylthio, Ci-C 6 alkylsulfoxide, arylsulfoxide, Ci-C 6 alkylsulfone, arylsulfone, cyano, halo, C 2 -C 8 acyl, C 2 -C 8 acyloxy, nitro, Ci-C 6 haloalkyl, Ci-C 6 fluoroalkyl, and amino, including Ci-C 6 alkylamino, and the protected derivatives thereof.
• the protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.
• alkyl groups described herein are optionally substituted with an O that is connected to two adjacent carbon atoms (i.e., forming an epoxide).
• terapéuticaally effective amount refers to a sufficient amount of a therapeutically active agent to provide a desired effect in a subject or individual.
• a "therapeutically effective amount” or an “effective amount” of an ASBTI refers to a sufficient amount of an ASBTI to treat cholestasis or a cholestatic liver disease in a subject or individual.
• enteroendocrine L-cells play a role in repair.
• the epithelial barrier is also a key component in host defence.
• a further pre-proglucagon splice product, GLP-2 is secreted by enteroendocrine L-cells in the distal small intestine and has been shown to improve intestinal wound healing in a TGF-B (anti-inflammatory cytokine TGF-B), mediated process, small bowel responding better than large bowel.
• TGF-B anti-inflammatory cytokine TGF-B
• GLP-2 has also been shown to ameliorate the barrier dysfunction induced by experimental stress and food allergy.
• L-cells are activated by luminal nutrients, and the barrier compromise observed in TPN may partly reflect its hyposecretion in the absence of enteral stimuli.
• GLP-2 is also responsible, at least in part for growth and adaptation observed in short-bowel models. Therefore, abnormal enteroendocrine cells (EEC) function may predispose to GI inflammatory disorders, and the underlying nutrient-EEC-vagal pathways are targets in the injured gut as contemplated in the present embodiments.
• EEC enteroendocrine cells
• L-cells are scattered throughout the epithelial layer of the gut from the duodenum to the rectum, with the highest numbers occurring in the ileum, colon, and rectum. They are characterized by an open-cell morphology, with apical microvilli facing into the gut lumen and secretory vesicles located adjacent to the basolateral membrane, and are therefore in direct contact with nutrients in the intestinal lumen. Furthermore, L-cells are located in close proximity to both neurons and the microvasculature of the intestine, thereby allowing the L-cell to be affected by both neural and hormonal signals.
• L-cells also secrete peptide YY (PYY), and glutamate.
• the cells are just one member of a much larger family of enteroendocrine cells that secrete a range of hormones, including ghrelin, GIP, cholecystokinin, somatostatin, and secretin, which are involved in the local coordination of gut physiology, as well as in playing wider roles in the control of cytokine release and/or controlling the adaptive process, attenuating intestinal injury, reducing bacterial translocation, inhibiting the release of free radical oxygen, or any combination thereof.
• L-cells are unevenly distributed in the gastrointestinal tract, within higher concentrations in the distal portion of the gastrointestinal tract (e.g., in the distal ileum, colon and rectum).
• Bile contains water, electrolytes and a numerous organic molecules including bile acids, cholesterol, phospholipids and bilirubin. Bile is secreted from the liver and stored in the gall bladder, and upon gall bladder contraction, due to ingestion of a fatty meal, bile passes through the bile duct into the intestine. Bile acids/salts are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adult humans produce 400 to 800 niL of bile daily. The secretion of bile can be considered to occur in two stages.
• hepatocytes secrete bile into canaliculi, from which it flows into bile ducts and this hepatic bile contains large quantities of bile acids, cholesterol and other organic molecules. Then, as bile flows through the bile ducts, it is modified by addition of a watery, bicarbonate -rich secretion from ductal epithelial cells. Bile is concentrated, typically five-fold, during storage in the gall bladder.
• Bile acids/salts are derivatives of cholesterol. Cholesterol, ingested as part of the diet or derived from hepatic synthesis, are converted into bile acids/salts in the hepatocyte. Examples of such bile acids/salts include cholic and chenodeoxycholic acids, which are then conjugated to an amino acid (such as glycine or taurine) to yield the conjugated form that is actively secreted into cannaliculi. The most abundant of the bile salts in humans are cholate and deoxycholate, and they are normally conjugated with either glycine or taurine to give glycocholate or taurocholate respectively.
• Free cholesterol is virtually insoluble in aqueous solutions, however in bile it is made soluble by the presence of bile acids/salts and lipids. Hepatic synthesis of bile acids/salts accounts for the majority of cholesterol breakdown in the body. In humans, roughly 500 mg of cholesterol are converted to bile acids/salts and eliminated in bile every day. Therefore, secretion into bile is a major route for elimination of cholesterol. Large amounts of bile acids/salts are secreted into the intestine every day, but only relatively small quantities are lost from the body. This is because approximately 95% of the bile acids/salts delivered to the duodenum are absorbed back into blood within the ileum, by a process is known as "Enterohepatic Recirculation".
• Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the approximate 800 mg/day of cholesterol that an average adult uses up in metabolic processes. In comparison, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day.
• Bile acids/salts are amphipathic, with the cholesterol-derived portion containing both hydrophobic (lipid soluble) and polar (hydrophilic) moieties while the amino acid conjugate is generally polar and hydrophilic. This amphipathic nature enables bile acids/salts to carry out two important functions:
• Bile acids/salts have detergent action on particles of dietary fat which causes fat globules to break down or to be emulsified. Emulsification is important since it greatly increases the surface area of fat available for digestion by lipases which cannot access the inside of lipid droplets. Furthermore, bile acids/salts are lipid carriers and are able to solubilize many lipids by forming micelles and are critical for transport and absorption of the fat-soluble vitamins.
• compositions described herein are administered for delivery of
• any compositions described herein are formulated for ileal, rectal and/or colonic delivery.
• the composition is formulated for non-systemic or local delivery to the rectum and/or colon. It is to be understood that as used herein, delivery to the colon includes delivery to sigmoid colon, transverse colon, and/or ascending colon.
• delivery to the colon includes delivery to sigmoid colon, transverse colon, and/or ascending colon.
