WO2022076683A1 - Méthodes de traitement d'une infection à coronavirus à l'aide d'acide obéticholique - Google Patents
Méthodes de traitement d'une infection à coronavirus à l'aide d'acide obéticholique Download PDFInfo
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- WO2022076683A1 WO2022076683A1 PCT/US2021/053968 US2021053968W WO2022076683A1 WO 2022076683 A1 WO2022076683 A1 WO 2022076683A1 US 2021053968 W US2021053968 W US 2021053968W WO 2022076683 A1 WO2022076683 A1 WO 2022076683A1
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- pharmaceutically acceptable
- acceptable salt
- amino acid
- obeticholic acid
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Classifications
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- Coronaviruses are enveloped, non-segmented, positive sense RNA viruses belonging to the family coronaviridae. Coronaviruses can cause multiple system infections, mainly respiratory tract infections, in humans, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
- SARS severe acute respiratory syndrome
- MERS Middle East respiratory syndrome
- 2019-nCoV or SARS-CoV-2 is the pathogen that causes COVID-19, a global respiratory viral pandemic.
- the present application provides a method of treating, preventing, or alleviating a coronavirus infection or a condition or symptom associated with the infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of obeticholic acid: obeticholic acid (also known as INT-747) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, optionally in combination with a second therapeutic agent.
- obeticholic acid also known as INT-747
- a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof optionally in combination with a second therapeutic agent.
- the coronavirus is SARS-CoV, MERS-CoV, or SARS-CoV-2. In one embodiment, the coronavirus is SARS-CoV-2. In one embodiment, the condition or symptom of a coronavirus infection is SARS, MERS, or COVID-19. In one embodiment, the condition or symptom of the coronavirus infection is CO VID-19. In one embodiment, the condition or symptom of the coronavirus infection is fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea.
- the condition or symptom of the coronavirus infection is fever or chills, cough, shortness of breath, or loss of smell.
- the subject has or is suspected of having a coronavirus infection.
- the subject has been or thought to have been exposed to a coronavirus and has not yet developed a symptom of a coronavirus infection.
- the second therapeutic agent is an antiviral drug, an immune booster drug, vitamin C, vitamin D, or any combination thereof.
- the antiviral drug is Remdesivir.
- the antiviral drug is Molnupiravir.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered by inhalation, nasally, orally, intravenously, or any combination thereof. In one embodiment, obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered orally.
- the present application provides obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, optionally in combination with a second therapeutic agent, for use in the manufacture of a medicament for treating, preventing, or alleviating a coronavirus infection or a condition or symptom associated with the infection in a subject in need thereof.
- the present application provides use of obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, optionally in combination with a second therapeutic agent, in the manufacture of a medicament for treating, preventing, or alleviating a coronavirus infection or a condition or symptom associated with the infection in a subject in need thereof.
- the present application provides use of obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, optionally in combination with a second therapeutic agent, in treating, preventing, or alleviating a coronavirus infection or a condition or symptom associated with the infection in a subject in need thereof.
- the present application provides obeticholic acid: obeticholic acid
- INT-747 also known as INT-747
- a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof for the treatment, prevention, or alleviation of a coronavirus infection or a condition or symptom associated with the infection, such as COVID-19, SARS, and MERS.
- the present application provides a method of treating, preventing, or alleviating a coronavirus infection or a condition or symptom associated with the infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, optionally in combination with a second therapeutic agent.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of 1-100 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 5 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 10 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 15 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 20 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 25 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 30 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 50 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 75 mg.
- obeticholic acid or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof is administered at a daily dose of about 100 mg.
- Obeticholic acid is the 6-ethyl derivative of chenodeoxycholic acid (CDCA).
- DSA non-alcoholic steatohepatitis
- PAH pulmonary arterial hypertension
- OCA treatment ameliorates lung damage and improves pulmonary function in animal models.
- OCA exhibits functional cardiopulmonary protective effects in monocrotaline-induced PAH.
- OCA also prevents and treats bleomycin-induced lung inflammation and fibrosis, by abating inflammation, correcting vascular remodeling, inhibiting the progression of lung fibrosis, counteracting interstitial thickening and collagen deposition, and reducing pro-inflammatory cytokines (IL- ip, IL-6) and markers of fibrosis and tissue remodeling.
- IL- ip pro-inflammatory cytokines
- OCA treatment upregulates ACE2 expression in lung homogenates in the monocrotaline model of PAH.
