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WO2025075624A1 - Compositions pharmaceutiques contenant du maralixibat et leurs utilisations - Google Patents

Compositions pharmaceutiques contenant du maralixibat et leurs utilisations Download PDF

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Publication number
WO2025075624A1
WO2025075624A1 PCT/US2023/034580 US2023034580W WO2025075624A1 WO 2025075624 A1 WO2025075624 A1 WO 2025075624A1 US 2023034580 W US2023034580 W US 2023034580W WO 2025075624 A1 WO2025075624 A1 WO 2025075624A1
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Prior art keywords
maralixibat
composition
pharmaceutically acceptable
acceptable salt
iii
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Inventor
Parag VED
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Mirum Pharmaceuticals Inc
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Mirum Pharmaceuticals Inc
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Priority to PCT/US2023/034580 priority Critical patent/WO2025075624A1/fr
Publication of WO2025075624A1 publication Critical patent/WO2025075624A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutical compositions and dosage forms comprising maralixibat, methods of administering the same, methods of preparing the same, and methods of treating cholestatic pruritus and cholestatic liver disease comprising administering pharmaceutical compositions and oral dosage forms of maralixibat.
  • Hypercholemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (i.e., cholestasis), associated with and often secondary to the intracellular accumulation of bile acids/salts in the hepatocyte.
  • Hypercholemia is characterized by increased serum concentration of bile acid or bile salt.
  • Cholestasis can be categorized clinicopathologically into two principal categories of obstructive, often extrahepatic, cholestasis, and nonobstructive, or intrahepatic, cholestasis.
  • Nonob structive intrahepatic cholestasis can further be classified into two principal subgroups of primary intrahepatic cholestasis that result from constitutively defective bile secretion, and secondary intrahepatic cholestasis that result from hepatocellular injury.
  • Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which is predominantly an adult form with similar clinical symptoms, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, 3, 4, 5, and 6, which are diseases that affect children.
  • PFIC familial intrahepatic cholestasis
  • Alagille syndrome is an inherited condition in which bile builds up in the liver.
  • One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts.
  • Alagille syndrome is associated with abnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance.
  • Cholestatic pruritus is an itching sensation that can lead to excessive scratching, rashes or lesions caused by scratching, sleep deprivation, depression, and suicidal ideations. Cholestatic pruritus is a symptom of cholestasis, which is the obstructing or disrupting of bile flow through the biliary system. This can be caused from problems in the liver, gallbladder, and/or biliary tract. These problems can be caused by biliary stricture, bile duct obstructions, liver diseases, hepatitis, pregnancy, parenteral nutrition, and medications. It may be caused by Alagille syndrome.
  • Maralixibat (as maralixibat chloride) is currently the only approved medication to treat pruritus in people with Alagille syndrome. It is known that maralixibat chloride inhibits apical sodium co-dependent bile acid transport (U.S. Pat. No. 5,994,391). Maralixibat is currently available as an oral solution.
  • composition comprising maralixibat, or a pharmaceutically acceptable salt thereof, and:
  • composition comprising maralixibat, or a pharmaceutically acceptable salt thereof, and:
  • composition comprising about 10.5% (w/w) maralixibat chloride and
  • composition comprising about 10.5% (w/w) maralixibat chloride and (i) about 62.5% (w/w) MCC and about 23.5% (w/w) lactose monohydrate;
  • an oral dosage form comprising about 5 mg to about 50 mg maralixibat, or a pharmaceutically acceptable salt thereof, based on the free base weight of maralixibat, and one or more excipients, wherein: about 100% of maralixibat, or a pharmaceutically acceptable salt thereof, dissolves in an acidic pH environment of a pH less than about 5.0; and upon pH increase from the acidic pH environment to a pH of about 6.0 to about 7.4, at least about 65% of maralixibat, or a pharmaceutically acceptable salt thereof, remains dissolved for at least about 1 hour.
  • the oral dosage form as described above is formulated for once- daily or twice-daily administration.
  • Also provided herein is a method of administering maralixibat, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, comprising administering to the subject the dosage form as described herein.
  • a method of preparing the pharmaceutical composition as described herein comprising: milling maralixibat, or a pharmaceutically acceptable salt thereof; combining the milled maralixibat, or a pharmaceutically acceptable salt thereof, with the diluent, the glidant, the lubricant; and optionally the disintegrant to form an admixture; and compacting the admixture to form the pharmaceutical composition.
  • Also provided herein is a method of treating cholestatic pruritus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition as described herein.
  • Also provided herein is a method of treating cholestatic liver disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition as described herein.
  • a method of preparing the dosage form as described herein comprising: milling maralixibat, or a pharmaceutically acceptable salt thereof; combining the milled maralixibat, or a pharmaceutically acceptable salt thereof, with the diluent, the glidant, the lubricant; and optionally the disintegrant to form an admixture; and compacting the admixture to form the dosage form.
  • Also provided herein is a method of treating cholestatic pruritus in a subject in need thereof, comprising administering to the subject the dosage form as described herein.
  • Also provided herein is a method of treating cholestatic liver disease or condition in a subject in need thereof, comprising administering to the subject the dosage form as described herein.
  • Figure 7 shows maralixibat chloride post comilling in Sample 1 (229pm) screen.
  • Figure 15 shows dissolution result plot of a media exchange run with 50mg dose tablets of Formulation 7.