• the composition is formulated for non- systemic or local delivery to the rectum and/or colon is administered rectally.
• the composition is formulated for non-systemic or local delivery to the rectum and/or colon is administered orally.
• composition comprising an enteroendocrine peptide secretion enhancing agent and, optionally, a pharmaceutically acceptable carrier for alleviating symptoms of pediatric cholestasis or a pediatric cholestatic liver disease in an individual.
• the composition comprises an enteroendocrine peptide secretion enhancing agent and an absorption inhibitor.
• the absorption inhibitor is an inhibitor that inhibits the absorption of the (or at least one of the) specific enteroendocrine peptide secretion enhancing agent with which it is combined.
• the composition comprises an enteroendocrine peptide secretion enhancing agent, an absorption inhibitor and a carrier (e.g., an orally suitable carrier or a rectally suitable carrier, depending on the mode of intended administration).
• the composition comprises an enteroendocrine peptide secretion enhancing agent, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.
• compositions described herein are administered orally for non-systemic delivery of the bile salt active component to the rectum and/or colon, including the sigmoid colon, transverse colon, and/or ascending colon.
• compositions formulated for oral administration are, by way of non-limiting example, enterically coated or formulated oral dosage forms, such as, tablets and/or capsules. It is to be understood that the terms "subject” and “individual” are utilized interchangeably herein and include, e.g., humans and human patients in need of treatment.
• Absorption Inhibitors are utilized interchangeably herein and include, e.g., humans and human patients in need of treatment.
• composition described herein as being formulated for the non-systemic delivery of ASBTI further includes an absorption inhibitor.
• an absorption inhibitor includes an agent or group of agents that inhibit absorption of a bile acid/salt.
• Suitable bile acid absorption inhibitors include, by way of non-limiting example, anionic exchange matrices, polyamines, quaternary amine containing polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam, colesevelam hydrochloride, CholestaGel (N,N,N-trimethyl-6-(2-propenylamino)-l-hexanaminium chloride polymer with (chloromethyl)oxirane, 2-propen-l -amine and N-2-propenyl-l -decanamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, carbohydrates which bind bile acids, lipids which bind bile acids, proteins and proteinaceous materials which bind bile acids, and antibodies and albumins which bind bile acids.
• anionic exchange matrices include, by way of non-limiting example, anionic exchange matric
• Suitable cyclodextrins include those that bind bile acids/salts such as, by way of non-limiting example, ⁇ -cyclodextrin and hydroxypropyl-P-cyclodextrin.
• Suitable proteins include those that bind bile acids/salts such as, by way of non- limiting example, bovine serum albumin, egg albumin, casein, a -acid glycoprotein, gelatin, soy proteins, peanut proteins, almond proteins, and wheat vegetable proteins.
• the absorption inhibitor is cholestyramine.
• cholestyramine is combined with a bile acid.
• Cholestyramine, an ion exchange resin is a styrene polymer containing quaternary ammonium groups crosslinked by divinylbenzene.
• the absorption inhibitor is colestipol.
• colestipol is combined with a bile acid.
• Colestipol an ion exchange resin
• Colestipol is a copolymer of diethylenetriamine and l-chloro-2,3-epoxypropane.
• the ASBTI is linked to an absorption inhibitor, while in other embodiments the ASBTI and the absorption inhibitor are separate molecular entities.
• the bile acid, bile acid mimic or the modified bile acid is linked to a bile acid adsorption inhibitor described herein.
• a composition described herein optionally includes at least one cholesterol absorption inhibitor.
• Suitable cholesterol absorption inhibitors include, by way of non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogues, ⁇ -lactam cholesterol absorption inhibitors, sulfate polysaccharides, neomycin, plant sponins, plant sterols, phytostanol preparation FM-VP4, Sitostanol, ⁇ -sitosterol, acyl-CoA:cholesterol- O-acyltransferase (ACAT) inhibitors, Avasimibe, Implitapide, steroidal glycosides and the like.
• ezetimibe SCH 58235
• ezetimibe analogs include, by way of non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastan
• Suitable enzetimibe analogs include, by way of non-limiting example, SCH 48461, SCH 58053 and the like.
• Suitable ACT inhibitors include, by way of non-limiting example, trimethoxy fatty acid anilides such as Cl-976, 3- [decyldimethylsilyl]-N-[2-(4-methylphenyl)-l-phenylethyl]-propanamide, melinamide and the like
• ⁇ -lactam cholesterol absorption inhibitors include, by way of non-limiting example, (3R-4S)-l,4-bis-(4- methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone and the like.
• compositions described herein optionally include at least one peptidase inhibitor.
• peptidase inhibitors include, but are not limited to, dipeptidyl peptidase-4 inhibitors (DPP-4), neutral endopeptidase inhibitors, and converting enzyme inhibitors.
• Suitable dipeptidyl peptidase-4 inhibitors include, by way of non-limiting example, Vildaglipti, 25)-l - ⁇ 2-[(3-hydroxy-l - adamantyl)amino] acetyl ⁇ pyrrolidine -2-carbonitrile, Sitagliptin, (3R)-3-amino-l-[9-(trifluoromethyl)-l, 4,7,8- tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, Saxagliptin, and (1S,3S,5S)- 2-[(2S)-2-amino-2-(3-hydroxy-l-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile.
• neutral endopeptidase inhibitors include, but are not limited to,
• the composition described herein optionally comprises a spreading agent.
• a spreading agent is utilized to improve spreading of the composition in the colon and/or rectum.
• Suitable spreading agents include, by way of non- limiting example, hydroxyethylcellulose, hydroxypropymethyl cellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbophil, di-n-octyl ethers, CetiolTMOE, fatty alcohol polyalkylene glycol ethers, AethoxalTMB), 2-ethylhexyl palmitate, CegesoftTMC 24), and isopropyl fatty acid esters.
• compositions described herein optionally comprise a wetting agent.
• a wetting agent is utilized to improve wettability of the composition in the colon and rectum.
• Suitable wetting agents include, by way of non-limiting example, ionic or non-ionic surfactants.