- ACE2 the receptor for SARS- CoV-2
- higher ACE2 expression is observed in females and young people known to be less susceptible to severe or fatal COVID-19 outcome.
- ACE2 expression is low in males, and further decreases with age and type 2 diabetes, suggesting a negative correlation between ACE2 expression and COVID-19 severity.
- FXR agonists such as OCA have also shown inhibitory effects on infection by various RNA and DNA viruses, including HCV, rotavirus, and influenza A virus.
- OCA represses HBV replication, by inhibiting viral mRNA, DNA, and protein production and reducing covalently closed circular (ccc) DNA pool size.
- 6-ethyl chenodeoxycholic acid refers to a compound having the chemical structure:
- obeticholic acid examples include: 3a,7a-dihydroxy-6a-ethyl-5P- cholan-24-oic acid, 6a-ethyl-chenodeoxy cholic acid, 6-ethyl-CDCA, 6ECDCA, (3a,5p, 6a,7a)-6-ethyl-3,7-dihydroxy-cholan-24-oic acid and INT-747.
- the CAS registry number for obeticholic acid is 459789-99-2.
- obeticholic acid including a pharmaceutically acceptable salt or an amino acid conjugate (e.g., glycine, taurine or sarcosine conjugate) thereof can be used as an active pharmaceutical ingredient in the compositions and methods described herein.
- an amino acid conjugate e.g., glycine, taurine or sarcosine conjugate
- SARS Severe Acute Respiratory Syndrome, which is caused by or associate with infection by coronavirus.
- SARS-CoV Severe Acute Respiratory
- SARS-CoV-1 means Severe Acute Respiratory Syndrome Coronavirus 1
- SARS-CoV-2 means Severe Acute Respiratory Syndrome Coronavirus 2.
- COVID-19 means a respiratory illness caused by or associated with infection by SARS- CoV-2.
- MERS Middle East Respiratory Syndrome.
- the term “effective amount” as used herein refers to an amount of an active pharmaceutical ingredient, e.g., obeti cholic acid, that produces an acute or chronic therapeutic effect upon appropriate dose administration.
- the effect includes the prevention, correction, inhibition, or reversal of the symptoms, signs and underlying pathology of a disease/condition (e.g., COVID-19) and related complications to any detectable extent.
- a therapeutically effective amount means the amount of a pharmaceutically active ingredient, e.g., obeticholic acid, that, when administered to a subject (e.g., a human or an animal) for treating a disease, is sufficient to effect such treatment for the disease.
- a pharmaceutically active ingredient e.g., obeticholic acid
- the “therapeutically effective amount” will vary depending on the active pharmaceutical ingredient, the disease and its severity and the age, weight, etc., of the subject to be treated.
- a therapeutically effective amount can refer to a dose as set forth herein.
- Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
- Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
- a therapeutically effective amount of an active pharmaceutical ingredient e.g., obeticholic acid
- a pharmaceutically acceptable carrier for administration to a subject (e.g., a human or an animal).
- obeticholic acid or its formulations can be administered, for example, via oral, parenteral, or topical routes, to provide an effective amount of the compound.
- obeticholic acid prepared in accordance with the present application can be used to coat or impregnate a medical device, e.g., a stent.
- Treating includes any effect, e.g., lessening, slowing down, reducing, reversing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
- Treating or “treatment” of a disease state includes: arresting the development of the disease state or its clinical symptoms; or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
- Preventing the disease state includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
- inhibitors refers to any detectable positive effect on the development or progression of a disease or condition. Such a positive effect may include the delay or prevention of the onset of at least one symptom or sign of the disease or condition, alleviation or reversal of the symptom(s) or sign(s), and slowing or prevention of the further worsening of the symptom(s) or sign(s).
- Disease state means any disease, disorder, condition, symptom, or indication.
- administering refers to the act of delivering obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration.
- Parenteral administration includes intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration.
- the term can also refer to the frequency (e.g., daily, weekly, monthly, etc.) of providing obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein to a patient.
- Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).
- administration as used herein refers to oral administration.
- co-administration refers to administration of two or more agents (e.g., obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein and another active agent).
- the timing of coadministration depends in part of the combination and the compositions administered and can include administration at the same time, prior to, or after the administration of one or more additional therapies.
- Obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same of the instant invention can be administered alone or can be co-administered to the patient.