  • Figure 17 shows dissolution in pH 6.8 phosphate buffer of 50mg unmilled maralixibat filled into capsules.
  • Figure 18 shows dissolution results of Formulation 8.
  • Figure 23 shows the 50mg capsule dissolution results of Formulations 12A-12F.
  • Figure 24 shows a photo of tooling with picking of Formulation 13 A.
  • Figure 25 shows dissolution results of Formulation 14 in 0.1N HC1.
  • Figure 27 shows dissolution results of 50mg dose tablets of Formulation 13 in 0.1N
  • Figure 28 shows dissolution results of Formulation 15 in 0.1N HC1.
  • Figure 29 shows dissolution results of Formulation 15 in pH 4.5 acetate buffer.
  • Figure 31 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in 0.1N HC1.
  • Figure 32 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in pH 4.5 acetate buffer.
  • Figure 33 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in pH 6.8 phosphate buffer.
  • Figure 34 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in pH 7.4 phosphate buffer.
  • Figure 35 shows an overlay of maralixibat dissolution profiles of tablets and oral solution through media exchange from 0.1N HC1 to pH 6.8 phosphate buffer.
  • Figure 36 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in Fasted State Simulated Intestinal Fluid (FaSSIF) media.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • Figure 37 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in Fed State Simulated Intestinal Fluid (FeSSZF) media.
  • FeSSZF Fed State Simulated Intestinal Fluid
  • Figure 38 shows an overlay of maralixibat dissolution profiles of tablets and oral solution in Fasted State Simulated Gastric Fluid (FaSSGF) media.
  • Fasted State Simulated Gastric Fluid Fasted State Simulated Gastric Fluid
  • Figure 39 shows Formulation 15 lab-scale manufacturing process.
  • the term “active pharmaceutical ingredient” or “API” refers to a biologically active compound.
  • exemplary APIs include maralixibat or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • Maralixibat is known as Livmarli, SHP625, LUM001, lopixibat, or l-[[4-[[4-[(47?,57?)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-l,l- dioxido-l-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-l- azoniabicyclo[2.2.2]octane.
  • the structure of maralixibat in the free base form is shown below:
  • maralixbiat salt refers to maralixibat chloride.
  • AcDiSol refers to sodium carboxymethyl cellulose.
  • animal includes, but is not limited to, humans and nonhuman vertebrates such as wild, domestic, and farm animals.
  • vicel As used herein, the term “Avicel”, “Avicel PH-302”, or “Avicel PH-102” refers to microcrystalline cellulose (MCC).
  • the weight or weight percentage of “maralixibat, or a pharmaceutically acceptable salt thereof’ is based on the weight of the free base of maralixibat.
  • the weight or the weight percentage of the salt is specifically indicated, for example, in a “composition of comprising about 10.5% (w/w) maralixibat chloride”, the weight percentage is based on the weight of the maralixibat chloride.
  • a “binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).
  • composition generally refers to a composition of two or more components, usually one or more drugs (e.g., maralixibat or a pharmaceutically acceptable salt) and one or more pharmaceutical excipients.
  • drugs e.g., maralixibat or a pharmaceutically acceptable salt
  • the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open- ended and do not exclude additional, unrecited elements or method steps.
  • Compritol 888 ATO or “Compritol 888” refers to a glyceride, known as glyceryl dibehenate, comprised of a blend of behenic acid esters with glycerol.
  • a “disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • a “diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • DS refers to drug substance.
  • dv90 refers to the point in the size distribution wherein 90% of the total volume of material in the sample falls below (e.g., if the dv90 is 850 nm, then 90% of the sample has a size of 850 nm or smaller).
  • an “excipient” includes functional and non-functional ingredients in a pharmaceutical composition.
  • the term “fasted” is defined as follows: the dosing state which is defined following an overnight fast (wherein 0 caloric intake has occurred) of at least 10 hours (i.e., >10 hours). Subjects may administer the dosage form with 240 mL of water. No food should be allowed for at least 4 hours post-dose. Water may be allowed as desired except for one hour before and after drug administration.
  • a “glidant” is an excipient that imparts a pharmaceutical composition with enhanced flow properties.
  • hydroxy or “hydroxyl” means an -OH group.
  • a “loop mill” refers to a “mill” that performs “loop milling” which is a process that uses pressurized gas to create high particle velocity and high-energy impact between particles and between the particles and the mill chamber.
  • a “lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets.
  • the lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.
  • Lubritab or “LubriTab” refers to a plant-derived lubricant, specifically a hydrogenated cottonseed oil.
  • lactose FF316 or “lactose monohydrate FF316” refers to lactose monohydrate.
  • mill refers to a device that breaks solid materials down through mechanical forces into smaller pieces.
  • milling refers to the process of breaking solid materials into smaller pieces.
  • PEG 8000 refers to polyethylene glycol with an average molecular weight of about 8000.
  • a “pin mill” refers to a “mill” comprising two discs or plates each containing circular rows of pins or vertical projections that are arranged in concentric circles moving past one another. “Pin milling” refers to the process of particles repeatedly impacting pins as the material is fed into the space between the discs of the milling chamber.
  • Poly oxamer 188 refers to a nonionic block copolymer comprised of poly(ethylene oxide) and polypropylene oxide).
  • “Precirol ATO 5” or “Precirol” refers to glyceryl palmitostearate.