• surfactants are selected from, by way of non-limiting example, SLS, poloxamers (e.g., poloxamer 188), polysorbate (e.g., 20 or 80), stearyl hetanoate, caprylic/capric fatty acid esters of saturated fatty alcohols of chain length C 12 -C18, isostearyl diglycerol isostearic acid, sodium dodecyl sulphate, isopropyl myristate, isopropyl palmitate, and isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.
• SLS poloxamers
• poloxamers e.g., poloxamer 188
• polysorbate e.g., 20 or 80
• stearyl hetanoate e.g., caprylic/capric fatty acid esters of saturated fatty alcohols of chain length C 12 -C18
• the methods provided herein further comprise administering one or more vitamins.
• the vitamin is vitamin A, Bl, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.
• the vitamin is a fat soluble vitamin such as vitamin A, D, E, K, retinol, beta carotene, cholecalciferol, tocopherols, phylloquinone.
• the fat soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).
• a labile bile acid sequestrant is an enzyme dependent bile acid sequestrant.
• the enzyme is a bacterial enzyme.
• the enzyme is a bacterial enzyme found in high concentration in human colon or rectum relative to the concentration found in the small intestine.
• micro-flora activated systems include dosage forms comprising pectin, galactomannan, and/or Azo hydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, ⁇ -D- xylopyranoside or the like) of the active agent.
• gastrointestinal micro-flora enzymes include bacterial glycosidases such as, for example, D-galactosidase, ⁇ -D-glucosidase, a-L-arabinofuranosidase, ⁇ - D-xylopyranosidase or the like.
• a labile bile acid sequestrant is a time dependent bile acid sequestrant. In some embodiments, a labile bile acid sequestrant releases a bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of sequestration. In some embodiments, a labile bile acid sequestrant releases a bile acid or is degraded after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of sequestration. In some embodiments, a labile bile acid sequestrant releases a bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of sequestration.
• a labile bile acid sequestrant releases a bile acid or is degraded after about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of sequestration. In some embodiments, a labile bile acid sequestrant releases a bile acid or is degraded after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of sequestration. In some embodiments, a labile bile acid sequestrant releases a bile acid or is degraded after 1 , 2, or 3 days of sequestration.
• the labile bile acid sequestrant has a low affinity for bile acid. In certain embodiments, the labile bile acid sequestrant has a high affinity for a primary bile acid and a low affinity for a secondary bile acid.
• the labile bile acid sequestrant is a pH dependent bile acid sequestrant.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 6 or below and a low affinity for bile acid at a pH above 6.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 6.5 or below and a low affinity for bile acid at a pH above 6.5.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7 or below and a low affinity for bile acid at a pH above 7.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.1 or below and a low affinity for bile acid at a pH above 7.1. In certain embodiments, the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.2 or below and a low affinity for bile acid at a pH above 7.2. In certain embodiments, the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.3 or below and a low affinity for bile acid at a pH above 7.3.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.4 or below and a low affinity for bile acid at a pH above 7.4. In certain embodiments, the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.5 or below and a low affinity for bile acid at a pH above 7.5. In certain embodiments, the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.6 or below and a low affinity for bile acid at a pH above 7.6.
• the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.7 or below and a low affinity for bile acid at a pH above 7.7. In certain embodiments, the pH dependent bile acid sequestrant has a high affinity for bile acid at a pH of 7.8 or below and a low affinity for bile acid at a pH above 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 6.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.
• the pH dependent bile acid sequestrant degrades at a pH above 7.1. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.2. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.3. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.4. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.7. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH above 7.9.
• the labile bile acid sequestrant is lignin or a modified lignin. In some embodiments, the labile bile acid sequestrant is a polycationic polymer or copolymer. In certain embodiments,
• the labile bile acid sequestrant is a polymer or copolymer comprising one or more 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 a combination thereof.
• the bile acid binder is cholestyramine, and various compositions including cholestyramine, which are described, for example, in U. S. Patent Nos. 3,383, 281 ; 3,308, 020; 3,769, 399; 3,846, 541 ; 3,974, 272; 4,172, 120; 4,252, 790; 4,340, 585; 4,814, 354; 4,874, 744; 4,895, 723; 5,695, 749; and 6,066, 336.
• the bile acid binder is cholestipol or cholesevelam.
• kits for treating pediatric cholestasis or a pediatric cholestatic liver disease comprising non-systemic administration of a therapeutically effective amount of an ASBTL
• methods for treating pediatric cholestasis or a pediatric cholestatic liver disease comprising contacting the gastrointestinal tract, including the distal ileum and/or the colon and/or the rectum, of an individual in need thereof with an ASBTL
• methods for reducing intraenterocyte bile acids, reducing damage to hepatocellular or intestinal architecture caused by cholestasis or a cholestatic liver disease, of an individual comprising administration of a therapeutically effective amount of an ASBTI to an individual in need thereof.
• provided herein is a method of treating pediatric cholestasis or a pediatric cholestatic liver disease in an individual comprising delivering to ileum or colon of the individual a therapeutically effective amount of any ASBTI described herein.
• methods for reducing damage to hepatocellular or intestinal architecture or cells from cholestasis or a cholestatic liver disease comprising administration of a therapeutically effective amount of an ASBTI.
• methods for reducing intraenterocyte bile acids/salts comprising administration of a therapeutically effective amount of an ASBTI to an individual in need thereof.
• the methods provide for inhibition of bile salt recycling upon administration of any of the compounds described herein to an individual.
• an ASBTI described herein is systemically absorbed upon administration.
• an ASBTI described herein is not absorbed systemically.
• an ASBTI herein is administered to the individual orally.
• an ASBTI described herein is delivered and/or released in the distal ileum of an individual.
• contacting the distal ileum of a pediatric individual with an ASBTI inhibits bile acid reuptake and increases the concentration of bile acids/salts in the vicinity of L-cells in the distal ileum and/or colon and/or rectum, thereby reducing intraenterocyte bile acids, reducing serum and/or hepatic bile acid levels, reducing overall bile acid load, and/or reducing damage to ileal architecture caused by cholestasis or a cholestatic liver disease.
