WO2023039276A1 - Use of ibat inhibitors and antimicrobials for the treatment of diseases - Google Patents

Use of ibat inhibitors and antimicrobials for the treatment of diseases Download PDF

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Publication number
WO2023039276A1
WO2023039276A1 PCT/US2022/043300 US2022043300W WO2023039276A1 WO 2023039276 A1 WO2023039276 A1 WO 2023039276A1 US 2022043300 W US2022043300 W US 2022043300W WO 2023039276 A1 WO2023039276 A1 WO 2023039276A1
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alkyl
hydrogen
pharmaceutically acceptable
carbamoyl
solvate
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PCT/US2022/043300
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French (fr)
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Mark G. Currie
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Curtails Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to methods of using IBAT inhibitors and pharmaceutically acceptable salts thereof in combination with rifaximin for the treatment of gastrointestinal disorders or encephalopathies.
  • IBS Irritable bowel syndrome
  • GI chronic functional gastrointestinal
  • IBS is often associated with abdominal distension and bloating.
  • QOL quality of life
  • IBS is one of the most frequently diagnosed disorders in the United States; data suggest that IBS prevalence is 11-14% of the adult population.
  • IBS is subtyped based on three predominant stool forms, IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), or IBS mixed (IBS-M; mixed constipation and diarrhea), according to the Rome diagnostic criteria.
  • the invention provides a method of treating a subject having a gastrointestinal disorder, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof, and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • the gastrointestinal disorder is travelers’ diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
  • the invention provides a method of treating an encephalopathy in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • IBAT ileal bile acid transporter
  • the encephalopathy is Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder.
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having an encephalopathy.
  • the invention provides a therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having a gastrointestinal disorder.
  • the invention provides a therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having an encephalopathy related to a gastrointestinal disorder.
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea.
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having diarrhea predominant irritable bowel syndrome.
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having hepatic encephalopathy.
  • the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having overt hepatic encephalopathy.
  • the invention provides a method of treating a gastrointestinal disorder, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • IBAT ileal bile acid transporter
  • the gastrointestinal disorder is traveler’s diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
  • IBS-D diarrhea predominant irritable bowel syndrome
  • SUDD symptomatic uncomplicated diverticular disease
  • Travelers’ diarrhea is the most predictable travel-related illness, according to the Center for Disease Control and Prevention (CDC). Attack rates range from 30 to 70% of travelers, depending on the destination and season of travel.
  • TD is a clinical syndrome that can result from a variety of intestinal pathogens. Bacterial pathogens are the predominant risk, thought to account for up to 80-90% of TD. Overall, the most common pathogen identified is enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Enteroaggregative and other E. coli strains are also commonly found in cases of TD. There is increasing discussion of Aeromonas spp., Plesiomonas spp., and newly recognized pathogens (Acrobacter, Larobacter, and enterotoxigenic Bacteroides fragilis) as potential causes of TD as well.
  • intestinal viruses may account for at least 5-15% of TD.
  • Some of the viruses identified in TD cases include norovirus, rotavirus, and astrovirus.
  • TD TD-rehydration therapy
  • antimotility agents and antibiotics such as fluoroquinolones, azithromycin, rifaximin, loperamide, lopramide, and combinations thereof.
  • IBS-D Diarrhea predominant irritable bowel syndrome
  • IBS Irritable bowel syndrome
  • GI gastrointestinal
  • IBS is a prevalent functional gastrointestinal (GI) disorder that affects up to 15% of the general global population. IBS is characterized by symptoms of abdominal pain or discomfort that are relieved by defecation, and is associated with disordered bowel function (i.e., constipation, diarrhea, or alternating constipation and diarrhea). IBS can be diagnosed and subclassified according to the patient’s predominant stool pattern as either constipation- or diarrhea-predominant, mixed type, or unsubtyped/unclassified. Up to 40% of patients with IBS have diarrhea as the predominant bowel symptom (IBS-D).
  • IBS-D the predominant bowel symptom
  • Patients with IBS-D typically present with abdominal pain associated with frequent loose stools and cramping, urgency that is not relieved by defecation, and mucus in the stool.
  • the occurrence of additional comorbid functional GI and extraintestinal symptoms or disorders e.g., gastroesophageal reflux disease, dyspepsia, interstitial cystitis, migraine headaches, and fibromyalgia
  • Symptoms may be mild and infrequent, moderate and somewhat bothersome, or severe enough to interfere with daily function, but all typically require an ongoing management strategy to control symptoms.
  • IBS-D is typically treated with antimotility agents (e.g., lopramide), probiotics, dietary modification, serotonergic agents, antidepressants, fecal microbiota transplant, and/or non-systemic antibiotics.
  • antimotility agents e.g., lopramide
  • diverticulosis The presence of diverticula is known as diverticulosis.
  • diverticulitis can cause severe abdominal pain, fever, nausea and a marked change in bowel habits.
  • Mild diverticulitis can be treated with rest, changes in diet and antibiotics. Severe or recurring diverticulitis may require surgery.
  • SUDD symptomatic uncomplicated diverticular disease
  • SUDD is defined as the concomitant presence of diverticula and symptoms of abdominal pain and bloating, bowel habit changes that include diarrhea and constipation or a mixed bowel habit, in the absence of macroscopic inflammation.
  • Encephalopathy can result from gastrointestinal dysbiosis, wherein the proliferation of urease producing bacteria increase blood ammonia. Increased blood ammonia can damage the liver and enter the brain to produce symptoms resembling hepatic encephalopathy.
  • the invention provides a method of treating an encephalopathy, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • IBAT ileal bile acid transporter
  • the encephalopathy is Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
  • Encephalopathy refers to any disorder or disease of the brain, especially chronic degenerative conditions. Generally, encephalopathy does not refer to a single disease, but rather a syndrome of overall brain dysfunction; this syndrome has many possible causes. There are numerous types of encephalopathy, of which the present disclosure focuses on Hepatic Encephalopathy (HE) and Overt Hepatic Encephalopathy (OHE). Hepatic Encephalopathy (HE)
  • Hepatic encephalopathy is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients.
  • HE can be divided into two broad categories: covert HE (CHE) and overt HE (OHE), which are both part of the spectrum of neurocognitive impairment in cirrhosis.
  • covert HE CHE
  • OHE overt HE
  • the prevalence of CHE has been reported in 30-85% of cirrhotics when tested, whereas OHE is estimated to occur in up to 30-50% in patients with cirrhosis, with an annual risk for development of 20%.
  • Development of OHE is associated with high rates of hospitalization, along with increased healthcare cost.
  • Clinical OHE includes personality changes, alterations in consciousness progressive disorientation in time and space, somnolence, stupor and, finally, coma.
  • Treatment of OHE includes supportive therapies, treatment of precipitating factors, lactulose and/or rifaximin.
  • the terms “subject” and “patient” are used interchangeably to refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a “mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, or mouse) and a primate (e.g., a monkey, chimpanzee or a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, or mouse
  • a primate e.g., a monkey, chimpanzee or a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject or patient is a human.
  • the term a “patient in need thereof’ is used to refer to a patient suffering from one of the gastrointestinal disorders here described, for example travelers’ diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
  • the “patient in need thereof’ is a patient with an encephalopathy, for example a patient diagnosed with Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
  • HE Hepatic Encephalopathy
  • OOE Overt Hepatic Encephalopathy
  • a “patient in need thereof’ experiences symptoms of one of the gastrointestinal disorders or encephalopathies described herein even though a diagnosis may not yet have been made.
  • the term “treat”, “treating” or “treatment” refers to alleviating the cause and/or effects or symptoms or clinical manifestations of the disorder or disease.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration or slowing down of the progression, severity and/or duration of gastrointestinal disorders or encephalopathies.
  • the terms “treat”, “treatment” and “treating” refer to the reduction, amelioration or slowing down of the progression, the severity and/or the duration of one or more symptoms or clinical manifestations (preferably, one or more measurable symptoms or clinical manifestations) of a gastrointestinal disorder or encephalopathy, as a result of the administration of one or more therapies (e.g., an IBAT inhibitor or a pharmaceutically acceptable salt thereof and rifaximin or a pharmaceutically acceptable salt thereof).
  • therapies e.g., an IBAT inhibitor or a pharmaceutically acceptable salt thereof and rifaximin or a pharmaceutically acceptable salt thereof.
  • the terms “treat,” “treatment” and “treating” refer to delaying the onset of a symptom or set of symptoms or clinical manifestations or to delaying the onset of a loss in certain physical function.
  • the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical manifestation of a gastrointestinal disorder or encephalopathy. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction, inhibition or slowing down of the progression of said condition, either physically by, e.g., stabilization of a measurable symptom or set of symptoms , or physiologically by, e.g., stabilization of a measurable parameter, or both.
  • treating also refers to averting the cause and/or effects or clinical manifestation of a gastrointestinal disorder or encephalopathy or one of the symptoms developed as a result of the gastrointestinal disorder or encephalopathy prior to disease or disorder fully manifesting itself.
  • Treatment can involve administering a compound described herein to a patient diagnosed with a gastrointestinal disorder or encephalopathy herein described and may involve administering the two compounds to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a gastrointestinal disorder or encephalopathy, or to a patient reporting one or more of the symptoms of a gastrointestinal disorder or encephalopathy, even though a diagnosis may not have been made.
  • therapeutically effective amount means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms without serious adverse effects.
  • the IBAT inhibitor and rifaximin are each administered in an effective amount (i.e., in an amount which would be therapeutically effective if administered alone). In another embodiment, the IBAT inhibitor and rifaximin are each administered in an amount which alone does not provide a therapeutic effect ("a sub- therapeutic dose"). In yet another embodiment, the IBAT inhibitor or rifaximin can be administered in an effective amount, while the IBAT inhibitor or rifaximin is administered in a sub-therapeutic dose.
  • prophylactically effective amount refers to an amount effective in preventing or substantially lessening the chances of developing a disorder or in reducing the severity of the disorder or one or more of its symptoms before it is acquired or the symptoms fully develop further.
  • a method of treating a subject having a gastrointestinal disorder comprising administering to a subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • IBAT ileal bile acid transporter
  • a method of treating an encephalopathy comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
  • IBAT ileal bile acid transporter
  • the invention provides use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof for the treatment of a gastrointestinal disorder.
  • IBAT ileal bile acid transporter
  • the invention provides use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof for the treatment of an encephalopathy.
  • the invention provides a use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a gastrointestinal disorder in a subject in need thereof.
  • the invention provides a use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an encephalopathy in a subject in need thereof.
  • IBAT ileal bile acid transporter
  • the invention provides pharmaceutical compositions comprising (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, for use in the treatment of a gastrointestinal disorder in a subject in need thereof.
  • IBAT ileal bile acid transporter
  • the invention provides pharmaceutical compositions comprising (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, for use in the treatment of an encephalopathy in a subject in need thereof.
  • IBAT ileal bile acid transporter
  • Bacterial and viral TD presents with the sudden onset of bothersome symptoms that can range from mild cramps and urgent loose stools to severe abdominal pain, fever, vomiting, and bloody diarrhea, although with norovirus vomiting may be more prominent.
  • Protozoal diarrhea such as that caused by Giardia intestinalis or E. histolytica, generally has a more gradual onset of low-grade symptoms, with 2-5 loose stools per day.
  • Bacterial toxins generally cause symptoms within a few hours.
  • Bacterial and viral pathogens have an incubation period of 6-72 hours.
  • Protozoal pathogens generally have an incubation period of 1-2 weeks and rarely present in the first few days of travel. An exception can be Cyclospora cayetanensis, which can present quickly in areas of high risk.
  • Untreated bacterial diarrhea usually lasts 3-7 days. Viral diarrhea generally lasts 2-3 days. Protozoal diarrhea can persist for weeks to months without treatment. An acute bout of gastroenteritis can lead to persistent gastrointestinal symptoms, even in the absence of continued infection. This presentation is commonly referred to as postinfectious irritable bowel syndrome. Other postinfectious sequelae may include reactive arthritis or Guillain- Barre syndrome. ii. Diarrhea predominant - Irritable Bowel Syndrome (IBS-D)
  • Symptoms may be mild and infrequent, moderate and somewhat bothersome, or severe enough to interfere with daily function, but all typically require an ongoing management strategy to control symptoms. Symptoms include recurrent abdominal pain or discomfort for at least 3 days per month in the preceding 3 months, loose or watery stool for at least 25% of bowel movements, and hard or lumpy stool for less than 25% of bowel movements. iii. Diverculitis
  • SUDD is defined as the concomitant presence of diverticula and symptoms of abdominal pain and bloating, bowel habit changes that include diarrhea and constipation or a mixed bowel habit, in the absence of macroscopic inflammation.