  • pharmaceutically acceptable means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • salts include, but is not limited to, salts of acidic or basic groups.
  • Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts.
  • the present embodiments include pharmaceutically acceptable salt of the compounds described herein.
  • the present embodiments also include quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moieties.
  • the term “relative humidity” or “RH” is a measure of a present state of how much water vapor is in a water-air mixture compared to the maximum amount possible given the same temperature.
  • the term “solid dosage form” generally refers to a pharmaceutical composition, which when used in an oral mode of administration includes 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.
  • solution/suspension means a liquid composition wherein a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form, in suspension in a liquid matrix.
  • the phrase “therapeutically effective amount” means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutic effect is dependent upon the disorder being treated or the biological effect desired.
  • the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, elimination or amelioration of a disorder, or side-effects.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject’s response to treatment.
  • the term “treat,” “treated,” or “treating” means therapeutic treatment wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.
  • oral dosage form generally refers to a pharmaceutical composition, which when used in an oral mode of administration include, but are not limited to, liquid dosage forms (e.g., solutions, elixers, suspensions, syrups, emulsions, aerosols, slurries, dispersions, and colloids) and solid dosage forms (e.g., capsules, tablets, pills, powders and granules).
  • liquid dosage forms e.g., solutions, elixers, suspensions, syrups, emulsions, aerosols, slurries, dispersions, and colloids
  • solid dosage forms e.g., capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier.
  • percentage or “%” of a component refers to the weight percentage (w/w) of the component, which is the weight of the component over the total weight of the composition.
  • the present embodiments encompass the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds, and mixtures thereof, are within the scope of the embodiments.
  • the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the compounds can be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated.
  • Cis and trans geometric isomers of the compounds are also included within the scope of the embodiments and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art, including, for example, chiral HPLC and fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and the various optically active camphorsulfonic acids such as P-camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include, but are not limited to, stereoisomerically pure forms of a- methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-l,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds also include hydrates and solvates, as well as anhydrous and nonsolvated forms.
  • Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. [0089] In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation can include, for example, a composition enriched in the compound of the embodiments. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the embodiments, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • thioamides and thioesters are anticipated to have very similar properties.
  • the distance between aromatic rings can impact the geometrical pattern of the compound and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine.
  • the distance between and the relative orientation of monomers within the compounds can also be altered by replacing the amide bond with a surrogate having additional atoms.
  • the compounds also include derivatives referred to as prodrugs.
  • variable can be any option described herein, except as otherwise noted or dictated by context.
  • composition comprising maralixibat, or a pharmaceutically acceptable salt thereof, and:
  • composition comprising maralixibat, or a pharmaceutically acceptable salt thereof, and:
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, aerosols (as a solid), soft and hard gelatin capsules, and sterile packaged powders.
  • the pharmaceutical composition of the invention is a solid dosage form, such as a tablet, a granule, a sachet, or a powder.
  • pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in the form of a dissolving tablet, a dissolving wafer, a capsule, or a gel capsule.
  • solid dosage forms described herein comprise a solid vehicle (e.g., as used in a tablet), and/or a gaseous vehicle (e.g., as used in dry powder inhalation (DPI)).
  • a solid vehicle e.g., as used in a tablet
  • a gaseous vehicle e.g., as used in dry powder inhalation (DPI)
  • the composition is in a solid dosage form.
  • the composition is formulated as a capsule, a pill, a cachet, a tablet, a granule, a multi-particulate, a mini-tablet, or powder.
  • the composition is formulated as a tablet.
  • a composition is in a unit dose formulation for oral, intranasal, or other administration to a patient.
  • unit dose refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [00102] In some embodiments, the composition comprises about 1 mg to about 250 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 1 mg to about 250 mg, about 1 mg to about 220 mg, about 1 mg to about 200 mg, about 1 mg to about 180 mg, about 1 mg to about 160 mg, about 1 mg to about 150 mg, about 1 mg to about 140 mg, about 1 mg to about 120 mg, about 1 mg to about 110 mg, about 1 mg to about 100 mg, about 1 mg to about 95 mg, about 1 mg to about 90 mg, about 1 mg to about 85 mg, about 1 mg to about 80 mg, about 1 mg to about 75 mg, about 1 mg to about 70 mg, about 1 mg to about 65 mg, about 1 mg to about 60 mg, about 1 mg to about 55 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 250 mg, about 5 mg to about 2 mg, about 1
  • the composition comprises about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, or about 250 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 5 mg to about 50 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 5 mg, about 10 mg, about 30 mg, or about 50 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 1% to about 90% (w/w) maralixibat or a pharmaceutically acceptable salt thereof.
  • the composition comprises about 1% to about 90%, about 1% to about 75%, about 1% to about 50%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 22%, about 1% to about 20%, about 1% to about 17%, about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, about 1% to about 7%, about 1% to about 5%, about 1% to about 2%, about 2% to about 90%, about 2% to about 75%, about 2% to about 50%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 22%, about 2% to about 20%, about 2% to about 17%, about 2% to about 15%, about 2% to about 12%, about
  • the composition comprises about 1%, about 2%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 30%, about 35%, about 40%, about 50%, about 75%, or about 90% (w/w) maralixibat or a pharmaceutically acceptable salt thereof.