• ASBTI e.g., any ASBTI described herein
• Administration of a compound described herein is achieved in any suitable manner including, by way of non-limiting example, by oral, enteric, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Any compound or composition described herein is administered in a method or formulation appropriate to treat a new born or an infant. Any compound or composition described herein is administered in an oral formulation (e.g., solid or liquid) to treat a new born or an infant.
• oral formulation e.g., solid or liquid
• the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, orally disintegrating strip, and sprinkle oral powder or granules.
• a compound or composition described herein is administered in a method or pediatric dosage form formulation appropriate to treat children.
• a compound or composition described herein is administered in a method or pediatric dosage form formulation appropriate to treat adolescents.
• a compound or composition described herein is administered in a method or pediatric dosage form formulation appropriate to treat a newborn or an infant.
• a compound or composition described herein is administered in an oral formulation (e.g., solid or liquid) to treat a newborn or an infant.
• the pediatric dosage form described herein is administered prior to ingestion of food, with food or after ingestion of food.
• a compound or a composition comprising a compound described herein is administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to an individual already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
• amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the individual's health status, weight, and response to the drugs, and the judgment of the treating physician.
• compounds or compositions containing compounds described herein are administered to an individual susceptible to or otherwise at risk of a particular disease, disorder or condition.
• the precise amounts of compound administered depend on the individual's state of health, weight, and the like.
• effective amounts for this use depend on the severity and course of the disease, disorder or condition, previous therapy, the individual's health status and response to the drugs, and the judgment of the treating physician.
• a compound or composition described herein is optionally administered chronically, that is, for an extended period of time, including throughout the duration of the individual's life in order to ameliorate or otherwise control or limit the symptoms of the individual's disorder, disease or condition.
• an effective amount of a given agent varies depending upon one or more of a number of factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, and is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• doses administered include those up to the maximum tolerable dose. In some embodiments, doses administered include those up to the maximum tolerable dose by a newborn or an infant.
• about 0.001-5000 mg per day, from about 0.001-1500 mg per day, about 0.001 to about 100 mg/day, about 0.001 to about 50 mg/day, or about 0.001 to about 30 mg/day, or about 0.001 to about 10 mg/day of a compound described herein is administered to an individual in need thereof.
• the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• a single dose is from about 0.001 mg/kg to about 500 mg/kg.
• a single dose is from about 0.001, 0.01, 0.1, 1, or 10 mg/kg to about 10, 50, 100, or 250 mg/kg.
• a single dose of an ASBTI is from about 0.001 mg/kg to about 100 mg/kg.
• a single dose of an ASBTI is from about 0.001 mg/kg to about 50 mg/kg.
• a single dose of an ASBTI is from about 0.001 mg/kg to about 10 mg/kg.
• a single dose of an 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.
• an ASBTI is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
• the length of the drug holiday optionally varies between 2 days and 1 year, including 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 dose reduction during a drug holiday includes from 10%- 100%, 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%.
• the total single dose of an ASBTI is in the range described above.
• a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
• Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50%> of the population) and the ED 50 (the dose therapeutically effective in 50%> of the population).
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
• Compounds exhibiting high therapeutic indices are preferred.
• data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human.
• the dosage of compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
• the systemic exposure of a therapeutically effective amount of any non- systemic ASBTI described herein is reduced when compared to the systemic exposure of a therapeutically effective amount of any systemically absorbed ASBTI (e.g. Compounds 100A, lOOC).
• a therapeutically effective amount of any systemically absorbed ASBTI e.g. Compounds 100A, lOOC.
• the AUC of a therapeutically effective amount of any non-systemic ASBTI described herein is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%> reduced when compared to the AUC of any systemically absorbed ASBTI (e.g. Compounds 100A, lOOC).
• the systemic exposure of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the systemic exposure of a therapeutically effective amount of a compound of Formula II that is not systemically absorbed is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula II that is not systemically absorbed is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%) reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula II that is not systemically absorbed is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula II that is not systemically absorbed is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the systemic exposure of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound lOOC.
• the AUC of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 10%, about 20%, about 30%, about 40%, about 50%), about 60%), about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C.
• the AUC of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C. In other embodiments, the AUC of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C.
• the systemic exposure of a therapeutically effective amount of a compound of Formula IV that is not systemically absorbed is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula IV that is not systemically absorbed is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula IV that is not systemically absorbed is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula IV that is not systemically absorbed is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the systemic exposure of a therapeutically effective amount of a compound of Formula V that is not systemically absorbed is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula V that is not systemically absorbed is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%) reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the systemic exposure of a therapeutically effective amount of a compound of Formula VI or VID that is not systemically absorbed is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula VI or VID that is not systemically absorbed is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%), about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula VI or VID that is not systemically absorbed is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
• the AUC of a therapeutically effective amount of a compound of Formula I that is not systemically absorbed is about 75% reduced when compared to the AUC of a compound of Formula I that is not systemically absorbed (e.g., a compound of Formula VI or VID that comprises a non-systemic moiety such as L-K or other groups described herein) is about 75% reduced when compared to the AUC of a compound of Formula I that is not systemically absorbed (e.g., a compound of Formula VI or VID that comprises a non-systemic moiety such as L-K or other groups described herein) is about 75% reduced when compared to the AUC of a compound of Formula I that is not systemically absorbed (e.g., a compound of Formula VI or VID that comprises a non-systemic moiety such as L-K or other groups described herein) is about 75% reduced when compared to the AUC of a compound of Formula I that is not systemically absorbed (e.g., a compound of Formula VI or VID
• the Cmax of a therapeutically effective amount of any non-systemic ASBTl described herein is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%), at least 80% or at least 90% reduced when compared to the Cmax of any systemically absorbed ASBTl (e.g.Compound 100A).
• the Cmax of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%) or about 90% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C.
• the Cmax of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 25% reduced when compared to the Cmax of a therapeutically effective amount of Compound lOOC.
• the Cmax of a therapeutically effective amount of a compound of III, IIIA or IIIB is about 50% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C. In other embodiments, the Cmax of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 75% reduced when compared to the Cmax of a therapeutically effective amount of Compound 100C.
• the pharmaceutical composition administered includes a therapeutically effective amount of a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor and a carrier (e.g., an orally suitable carrier or a rectally suitable carrier, depending on the mode of intended
• the pharmaceutical composition used or administered comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.