- Co-administration is meant to include simultaneous or sequential administration of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same individually or in combination (more than one compound or agent).
- 257693085 can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
- Obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be used in combination with each other (/. ⁇ ?., two different obeticholic acid compositions), with other active agents known to be useful in treating a disease, or with adjunctive agents that are not effective alone, but can contribute to or enhance the efficacy of the active agent.
- the term “regimen” refers to a protocol for dosing and/or timing the administration of one or more therapies (e.g., obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein) for treating a disease, disorder, or condition described herein.
- a regimen can include periods of active administration and periods of rest as known in the art.
- a regimen can also include a period of active administration, followed by a period in which administration is suspended, i.e., interrupted, because of occurrence or development of undesirable effects suspected as a result of active administration, such as occurrence or development of clinical signs or symptoms or biochemical abnormalities suggestive of liver injury and/or hepatic impairment, for example, as those described herein.
- a regimen can further include another period of active administration, i.e., resumption, after the period of suspension, once the undesirable effects disappear or reduce in their intensity, frequency, or grade, or a combination thereof.
- a regimen can further include permanent discontinuation of active administration.
- Active administration periods include administration of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein in a defined course of time, including, for example, the number of and timing of dosages of the compositions.
- one or more rest periods or suspension periods can be included where no compound is actively administered, and in certain instances, includes time periods where the efficacy of such compounds can be minimal.
- a "pharmaceutical composition” is a formulation containing obeticholic acid in a form suitable for administration to a subject.
- the methods described herein relate to pharmaceutical compositions of obeticholic acid described in U.S. Patents Nos. 9,238,673; 9,982,008; 10,174,073; and 10,052,337.
- the pharmaceutical composition is in bulk or in unit dosage form. It can be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit
- a pharmaceutical composition of the application is formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, e.g, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
- a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
- “Pharmaceutically acceptable salts” refer to derivatives of the compounds of the disclosure wherein the parent compound is modified by making acid or base salts thereof.
- Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic,
- compositions include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
- the disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, meglumine, and the like.
- a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
- organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, meglumine, and the like.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient as described herein.
- the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
- the quantity obeti cholic acid e.g., a formulation of obeti cholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof) in a unit dose of composition is an effective amount and is varied
- obeticholic acid is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
- the pharmaceutical composition comprises a therapeutically effective amount of obeticholic acid (or a pharmaceutically acceptable salt or amino acid conjugate thereof) and a pharmaceutically acceptable excipient.
- the pharmaceutical composition further comprises one or more pharmaceutical excipients.
- the excipient can be one or more selected from the group consisting of diluents, sweeteners, viscosity enhancing agents, dispersing agents, preservatives, flavoring agents and the like.
- One excipient can perform more than one function.
- the one or more pharmaceutical excipients include a lubricant and/or a diluent.
- the excipient can be any excipient present in the composition comprising obeticholic acid (or a pharmaceutically acceptable salt or amino acid conjugate thereof).
- excipients include, but are not limited to, calcium phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium stearate, or a combination thereof.
- the excipient can be any excipient known in the art.
- the excipient is selected from calcium phosphate, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
- the excipient is selected from microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
- the excipient is the excipient is magnesium stearate.
- the excipient is microcrystalline cellulose.
- the excipient is sodium starch glycolate.
- Non-limiting examples of sweeteners include natural sweeteners such as sugars, e.g., fructose, glucose, sucrose, sugar alcohols such as mannitol, sorbitol or mixtures thereof and artificial sweeteners such as sodium saccharine, sodium cyclamate and aspartame.
- the sweetener can be any sweetener known in the art.
- the sweetener can be any sweetener known in the art.
- the sweetener is selected from fructose, glucose, sucrose, mannitol, and sorbitol, or a combination thereof.
- Dispersing agents include, but are not limited to, colloidal silicon dioxide and surfactants, wherein the surfactant is used alone or as an admixture with one or more surfactant.
- the dispersing agent can be any dispersing agent known in the art. Combinations of colloidal silicon dioxide with one or more surfactants can also be used.
- the lubricant can be any lubricant known in the art.
- Nonlimiting examples of lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate, and/or a combination thereof.
- the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate.
- the lubricant is calcium stearate.
- the lubricant is stearic acid.
- the lubricant is magnesium stearate.
- the diluent can be any diluent known in the art.