  • the composition comprises about 5% to about 40% (w/w) maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 10% to about 25% (w/w) maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises about 5% or about 15% (w/w) maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the composition comprises maralixibat chloride.
  • the active compound in preparing a formulation, can be milled to provide the appropriate particle size prior to combining with the other ingredients.
  • the maralixibat, or a pharmaceutically acceptable salt thereof is loop milled.
  • the maralixibat, or a pharmaceutically acceptable salt thereof is pin milled.
  • the particle size of the maralixibat, or a pharmaceutically acceptable salt thereof is about 20 pm to about 2500 pm. In some embodiments, the particle size of the maralixibat, or a pharmaceutically acceptable salt thereof is about 20 pm to about 2500 pm, about 20 pm to about 2000 pm, about 20 pm to about 1500 pm, about 20 pm to about 1000 pm, about 20 pm to about 850 pm, about 20 pm to about 800 pm, about 20 pm to about 750 pm, about 20 pm to about 700 pm, about 20 pm to about 650 pm, about 20 pm to about 600 pm, about 20 ⁇ m to about 550 ⁇ m, about 20 ⁇ m to about 500 ⁇ m, about 20 ⁇ m to about 450 ⁇ m, about 20 ⁇ m to about 400 ⁇ m, about 20 ⁇ m to about 350 ⁇ m, about 20 ⁇ m to about 300 ⁇ m, about 20 ⁇ m to about 250 ⁇ m, about 20 ⁇ m to about 200 ⁇ m, about 20 ⁇ m to about 150 ⁇
  • the particle size of the maralixibat, or a pharmaceutically acceptable salt thereof is about 20 ⁇ m, about 40 ⁇ m, about 60 ⁇ m, about 80 ⁇ m, about 100 ⁇ m, about 125 ⁇ m, about 150 ⁇ m, about 200 ⁇ m, about 250 ⁇ m, about 300 ⁇ m, about 350 ⁇ m, about 400 ⁇ m, about 450 ⁇ m, about 500 ⁇ m, about 550 ⁇ m, about 600 ⁇ m, about 650 ⁇ m, about 700 ⁇ m, about 750 ⁇ m, about 800 ⁇ m, about 850 ⁇ m, about 1000 ⁇ m, about 1500 ⁇ m, about 2000 ⁇ m, or about 2500 ⁇ m.
  • the particle size distribution of the maralixibat, or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 850 ⁇ m.
  • the particle size distribution of the maralixibat, or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 100 ⁇ m.
  • the particle size distribution of the maralixibat, or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 60 ⁇ m.
  • the pharmaceutical composition comprises maralixibat, or a pharmaceutically acceptable salt thereof, and: ( i) a diluent; (ii) a glidant; (iii) a lubricant in an amount of about 0.2% to about 12% (w/w); and (iv) a disintegrant in an amount of about 1% to about 10% (w/w).
  • the pharmaceutical composition comprises maralixibat, or a pharmaceutically acceptable salt thereof, and: ( i) a diluent; (ii) a glidant; (iii) a lubricant in an amount of about 6% to about 12% (w/w); and (iv) a disintegrant in an amount of about 3% to about 7% (w/w).
  • the pharmaceutical composition comprises maralixibat, or a pharmaceutically acceptable salt thereof, and:
  • a glidant in an amount of about 0.1 to about 2% (w/w);
  • the composition comprises about 0.05% to about 35% (w/w) lubricant.
  • the composition comprises about 0.05% to about 35%, about 0.05% to about 30%, about 0.05% to about 25%, about 0.05% to about 20%, about 0.05% to about 15%, about 0.05% to about 12%, about 0.05% to about 10%, about 0.05% to about 9%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 3%, about 0.05% to about 1%, about 0.05% to about 0.75%, about 0.05% to about 0.5%, about 0.05% to about 0.2%, about 0.05% to about 0.1%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0. 0.
  • the composition comprises about 0.05%, about 0.1%, about 0.2%, about 0.5%, about 0.75%, about 1%, about 3%, about 5%, about 6%, about 7%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30%, or about 35% (w/w) lubricant.
  • the composition comprises about 0.2% to about 12% (w/w) lubricant.
  • the composition comprises about 0.2% to about 6%, or about 6% to about 12% (w/w) lubricant.
  • the composition comprises about 0.5%, 0.75%, 1%, 3%, or 9% (w/w) lubricant.
  • the composition comprises about 9% (w/w) lubricant.
  • the lubricant is selected from the group consisting of magnesium stearate, talc, calcium stearate, zinc stearate, sodium stearate, sodium stearyl fumarate, sodium lauryl sulfate, stearic acid, aluminum stearate, leucine, glyceryl behenate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, and any combinations thereof.
  • the hydrogenated vegetable oil is Lubritab.
  • the lubricant is glyceryl palmitostearate.
  • glyceryl palmitostearate is Precirol ATO 5.
  • the composition comprises about 0.25% to about 30% (w/w) disintegrant. In some embodiments, the composition comprises about 0.25% to about 30%, about 0.25% to about 20%, about 0.25% to about 15%, about 0.25% to about 10%, about 0.25% to about 9%, about 0.25% to about 8%, about 0.25% to about 7%, about 0.25% to about 6%, about 0.25% to about 5%, about 0.25% to about 4%, about 0.25% to about 3%, about 0.25% to about 2%, about 0.25% to about 1%, about 0.25% to about 0.75%, about 0.25% to about 0.5%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% to about 15%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 0.5%
  • the composition comprises about 0.25%, about 0.5%, about 0.75%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, or about 30% (w/w) disintegrant.