• the pharmaceutical composition used to prepare a rectal dosage form or administered rectally comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor, a rectally suitable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional wetting agent.
• rectally administered compositions evokes an anorectal response.
• the anorectal response is an increase in secretion of one or more enteroendocrine by cells (e.g., L-cells) in the colon and/or rectum (e.g., in the epithelial layer of the colon and/or rectum).
• the anorectal response persists for at least 1, 2, 3, 4 ,5 ,6 ,7 ,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours.
• the anorectal response persists for a period between 24 hours and 48 hours, while in other embodiments the anorectal response persists for persists for a period greater than 48 hours.
• the pharmaceutical composition used to prepare an oral dosage form or administered orally comprises a bile salt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor, an orally suitable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional wetting agent.
• the orally administered compositions evokes an anorectal response.
• the anorectal response is an increase in secretion of one or more enteroendocrine by cells in the colon and/or rectum (e.g., in L-cells the epithelial layer of the colon and/or rectum).
• the anorectal response persists for at least 1, 2, 3, 4 ,5 ,6 ,7 ,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. In other embodiments the anorectal response persists for a period between 24 hours and 48 hours, while in other embodiments the anorectal response persists for persists for a period greater than 48 hours.
• compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reuptake, or reduce serum or hepatic bile acid levels.
• the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively.
• the compositions described herein are combined with a device for local delivery of the compositions to the rectum and/or colon (sigmoid colon, transverse colon, or ascending colon).
• compositions described herein are formulated as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.
• compositions described herein are formulated for oral administration.
• compositions or methods described herein are non-systemic.
• compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum and not systemically (e.g., a substantial portion of the enteroendocrine peptide secretion enhancing agent is not systemically absorbed).
• oral compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum and not systemically (e.g., a substantial portion of the enteroendocrine peptide secretion enhancing agent is not systemically absorbed).
• rectal compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum and not systemically (e.g., a substantial portion of the enteroendocrine peptide secretion enhancing agent is not systemically absorbed).
• non-systemic compositions described herein deliver less than 90% w/w of the ASBTI systemically.
• non-systemic compositions described herein deliver less than 80% w/w of the ASBTI systemically.
• non-systemic compositions described herein deliver less than 70%> w/w of the ASBTI systemically.
• non-systemic compositions described herein deliver less than 60%> w/w of the ASBTI systemically. In certain embodiments, non- systemic compositions described herein deliver less than 50% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 40% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 30% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 25% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 20% w/w of the ASBTI systemically.
• non- systemic compositions described herein deliver less than 15% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 10% w/w of the ASBTI systemically. In certain embodiments, non-systemic compositions described herein deliver less than 5% w/w of the ASBTI systemically. In some embodiments, systemic absorption is determined in any suitable manner, including the total circulating amount, the amount cleared after administration, or the like.
• compositions and/or formulations described herein are administered at least once a day.
• the formulations containing the ASBTI are administered at least twice a day, while in other embodiments the formulations containing the ASBTI are administered at least three times a day.
• the formulations containing the ASBTI are administered up to five times a day. It is to be understood that in certain embodiments, the dosage regimen of composition containing the ASBTI described herein to is determined by considering various factors such as the patient's age, sex, and diet.
• the concentration of the ASBTI administered in the formulations described herein ranges from about 1 mM to about 1 M. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 1 mM to about 750 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM.
• the concentration of the administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments the concentration of the ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.
• any composition described herein comprises a therapeutically effective amount (e.g., to treat cholestasis or a cholestatic liver disease) of ursodiol.
• ursodiol may be substituted for any other therapeutic bile acid or salt.
• compositions described herein comprise or methods described herein comprise administering about 0.01 mg to about 10 g of ursodiol.
• a composition described herein comprises or a method described herein comprises administering about 0.1 mg to about 500 mg of ursodiol.
• a composition described herein comprises or a method described herein comprises administering about 0.1 mg to about 100 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.1 mg to about 50 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.1 mg to about 10 mg of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.5 mg to about 10 mg of ursodiol.
• compositions described herein comprise or methods described herein comprise administering about 0.1 mmol to about 1 mol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.01 mmol to about 500 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.1 mmol to about 100 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.5 mmol to about 30 mmol of ursodiol.
• a composition described herein comprises or a method described herein comprises administering about 0.5 mmol to about 20 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 1 mmol to about 10 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.01 mmol to about 5 mmol of ursodiol. In certain embodiments, a composition described herein comprises or a method described herein comprises administering about 0.1 mmol to about 1 mmol of ursodiol.
• certain bile acids/salts have different potencies and dosing is optionally adjusted accordingly.
• the investigation in TGR5-transfected CHO cells of TGR5 agonist potency of natural bile acids/salts indicates the following rank of potency: Lithocholic acid (LCA) >deoxycholic acid (DCA) > murocholic acid (Muro- CA) >lagodeoxycholic acid (lago-DCA) > chenodeoxycholic (CDCA) > cholic acid (CA) > hyodeoxycholic acid (HDCA > ursodeoxycholic acid (UDCA); and assays on TGR5-transfected CHO cells demonstrate that EC 50 (in ⁇ ) for UDCA was 36.4, TauroCA (TCA) 4.95 and LCA 0.58.
• compositions and methods described herein provide efficacy (e.g., in reducing microbial growth and/or alleviating symptoms of cholestasis or a cholestatic liver disease) with a reduced dose of
• enteroendocrine peptide secretion enhancing agent e.g., as compared to an oral dose that does not target the distal gastrointestinal tract.
• compositions described herein for the non-systemic delivery of a compound described herein to the rectum and/or colon are formulated for rectal administration as rectal enemas, rectal foams, rectal gels, and rectal suppositories.
• rectal formulations comprise rectal enemas, foams, gels, or suppositories.