  • Pain associated with SUDD is normally located in the iliac fossa and is more sustained, with a history of pain lasting more than 24 hrs, and is not relieved by bowel movement, as is often the case with IBS.
  • HE Hepatic Encephalopathy
  • the mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated by neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability.
  • the first stage of hepatic encephalopathy is characterized by an inverted sleep-wake pattern (sleeping by day, awake at night).
  • the second stage is marked by lethargy and personality changes.
  • the third stage is marked by worsened confusion.
  • the fourth stage is marked by a progression to coma. ii. Overt Hepatic Encephalopathy (OHE)
  • Symptoms of OHE include lack of energy or interest, confusion, disorientation, inappropriate behavior, severe personality changes, sleepiness or change in sleep patterns, worsening handwriting, loss of small hand movements, tremors or shaking of hands or arms, and/or breath with a musty or sweet odor.
  • the liver produces bile acids that are stored in the gallbladder and released through common bile ducts into the duodenum after consuming a meal.
  • Liver dysfunction can result in decreased bile acid production, which can lead to overgrowth of harmful bacteria in the small intestines.
  • gastrointestinal disorders related to proliferation of harmful bacterial including traveler’s diarrhea, diverticulitis, and types of IBD can be exacerbated by reduced bile acids from liver dysfunction.
  • the ileal bile acid transporter (IBAT) recycles bile acids from the distal ileum back to the liver. Administering a compound that inhibits IBAT increases bile acids in the ileum. Increased bile acids can reduce proliferation of harmful bacteria.
  • Oral administration of rifaximin remains in the gastrointestinal tract and reduces the proliferation of harmful bacteria.
  • adequate bile acids in the small intestines is required for rifaximin to be fully solubilized.
  • Using an IBAT inhibitor can increase the solubility and thus bioavailability of rifaximin, and therefore the treatment efficacy of gastrointestinal disorders related to the proliferation of harmful bacteria.
  • the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin results in an improved solubility of the IBAT inhibitor and/or rifaximin in the colon.
  • the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin results in an improved antibacterial activity of rifaximin in the colon.
  • the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin results in a decrease of abdominal pain.
  • the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin results in an improved duration of treatment effect.
  • Ammonia is a toxic metabolite produced from the metabolism of protein and nitrogen containing compounds, and is converted to urea in the liver for disposal through the kidneys, muscles, and intestinal tract. Increased blood ammonia can occur from dysfunction of the liver urea cycle due to cirrhosis, urease-producing bacterial in the intestines, and catabolism of glutamine to ammonia and glutamate by enterocyte glutaminase. Increased blood ammonia passes through the blood brain barrier and is taken up by astrocytes where it is combined with glutamine to produce glutamate.
  • the administration of rifaximin reduces blood ammonia by decreasing proliferation of urease-producing bacteria; reducing blood ammonia also improves liver function, such as urea cycle efficiency and bile acid production.
  • reducing blood ammonia also improves liver function, such as urea cycle efficiency and bile acid production.
  • combining rifaximin administration with an IBAT inhibitor will increase bile acid, which increases rifaximin bioavailability and therefore efficacy in decreasing urease-producing bacteria, lowering blood ammonia, and improving liver function and encephalopathy symptoms.
  • the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin improves symptoms of encephalopathy by reducing harmful bacteria causing a gastrointestinal disorder.
  • the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin improves symptoms of encephalopathy by reducing high blood ammonia resulting from an overgrowth of harmful bacteria in a gastrointestinal disorder.
  • the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin improves symptoms of hepatic encephalopathy by reducing high blood ammonia resulting from the overgrowth of harmful bacteria, thereby improving liver function to reduce ammonia levels further by the urea cycle and increased production of bile acids.
  • the administration of an IB AT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin improves symptoms of overt hepatic encephalopathy by reducing high blood ammonia resulting from the overgrowth of harmful bacteria, thereby improving liver function to reduce ammonia levels further by the urea cycle and increased production of bile acids.
  • the harmful bacteria is urease-producing bacteria.
  • the IBAT inhibitor is a compound of formula (I): wherein:
  • R v and R w are independently selected from hydrogen or C 1-6 -alkyl
  • R 1 and R 2 are independently selected from C 1-6 -alkyl
  • R x and R y are independently selected from hydrogen or C 1-6 -alkyl, or one of R x and R y is hydrogen or C 1-6 -alkyl and the other is hydroxy or C 1-6 -alkoxy;
  • R z is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 -alkyl, C2-6-alkenyl, C2-6-alkynyl, C 1-6 -alkoxy, C 1-6 -alkanoyl, C 1-6 - alkanoyloxy, N-(C 1-6 -alkyl)amino, A,A-(C 1-6 -alkyl)2amino, C 1-6 -alkanoylamino, A-(CI-6- alkyl)carbamoyl, N,N-(C 1-6 -alkyl)2carbamoyl, C 1-6 -alkylS(O) a wherein a is 0 to 2, C 1-6 - alkoxycarbonyl, C 1-6 -alkoxycarbonylamino, ureido, A-(C 1-6 -
  • V is 0-5; one ofR 4 and R 5 is a group of formula (IA):
  • 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 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-4 -alkoxy, C 1-4 -alkanoyl, C 1-4 -alkanoyloxy, A-(C 1-4 -alkyl)amino, A,A-(C 1-4 - alkyl)2amino, C 1-4 -alkanoylamino, A-(C 1-4 -alkyl)carbamoyl,A,A-(C 1-4 -alkyl)2carbamoyl, C 1-4 - alkylS(O) a wherein a is 0 to 2, C 1-4 -alkoxycarbonyl, A-(C 1-4 -alky
  • D is -O-, -N(R a )-, -S(O)b- or -CH(R a )-; wherein R a is hydrogen or C 1-6 -alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R 17 ;
  • R 7 is hydrogen, C 1-4 -alkyl, carbocyclyl or heterocyclyl; wherein R 7 is optionally substituted by one or more substituents selected from R 18 ;
  • R 8 is hydrogen or C 1-4 -alkyl
  • R 9 is hydrogen or C 1-4 -alkyl
  • R 10 is hydrogen, C 1-4 -alkyl, carbocyclyl or heterocyclyl; wherein R 10 is optionally substituted by one or more substituents selected from R 19 ;
  • R n is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR c )(OR d ), -P(O)(OH)(OR C ), -P(O)(OH)(R d ) or -P(O)(OR c )(R d ) wherein R c and R d are independently selected from C 1-6 - alkyl; or R 11 is a group of formula (IB): wherein:
  • X is -N(R q )-, -N(R q )C(O)-, -O-, and -S(O) a -; wherein a is 0-2 and R q is hydrogen or C 1-4 - alkyl;
  • R 12 is hydrogen or C 1-4 -alkyl
  • R 13 and R 14 are independently selected from hydrogen, C 1-4 -alkyl, carbocyclyl, heterocyclyl or R 23 ; wherein said C 1-4 -alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R 20 ;
  • R 15 is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), - P(O)(OH)(R e ) or -P(O)(OR e )(R f ) wherein R e and R f are independently selected from C 1-6 - alkyl; or R 15 is a group of formula (IC): wherein:
  • R24 is selected from hydrogen or C 1-4 -alkyl
  • R 25 is selected from hydrogen, C 1-4 -alkyl, carbocyclyl, heterocyclyl or R 27 ; wherein said C1salkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R 28 ;
  • R 26 is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(OR g )(OR h ), - P(O)(OHxOR g ), -P(O)(OH)(R g ) or -P(O)(OR g )(R h ) wherein R g and R h are independently selected from C 1-6 -alkyl; wherein subscripts of the above markush structures are p is 1-3, wherein the values of R 13 may be the same or different; q is 0-1; r is 0-3, wherein the values of R 14 may be the same or different; m is 0-2, wherein the values of R 10 may be the same or different; n is 1-3, wherein the values of R 7 may be the same or different; z is 0-3, wherein the values of R 25 may be the same or different;
  • R 16 , R 17 and R 18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-4 - alkoxy, C 1-4 -alkanoyl, C 1-4 -alkanoyloxy, N-(C 1-4 -alkyl)amino, N,N-(C 1-4 -alkyl)2amino, C 1-4 - alkanoylamino, N-(C 1-4 -alkyl)carbamoyl, N,N-(C 1-4 -alkyl)2carbamoyl, C 1-4 -alkylS(O) a wherein a is 0 to 2, C 1-4 -alkoxycarbonyl, 7V-( C 1-4 -alkyl)sulphamo
  • R 19 , R 20 , R 23 , R 27 and R 28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1- 4 -alkoxy, C 1-4 -alkanoyl, C 1-4 -alkanoyloxy,N-(C 1-4 -alkyl)amino, N,N-(C 1-4 alkyl)2amino, C 1-4 - alkanoylamino, N-(C 1-4 -alkyl)carbamoyl, N,N-(C 1-4 -alkyl)2carbamoyl, C 1-4 -alkylS(O) a wherein a is 0 to 2, C 1-4 -alkoxycarbonyl, N-(C 1-4 -alkyl
  • R 21 and R 22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, /V-mcthylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, /V-mcthylsulphamoyl and N,N- dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydroly
  • R v and R w are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R 1 and R 2 are independently selected from ethyl, propyl or butyl or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R x and R y are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R z is selected from halo, amino, C 1-6 -alkyl, C 1-6 - alkoxycarbonylamino or N'-(C 1-6 -alkyl)ureido or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • v is 0 or 1 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R 3 is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • the R 4 or R 5 that is not the group of formula (IA) is selected from hydrogen, halo, C 1-4 -alkoxy or C 1-4 -alkylS(O) a wherein a is 0 to 2; wherein that R 4 or R 5 may be optionally substituted on carbon by one or more R 16 ; wherein R 16 is independently selected from hydroxy, carboxy and N,N-(C 1-4 -alkyl)2amino or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof [0092] In some embodiments, R 5 is a group of formula (IA) and R 4 is methylthio or a pharmaceutically acceptable salt, solvate, solvate of
  • D is -O- or -S-;
  • Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;
  • R 7 is hydrogen, methyl or phenyl
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen or methyl
  • R 10 is hydrogen
  • M is 0-2 wherein the values of R 10 may be the same or different.
  • R n is carboxy, -P(O)(OH)(OEt) or a group of formula (IB); or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R 12 is hydrogen or methyl
  • R 13 is hydrogen, methyl, ethyl, butyl or phenyl or R 23 ; wherein R 13 is optionally substituted by one or more substituents selected from R 20 ; R 20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R 20 may be independently optionally substituted on carbon by one or more hydroxy; R 23 is carboxy;
  • X is -NH- or -NHC(O)-
  • R 14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxy;
  • R 15 is carboxy, sulpho, phosphono, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), - P(O)(OH)(R e ) or -P(O)(OR e )(R f ) wherein R e and R f are independently selected from methyl or ethyl or R 15 is a group of formula (IC); p is 1-3, wherein the values of R 13 may be the same or different; q is 0-1; and r is 0-3, wherein the values of R 14 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R 24 is hydrogen
  • R 25 is hydrogen
  • R 26 is carboxy; and z is 1; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • R v and R w are both hydrogen
  • R 1 and R 2 are independently selected from C 1-4 -alkyl
  • R x and R y are both hydrogen
  • R z is selected from halo, amino, C 1-6 -alkyl, C 1-6 -alkoxycarbonylamino or A'-(CI-6- alkyl)ureido;
  • V is 0 or 1 ;
  • R 3 and R 6 are hydrogen; one ofR 4 and R 5 is a group of formula (IA) and the other is selected from hydrogen, halo, C 1-4 -alkoxy or C 1-4 -alkylS(O) a wherein a is 0 to 2; wherein that R 4 or R 5 may be optionally substituted on carbon by one or more R 16 ; wherein R 16 is independently selected from hydroxy, carboxy and A,A-(C 1-4 -alkyl)2amino;
  • D is -O- or -S-;
  • R 7 is hydrogen, methyl or phenyl
  • R 8 is hydrogen or methyl
  • Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R 17 ; wherein R 17 is selected from halo, hydroxy, C 1-4 -alkyl or C 1-4 - alkoxy; wherein R 17 may be optionally substituted on carbon by one or more R 21 ; wherein R 21 is selected from halo;
  • R 9 is hydrogen or methyl
  • R 10 is hydrogen
  • R n is carboxy, -P(O)(OH)(OR C ) wherein R c is selected from C 1-4 -alkyl or a group of formula (IB);
  • R 12 is hydrogen or methyl;
  • X is -NH- or -NHC(O)-;
  • R 13 is hydrogen, C 1-4 -alkyl, carbocyclyl or R 23 ; wherein R 13 is optionally substituted by one or more substituents selected from R 20 ; wherein R 20 is hydroxy, C 1-4 -alkylS(O) a wherein a is 0, C 1-4 -alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R 20 may be independently optionally substituted on carbon by one or more R 22 ; R 22 is selected from hydroxy; and R 23 is carboxy;
  • R 14 is selected from hydrogen, C 1-4 -alkyl or carbocyclyl; wherein said C 1-4 -alkyl or carbocyclyl may be optionally substituted by one or more substituents selected from R 20 ; and R 20 is hydroxy;
  • R 15 is carboxy, sulpho, phosphono, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), - P(O)(OH)(R e ) or -P(O)(OR e )(R f ) wherein R e and R f are independently selected from C 1-4 - alkyl or R 15 is a group of formula (IC)
  • R 24 is hydrogen
  • R25 is hydrogen
  • R 26 is carboxy; p is 1-3; wherein the values of R 13 may be the same or different; q is 0-1; r is 0-3; wherein the values of R 14 may be the same or different; m is 0-2; wherein the values of R 10 may be the same or different; n is 1-2; wherein the values of R 7 may be the same or different; z is 0-1; wherein the values of R 25 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
  • the IBAT inhibitor is selected from:
  • Rifaximin is a structural analog of rifampin and a non-systemic, gastrointestinal sitespecific antibiotic. Rifaximin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis and contributes to restoring intestinal microflora imbalance. It is FDA approved for the treatment of travelers’ diarrhea, reduction in risk of overt hepatic encephalopathy (HE) recurrence and treatment of irritable bowel syndrome with diarrhea. Common side effects are: black, tarry stools; dizziness or lightheadedness; muscle spasm; rapid breathing; shortness of breath; trouble sleeping. Co-administration of cyclosporine, with the Rifaximin brand Xifaxan resulted in 83-fold and 124-fold increases in rifaximin mean Cmax in healthy subjects.