  • the composition comprises about 1% to about 10% (w/w) disintegrant.
  • the composition comprises about 3% to about 7% (w/w) disintegrant.
  • the composition comprises about 5% (w/w) disintegrant.
  • the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, starch, sodium starch glycolate, and any combinations thereof.
  • the disintegrant is crospovidone.
  • the composition comprises about 0.025% to about 6% (w/w) glidant. In some embodiments, the composition comprises about 0.025% to about 6%, about 0.025% to about 5%, about 0.025% to about 3%, about 0.025% to about 2%, about 0.025% to about 1.5%, about 0.025% to about 1%, about 0.025% to about 0.75%, about 0.025% to about 0.5%, about 0.025% to about 0.4%, about 0.025% to about 0.25%, about 0.025% to about 0.1%, about 0.025% to about 0.075%, about 0.025% to about 0.05, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.05% to about 1.5%, about 0.05% to about 1%, about 0.05% to about 0.75%, about 0.05% to about 0.5%, about 0.05% to about 0.4%, about 0.05% to about 0.25%, about 0.05% to about 0.05% to about 1%
  • the composition comprises about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.25%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 3%, about 5%, or about 6% (w/w) glidant.
  • the composition comprises about 0.1 to about 2% (w/w) glidant.
  • the composition comprises about 0.5% (w/w) glidant.
  • the glidant is silicon dioxide.
  • the silicon dioxide is Cab-O-Sil.
  • the composition comprises about 25% to about 99% (w/w) diluent. In some embodiments, the composition comprises about 25% to about 99%, about 25% to about 95%, about 25% to about 92%, about 25% to about 90%, about 25% to about 89%, about 25% to about 88%, about 25% to about 87%, about 25% to about 86%, about 25% to about 85%, about 25% to about 84%, about 25% to about 82%, about 25% to about 80%, about 25% to about 77%, about 25% to about 75%, about 25% to about 72%, about 25% to about 70%, about 25% to about 69%, about 25% to about 67%, about 25% to about 65%, about 25% to about 60%, about 25% to about 50%, about 50% to about 99%, about 50% to about 95%, about 50% to about 92%, about 50% to about 90%, about 50% to about 89%, about 50% to about 88%, about 50% to about 87%, about 50% to about 86%, about
  • the composition comprises about 25%, about 50%, about 60%, about 65%, about 67%, about 69%, about 70%, about 72%, about 75%, about 77%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 92%, about 95%, or about 99% (w/w) diluent.
  • the composition comprises about 65% to about 90% (w/w) diluent.
  • the composition comprises about 65% to about 80%, about 70% to about 85%, or about 70% to about 80% (w/w) diluent.
  • the composition comprises about 69%, 75%, 84%, 86%, 88%, or 89% (w/w) diluent.
  • the diluent is selected from the group consisting of a sugar, dextrates, dextrin, dextrose, lactose, lactose monohydrate, mannitol, sorbitol, starch, cellulose, and modified celluloses, and any combination thereof.
  • the diluent is microcrystalline cellulose (MCC), lactose monohydrate, mannitol, dicalcium phosphate, or a combination thereof.
  • MMC microcrystalline cellulose
  • lactose monohydrate lactose monohydrate
  • mannitol mannitol
  • dicalcium phosphate or a combination thereof.
  • the diluent is microcrystalline cellulose (MCC), lactose monohydrate, or a combination thereof.
  • the MCC is Avicel PH-302.
  • the formulations can additionally include: wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; coloring agents; anti-adherent agents; stabilizing agents; release-modifying agents; solvent agents; antioxidant agents; buffering agents; disintegrating agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the composition further comprises a binder.
  • the binder is polyvinylpyrrolidone (povidone), dibasic calcium phosphate, sucrose, com starch, gelatin, glucose, lactose, lactose monohydrate, sodium alginate, modified cellulose, hydroxypropyl methylcellulose E3 (HPMC E3), or a combination thereof.
  • the composition comprising maralixibat, or a pharmaceutically acceptable salt thereof further comprises one or more of the following excipients:
  • the solubilizing agent is selected from the group consisting of sodium lauryl sulfates; poloxamers; alcohols such as ethanol; sugars such as sorbitol; polyethylene glycols; propylene glycol; glycerin; N-methyl-2-pyrrolidone; dimethylacetamide; dimethylsulfoxide; cyclodextrins; phospholipids; long and medium chain fatty acid mono, di, and triglycerides; long chain fatty acid esters of polyethylene glycols (i.e., poly oxy ethylated glycerides); polysorbates; propylene glycol mono-and di-esters of glycerol monocaprylocaprate, glycerol monocaprylate, glycerol mono/dicaprates, and medium chain fatty acids such as propylene glycol monocaprylate and propylene glycol monolaurate, or a combination thereof.
  • alcohols such as ethanol
  • sugars such as
  • the channeling agent is selected from the group consisting of sodium chloride, sugars such as lactose, lactose monohydrate, microcrystalline cellulose, polyols such as mannitol, dicalcium phosphate, polyvinylpyrrolidone (PVP), and polyethylene glycols (PEG), and a combination thereof.