• liquid carrier vehicles or co-solvents in the compositions and/or formulations described herein include, by way of non-limiting example, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethyleneglycol, ethanol, 1-propanol, 2-propanol, l-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, formamide, methyl formamide, dimethyl formamide, ethyl formamide, diethyl formamide, acetamide, methyl acetamide, dimethyl acetamide, ethyl acetamide, diethyl acetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea, l,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-
• stabilizers used in compositions and/or formulations described herein include, but are not limited to, partial glycerides of polyoxyethylenic saturated fatty acids.
• surfactants/emulsifiers used in the compositions and/or formulations described herein include, by way of non-limiting example, mixtures of cetostearylic alcohol with sorbitan esterified with polyoxyethylenic fatty acids, polyoxyethylene fatty ethers, polyoxyethylene fatty esters, fatty acids, sulfated fatty acids, phosphated fatty acids, sulfosuccinates, amphoteric surfactants, non-ionic poloxamers, non-ionic meroxapols, petroleum derivatives, aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbionate, non-ionic acid
• non-ionic surfactants used in compositions and/or formulations described herein include, by way of non-limiting example, phospholipids, alkyl poly( ethylene oxide), poloxamers (e.g., poloxamer 188), polysorbates, sodium dioctyl sulfosuccinate, BrijTM-30 (Laureth-4), BrijTM-58 (Ceteth-20) and BrijTM-78 (Steareth-20), BrijTM-721 (Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40), Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40 Stearate), Myrj- 53 (PEG-50 Stearate), PluronicTM F77 (Poloxamer 217), PluronicTM F87 (Poloxamer 237), PluronicTM F98 (Poloxamer 288), PluronicTM L62 (Polo
• PluracareTM F 127 NF Polyxamer 407 and combinations thereof.
• PluronicTM polymers are commercially purchasable from BASF, USA and Germany.
• anionic surfactants used in compositions and/or formulations described herein include, by way of non-limiting example, sodium laurylsulphate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, alkyl sulfate salts, alkyl benzene sulfonate, and combinations thereof.
• the cationic surfactants used in compositions and/or formulations described herein include, by way of non-limiting example, benzalkonium chloride, benzethonium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide, other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow and combinations thereof.
• the thickeners used in compositions and/or formulations described herein include, by way of non-limiting example, natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof.
• Natural polysaccharides include, by way of non-limiting example, acacia, agar, alginates, carrageenan, guar, arabic, tragacanth gum, pectins, dextran, gellan and xanthan gums.
• Semi-synthetic polymers include, by way of non-limiting example, cellulose esters, modified starches, modified celluloses, carboxymethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
• Synthetic polymers include, by way of non- limiting example, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates,
• carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinylacetate, polyethylene glycols and poloxamer.
• Other thickeners include, by way of nonlimiting example, polyoxyethyleneglycol isostearate, cetyl alcohol, Polyglycol 300 isostearate, propyleneglycol, collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid and the like).
• chelating agents used in the compositions and/or formulations described herein include, by way of non-limiting example, ethylenediaminetetraacetic acid (EDTA) or salts thereof, phosphates and combinations thereof.
• EDTA ethylenediaminetetraacetic acid
• the concentration of the chelating agent or agents used in the rectal formulations described herein is a suitable concentration, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w/v).
• preservatives used in compositions and/or formulations described herein include, by way of non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated
• antioxidants used in compositions and/or formulations described herein include, by way of non-limiting example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulphite, sodium metabisulfite, oxygen, quinones, t-butyl hydroquinone, erythorbic acid, olive (olea eurpaea) oil, pentasodium penetetate, pentetic acid, tocopheryl, tocopheryl acetate and combinations thereof.
• ascorbic acid ascorbyl palmitate
• butylated hydroxyanisole butylated hydroxytoluene
• hypophosphorous acid monothioglycerol
• propyl gallate sodium ascorbate
• compositions include quaternary ammonium salts such as
• benzalkonium chloride alcohols such as benzyl alcohol, organic acids or salts and derivatives thereof such as benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, propionic acid, sodium propionate, parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethyl parahydroxybenzoate or butyl parahydroxybenzoate, aqua conservans; chlorhexidine diacetate,-digluconate.
• the preservatives are preferably suitable for pediatric use.
• Preferred preservatives are parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, ethyl parahydroxybenzoate or butyl parahydroxybenzoate, in particular methyl parahydroxybenzoate or propyl parahydroxybenzoate.
• the preservatives are present in a composition in a concentration in order to provide sufficient antimicrobial activity in the preconcentrate composition or in the liquid composition upon reconstitution.
• the concentration of the preservatives in a resulting reconstituted liquid composition ranges up to about 3% (w/w), more preferably up to about 2.5% (w/w), more preferably up to about 2% (w/w), depending on the actual preservative being used.
• the composition of the present invention may also contain one or more anti-oxidants, such as, for example, sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, BHA (butylhydroxyanisol), BHT (butylhydroxytoluene), vitamine E, propylgallate, ascorbyl palmitate, or complex forming agents such as EDTA (ethylenediaminetetraacetic acid), citric acid, tartaric acid, sodium- hexametaphosphate and the like.
• the antioxidants or the complex forming agents are preferably suitable for pediatric use.
• Preferred antioxidants are BHA, BHT, vitamin E or propylgallate.
• concentration of the antioxidant or antioxidants used in the rectal formulations described herein is sufficient to achieve a desired result, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w/v).
• lubricating agents used in compositions and/or formulations described herein include, by way of non-limiting example, natural or synthetic fat or oil (e.g., a tris-fatty acid glycerate and the like).
• lubricating agents include, by way of non-limiting example, glycerin (also called glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycols (PEGs), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose,
• mucoadhesive and/or bioadhesive polymers are used in the compositions and/or formulations described herein as agents for inhibiting absorption of the enteroendocrine peptide secretion enhancing agent across the rectal or colonic mucosa.
• Bioadhesive or mucoadhesive polymers include, by way of non-limiting example, hydroxypropyl cellulose, polyethylene oxide homopolymers, polyvinyl ether-maleic acid copolymers, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, polycarbophil, polyvinylpyrrolidone, carbopol, polyurethanes, polyethylene oxide -polypropyline oxide copolymers, sodium carboxymethyl cellulose, polyethylene, polypropylene, lectins, xanthan gum, alginates, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and ester derivatives thereof, vinyl acetate homopolymer, calcium polycarbophil, gelatin, natural gums, karaya, tragacanth, algin, chitosan, starches,
• buffers/pH adjusting agents used in compositions and/or formulations described herein include, by way of non-limiting example, phosphoric acid, monobasic sodium or potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, sodium citrate anhydrous, sodium citrate dihydrate and combinations thereof.