  • RNA ribonucleic acid
  • Rifaximin has the chemical structure:
  • the IBAT inhibitor and rifaximin may be provided as (i) the compounds themselves (e.g., as the free base); (ii) a pharmaceutically acceptable salt of one of both of the compounds; and/or (iii) part of a pharmaceutical composition.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
  • the salts of the compounds described herein will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds described herein.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt there can be multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion(s).
  • salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • the salts can be prepared in situ during the final isolation and purification of the compounds.
  • the salts can be prepared from the free form of the compound in a separate synthetic step.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'- dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine,
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2 -
  • the IBAT inhibitor and rifaximin are administered before a symptom of the gastrointestinal disorder or an encephalopathy fully develops in a subject. In other embodiments, the IBAT inhibitor and rifaximin are administered after one or more symptoms of the gastrointestinal disorder or encephalopathy develops in a subject.
  • the IBAT inhibitor is administered prior to, at the same time, or after the administration of rifaximin. [0108] In some embodiments, the IBAT inhibitor is administered simultaneously with rifaximin.
  • the above pharmaceutical compositions comprise (a) an IBAT inhibitor as discussed above or a pharmaceutically acceptable salt thereof and rifaximin or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant.
  • Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of each compound amount, or in multiple, separate capsules or tablets for each.
  • co-administration also encompasses use of each compound in a sequential manner in either order.
  • co- administration involves the separate administration of the first amount of an IBAT inhibitor and a second amount of rifaximin, the compounds are administered sufficiently close in time to have the desired therapeutic effect.
  • the period of time between each administration can result in the desired therapeutic effect, can range from minutes to hours and can be determined by taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and pharmacokinetic profile.
  • an IBAT inhibitor and rifaximin can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, within about 30 minutes of each other, or within about 5 minutes of each other, etc.
  • an IBAT inhibitor e.g., prophylactic or therapeutically
  • an IBAT inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration rifaximin to a subject.
  • a typical formulation is prepared by mixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound described herein is being formulated.
  • Solvents are generally selected for being recognized by persons skilled in the art as safe (e.g., one described in the GRAS (Generally Recognized as Safe) database) to be administered to a mammal.
  • safe solvents are non -toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an aesthetic presentation of the compounds described herein or pharmaceutical composition thereof or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants,
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., one or more of the compounds described herein, a pharmaceutically acceptable salt thereof, or a stabilized form of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent
  • a suitable solvent in the presence of one or more of the excipients described above.
  • a compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution.
  • Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, and may range from about 3 to about 8.
  • a compound described herein or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • Pharmaceutical formulations of compounds described herein, or a pharmaceutically acceptable salt thereof may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound.
  • the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition (weight/weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution to ensure that an infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • compositions described herein will be formulated, dosed, and administered in a fashion, (i.e., amounts, concentrations, schedule, vehicles, and route of administration), consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the individual subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual subject.
  • a prophylactically effective amount of an IBAT inhibitor and rifaximin prevents the symptoms of intestinal diseases associated with bacterial overgrowth and intestinal bacterial biofilm formation. These diseases include IBS-D, HE, diverticulitis and inflammatory bowel disease, Ulcerative colitis and Crohn’s disease (UC and CD).
  • Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; proteins, such as serum albumin, gelatin, and immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, and lysine; carbohydrates including monos
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, micro emulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, micro emulsions, nano-particles and nanocapsules
  • Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21 st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's").
  • Controlled drug delivery systems supply the drug to the subject in a manner precisely controlled to suit the drug and the conditions being treated.
  • the primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time.
  • controlled release is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release”, “delayed release”, “modified release” or “sustained release”.
  • sustained-release preparations are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, wherein matrices are in the form of shaped articles, e.g., films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacry late), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • Gastroretentive formulations are preparations designed to have increased retention in the stomach cavity. In some cases, they are used where a drug is preferentially or primarily absorbed via the stomach, is designed to treat the stomach directly, or where drug dissolution or absorption is aided by prolonged exposure to gastric acids.
  • gastroretentive formulations include but are not limited to, high-density formulations, where the density of the formulation is higher than gastric fluid; floating formulations, which can float on top of gastric fluids due to increased buoyancy or lower density of the formulation; temporarily expandable formulations that are temporarily larger than the gastric opening; muco- and bio-adhesive formulations; swellable gel formulations; and in situ gel forming formulations. (See, e.g., Bhardwaj, L. et al., African J. of Basic & Appl. Sci. 4(6): 300-312 (2011)).
  • IBAT preparations may also be prepared.
  • the objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
  • the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in an immediate release formulation.
  • the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in a delayed release formulation.
  • the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in a bilayer delivery system.
  • the bilayer delivery system comprises (i) an immediate release formulation layer and (ii) a delayed release formulation layer.
  • the delayed release formulation layer contains a higher amount (e.g., 1.5 fold to 10 fold) of the IBAT inhibitor and rifaximin compared to amount of the IBAT inhibitor and rifaximin in the immediate release formulation layer.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
  • implantable medical devices such as beads, or co-formulated with a polymer or other molecule
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics for the composition.
  • the formulations include those suitable for the administration routes detailed herein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly combining the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • administer in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the subject in need of treatment.
  • compositions described herein may be administered systemically or locally, for example, orally using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like; by inhalation using an aerosol, gas, inhaler, nebulizer or the like; to the ear using ear drops; topically using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.; ophthalmically using eye drops, ophthalmic gels, ophthalmic ointments; rectally using enemas or suppositories; vaginally using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets; nasally; buccally; parenterally depending on the severity and type of the disease being treated, or via an implanted reservoir or the like.
  • parenteral includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions are administered orally, intraperitoneally or intravenously. In some embodiments, the compositions are administered orally.
  • compositions are administered rectally.
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution-retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a water soluble taste masking material such as hydroxypropyl -methylcellulose or hydroxypropyl-cellulose may be employed.
  • Formulations of a compound described herein that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, (e.g., gelatin capsules, syrups or elixirs).
  • Formulations of a compound intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, and optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • the active compounds may also be prepared in a microencapsulated form with one or more excipients as noted above.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcent, preservative, antioxidant, flavoring, and coloring agent.
  • Sterile injectable forms of the compositions described herein may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
  • Oily suspensions may be formulated by suspending a compound described herein in a vegetable oil, for example arachis oil, olive oil, sesame oil, coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisol or alphatocopherol.
  • Aqueous suspensions of compounds described herein contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as the naturally occurring phosphatide lecithin, a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), and a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • the injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Drug-depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Other formulations suitable for vaginal administration may be presented as pess
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, between 0.075 % and 20% w/w.
  • the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of emulsions prepared using compounds described herein may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of compounds described herein include TweenTM-60, SpanTM-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono -stearate and sodium lauryl sulfate.
  • compositions may also be administered by nasal aerosol or by inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Formulations suitable for intrapulmonary or nasal administration may have a mean particle size in the range of, for example, 0.1 to 500 microns (including particles with a mean particle size in the range between 0.1 and 500 microns in increments such as 0.5, 1, 30, 35 microns, etc.), which may be administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • the pharmaceutical composition (or formulation) for use may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • a compound described herein or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.
  • compositions may be administered parenterally, orally or by any other desired route.
  • Compounds, compositions and kits of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle. Kits
  • the pharmaceutical formulations described herein may be contained in a kit.
  • the kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination.
  • one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container.
  • the container or containers are placed within a package, and the package can optionally include administration or dosage instructions.
  • a kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation.
  • kits can comprise: (a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) another therapeutic agent and a pharmaceutically acceptable carrier, vehicle or diluent in one or more containers or separate packaging.
  • the kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g., preventing or treating one or more of the diseases and disorders described herein).
  • the pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
  • a kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
  • the container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
  • kits are so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like).
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • recesses are formed in the plastic foil.
  • the recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed.
  • the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide written memory aid containing information and/or instructions for the physician, pharmacist or subject regarding when the medication is to be taken.
  • a "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • kits can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed.
  • a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • An IB AT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder is an IB AT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder.
  • An IB AT inhibitor and rifaximin for use in treating a subject having an encephalopathy is an IB AT inhibitor and rifaximin for use in treating a subject having an encephalopathy.
  • a therapeutic pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having a gastrointestinal disorder.
  • a therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having an encephalopathy.
  • An IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea An IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea.
  • An IBAT inhibitor and rifaximin for use in treating a subject having diarrhea predominant irritable bowel syndrome.
  • An example for measuring the effect of the combination of IBAT inhibitors and rifaximin could be with in vitro or in vivo assays.
  • IBAT inhibitory activity may be assessed, for example, using an in vitro assay for studying the inhibitor effect on bile acid uptake in IBAT-transfected cells (see methods in Smith L., Price- Jones M. J., Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227-230), or in vivo by studying the effect on radiolabelled bile acid absorption in mice/rats (Lewis M. C, Brieaddy L. E. and Root C, J., J Lip Res 1995, 36, 1098-1105).
  • the assay could have mice strains with ApoE knocked out; Sub strain C57BL/6; sex female; Total No. of animals 70; body weight range 20 g to 22 g.
  • the gall bladder and the whole intestine are removed, and the feces during the 24-hour period after 75 SeHCAT administration collected for each mouse.
  • the gamma radioactivities of 75 SeHCAT in the feces and in the gall bladder-intestine are separately counted by 1282 CompuGamma CS Gamma counter (Wallac oy, Turku, Finland).
  • the stability as well as the quantity of the 75 SeHCAT administered to each mouse, can be controlled with an additional 75 SeHCAT aliquot following the same experimental process as other tested samples in the study.
  • the sum of the gamma counts from both the feces and the gall bladder-intestine can be considered as the total recovered 75 SeHC AT.
  • the percentage of the 75 SeHCAT detected in the feces can be considered as the fecal excretion, while that in the gall bladder-intestine as body retention.
  • Inhibitory effect of the IBAT inhibitor + rifaximin combination on 75 SeHCAT intestinal absorption can be calculated following the 75 SeHCAT body retention and the fecal excretion, and the ED50 of the compound can be estimated following the dose-effect curve.
  • the mean IBAT inhibitory effect (%) can be reported at a dose of pmol/kg.
  • solubility and efficacy For example, to assess solubility and efficacy one could take a series of colonic samples after the administration of rifaximin alone and in combination with the IBAT inhibitors. Then, solubility and efficacy could be measured. One could also document the increase in colonic bile acid concentrations.