  • the channeling agent is PEG 8000.
  • the chelating agent is selected from the group consisting of betadex sulfobutyl ether sodium; calcium acetate; citric acid monohydrate; cyclodextrins; disodium edetate; edetic acid; fumaric acid; galactose; glutamic acid; histidine; hydroxypropyl betadex; malic acid; pentetic acid; phytochelatins; poly(methyl vinyl ether-alt-maleic anhydride); potassium citrate; sodium citrate dihydrate; sodium phosphate, dibasic; sodium phosphate, monobasic; tartaric acid; and trehalose, or a combination thereof.
  • the chelating agent is EDTA.
  • the film coating agent is selected from the group consisting of hydrophilic polymeric materials, including but not limited to as individual component polymers or co-polymers: hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinylacetal diethylaminoacetate, polyethylene glycol, copolyvidone, polyvinylpyrrolidone, poly(methacrylic acid), aminoalkyl methacrylate copolymers, polyethylene glycol-polyvinyl alcohol (PEG-PVA) grafted copolymer, poly (acrylic acid), poly(ethyl acrylate), polysaccharides such as pullulan, and other water-soluble polymers; titanium dioxide; talc; lecithin; triethyl cit
  • the film coating agent is Polyvinyl alcohol (PVA).
  • the film coating agent is OPADRY II.
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 25% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and
  • the composition comprises about 9.8% (w/w) maralixibat chloride and
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition comprises about 10.5% (w/w) maralixibat chloride and:
  • the composition is stable at room temperature and 60% relative humidity (RH) for at least 6 months.
  • the composition is stable at 25°C and 60% RH for at least 6 months.
  • the composition is stable at -4°C and 75% RH for at least 6 months.
  • the composition is stable at 25°C and 75% RH for at least 6 months.
  • the composition is stable at 25°C and 85% RH for at least 6 months.
  • the composition is stable at 30°C and 85% RH for at least 6 months.
  • the composition is stable at 25°C and 50% RH for at least 6 months.
  • the composition is stable at 30°C and 50% RH for at least 6 months.
  • the acidic pH environment has a pH of about 1.0 to about 4.0.
  • about 100% maralixibat, or a pharmaceutically acceptable salt thereof remains dissolved in the acidic pH environment for about 2 hours upon contact with the acid pH environment.
  • the dosage form comprises about 5 mg to about 50 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat.
  • the dosage form comprises about 1 mg to about 250 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat. In some embodiments, the dosage form comprises about 1 mg to about 250 mg, about 1 mg to about 220 mg, about 1 mg to about 200 mg, about 1 mg to about 180 mg, about 1 mg to about 160 mg, about 1 mg to about 150 mg, about 1 mg to about 140 mg, about 1 mg to about 120 mg, about 1 mg to about 110 mg, about 1 mg to about 100 mg, about 1 mg to about 95 mg, about 1 mg to about 90 mg, about 1 mg to about 85 mg, about 1 mg to about 80 mg, about 1 mg to about 75 mg, about 1 mg to about 70 mg, about 1 mg to about 65 mg, about 1 mg to about 60 mg, about 1 mg to about 55 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about
  • the dosage form comprises about 50 mg maralixibat or a pharmaceutically acceptable salt thereof based on the free base weight of maralixibat, wherein upon the pH increase, at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% of maralixibat, or a pharmaceutically acceptable salt thereof, remains dissolved for at least about 1 hour.
  • the dosage form comprising maralixibat, or a pharmaceutically acceptable salt thereof, further comprises the following excipients:
  • the glidant is selected from the group consisting of silicon dioxide, talc, corn starch, and any combinations thereof;
  • the lubricant is selected from the group consisting of talc, stearic acid, leucine, glyceryl behenate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, and any combinations thereof; and/or
  • the disintegrant is selected from the group consisting of crospovidone, starch, and a combination thereof.
  • the dosage form comprising about 5 mg to about 50 mg maralixibat, or a pharmaceutically acceptable salt thereof, based on the free base weight of maralixibat, and:
  • a method of preparing the pharmaceutical composition comprising: milling maralixibat, or a pharmaceutically acceptable salt thereof; combining the milled maralixibat, or a pharmaceutically acceptable salt thereof, with the diluent, the glidant, the lubricant; and optionally the disintegrant to form an admixture; and compacting the admixture to form the pharmaceutical composition.
  • the milling process applies energy through mechanical forces to break down larger particles into smaller sizes.
  • pin milling is performed with a pin mill, pin mill grinder, or disc mill.
  • the milled maralixibat or a pharmaceutically acceptable salt thereof, has a particle size distribution with a Dv90 of less than about 700 pm.
  • the milled maralixibat or a pharmaceutically acceptable salt thereof, has a particle size distribution with a Dv90 of less than about 500 pm.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • cholestatic pruritus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition.
  • the subject has Alagille syndrome (ALGS).
  • AGS Alagille syndrome
  • the subject is 3 months of age and older.
  • the composition decreases the levels of serum bile acids or hepatic bile acids, reduces bilirubin, reduces liver enzymes, lowers intraenterocyte bile acids/salts, or reduces necrosis and/or damage to hepatocellular architecture.
  • the composition decreases serum bile acid or hepatic bile acid levels in the patient by at least about 10%.
  • the composition decreases serum bile acid or hepatic bile acid levels in the patient by at least about 20%.