• an acid or a base is added to adjust the pH. Suitable acids or bases include, by way of non-limiting example, HCL, NaOH and KOH.
• concentration of the buffering agent or agents used in the rectal formulations described herein is sufficient to achieve or maintain a physiologically desirable pH, e.g., about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w/w).
• the tonicity modifiers used in compositions and/or formulations described herein include, by way of non-limiting example, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol or glucose.
• a pediatric dosage formulation or composition comprising a therapeutically effective amount of any compound described herein.
• the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).
• suitable dosage forms include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candy, orally disintegrating tablets, powders for reconstitution as suspension or solution, sprinkle oral powder or granules, dragees, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
• aqueous or non-aqueous oral dispersions liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candy, orally disintegrating tablets, powders for reconstitution as suspension or solution, sprinkle oral powder or gran
• a pharmaceutical composition wherein the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, gummy candy, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, orally disintegrating strip, sachet, and sprinkle oral powder or granules.
• a pharmaceutical composition wherein at least one excipient is a flavoring agent or a sweetener.
• a coating In some embodiments, provided herein is a taste-masking technology selected from coating of drug particles with a taste -neutral polymer by spray-drying, wet granulation, fluidized bed, and microencapsulation; coating with molten waxes of a mixture of molten waxes and other pharmaceutical adjuvants; entrapment of drug particles by complexation, flocculation or coagulation of an aqueous polymeric dispersion; adsorption of drug particles on resin and inorganic supports; and solid dispersion wherein a drug and one or more taste neutral compounds are melted and cooled, or co-precipitated by a solvent evaporation.
• a delayed or sustained release formulation comprising drug particles or granules in a rate controlling polymer or matrix.
• Suitable sweeteners include sucrose, glucose, fructose or intense sweeteners, i.e. agents with a high sweetening power when compared to sucrose (e.g. at least 10 times sweeter than sucrose).
• Suitable intense sweeteners comprise aspartame, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidine dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, Magnasweet(R).
• the total concentration of the sweeteners may range from effectively zero to about 300 mg/ml based on the liquid composition upon reconstitution.
• one or more taste-making agents may be added to the composition in order to mask the taste of the ASBT inhibitor.
• a taste-masking agent can be a sweetener, a flavoring agent or a combination thereof.
• the taste-masking agents typically provide up to about 0.1% or 5% by weight of the total pharmaceutical composition.
• the composition contains both sweetener(s) and flavor(s).
• a flavoring agent herein is a substance capable of enhancing taste or aroma of a composition.
• Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).
• Non-limiting examples of flavoring agents and/or sweeteners useful in the formulations described herein include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, 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, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammoni
• Flavoring agents can be used singly or in combinations of two or more.
• the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 5.0% the volume of the aqueous dispersion.
• the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a
• the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a
• the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 1.0% the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 0.5% the volume of the aqueous dispersion.
• compositions are formulated in a conventional manner using one or more physiologically acceptable carriers including, e.g., excipients and auxiliaries which facilitate processing of the active compounds into preparations which are suitable for pharmaceutical use.
• physiologically acceptable carriers including, e.g., excipients and auxiliaries which facilitate processing of the active compounds into preparations which are suitable for pharmaceutical use.
• proper formulation is dependent upon the route of administration chosen.
• a summary of pharmaceutical compositions described herein is found, for example, in 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, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &
• a pharmaceutical composition refers to a mixture of a compound described herein, such as, for example, a compound of Formula I- VI, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• the pharmaceutical composition facilitates administration of the compound to an individual or cell.
• therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to an individual having a disease, disorder, or condition to be treated.
• the individual is a human.
• the compounds described herein are either utilized singly or in combination with one or more additional therapeutic agents.
• the pharmaceutical formulations described herein are administered to an individual in any manner, including one or more of multiple administration routes, such as, by way of non- limiting example, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
• oral parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
• a pharmaceutical compositions described herein includes one or more compound described herein as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
• the compounds described herein are utilized as an N-oxide or in a crystalline or amorphous form (i.e., a polymorph).
• a compound described herein exists as tautomers. All tautomers are included within the scope of the compounds presented herein.
• a compound described herein exists in an unsolvated or solvated form, wherein solvated forms comprise any pharmaceutically acceptable solvent, e.g., water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.
• a “carrier” includes, in some embodiments, a pharmaceutically acceptable excipient and is selected on the basis of compatibility with compounds described herein, such as, compounds of any of Formula I- VI, and the release profile properties of the desired dosage form.
• exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of
• the pharmaceutical compositions described herein are formulated as a dosage form.
• a dosage form comprising a compound described herein, suitable for administration to an individual.
• suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
• the composition or formulation containing one or more compounds described herein is orally administered for local delivery of an ASBTI, or a compound described herein to the colon and/or rectum.
• Unit dosage forms of such compositions include a pill, tablet or capsules formulated for enteric delivery to colon.
• such pills, tablets or capsule contain the compositions described herein entrapped or embedded in microspheres.
• microspheres include, by way of non-limiting example, chitosan microcores HPMC capsules and cellulose acetate butyrate (CAB) microspheres.
• oral dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation.
• tablets are manufactured using standard tablet processing procedures and equipment.
• An exemplary method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like.
• tablets are prepared using wet-granulation or dry-granulation processes.
• tablets are molded rather than compressed, starting with a moist or otherwise tractable material.
• tablets prepared for oral administration contain various excipients, including, by way of non-limiting example, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, flavoring agents and the like.
• binders are used to impart cohesive qualities to a tablet, ensuring that the tablet remains intact after compression.
• Suitable binder materials include, by way of non-limiting example, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate,
• polyvinylpyrrolidone cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl
• diluents are utilized to increase the bulk of the tablet so that a practical size tablet is provided.