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Abstract

The present disclosure relates to methods, uses, pharmaceutical compositions and kits comprising an IBAT inhibitor or a pharmaceutically acceptable salt thereof in combination with rifaximin or a pharmaceutically acceptable salt, for the treatment of gastrointestinal disorders or encephalopathies.

Description

USE OFIBAT INHIBITORS AND ANTIMICROBIALS FOR THE TREATMENT OF
DISEASES
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of priority to U.S. Provisional patent application with Serial No. 63/243,235, filed September 13, 2021, the entire content is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to methods of using IBAT inhibitors and pharmaceutically acceptable salts thereof in combination with rifaximin for the treatment of gastrointestinal disorders or encephalopathies.
BACKGROUND
[0003] Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder characterized by recurrent abdominal pain associated with defecation and/or a change in stool frequency or form. In addition to the characteristic abdominal pain, IBS is often associated with abdominal distension and bloating. In moderate to severe cases of IBS, an overall deterioration in quality of life (QOL) is often present. IBS is one of the most frequently diagnosed disorders in the United States; data suggest that IBS prevalence is 11-14% of the adult population. IBS is subtyped based on three predominant stool forms, IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), or IBS mixed (IBS-M; mixed constipation and diarrhea), according to the Rome diagnostic criteria.
[0004] Currently, there are very few FDA approved therapies for the treatment of IBS-D stool form or symptoms, abdominal pain or discomfort associated. Therefore, there remains an unmet medical need for additional, well-tolerated, and effective therapies to treat abdominal pain and discomfort associated with IBS-D and other conditions associated with the gastrointestinal system.
SUMMARY OF THE INVENTION
[0005] In one aspect, the invention provides a method of treating a subject having a gastrointestinal disorder, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof, and (ii) rifaximin or a pharmaceutically acceptable salt thereof. [0006] In some embodiments, the gastrointestinal disorder is travelers’ diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
[0007] In another aspect, the invention provides a method of treating an encephalopathy in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
[0008] In some embodiments, the encephalopathy is Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
[0009] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder.
[0010] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having an encephalopathy.
[0011] In another aspect, the invention provides a therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having a gastrointestinal disorder.
[0012] In another aspect, the invention provides a therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having an encephalopathy related to a gastrointestinal disorder.
[0013] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea.
[0014] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having diarrhea predominant irritable bowel syndrome.
[0015] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having hepatic encephalopathy.
[0016] In another aspect, the invention provides an IBAT inhibitor and rifaximin for use in treating a subject having overt hepatic encephalopathy.
DETAILED DESCRIPTION
[0017] While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. The invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but includes any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls. The compounds described herein may be defined by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
Gastrointestinal Disorders
[0018] In one aspect, the invention provides a method of treating a gastrointestinal disorder, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
[0019] In some embodiments, the gastrointestinal disorder is traveler’s diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
Travelers’ Diarrhea (TD)
[0020] Travelers’ diarrhea (TD) is the most predictable travel-related illness, according to the Center for Disease Control and Prevention (CDC). Attack rates range from 30 to 70% of travelers, depending on the destination and season of travel.
[0021] TD is a clinical syndrome that can result from a variety of intestinal pathogens. Bacterial pathogens are the predominant risk, thought to account for up to 80-90% of TD. Overall, the most common pathogen identified is enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella spp., and Salmonella spp. Enteroaggregative and other E. coli strains are also commonly found in cases of TD. There is increasing discussion of Aeromonas spp., Plesiomonas spp., and newly recognized pathogens (Acrobacter, Larobacter, and enterotoxigenic Bacteroides fragilis) as potential causes of TD as well.
[0022] As multiplex molecular diagnostic assays increase their detection, intestinal viruses may account for at least 5-15% of TD. Some of the viruses identified in TD cases include norovirus, rotavirus, and astrovirus.
[0023] Infections with protozoal pathogens are slower to manifest symptoms and collectively account for approximately 10% of TD diagnoses in longer-term travelers. Giardia is the main protozoal pathogen found in TD. Entamoeba histolytica is a relatively uncommon cause of TD, and Cryptosporidium is also relatively uncommon. The risk for Cyclospora is highly geographic and seasonal: the most well-known risks are in Nepal, Peru, Haiti, and Guatemala. Dientamoeba fragilis is a flagellate occasionally associated with diarrhea in travelers.
[0024] The most common treatment for TD is oral rehydration therapy, administration of antimotility agents and antibiotics, such as fluoroquinolones, azithromycin, rifaximin, loperamide, lopramide, and combinations thereof.
Diarrhea predominant irritable bowel syndrome (IBS-D)
[0025] Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal (GI) disorder that affects up to 15% of the general global population. IBS is characterized by symptoms of abdominal pain or discomfort that are relieved by defecation, and is associated with disordered bowel function (i.e., constipation, diarrhea, or alternating constipation and diarrhea). IBS can be diagnosed and subclassified according to the patient’s predominant stool pattern as either constipation- or diarrhea-predominant, mixed type, or unsubtyped/unclassified. Up to 40% of patients with IBS have diarrhea as the predominant bowel symptom (IBS-D).
[0026] Patients with IBS-D typically present with abdominal pain associated with frequent loose stools and cramping, urgency that is not relieved by defecation, and mucus in the stool. The occurrence of additional comorbid functional GI and extraintestinal symptoms or disorders (e.g., gastroesophageal reflux disease, dyspepsia, interstitial cystitis, migraine headaches, and fibromyalgia) may increase the probability of a positive IBS diagnosis. Symptoms may be mild and infrequent, moderate and somewhat bothersome, or severe enough to interfere with daily function, but all typically require an ongoing management strategy to control symptoms.
[0027] IBS-D is typically treated with antimotility agents (e.g., lopramide), probiotics, dietary modification, serotonergic agents, antidepressants, fecal microbiota transplant, and/or non-systemic antibiotics. Diverculitis
[0028] Diverticula are small, bulging pouches that can form in the lining of the digestive system. They are found most often in the lower part of the large intestine (colon). Diverticula are common, especially after age 40, and seldom cause problems.
[0029] The presence of diverticula is known as diverticulosis. When one or more of the pouches become inflamed, and in some cases infected, the condition is known as diverticulitis. Diverticulitis can cause severe abdominal pain, fever, nausea and a marked change in bowel habits.
[0030] Mild diverticulitis can be treated with rest, changes in diet and antibiotics. Severe or recurring diverticulitis may require surgery.
Symptomatic uncomplicated diverticular disease (SUDD)
[0031] Patients with diverticulosis who develop a constellation of persistent abdominal symptoms that include pain and changes in bowel habits that are not, however, associated with macroscopic inflammation or elevated systemic markers of inflammation, may have a condition known as symptomatic uncomplicated diverticular disease (SUDD).
[0032] SUDD is defined as the concomitant presence of diverticula and symptoms of abdominal pain and bloating, bowel habit changes that include diarrhea and constipation or a mixed bowel habit, in the absence of macroscopic inflammation.
Encephalopathy
[0033] Encephalopathy can result from gastrointestinal dysbiosis, wherein the proliferation of urease producing bacteria increase blood ammonia. Increased blood ammonia can damage the liver and enter the brain to produce symptoms resembling hepatic encephalopathy. In one aspect, the invention provides a method of treating an encephalopathy, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
[0034] In some embodiments, the encephalopathy is Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
[0035] Encephalopathy refers to any disorder or disease of the brain, especially chronic degenerative conditions. Generally, encephalopathy does not refer to a single disease, but rather a syndrome of overall brain dysfunction; this syndrome has many possible causes. There are numerous types of encephalopathy, of which the present disclosure focuses on Hepatic Encephalopathy (HE) and Overt Hepatic Encephalopathy (OHE). Hepatic Encephalopathy (HE)
[0036] Hepatic encephalopathy (HE) is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients.
Overt Hepatic Encephalopathy (OHE)
[0037] HE can be divided into two broad categories: covert HE (CHE) and overt HE (OHE), which are both part of the spectrum of neurocognitive impairment in cirrhosis. The prevalence of CHE has been reported in 30-85% of cirrhotics when tested, whereas OHE is estimated to occur in up to 30-50% in patients with cirrhosis, with an annual risk for development of 20%. Development of OHE is associated with high rates of hospitalization, along with increased healthcare cost.
[0038] Clinical OHE includes personality changes, alterations in consciousness progressive disorientation in time and space, somnolence, stupor and, finally, coma. Treatment of OHE includes supportive therapies, treatment of precipitating factors, lactulose and/or rifaximin.
Methods of Treatment
[0039] As used herein, the terms “subject” and “patient” are used interchangeably to refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a “mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, or mouse) and a primate (e.g., a monkey, chimpanzee or a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject or patient is a human.
[0040] As used herein, the term a “patient in need thereof’ is used to refer to a patient suffering from one of the gastrointestinal disorders here described, for example travelers’ diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD). [0041] In some embodiments, the “patient in need thereof’ is a patient with an encephalopathy, for example a patient diagnosed with Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
[0042] In some instances, a “patient in need thereof’ experiences symptoms of one of the gastrointestinal disorders or encephalopathies described herein even though a diagnosis may not yet have been made.
[0043] As used herein, the term “treat”, “treating” or “treatment” refers to alleviating the cause and/or effects or symptoms or clinical manifestations of the disorder or disease. As used herein, the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration or slowing down of the progression, severity and/or duration of gastrointestinal disorders or encephalopathies.
[0044] In some embodiments, the terms “treat”, “treatment” and “treating” refer to the reduction, amelioration or slowing down of the progression, the severity and/or the duration of one or more symptoms or clinical manifestations (preferably, one or more measurable symptoms or clinical manifestations) of a gastrointestinal disorder or encephalopathy, as a result of the administration of one or more therapies (e.g., an IBAT inhibitor or a pharmaceutically acceptable salt thereof and rifaximin or a pharmaceutically acceptable salt thereof).
[0045] In some embodiments, the terms “treat,” “treatment” and “treating” refer to delaying the onset of a symptom or set of symptoms or clinical manifestations or to delaying the onset of a loss in certain physical function.
[0046] In some embodiments, the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical manifestation of a gastrointestinal disorder or encephalopathy. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction, inhibition or slowing down of the progression of said condition, either physically by, e.g., stabilization of a measurable symptom or set of symptoms , or physiologically by, e.g., stabilization of a measurable parameter, or both. As used herein, the term “treating”, “treat” or “treatment” also refers to averting the cause and/or effects or clinical manifestation of a gastrointestinal disorder or encephalopathy or one of the symptoms developed as a result of the gastrointestinal disorder or encephalopathy prior to disease or disorder fully manifesting itself.
[0047] “Treatment” can involve administering a compound described herein to a patient diagnosed with a gastrointestinal disorder or encephalopathy herein described and may involve administering the two compounds to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a gastrointestinal disorder or encephalopathy, or to a patient reporting one or more of the symptoms of a gastrointestinal disorder or encephalopathy, even though a diagnosis may not have been made.
[0048] The term “therapeutically effective amount” as used herein means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms without serious adverse effects.
[0049] In one embodiment of this invention, the IBAT inhibitor and rifaximin are each administered in an effective amount (i.e., in an amount which would be therapeutically effective if administered alone). In another embodiment, the IBAT inhibitor and rifaximin are each administered in an amount which alone does not provide a therapeutic effect ("a sub- therapeutic dose"). In yet another embodiment, the IBAT inhibitor or rifaximin can be administered in an effective amount, while the IBAT inhibitor or rifaximin is administered in a sub-therapeutic dose.
[0050] The term “prophylactically effective amount” refers to an amount effective in preventing or substantially lessening the chances of developing a disorder or in reducing the severity of the disorder or one or more of its symptoms before it is acquired or the symptoms fully develop further.
[0051] In one aspect, a method of treating a subject having a gastrointestinal disorder, the method comprising administering to a subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
[0052] In one aspect, a method of treating an encephalopathy, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
[0053] In a further aspect, the invention provides use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof for the treatment of a gastrointestinal disorder.
[0054] In a further aspect, the invention provides use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof for the treatment of an encephalopathy. [0055] In a further aspect, the invention provides a use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a gastrointestinal disorder in a subject in need thereof.
[0056] In a further aspect, the invention provides a use of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an encephalopathy in a subject in need thereof.
[0057] In another aspect, the invention provides pharmaceutical compositions comprising (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, for use in the treatment of a gastrointestinal disorder in a subject in need thereof.