  • the composition decreases serum bile acid or hepatic bile acid levels in the patient by at least about 50%.
  • less than 10% of maralixibat, or a pharmaceutically acceptable salt thereof, is systemically absorbed upon oral administration.
  • the composition decreases pruritus.
  • compositions and dosage forms for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the present compositions and dosage forms in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
  • compositions and dosage forms of this invention can be administered to a patient at risk for developing the condition or disorder, typically on the advice and under the supervision of a physician, in the dosage forms described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the composition is administered orally.
  • the composition is administered once daily.
  • the composition is administered as an ileal-pH sensitive release or an enterically coated formulation.
  • a method of preparing a dosage form as described herein comprising: milling maralixibat, or a pharmaceutically acceptable salt thereof; combining the milled maralixibat, or a pharmaceutically acceptable salt thereof, with the diluent, the glidant, the lubricant; and optionally the disintegrant to form an admixture; and compacting the admixture to form the dosage form.
  • the milled maralixibat, or a pharmaceutically acceptable salt thereof has a particle size distribution with a Dv90 of less than about 100 pm.
  • the milled maralixibat, or a pharmaceutically acceptable salt thereof has a particle size distribution with a Dv90 of less than about 60 pm.
  • Also provided herein is a method of treating cholestatic pruritus in a subject in need thereof, comprising administering to the subject a dosage form as described herein.
  • Also provided herein is a method of treating a disease or condition characterized by cholestatic pruritus in a subject in need thereof, comprising administering to the subject a dosage form as described herein.
  • the cholestatic pruritus is associated with Alagille syndrome (ALGS).
  • AGS Alagille syndrome
  • the subject has Alagille syndrome (ALGS).
  • AGS Alagille syndrome
  • the subject is 2 months of age and older.
  • the subject is 3 months of age and older.
  • the subject is a pediatric subject between 2 months and 18 years of age. In one embodiment, the subject is an adult who is 18 years of age or older.
  • Also provided herein is a method of treating cholestatic liver disease or condition in a subject in need thereof, comprising administering to the subject a dosage form as described herein.
  • the cholestatic liver disease or condition is selected from the group consisting of obstructive cholestasis, non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, PFIC type 4, PFIC type 5, PFIC type 6, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total parenteral nutrition associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, drug-associated cholestasis, infection-associated cholestasis, Dubin-Johnson Syndrome
  • the cholestatic liver disease or condition is Alagille syndrome (ALGS).
  • AGS Alagille syndrome
  • the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC).
  • PFIC familial intrahepatic cholestasis
  • BA biliary atresia
  • the dosage form decreases the levels of serum bile acids or hepatic bile acids, reduces bilirubin, reduces liver enzymes, lowers intraenterocyte bile acids/salts, and/or reduces necrosis and/or damage to hepatocellular architecture.
  • the dosage form decreases serum bile acid or hepatic bile acid levels in the patient by at least about 20%.
  • the dosage form decreases serum bile acid or hepatic bile acid levels in the patient by at least about 30%.
  • the dosage form decreases serum bile acid or hepatic bile acid levels in the patient by at least about 40%.
  • less than 10% of maralixibat, or a pharmaceutically acceptable salt thereof, is systemically absorbed upon oral administration.
  • the dosage form decreases pruritus.
  • the dosage form is administered with a second agent selected from a bile acid sequestrant or binder.
  • the dosage form is administered less than about 60 minutes or less than about 30 minutes before ingestion of food.
  • the dosage form is administered orally.
  • the dosage form is administered once daily (QD) or twice daily (BID).
  • the dosage form is administered once daily.
  • the dosage form is administered as an ileal-pH sensitive release or an enterically coated formulation.
  • the vitamin supplement comprises a fat-soluble vitamin.
  • the fat-soluble vitamin is selected from the group consisting of vitamin A, D, E, and K.
  • kits useful for example, in the treatment or prevention of diseases which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of maralixibat or a pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Delivery devices are important not only for delivering the compounds of the invention, but also for providing an appropriate environment for storage. This would include protection from microbial contamination and chemical degradation.
  • the device and formulation should be compatible so as to avoid potential leaching or adsorption.
  • the delivery device (or its packaging) can be optionally provided with a label and/or with instructions for use indicating that the composition should be used intranasally.
  • roller compaction was selected to densify the formulation and to potentially resolve the weight variation issue.
  • Table 2.3 exhibits the roller compaction parameters used.
  • DC Formulation 5 was prepared as shown in Table 2.14. This formulation used the same drug loading at 10%, the amount of Avicel PH302 was increased, and the amount of lactose FF316 was reduced to see if improved compression performance could be achieved. The same batch size and level of lubricant in the formulation was used.
  • Formulation 7 was generated by removing croscarmellose sodium and reducing the amount of lubricant to 0.75%. Formulation 7 is presented in Table 2.18. Compression profile is presented in Table 2. 19. Dissolution was tested as a media exchange run ( Figure 15, Table 2.20) and in three media ( Figure 16, Table 2.21). The dissolution was performed in 750 mL of 0.1N HC1 media for 120min and then 250mL of pH 6.8 0.2M phosphate buffer was added and the dissolution continued out to 180min.
  • stearic acid formulation was selected to proceed with further testing.
  • Formulation 11 was prepared without croscarmellose sodium and with stearic acid as lubricant at 1.0% level.