• Suitable diluents include, by way of non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and combinations thereof.
• lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, by way of non-limiting example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, glycerin, magnesium stearate, calcium stearate, stearic acid and combinations thereof.
• disintegrants are used to facilitate disintegration of the tablet, and include, by way of non-limiting example, starches, clays, celluloses, algins, gums, crosslinked polymers and combinations thereof.
• Fillers include, by way of non-limiting example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol.
• stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.
• surfactants are anionic, cationic, amphoteric or nonionic surface active agents.
• ASBTIs, or other compounds described herein are orally administered in association with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., distal ileum, colon, and/or rectum).
• a carrier suitable for delivery to the distal gastrointestinal tract e.g., distal ileum, colon, and/or rectum.
• a composition described herein comprises an ASBTI, or other compounds described herein in association with a matrix (e.g., a matrix comprising hypermellose) that allows for controlled release of an active agent in the distal part of the ileum and/or the colon.
• a composition comprises a polymer that is pH sensitive (e.g., a MMXTM matrix from Cosmo Pharmaceuticals) and allows for controlled release of an active agent in the distal part of the ileum.
• pH sensitive polymers suitable for controlled release include and are not limited to polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylic acid esters, e.g., Carbopol® polymers) that comprise acidic groups (e.g., -COOH, -S0 3 H) and swell in basic pH of the intestine (e.g., pH of about 7 to about 8).
• a composition suitable for controlled release in the distal ileum comprises microparticulate active agent (e.g., micronized active agent).
• a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of an enteroendocrine peptide secretion enhancing agent (e.g., bile acid) to the distal ileum.
• an enteroendocrine peptide secretion enhancing agent e.g., bile acid
• a dosage form comprising an enteroendocrine peptide secretion enhancing agent e.g., bile acid
• an enteric polymer e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinylacetate phthalate,
• bacterially activated systems are suitable for targeted delivery to the distal part of the ileum.
• micro-flora activated systems include dosage forms comprising pectin, galactomannan, and/or Azo hydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, ⁇ -D-xylopyranoside or the like) of the active agent.
• gastrointestinal micro-flora enzymes include bacterial glycosidases such as, for example, D- galactosidase, ⁇ -D-glucosidase, ot-L-arabinofuranosidase, ⁇ -D-xylopyranosidase or the like.
• the pharmaceutical composition described herein optionally include an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
• a compatible carrier such as those described in
• a film coating is provided around the formulation of the compound of Formula I.
• a compound described herein is in the form of a particle and some or all of the particles of the compound are coated.
• some or all of the particles of a compound described herein are microencapsulated.
• the particles of the compound described herein are not microencapsulated and are uncoated.
• a tablet or capsule comprising an ASBTI or other compounds described herein is film-coated for delivery to targeted sites within the gastrointestinal tract.
• enteric film coats include and are not limited to hydroxypropylmethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methyl cellulose, pseudo ethylcellulose, amylopectin and the like.
• Solid dosage forms for pediatric administration of the present invention can be manufactured by standard manufacturing techniques. Non-limiting examples of oral solid dosage forms for pediatric administration are described below.
• compositions of the invention may be prepared according to techniques well- known in the art of pharmacy.
• Effervescent formulations contain and effervescent couple of a base component and an acid component, which components reach in the presence of water to generate a gas.
• the base component may comprise, for example, an alkali metal or alkaline earth metal carbonate, or bicarbonate.
• the acid component may comprise, for example, an aliphatic carboxylic acid or a salt thereof, such as citric acid.
• the base and acid components may each independently constitute, for example, 25% to 55%) (w/w) of the effervescent composition.
• the ratio of acid component to base component may be within the range of 1 :2 to 2: 1.
• compositions of the invention may be formulated using additional
• compositions may take the form of, for example, tablets, granules or powders, granules or powders presented in a sachet. Chewable Tablets
• the chewable tablets of the invention may be prepared according to techniques well-known in the art of pharmacy.
• Chewable tablets are tablets that are intended to disintegrate in the mouth under the action of chewing or sucking and where, in consequence, the active ingredient has greater opportunity to come into contact with the bitter-taste receptors on the tongue.
• Another approach involves forming the active ingredient into an aggregate along with a pre-swelled substantially anhydrous hydrocolloid.
• the hydrocolloid absorbs saliva and acquires a slippery texture which enables it to lubricate the particles of aggregate and mask the taste of the active ingredient. This approach is described in European patent application 0190826.
• Another approach involves employing a water-insoluble hygroscopic excipient such as
• the chewable tablets of the present invention can also contain other stand tabletting excipients such as a disintegrant and a taste -masking agent.
• the orodispersible tablets of the invention may be prepared according to techniques well-known in the art of pharmacy.
• the excipient mixtures is such as to provide it with a disintegration rate so that its disintegration in the buccal cavity occurs in an extremely short time and especially shorter than sixty seconds.
• the excipient mixture is characterized by the fact that the active substance is in the form of coated or non-coated microcrystals of microgranules.
• the orodispersible tablet comprises one or several disintegrating agents of the
• carboxymethylcellulose type or insoluble reticulated PVP type one or several swelling agents which may comprise a carboxymethylcellulose, a starch, a modified starch, or a microcrystalline cellulose or optionally a direct compression sugar.
• the powder for reconstitution pharmaceutical compositions of the invention may be prepared according to techniques well-known in the art of pharmacy.
• the powder for reconstitution compositions of the invention comprise an effective amount of at least one internal dehydrating agent.
• the internal dehydrating agent can enhance the stability of the powder.
• the internal dehydrating agent is magnesium citrate or disodium carbonate.
• the powder composition comprises a pharmaceutically acceptable diluents, such as sucrose, dextrose, mannitol, xylitol, or lactose.
• Powder compositions of the inventions may be placed in sachets or bottles for contemporaneous dissolution or for short term storage in liquid form (e.g. 7 days).
• liquid form e.g. 7 days.
• the gummy candies of the invention may be prepared according to techniques well-known in the art of pharmacy.
• the gummy candy pharmaceutical composition of the invention includes a binding agent, a sweetener, and an active ingredient.

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