[0058] In another aspect, the invention provides pharmaceutical compositions comprising (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof, for use in the treatment of an encephalopathy in a subject in need thereof.
Clinical Signs of Gastrointestinal Disorders and Encephalopathy
Gastrointestinal Disorders i. Travelers’ Diarrhea (TD)
[0059] Bacterial and viral TD presents with the sudden onset of bothersome symptoms that can range from mild cramps and urgent loose stools to severe abdominal pain, fever, vomiting, and bloody diarrhea, although with norovirus vomiting may be more prominent. Protozoal diarrhea, such as that caused by Giardia intestinalis or E. histolytica, generally has a more gradual onset of low-grade symptoms, with 2-5 loose stools per day.
[0060] The incubation period between exposure and clinical presentation can be a clue to the etiology:
Bacterial toxins generally cause symptoms within a few hours.
Bacterial and viral pathogens have an incubation period of 6-72 hours.
Protozoal pathogens generally have an incubation period of 1-2 weeks and rarely present in the first few days of travel. An exception can be Cyclospora cayetanensis, which can present quickly in areas of high risk.
[0061] Untreated bacterial diarrhea usually lasts 3-7 days. Viral diarrhea generally lasts 2-3 days. Protozoal diarrhea can persist for weeks to months without treatment. An acute bout of gastroenteritis can lead to persistent gastrointestinal symptoms, even in the absence of continued infection. This presentation is commonly referred to as postinfectious irritable bowel syndrome. Other postinfectious sequelae may include reactive arthritis or Guillain- Barre syndrome. ii. Diarrhea predominant - Irritable Bowel Syndrome (IBS-D)
[0062] Patients with IBS-D typically present with abdominal pain associated with frequent loose stools and cramping, urgency that is not relieved by defecation, and mucus in the stool. [0063] Symptoms may be mild and infrequent, moderate and somewhat bothersome, or severe enough to interfere with daily function, but all typically require an ongoing management strategy to control symptoms. Symptoms include recurrent abdominal pain or discomfort for at least 3 days per month in the preceding 3 months, loose or watery stool for at least 25% of bowel movements, and hard or lumpy stool for less than 25% of bowel movements. iii. Diverculitis
[0064] Signs and symptoms of diverticulitis include pain, nausea and vomiting, fever, abdominal tenderness, constipation, and less commonly, diarrhea. An area of macroscopic inflammation is identifiable.
[0065] Diverculitis pain may be constant and persist for several days. The lower left side of the abdomen is the usual site of the pain. Sometimes, however, the right side of the abdomen is more painful, especially in people of Asian descent. iv. Symptomatic Uncomplicated Diverticular Disease (SUDD)
[0066] SUDD is defined as the concomitant presence of diverticula and symptoms of abdominal pain and bloating, bowel habit changes that include diarrhea and constipation or a mixed bowel habit, in the absence of macroscopic inflammation.
[0067] Patients with SUDD have a heightened sensitivity of isobaric distension (visceral hypersensitivity) compared to asymptomatic patients.
[0068] Pain associated with SUDD is normally located in the iliac fossa and is more sustained, with a history of pain lasting more than 24 hrs, and is not relieved by bowel movement, as is often the case with IBS.
Encephalopathy i. Hepatic Encephalopathy (HE)
[0069] The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated by neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. The first stage of hepatic encephalopathy is characterized by an inverted sleep-wake pattern (sleeping by day, awake at night). The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma. ii. Overt Hepatic Encephalopathy (OHE)
[0070] Symptoms of OHE include lack of energy or interest, confusion, disorientation, inappropriate behavior, severe personality changes, sleepiness or change in sleep patterns, worsening handwriting, loss of small hand movements, tremors or shaking of hands or arms, and/or breath with a musty or sweet odor.
Treating Gastrointestinal Disorders with Rifaximin and IBAT Inhibitor
[0071] The liver produces bile acids that are stored in the gallbladder and released through common bile ducts into the duodenum after consuming a meal. Liver dysfunction can result in decreased bile acid production, which can lead to overgrowth of harmful bacteria in the small intestines. Thus, gastrointestinal disorders related to proliferation of harmful bacterial, including traveler’s diarrhea, diverticulitis, and types of IBD can be exacerbated by reduced bile acids from liver dysfunction. The ileal bile acid transporter (IBAT) recycles bile acids from the distal ileum back to the liver. Administering a compound that inhibits IBAT increases bile acids in the ileum. Increased bile acids can reduce proliferation of harmful bacteria. Oral administration of rifaximin remains in the gastrointestinal tract and reduces the proliferation of harmful bacteria. However, adequate bile acids in the small intestines is required for rifaximin to be fully solubilized. Using an IBAT inhibitor can increase the solubility and thus bioavailability of rifaximin, and therefore the treatment efficacy of gastrointestinal disorders related to the proliferation of harmful bacteria.
[0072] In some embodiments, the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, results in an improved solubility of the IBAT inhibitor and/or rifaximin in the colon.
[0073] In some embodiments, the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, results in an improved antibacterial activity of rifaximin in the colon.
[0074] In some embodiments, the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, results in a decrease of abdominal pain. [0075] In some embodiments, the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, results in an improved duration of treatment effect. Gastrointestinal Disorders to Reduce Proliferation of Harmful Bacteria Causal to Encephalopathy or Hepatic Encephalopathy
[0076] Ammonia is a toxic metabolite produced from the metabolism of protein and nitrogen containing compounds, and is converted to urea in the liver for disposal through the kidneys, muscles, and intestinal tract. Increased blood ammonia can occur from dysfunction of the liver urea cycle due to cirrhosis, urease-producing bacterial in the intestines, and catabolism of glutamine to ammonia and glutamate by enterocyte glutaminase. Increased blood ammonia passes through the blood brain barrier and is taken up by astrocytes where it is combined with glutamine to produce glutamate. High levels of glutamate disrupts the glutamine-glutamate cycle and causes neuronal excitotoxicity, increased reactive oxygen species, and inflammatory factors, which can result in brain edema and cognitive changes symptomatic of encephalopathy. Increased ammonia from urease-producing bacteria can cause liver damage, reducing ammonia elimination through the urea cycle and bile acids that reduce bacteria proliferation in the small intestines; in the presence of liver dysfunction, the disorder is hepatic encephalopathy.
[0077] In some embodiments, the administration of rifaximin reduces blood ammonia by decreasing proliferation of urease-producing bacteria; reducing blood ammonia also improves liver function, such as urea cycle efficiency and bile acid production. In further embodiments, combining rifaximin administration with an IBAT inhibitor will increase bile acid, which increases rifaximin bioavailability and therefore efficacy in decreasing urease-producing bacteria, lowering blood ammonia, and improving liver function and encephalopathy symptoms.
[0078] In some embodiments, the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, improves symptoms of encephalopathy by reducing harmful bacteria causing a gastrointestinal disorder.
[0079] In some embodiments, the administration of a composition including an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, improves symptoms of encephalopathy by reducing high blood ammonia resulting from an overgrowth of harmful bacteria in a gastrointestinal disorder.
[0080] In some embodiments, the administration of an IBAT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, improves symptoms of hepatic encephalopathy by reducing high blood ammonia resulting from the overgrowth of harmful bacteria, thereby improving liver function to reduce ammonia levels further by the urea cycle and increased production of bile acids. [0081] In some embodiments, the administration of an IB AT inhibitor or pharmaceutically acceptable salt thereof in combination with rifaximin, improves symptoms of overt hepatic encephalopathy by reducing high blood ammonia resulting from the overgrowth of harmful bacteria, thereby improving liver function to reduce ammonia levels further by the urea cycle and increased production of bile acids.
[0082] In some embodiments, the harmful bacteria is urease-producing bacteria.
IBAT Inhibitors
[0083] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed., 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, which are herein incorporated by reference in their entirety.
[0084] In some embodiments, the IBAT inhibitor is a compound of formula (I):
Figure imgf000014_0001
wherein:
Rv and Rw are independently selected from hydrogen or C1-6-alkyl;
R1 and R2 are independently selected from C1-6-alkyl;
Rx and Ry are independently selected from hydrogen or C1-6-alkyl, or one of Rx and Ry is hydrogen or C1-6-alkyl and the other is hydroxy or C1-6-alkoxy;
Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkanoyl, C1-6- alkanoyloxy, N-(C1-6-alkyl)amino, A,A-(C1-6-alkyl)2amino, C1-6-alkanoylamino, A-(CI-6- alkyl)carbamoyl, N,N-(C1-6-alkyl)2carbamoyl, C1-6-alkylS(O)a wherein a is 0 to 2, C1-6- alkoxycarbonyl, C1-6-alkoxycarbonylamino, ureido, A-(C1-6-alkyl)ureido, A-(CI-6- alkyl)ureido, N',N-(C1-6-alkyl)2ureido, N'-(C1-6-alkyl)-7V-(C1-6-alkyl)ureido, N',N-(C1-6- alkyl)2-/V-(C1-6-alkyl)ureido, N-(C 1-6-alkyl)sulphamoyl and N,N-(C 1-6-alkyl)2Sulphamoyl;
V is 0-5; one ofR4 and R5 is a group of formula (IA):
Figure imgf000015_0001
R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C1-4-alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy, A-(C1-4-alkyl)amino, A,A-(C1-4- alkyl)2amino, C1-4-alkanoylamino, A-(C1-4-alkyl)carbamoyl,A,A-(C1-4-alkyl)2carbamoyl, C1-4- alkylS(O)a wherein a is 0 to 2, C1-4-alkoxycarbonyl, A-(C1-4-alkyl)sulphamoyl and A,A-(CI-4- alkyl)2sulphamoyl; wherein R3 and R6 and the other of R4 and R5 may be optionally substituted on carbon by one or more R16;
D is -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-; wherein Ra is hydrogen or C1-6-alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17;
R7 is hydrogen, C1-4-alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted by one or more substituents selected from R18;
R8 is hydrogen or C1-4-alkyl;
R9 is hydrogen or C1-4-alkyl;
R10 is hydrogen, C1-4-alkyl, carbocyclyl or heterocyclyl; wherein R10 is optionally substituted by one or more substituents selected from R19;
Rn is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORC), -P(O)(OH)(Rd) or -P(O)(ORc)(Rd) wherein Rc and Rd are independently selected from C1-6- alkyl; or R11 is a group of formula (IB):
Figure imgf000015_0002
wherein:
X is -N(Rq)-, -N(Rq)C(O)-, -O-, and -S(O)a-; wherein a is 0-2 and Rq is hydrogen or C1-4- alkyl;
R12 is hydrogen or C1-4-alkyl;
R13 and R14 are independently selected from hydrogen, C1-4-alkyl, carbocyclyl, heterocyclyl or R23; wherein said C1-4-alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R20;
R15 is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), - P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from C1-6- alkyl; or R15 is a group of formula (IC):
Figure imgf000016_0001
wherein:
R24 is selected from hydrogen or C1-4-alkyl;
R25 is selected from hydrogen, C1-4-alkyl, carbocyclyl, heterocyclyl or R27; wherein said C1salkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R28;
R26 is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), - P(O)(OHxORg), -P(O)(OH)(Rg) or -P(O)(ORg)(Rh) wherein Rg and Rh are independently selected from C1-6-alkyl; wherein subscripts of the above markush structures are p is 1-3, wherein the values of R13 may be the same or different; q is 0-1; r is 0-3, wherein the values of R14 may be the same or different; m is 0-2, wherein the values of R10 may be the same or different; n is 1-3, wherein the values of R7 may be the same or different; z is 0-3, wherein the values of R25 may be the same or different;
R16, R17 and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C1-4- alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy, N-(C1-4-alkyl)amino, N,N-(C1-4-alkyl)2amino, C1-4- alkanoylamino, N-(C1-4-alkyl)carbamoyl, N,N-(C1-4-alkyl)2carbamoyl, C1-4-alkylS(O)a wherein a is 0 to 2, C1-4-alkoxycarbonyl, 7V-( C1-4-alkyl)sulphamoyl and /V,7V-(C1-4- alkyl)2sulphamoyl; wherein R16, R17 and R18 may be independently optionally substituted on carbon by one or more R21;
R19, R20, R23, R27 and R28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C1- 4-alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy,N-(C1-4-alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4- alkanoylamino, N-(C1-4-alkyl)carbamoyl, N,N-(C1-4-alkyl)2carbamoyl, C1-4-alkylS(O)a wherein a is 0 to 2, C1-4-alkoxycarbonyl, N-(C1-4-alkyl)sulphamoyl, N,N-( C1-4- alkyl)2sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, - P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra) or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-6-alkyl; wherein R19, R20, R23, R27 and R28 may be independently optionally substituted on carbon by one or more R22;