  • a 600g batch size was prepared to check if sticking will be observed during compression run.
  • Formulation and compression profile is presented in Table 2.27 and 2.28, respectively. Density test is shown in Table 2.29. Qualitatively, no breaking or sticking was observed across the runs. Tablet weight variability was low, as shown in Table 2.28, indicating good flow, as shown in Table 2.29, and friability is also low across compression runs. Photo of tablets for 5mg and 50mg is shown in Figures 21-22.
  • LubriTab, Compritol 888, Precirol ATO 5 and pol oxamer 188 had dissolution comparable to the DS alone in capsule.
  • the capsules with sodium lauryl sulfate had slow release, ⁇ 60% at 60min.
  • Formulations were next created with four of the alternative lubricants considered most viable - LubriTab, PEG8000, Compritol 888 ATO and Precirol ATO 5 - for evaluation as a compressed tablet.
  • a lOmg tablet was compressed for each formulation using 14” SRC tooling with compression force of ⁇ 2kN compression force at 3kp to 5kp hardness range.
  • LubriTab was evaluated up to 5% in 1% increments, and severe punch hazing was observed during compression at all of these lubricant levels.
  • PEG8000 was next evaluated at 1%, 3%, 5%, 8% and 10%. Broken tablets were observed after ⁇ 20 tablets were compressed at all levels of increasing PEG8000.
  • Compritol 888 was evaluated at 1%, 3% and 5%. Breakage was observed at 1% and 3% levels. No breakage was observed at the 5% level, but the punch face had hazing and clear evidence of material build-up.
  • Precirol was the next to be evaluated at 1%, 3%, 5% and 10%.
  • a formulation with 7.5% Precirol ATO 5 (Formulation 13B, Table 2.34) was evaluated to see if the lubricant level could be titrated down. Initially, this formulation looked okay, but then picking was observed after longer run. An addition of 1.5% lubricant for a total of 9% was added to the remaining batch to make Formulation 13C (Table 2.35). No picking was observed during compression of lOmg and 30mg dosage forms. Tablet samples of Formulation 13C were tested for dissolution and the tablets disintegrated slowly in the dissolution media. To address this, addition of 5% crospovidone in the remaining samples of Formulation 13C was made to yield Formulation 13 to reduce the disintegration time of the tablets.
  • Disintegration was slower for the Precirol formulation, Formulation 13, compared to the magnesium stearate formulation, Formulation 14 (Table 2.38) in the compression studies.
  • Formulation 14 had a fast release in 0. IN HC1 media across the dose range ( Figure 25) compared to in pH 6.8 phosphate buffer ( Figure 26).
  • final release percentage of each dosage form of Formulation 14 was proportional to dose with an unexpected and surprising finding that the lower dose has a lower final release percentage at the plateau ( Figures 25 and 26).
  • Dissolution results of Formulation 13 were different. Surprisingly, the 50mg tablets of Formulation 13 were dissolved faster in the pH 6.8 phosphate buffer than in the 0.

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Abstract

L'invention concerne une composition pharmaceutique contenant du maralixibat, ou un sel pharmaceutiquement acceptable de celui-ci, en tant que principe actif. L'invention concerne en outre l'utilisation de la composition pharmaceutique en tant que produit médicamenteux solide. L'invention concerne également l'utilisation de la composition pharmaceutique et du produit médicamenteux solide décrits ici pour traiter le prurit cholestatique et la maladie hépatique cholestatique.
PCT/US2023/034580 2023-10-05 2023-10-05 Compositions pharmaceutiques contenant du maralixibat et leurs utilisations Pending WO2025075624A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090142404A1 (en) * 2004-08-31 2009-06-04 Pfizer Inc Pharmaceutical dosage forms comprising a low-solubility drug and a polymer
US20110129530A1 (en) * 2009-11-30 2011-06-02 Eurand, Inc. Compressible-Coated Pharmaceutical Compositions and Tablets and Methods of Manufacture
US20120269891A1 (en) * 2011-01-19 2012-10-25 Pathologica Llc Controlled release oral pharmaceutical dosage forms comprising mgbg
US20140275090A1 (en) * 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease
US11185519B2 (en) * 2016-03-31 2021-11-30 Genfit Methods of treatment of cholestatic diseases
US20230190743A1 (en) * 2021-11-05 2023-06-22 Mirum Pharmaceuticals, Inc. Treatment with ileal bile acid transporter (ibat) inhibitors for increased event-free survival (efs)

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090142404A1 (en) * 2004-08-31 2009-06-04 Pfizer Inc Pharmaceutical dosage forms comprising a low-solubility drug and a polymer
US20110129530A1 (en) * 2009-11-30 2011-06-02 Eurand, Inc. Compressible-Coated Pharmaceutical Compositions and Tablets and Methods of Manufacture
US20120269891A1 (en) * 2011-01-19 2012-10-25 Pathologica Llc Controlled release oral pharmaceutical dosage forms comprising mgbg
US20140275090A1 (en) * 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease
US11185519B2 (en) * 2016-03-31 2021-11-30 Genfit Methods of treatment of cholestatic diseases
US20230190743A1 (en) * 2021-11-05 2023-06-22 Mirum Pharmaceuticals, Inc. Treatment with ileal bile acid transporter (ibat) inhibitors for increased event-free survival (efs)

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