R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, /V-mcthylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, /V-mcthylsulphamoyl and N,N- dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0085] In some embodiments, Rv and Rw are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0086] In some embodiments, R1 and R2 are independently selected from ethyl, propyl or butyl or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0087] In some embodiments, Rx and Ry are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0088] In some embodiments, Rz is selected from halo, amino, C1-6-alkyl, C1-6- alkoxycarbonylamino or N'-(C1-6-alkyl)ureido or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0089] In some embodiments, v is 0 or 1 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0090] In some embodiments, R3 is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof. [0091] In some embodiments, the R4 or R5 that is not the group of formula (IA) is selected from hydrogen, halo, C1-4-alkoxy or C1-4-alkylS(O)a wherein a is 0 to 2; wherein that R4 or R5 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and N,N-(C1-4-alkyl)2amino or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof [0092] In some embodiments, R5 is a group of formula (IA) and R4 is methylthio or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof. In some embodiments, R6 is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0093] In some embodiments, in the group of formula (IA):
D is -O- or -S-;
Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;
R7 is hydrogen, methyl or phenyl;
R8 is hydrogen or methyl;
R9 is hydrogen or methyl;
R10 is hydrogen;
M is 0-2 wherein the values of R10 may be the same or different; and
Rn is carboxy, -P(O)(OH)(OEt) or a group of formula (IB); or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0094] In some embodiments, in the group of formula (IB):
R12 is hydrogen or methyl;
R13 is hydrogen, methyl, ethyl, butyl or phenyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20; R20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R20 may be independently optionally substituted on carbon by one or more hydroxy; R23 is carboxy;
X is -NH- or -NHC(O)-;
R14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxy;
R15 is carboxy, sulpho, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), - P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from methyl or ethyl or R15 is a group of formula (IC); p is 1-3, wherein the values of R13 may be the same or different; q is 0-1; and r is 0-3, wherein the values of R14 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0095] In some embodiments, in the group of formula (IC):
R24 is hydrogen;
R25 is hydrogen;
R26 is carboxy; and z is 1; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0096] In some embodiments, in the group of formula (I):
Rv and Rw are both hydrogen;
R1 and R2 are independently selected from C1-4-alkyl;
Rx and Ry are both hydrogen;
Rz is selected from halo, amino, C1-6-alkyl, C1-6-alkoxycarbonylamino or A'-(CI-6- alkyl)ureido;
V is 0 or 1 ;
R3 and R6 are hydrogen; one ofR4 and R5 is a group of formula (IA) and the other is selected from hydrogen, halo, C1-4-alkoxy or C1-4-alkylS(O)a wherein a is 0 to 2; wherein that R4 or R5 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and A,A-(C1-4-alkyl)2amino;
D is -O- or -S-;
R7 is hydrogen, methyl or phenyl;
R8 is hydrogen or methyl;
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; wherein R17 is selected from halo, hydroxy, C1-4-alkyl or C1-4- alkoxy; wherein R17 may be optionally substituted on carbon by one or more R21; wherein R21 is selected from halo;
R9 is hydrogen or methyl;
R10 is hydrogen;
Rn is carboxy, -P(O)(OH)(ORC) wherein Rc is selected from C1-4-alkyl or a group of formula (IB);
R12 is hydrogen or methyl; X is -NH- or -NHC(O)-;
R13 is hydrogen, C1-4-alkyl, carbocyclyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20 ; wherein R20 is hydroxy, C1-4-alkylS(O)a wherein a is 0, C1-4-alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R20 may be independently optionally substituted on carbon by one or more R22; R22 is selected from hydroxy; and R23 is carboxy;
R14 is selected from hydrogen, C1-4-alkyl or carbocyclyl; wherein said C1-4-alkyl or carbocyclyl may be optionally substituted by one or more substituents selected from R20; and R20 is hydroxy;
R15 is carboxy, sulpho, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), - P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from C1-4- alkyl or R15 is a group of formula (IC)
R24 is hydrogen;
R25 is hydrogen;
R26 is carboxy; p is 1-3; wherein the values of R13 may be the same or different; q is 0-1; r is 0-3; wherein the values of R14 may be the same or different; m is 0-2; wherein the values of R10 may be the same or different; n is 1-2; wherein the values of R7 may be the same or different; z is 0-1; wherein the values of R25 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
[0097] In some embodiments, the IBAT inhibitor is selected from:
1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-mcthylthio-8-(N- {(R)- 1 ’-phenyl- 1 ’-[N' (carboxymethyl) carbamoyl]methyl}carbamoylmethoxy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'- (carboxymethyl)carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)- 1 ’-phenyl- 1 ’-[N'-(2- sulphoethyl)carbamoyl]methyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-l'-phenyl-r-[A’-(2- sulphoethyl)carbamoyl]methyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine; 1 , 1 -dioxo-3, 3-dibutyl-5-phcnyl-7-mcthylthio-8-GV- {(R)-a-[N'-(2- sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-(N- { (R)-a-[N'-(2-sulphoethyl ) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy)-2,3 ,4,5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl]benzyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- banzothiazepine;
1 , 1 -dioxo-3, 3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylniethoxy)-2, 3, 4, 5-tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-(N- { (R)-a-[N'-(5-carboxypentyl ) carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,5-benzothiazepine;
1 , 1 -dioxo-3, 3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,5- benzothiazepine; l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{a-[N'-(2-sulphoethyl)carbamoyl]- 2-fluorobenzyl} carbamoylmethoxy)-2,3 ,4,5 -tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-methylthio-8-(N- {(R)-a-[N'-(R)-(2 -hydroxy- 1 - carboxyethyl)carbamoyl]benzyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3 ,3-dibutyl-5 -phenyl-7-methyl th io-8-(N- {(R)-a-[N'-(R)-(2 -hydroxy- 1 - carboxyethyl)carbamoyl]benzyl} carbamoylmethoxy)- 2,3,4,5-tetrahydro-l,5- benzothiazepine;
1 , 1 -dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R)-a-(N'- {(R)- 1 -[7V"-(R)-(2- hydroxy- 1 -carboxyethyl)carbamoyl] -2- hydroxyethyl} carbamoyl)benzyl] carbamoylmethoxy} -2,3 ,4,5 -tetrahydro- 1 ,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-GV- { a-[N'- (carboxymethyl)carbamoyl] benzyl} carbamoylmethoxy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-mcthylthio-8-(N- {a-[N'- ((ethoxy)(methyl)phosphorylmethyl)carbanoyl]benzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- {N'-[(R)-a-(N' - {2- [(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5- tetrahydro-1 ,5-benzothiazepine; 1 , 1 -dioxo-3 ,3-dibutyl-5 -phenyl-7-methylthio-8-(N- {(R)-a-[N'-(2 -methylthio- 1 - carboxyethyl)carbamoyl]benzyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R)-a-(A- {2-[(methyl)(ethyl) phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R)-a-(N'- {2-[(methyl)(hydroxy) phosphoryl] ethyl} carbamoyl)-4-hydroxybenzyl] carbamoylmethoxy} -2, 3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(A- {(R)-a-[(R)-N'-(2- methylsulphinyl- l-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine; and l,l-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-'{(R)-a-[N'-(2- sulphoethyl)carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy]-2,3,4,5-tetrahydro- 1 ,5-benzothiazepine; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
Rifaximin
[0098] Rifaximin is a structural analog of rifampin and a non-systemic, gastrointestinal sitespecific antibiotic. Rifaximin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis and contributes to restoring intestinal microflora imbalance. It is FDA approved for the treatment of travelers’ diarrhea, reduction in risk of overt hepatic encephalopathy (HE) recurrence and treatment of irritable bowel syndrome with diarrhea. Common side effects are: black, tarry stools; dizziness or lightheadedness; muscle spasm; rapid breathing; shortness of breath; trouble sleeping. Co-administration of cyclosporine, with the Rifaximin brand Xifaxan resulted in 83-fold and 124-fold increases in rifaximin mean Cmax in healthy subjects.
[0099] Rifaximin has the chemical structure:
Figure imgf000023_0001
Pharmaceutically Acceptable Salts
[0100] In some embodiments, the IBAT inhibitor and rifaximin may be provided as (i) the compounds themselves (e.g., as the free base); (ii) a pharmaceutically acceptable salt of one of both of the compounds; and/or (iii) part of a pharmaceutical composition.
[0101] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein. For use in medicine, the salts of the compounds described herein will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds described herein. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt there can be multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion(s).
[0102] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.
[0103] When the compound described herein is acidic or contains a sufficiently acidic bioisostere, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'- dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
[0104] When the compound described herein is basic or contains a sufficiently basic bioisostere, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2 -hydroxy-3 - naphthoate)) salts.
[0105] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66: 1-19, incorporated herein by reference in its entirety.
Co-administration of IBAT Inhibitor and Rifaximin
[0106] In some embodiments, the IBAT inhibitor and rifaximin are administered before a symptom of the gastrointestinal disorder or an encephalopathy fully develops in a subject. In other embodiments, the IBAT inhibitor and rifaximin are administered after one or more symptoms of the gastrointestinal disorder or encephalopathy develops in a subject.
[0107] In some embodiments, the IBAT inhibitor is administered prior to, at the same time, or after the administration of rifaximin. [0108] In some embodiments, the IBAT inhibitor is administered simultaneously with rifaximin.
[0109] In some embodiments, the above pharmaceutical compositions comprise (a) an IBAT inhibitor as discussed above or a pharmaceutically acceptable salt thereof and rifaximin or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant.
[0110] " Co-administration" encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of each compound amount, or in multiple, separate capsules or tablets for each. In addition, co-administration also encompasses use of each compound in a sequential manner in either order. When co- administration involves the separate administration of the first amount of an IBAT inhibitor and a second amount of rifaximin, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration can result in the desired therapeutic effect, can range from minutes to hours and can be determined by taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and pharmacokinetic profile. For example, an IBAT inhibitor and rifaximin can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, within about 30 minutes of each other, or within about 5 minutes of each other, etc.
[0111] More specifically, as the first therapy an IBAT inhibitor (e.g., prophylactic or therapeutically) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration rifaximin to a subject. Pharmaceutical Compositions and Their Routes of Administration
[0112] The compounds herein disclosed, and their pharmaceutically acceptable salts, thereof may be formulated as pharmaceutical compositions or "formulations".
[0113] A typical formulation is prepared by mixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound described herein is being formulated. Solvents are generally selected for being recognized by persons skilled in the art as safe (e.g., one described in the GRAS (Generally Recognized as Safe) database) to be administered to a mammal. In general, safe solvents are non -toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an aesthetic presentation of the compounds described herein or pharmaceutical composition thereof or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[0114] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., one or more of the compounds described herein, a pharmaceutically acceptable salt thereof, or a stabilized form of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, and may range from about 3 to about 8. [0115] A compound described herein or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. Pharmaceutical formulations of compounds described herein, or a pharmaceutically acceptable salt thereof, may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition (weight/weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution to ensure that an infusion of a suitable volume at a rate of about 30 mL/hr can occur.
[0116] The pharmaceutical compositions described herein will be formulated, dosed, and administered in a fashion, (i.e., amounts, concentrations, schedule, vehicles, and route of administration), consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the individual subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual subject.
[0117] In some embodiments, a prophylactically effective amount of an IBAT inhibitor and rifaximin prevents the symptoms of intestinal diseases associated with bacterial overgrowth and intestinal bacterial biofilm formation. These diseases include IBS-D, HE, diverticulitis and inflammatory bowel disease, Ulcerative colitis and Crohn’s disease (UC and CD).
[0118] Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; proteins, such as serum albumin, gelatin, and immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, and lysine; carbohydrates including monosaccharides, disaccharides, glucose, mannose, and dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose and sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and non-ionic surfactants such as TWEEN™, PLURONICS™ and polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, micro emulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's").
[0119] " Controlled drug delivery systems" supply the drug to the subject in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release", "delayed release", "modified release" or "sustained release".
[0120] " Sustained-release preparations" are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, wherein matrices are in the form of shaped articles, e.g., films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacry late), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.
[0121] " Gastroretentive formulations" are preparations designed to have increased retention in the stomach cavity. In some cases, they are used where a drug is preferentially or primarily absorbed via the stomach, is designed to treat the stomach directly, or where drug dissolution or absorption is aided by prolonged exposure to gastric acids. Examples of gastroretentive formulations include but are not limited to, high-density formulations, where the density of the formulation is higher than gastric fluid; floating formulations, which can float on top of gastric fluids due to increased buoyancy or lower density of the formulation; temporarily expandable formulations that are temporarily larger than the gastric opening; muco- and bio-adhesive formulations; swellable gel formulations; and in situ gel forming formulations. (See, e.g., Bhardwaj, L. et al., African J. of Basic & Appl. Sci. 4(6): 300-312 (2011)).
[0122] "Immediate -release preparations" may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate. [0123] In some embodiments, the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in an immediate release formulation.
[0124] In some embodiments, the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in a delayed release formulation.
[0125] In some embodiments, the IBAT inhibitor or a pharmaceutically acceptable salt thereof, and rifaximin or a pharmaceutically acceptable salt thereof are provided or administered in a bilayer delivery system. In some embodiments, the bilayer delivery system comprises (i) an immediate release formulation layer and (ii) a delayed release formulation layer.
[0126] In embodiments where the bilayer delivery system is used, the delayed release formulation layer contains a higher amount (e.g., 1.5 fold to 10 fold) of the IBAT inhibitor and rifaximin compared to amount of the IBAT inhibitor and rifaximin in the immediate release formulation layer.
[0127] Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304, 121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics for the composition. [0128] The formulations include those suitable for the administration routes detailed herein.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly combining the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
[0129] The terms "administer", "administering" or "administration", in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the subject in need of treatment.
[0130] The compositions described herein may be administered systemically or locally, for example, orally using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like; by inhalation using an aerosol, gas, inhaler, nebulizer or the like; to the ear using ear drops; topically using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.; ophthalmically using eye drops, ophthalmic gels, ophthalmic ointments; rectally using enemas or suppositories; vaginally using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets; nasally; buccally; parenterally depending on the severity and type of the disease being treated, or via an implanted reservoir or the like. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
[0131] In particular embodiments, the compositions are administered orally, intraperitoneally or intravenously. In some embodiments, the compositions are administered orally.
[0132] In other embodiments, the compositions are administered rectally.
[0133] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0134] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution-retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite clay; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste masking material such as hydroxypropyl -methylcellulose or hydroxypropyl-cellulose may be employed.
[0135] Formulations of a compound described herein that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, (e.g., gelatin capsules, syrups or elixirs). Formulations of a compound intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.
[0136] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, and optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
[0137] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
[0138] The active compounds may also be prepared in a microencapsulated form with one or more excipients as noted above.
[0139] When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcent, preservative, antioxidant, flavoring, and coloring agent.
[0140] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
[0141] Oily suspensions may be formulated by suspending a compound described herein in a vegetable oil, for example arachis oil, olive oil, sesame oil, coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisol or alphatocopherol. [0142] Aqueous suspensions of compounds described herein contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as the naturally occurring phosphatide lecithin, a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), and a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0143] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[0144] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable drugdepot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide -polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Drug-depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[0145] The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
[0146] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.
[0147] The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [0148] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
[0149] The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
[0150] Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
[0151] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [0152] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, between 0.075 % and 20% w/w. When formulated in an ointment, the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
[0153] Alternatively, the active ingredients may be formulated in a cream with an oil-in- water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
[0154] The oily phase of emulsions prepared using compounds described herein may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of compounds described herein include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono -stearate and sodium lauryl sulfate.
[0155] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration may have a mean particle size in the range of, for example, 0.1 to 500 microns (including particles with a mean particle size in the range between 0.1 and 500 microns in increments such as 0.5, 1, 30, 35 microns, etc.), which may be administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
[0156] The pharmaceutical composition (or formulation) for use may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
[0157] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
[0158] Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. In another aspect, a compound described herein or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. Compounds, compositions and kits of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle. Kits
[0159] The pharmaceutical formulations described herein may be contained in a kit. The kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination. Thus, one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, and the package can optionally include administration or dosage instructions. A kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation. Thus, the kits can comprise: (a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and (b) another therapeutic agent and a pharmaceutically acceptable carrier, vehicle or diluent in one or more containers or separate packaging. The kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g., preventing or treating one or more of the diseases and disorders described herein). The pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
[0160] A kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet. The container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
[0161] An example of a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide written memory aid containing information and/or instructions for the physician, pharmacist or subject regarding when the medication is to be taken. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or other compositions of the kit can consist of several tablets or capsules. A kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
[0162] Other embodiments of the present invention include:
An IB AT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder.
An IB AT inhibitor and rifaximin for use in treating a subject having an encephalopathy.
A therapeutic pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having a gastrointestinal disorder.
A therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having an encephalopathy.
An IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea.
An IBAT inhibitor and rifaximin for use in treating a subject having diarrhea predominant irritable bowel syndrome. An IB AT inhibitor and rifaximin for use in treating a subject having hepatic encephalopathy.
An IB AT inhibitor and rifaximin for use in treating a subject having overt hepatic encephalopathy.
Other Embodiments
All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion and from the accompanying claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.
EXAMPLES
Example 1
Study A - Inhibition
[0163] An example for measuring the effect of the combination of IBAT inhibitors and rifaximin could be with in vitro or in vivo assays.
[0164] IBAT inhibitory activity may be assessed, for example, using an in vitro assay for studying the inhibitor effect on bile acid uptake in IBAT-transfected cells (see methods in Smith L., Price- Jones M. J., Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227-230), or in vivo by studying the effect on radiolabelled bile acid absorption in mice/rats (Lewis M. C, Brieaddy L. E. and Root C, J., J Lip Res 1995, 36, 1098-1105).
Study B - In Vivo Assays
[0165] An example for measuring the inhibitory effect of the combination of IBAT inhibitors and rifaximin could be demonstrated with in vivo assays after dosing animal models.
[0166] For example, the assay could have mice strains with ApoE knocked out; Sub strain C57BL/6; sex female; Total No. of animals 70; body weight range 20 g to 22 g. [0167] To analyze the inhibitory activity the animals could be orally administered vehicle (n=3) or the IBAT inhibitor + rifaximin combination. Thirty minutes later, a trace amount of 75SeHCAT (75Se-homo-tauro-cholic acid) (0.1 mCi per 0.1 mL per mouse) can be orally given to each mouse. Twenty-four hours after75SeHCAT administration, the animals can be killed by CO2 inhalation. At sacrifice, the gall bladder and the whole intestine are removed, and the feces during the 24-hour period after75SeHCAT administration collected for each mouse. The gamma radioactivities of 75SeHCAT in the feces and in the gall bladder-intestine are separately counted by 1282 CompuGamma CS Gamma counter (Wallac oy, Turku, Finland). The stability as well as the quantity of the75SeHCAT administered to each mouse, can be controlled with an additional75SeHCAT aliquot following the same experimental process as other tested samples in the study.
[0168] The sum of the gamma counts from both the feces and the gall bladder-intestine can be considered as the total recovered75 SeHC AT. Of the recovered radioactivity of75SeHCAT, the percentage of the75 SeHCAT detected in the feces can be considered as the fecal excretion, while that in the gall bladder-intestine as body retention. Inhibitory effect of the IBAT inhibitor + rifaximin combination on75 SeHCAT intestinal absorption can be calculated following the75 SeHCAT body retention and the fecal excretion, and the ED50 of the compound can be estimated following the dose-effect curve. The mean IBAT inhibitory effect (%) can be reported at a dose of pmol/kg.
Study C - Solubility and Efficacy
[0169] An example for measuring the effect of the combination of IBAT inhibitors and rifaximin solubility and efficacy could be demonstrated with in vivo assays after dosing animal models.
[0170] For example, to assess solubility and efficacy one could take a series of colonic samples after the administration of rifaximin alone and in combination with the IBAT inhibitors. Then, solubility and efficacy could be measured. One could also document the increase in colonic bile acid concentrations.

Claims

WHAT IS CLAIMED IS:
1. A method of treating a subject having a gastrointestinal disorder, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof, and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the gastrointestinal disorder is travelers’ diarrhea, diarrhea predominant irritable bowel syndrome (IBS-D), diverculitis, or symptomatic uncomplicated diverticular disease (SUDD).
3. A method of treating an encephalopathy in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of (i) an ileal bile acid transporter (IBAT) inhibitor or a pharmaceutically acceptable salt thereof and (ii) rifaximin or a pharmaceutically acceptable salt thereof.
4. The method of claim 3, wherein the encephalopathy is Hepatic Encephalopathy (HE) or Overt Hepatic Encephalopathy (OHE).
5. The method of any one of claims 1-4, wherein the IB AT inhibitor is a compound of formula (I):
Figure imgf000041_0001
wherein: Rv and Rw are independently selected from hydrogen or C1-6-alkyl;
R1 and R2 are independently selected from C1-6-alkyl;
Rx and Ry are independently selected from hydrogen or C1-6-alkyl, or one of Rx and Ry is hydrogen or C1-6-alkyl and the other is hydroxy or C1-6-alkoxy;
Rz is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C1-6-alkanoyl, C1-6- alkanoyloxy, N-(C1-6-alkyl)amino, N,N-(C1-6-alkyl)2amino, C1-6-alkanoylamino, N- (C1-6-alkyl)carbamoyl, A,A-(C1-6-alkyl)2carbamoyl, C1-6-alkylS(O)a wherein a is 0 to 2, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonylamino, ureido, N'-(C1-6-alkyl)ureido, N- (C1-6-alkyl)ureido, N',N-(C1-6-alkyl)2ureido, N'-(C1-6-alkyl)-N-(C1-6-alkyl)ureido, N',N'-(C1-6-alkyl)2-N-(C1-6-alkyl)ureido, N-(C1-6-alkyl)sulphamoyl and N,N-(C1-6- alkyl)2sulphamoyl;
V is 0-5; one of R4 and R5 is a group of formula (IA):
Figure imgf000042_0001
R3 and R6 and the other of R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C1-4-alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy, A-(CI-4- alkyl)amino, N,N-(C1-4-alkyl)2amino, C1-4-alkanoylamino, A-(CI-4- alkyl)carbamoyl,N,N-(C1-4-alkyl)2carbamoyl, C1-4-alkylS(O)a wherein a is 0 to 2, C1-4- alkoxycarbonyl, N-(C1-4-alkyl)sulphamoyl and N,N-(C 1-4-alkyl)2Sulphamoyl; wherein R3 and R6 and the other of R4 and R5 may be optionally substituted on carbon by one or more R16; D is -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-; wherein Ra is hydrogen or C1-6-alkyl and b is 0-2;
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17;
R7 is hydrogen, C1-4-alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted by one or more substituents selected from R18;
R8 is hydrogen or C1-4-alkyl;
R9 is hydrogen or C1-4-alkyl;
R10 is hydrogen, C1-4-alkyl, carbocyclyl or heterocyclyl; wherein R10 is optionally substituted by one or more substituents selected from R19;
Rn is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), - P(O)(OH)(ORC), -P(O)(OH)(Rd) or -P(O)(ORc)(Rd) wherein Rc and Rd are independently selected from C1-6-alkyl; or R11 is a group of formula (IB):
Figure imgf000043_0001
wherein:
X is -N(Rq)-, -N(Rq)C(O)-, -O-, and -S(O)a-; wherein a is 0-2 and Rq is hydrogen or C1-4-alkyl;
R12 is hydrogen or C1-4-alkyl;
R13 and R14 are independently selected from hydrogen, C1-4-alkyl, carbocyclyl, heterocyclyl or R23; wherein said C1-4-alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R20; R15 is carboxy, sulpho, sulphino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), - P(O)(OH)(ORe), -P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from C1-6-alkyl; or R15 is a group of formula (IC):
Figure imgf000044_0001
wherein:
R24 is selected from hydrogen or C1-4-alkyl;
R25 is selected from hydrogen, C1-4-alkyl, carbocyclyl, heterocyclyl or R27; wherein said C1-4-alkyl, carbocyclyl or heterocyclyl may be independently optionally substituted by one or more substituents selected from R28;
R26 is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl, - P(O)(ORg)(ORh), -P(O)(OHxORg), -P(O)(OH)(Rg) or -P(O)(ORg)(Rh) wherein Rg and Rh are independently selected from C1-6-alkyl; p is 1-3, wherein the values of R13 may be the same or different; q is 0-1; r is 0-3, wherein the values of R14 may be the same or different; m is 0-2, wherein the values of R10 may be the same or different; n is 1-3, wherein the values of R7 may be the same or different; z is 0-3, wherein the values of R25 may be the same or different;
R16, R17 and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C 1 4-alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy, N-(C1-4-alkyl)amino, N,N-(C1-4- alkyl)2amino, C1-4-alkanoylamino, N-(C1-4-alkyl)carbamoyl, N,N-(CI-4- alkyl)2carbamoyl, C1-4-alkylS(0)a wherein a is 0 to 2, C1-4-alkoxycarbonyl, N-(C1-4- alkyl)sulphamoyl and N,N-(C1-4-alkyl)2Sulphamoyl; wherein R16, R17 and R18 may be independently optionally substituted on carbon by one or more R21;
R19, R20, R23, R27 and R28 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C1-4-alkoxy, C1-4-alkanoyl, C1-4-alkanoyloxy, N-(C1-4-alkyl)amino, N,N- (C1-4-alkyl)2amino, C1-4-alkanoylamino, N-(C1-4-alkyl)carbamoyl, N,N-(C1-4- alkyl)2carbamoyl, C1-4-alkylS(O)a wherein a is 0 to 2, C1-4-alkoxycarbonyl, N-(C1-4- alkyl)sulphamoyl, N,N-(C1-4-alkyl)2Sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra) or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-6-alkyl; wherein R19, R20, R23, R27 and R28 may be independently optionally substituted on carbon by one or more R22;
R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimcthylcarbamoyl, methylthio, methylsulphinyl, mesyl, /V-mcthylsulphamoyl and N,N-di methyl sulphamoyl; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof,
6. The method of claim 5, wherein Rv and Rw are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
7. The method of claim 5, wherein R1 and R2 are independently selected from ethyl, propyl or butyl or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
8. The method of claim 5, wherein Rx and Ry are both hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
9. The method of claim 5, wherein Rz is selected from halo, amino, C1-6-alkyl, C1-6 - alkoxycarbonylamino or N'-(C1-6-alkyl)ureido or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
10. The method of claim 5, wherein v is 0 or 1 or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
11. The method of claim 5, wherein R3 is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
12. The method of claim 5, wherein the R4 or R5 that is not the group of formula (IA) is selected from hydrogen, halo, C1-4-alkoxy or C1-4-alkylS(O)a wherein a is 0 to 2; wherein that R4 or R5 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and N,N-(C1-4 -alkyl)2amino or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof
13. The method of claim 5, wherein R5 is a group of formula (I A) and R4 is methylthio or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
14. The method of claim 5, wherein R6 is hydrogen or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
15. The method of claim 5, wherein in the group of formula (IA):
D is -O- or -S-;
Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionally substituted by one or more substituents selected from halo, hydroxy, methoxy or trifluoromethyl;
R7 is hydrogen, methyl or phenyl;
R8 is hydrogen or methyl;
R9 is hydrogen or methyl;
R10 is hydrogen; M is 0-2 wherein the values of R10 may be the same or different; and
Rn is carboxy, -P(O)(OH)(OEt) or a group of formula (IB); or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
16. The method of claim 5, wherein in the group of formula (IB):
R12 is hydrogen or methyl;
R13 is hydrogen, methyl, ethyl, butyl or phenyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20; R20 is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto; wherein R20 may be independently optionally substituted on carbon by one or more hydroxy; R23 is carboxy;
X is -NH- or -NHC(O)-;
R14 is selected from hydrogen, methyl or phenyl; wherein said methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxy;
R15 is carboxy, sulpho, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), - P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from methyl or ethyl or R15 is a group of formula (IC); p is 1-3, wherein the values of R13 may be the same or different; q is 0-1; and r is 0-3, wherein the values of R14 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
17. The method of claim 5, wherein in the group of formula (IC):
R24 is hydrogen;
R25 is hydrogen; R26 is carboxy; and z is 1; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof. 8. The method of claim 5, wherein:
Rv and Rw are both hydrogen;
R1 and R2 are independently selected from C1-4-alkyl;
Rx and Ry are both hydrogen;
Rz is selected from halo, amino, C1-6-alkyl, C1-6-alkoxycarbonylamino or A'-(Cnalkyl)ureido; v is 0 or 1 ;
R3 and R6 are hydrogen; one of R4 and R5 is a group of formula (IA) and the other is selected from hydrogen, halo, C1-4-alkoxy or C1-4-alkylS(O)a wherein a is 0 to 2; wherein that R4 or R5 may be optionally substituted on carbon by one or more R16; wherein R16 is independently selected from hydroxy, carboxy and A,A-(C1-4-alkyl)2amino;
D is -O- or -S-;
R7 is hydrogen, methyl or phenyl;
R8 is hydrogen or methyl;
Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R17; wherein R17 is selected from halo, hydroxy, C1-4-alkyl or C1-4-alkoxy; wherein R17 may be optionally substituted on carbon by one or more R21; wherein R21 is selected from halo;
R9 is hydrogen or methyl; R10 is hydrogen;
Rn is carboxy, -P(O)(OH)(ORC) wherein Rc is selected from C1-4-alkyl or a group of formula (IB);
R12 is hydrogen or methyl;
X is -NH- or -NHC(O)-;
R13 is hydrogen, C1-4-alkyl, carbocyclyl or R23; wherein R13 is optionally substituted by one or more substituents selected from R20; wherein R20 is hydroxy, C1-4- alkylS(O)a wherein a is 0, C1-4-alkoxy, amino, carbocyclyl, heterocyclyl or mercapto; wherein R20 may be independently optionally substituted on carbon by one or more R22; R22 is selected from hydroxy; and R23 is carboxy;
R14 is selected from hydrogen, C1-4-alkyl or carbocyclyl; wherein said C1-4-alkyl or carbocyclyl may be optionally substituted by one or more substituents selected from R20; and R20 is hydroxy;
R15 is carboxy, sulpho, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), - P(O)(OH)(Re) or -P(O)(ORe)(Rf) wherein Re and Rf are independently selected from C1-4- alkyl or R15 is a group of formula (IC)
R24 is hydrogen;
R25 is hydrogen;
R26 is carboxy; p is 1-3, wherein the values of R13 may be the same or different; q is 0-1; r is 0-3, wherein the values of R14 may be the same or different; m is 0-2, wherein the values of R10 may be the same or different; n is 1-2, wherein the values of R7 may be the same or different; z is 0-1, wherein the values of R25 may be the same or different; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
19. The method of claim 5, wherein the IB AT inhibitor is selected from:
1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- {(R)- 1 ’-phenyl- 1 ’-[N- (carboxymethyl) carbamoyl] methyl } carbamoylmethoxy) -2 , 3 ,4 , 5 -tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N- (carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N- {(R)- 1 ’-phenyl- 1 '-[N'-(2- sulphoethyl)carbamoyl]methyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N- {(R)-T-phenyl-T-[A'-(2- sulphoethyl)carbamoyl]methyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- sulphoethyl)carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro- 1,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N- {(R)-a-[N'-(2- sulphoethyl) carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl]benzyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- banzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N- {(R)-a-[N'-(5- carboxypentyl) carbamoyl]benzyl}carbamoylmethoxy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phcnyl-7-mcthylthio-8-(N- {(R)-a-[N'-(2- carboxyethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,5- benzothiazepine; 1 , 1 -dioxo-3, 3-dibutyl-5-phcnyl-7-mcthylthio-8-GV- {a-[N'-(2- sulphoethyl)carbamoyl]-2-fluorobenzyl} carbamoylmethoxy)-2, 3,4,5- tetrahydro- 1,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-methylthio-8-GV- { (R)-a-[N'-(R)-(2- hydroxy- 1 -carboxyethyl)carbamoyl]benzyl} carbamoylmethoxy)-2,3 ,4,5- tetrahydro- 1,5-benzothiazepine;
1.1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-a-[N'-(R)-(2-hydroxy- l-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2, 3,4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- {N-[(R)-a-(N'- {(R)- 1 -[N"-(R)- (2 -hydroxy- 1 -carboxyethyl)carbamoyl] -2- hydroxyethyl} carbamoyl)benzyl]carbamoylmethoxy} -2, 3, 4, 5 -tetrahydro- 1 ,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-methylthio-8-GV- { a-[N'- (carboxymethyl)carbamoyl] benzyl} carbamoylmethoxy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1 , 1 -dioxo-3-butyl-3-cthyl-5-phcnyl-7-methylthio-8-GV- {a-[N'- ((ethoxy)(methyl)phosphorylmethyl)carbanoyl]benzyl} carbamoylmethoxy)-
2, 3, 4, 5-tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8- {N'-[(R)-a-(N' - {2- [(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-
2, 3, 4, 5-tetrahydro- 1 ,5-benzothiazepine;
1 , 1 -dioxo-3 ,3 -dibutyl-5 -phenyl -7-methyl th i o-8-GV- {(R} -a- [N'-(2-methyl th i o- 1 - carboxyethyl)carbamoyl]benzyl} carbamoylmetho xy)-2, 3, 4, 5-tetrahydro- 1,5- benzothiazepine;
1.1 -dioxo-3, 3 -dibutyl-5 -phenyl-7-methylthio-8- {N-[(R)-a-(N - {2- [(methyl)(ethyl) phosphoryl] ethyl} carbamoyl)-4- hydroxybenzyl]carbamoylmethoxy} -2, 3, 4, 5-tetrahydro- 1,5-benzothiazepine;
1.1 -dioxo-3, 3 -dibutyl-5 -phenyl-7-methylthio-8- {N-[(R)-a-(N'- {2- [(methyl)(hydroxy) phosphoryl]ethyl} carbamoyl)-4- hydroxybenzyl]carbamoylmethoxy} -2, 3, 4, 5-tetrahydro- 1,5-benzothiazepine;
1 , 1 -dioxo-3, 3-dibutyl-5-phcnyl-7-mcthylthio-8-GV- {(R)-a-[(R)-N'-(2- methylsulphinyl- 1 -carboxyethyl)carbamoyl]benzyl} carbamoylmethoxy)-
2, 3, 4, 5-tetrahydro- 1,5-benzothiazepine; and
1.1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-a-[N''-(2- sulphoethyl)carbamoyl]-4-hydroxybenzyl } carbamoylmethoxy]-2, 3,4,5- tetrahydro-1 ,5-benzothiazepine; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or an in vivo hydrolysable ester or amide thereof.
20. The method of any one of claims 1-19, wherein IBAT inhibitor or pharmaceutically acceptable salt thereof is administered at a dose of from about 0.1 mg to about 1000 mg.
21. The method of any one of claims 1-20, wherein the rifaximin or pharmaceutically acceptable salt thereof is administered at a dose of from about 50 mg to about 600 mg.
22. The method of any one of claims 1-21, wherein the IBAT inhibitor, or pharmaceutically acceptable salt thereof, is administered prior to, at the same time as, or after rifaximin or pharmaceutically acceptable salt thereof.
23. The method of any one of claims 1-22, wherein the IBAT inhibitor and rifaximin are administered in a single composition.
24. The method of claim 23, wherein the single composition is an oral administration form.
25. The method of claim 24, wherein the oral administration form is a syrup, pill, tablet, troche, capsule, or patch.
26. The method of claim 23, wherein the single composition is in an immediate release formulation.
27. The method of claim 23, wherein the single composition is in a delayed release formulation.
28. The method of claim 23, wherein the single composition is in a bilayer delivery system.
29. The method of claim 28, wherein the bilayer delivery system comprises (i) an immediate release formulation layer and (ii) a delayed release formulation layer.
30. The method of claim 29, wherein the delayed release formulation layer contains a higher amount (e.g., 1.5 fold to 10 fold) of the IBAT inhibitor and rifaximin compared to amount of the IBAT inhibitor and rifaximin in the immediate release formulation layer.
31. The method of any one of claims 24-30, wherein the single composition further comprises a pharmaceutically acceptable carrier.
32. An IBAT inhibitor and rifaximin for use in treating a subject having a gastrointestinal disorder.
33. An IBAT inhibitor and rifaximin for use in treating a subject having an encephalopathy.
34. A therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having a gastrointestinal disorder.
35. A therapeutic combination comprising a pharmaceutical composition comprising (i) an IBAT inhibitor and rifaximin, in a pharmaceutically acceptable carrier, for use in treating a subject having an encephalopathy.
36. An IBAT inhibitor and rifaximin for use in treating a subject having travelers’ diarrhea.
37. An IBAT inhibitor and rifaximin for use in treating a subject having diarrhea predominant irritable bowel syndrome.
38. An IBAT inhibitor and rifaximin for use in treating a subject having hepatic encephalopathy.
39. An IBAT inhibitor and rifaximin for use in treating a subject having overt hepatic encephalopathy.
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