- Non-limiting examples of diluents include starch, pregelatinized starch, microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, and sucrose, and/or a combination thereof.
- the diluent is selected from starch, pregelatinized starch, microcrystalline cellulose, calcium phosphate, lactose, sorbitol, mannitol, and sucrose.
- the diluent is calcium phosphate.
- the diluent is mannitol.
- the diluent is microcrystalline cellulose.
- the pharmaceutical composition may further comprise a coating agent such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents and delayed release coating agents or a coating composition comprising any combination thereof.
- a coating agent such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents and delayed release coating agents or a coating composition comprising any combination thereof.
- the coating agent can be any coating agent known in the art.
- coating agents include, but are not limited to, saccharose used alone or together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof; cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate,
- aminoalkyl methacrylate copolymers and polyvinylpyrrolidone polysaccharides such as pullulan; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; carboxymethyl ethyl cellulose; cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; natural substances such as shellac; titanium dioxide; polyvinyl alcohol (e.g., Opadry®); polyethylene glycol; talc; lecithin; and/or combinations thereof .
- polysaccharides such as pullulan
- hydroxypropyl methyl cellulose phthalate hydroxypropyl methyl cellulose acetate succinate
- carboxymethyl ethyl cellulose cellulose acetate phthalate
- acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid cop
- the coating agent is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, polyethylene glycol, and lecithin, or a combination thereof.
- the coating agent is Opadry® II (e.g., Opadry® II green, white, yellow, etc.).
- the pharmaceutically composition is in solid particle form.
- Any inert excipient that is commonly used as a carrier or diluent may be used in the pharmaceutical composition of the present application, such as for example, a gum, a starch, a sugar, a cellulosic material, a glycolate, an acrylate, or mixtures thereof.
- the filler/diluent is microcrystalline cellulose.
- the pharmaceutical composition may further comprise a disintegrating agent (e.g., sodium starch glycolate) and/or a lubricant (e.g., magnesium stearate).
- the pharmaceutical composition may comprise one or more additives selected from a buffer, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
- the pharmaceutical composition of the present application may be in the form of controlled release of immediate release formulations.
- the methods described herein refer generally to obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same set forth herein.
- the obeticholic acid composition useful in the methods of treating described herein is a composition that includes microcrystalline cellulose, sodium starch glycolate, and magnesium stearate as excipients.
- Such a composition can be provided in a dosage form set forth herein, e.g., an oral dosage form such as a tablet or coated tablet.
- the obeticholic acid composition useful in the methods is a tablet or coated tablet for oral administration.
- the oral dosage form of the obeticholic acid composition includes a film coating that includes one or more excipients selected from polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), talc, and iron oxide.
- excipients selected from polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), talc, and iron oxide.
- the percentage of the active ingredient (i.e., obeti cholic acid, or a pharmaceutically acceptable salt, or amino acid conjugate thereof) and various excipients in the pharmaceutical composition of the present application may vary.
- the composition may comprise between about 0.1 and about 99%, between about 1-50%, between about 1-25%, or about 1-6% by weight of active ingredient.
- the composition may comprise between about 20-99%, between about 45-97%, between about 65-96%, or between about 85-95% by weight microcrystalline cellulose as a filler or diluent.
- the composition may comprise between about 1-30%, between about 1-20%, or between about 2- 8% by weight sodium starch glycolate as a disintegrant.
- the composition may comprise between about 0.1-5% or about 0.5-2.0% by weight magnesium stearate as a lubricant.
- Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
- a lubricant such as magnesium stearate
- a glidant such as colloidal silicon dioxide
- a sweetening agent such as sucrose or
- the pharmaceutical composition of the present application is about 0.1% to about 10% by weight of active ingredient i.e., obeticholic acid, or a pharmaceutically acceptable salt, or amino acid conjugate thereof), about 0.1% to about 20 % by weight of sodium starch glycolate, about 0.01% to about 8.0% by weight of magnesium stearate, and about 65% to about 99% by weight of microcrystalline cellulose.
- the pharmaceutical composition of the present application is about 0.5% to about 8% by weight of active ingredient, about 1% to about 10 % by weight of sodium starch glycolate, about 0.05% to about 4.0% by weight of magnesium stearate, and about 75% to about 97 % by weight of microcrystalline cellulose.
- the pharmaceutical composition of the present application is about 1% to about 6% by weight of
- active ingredient about 2% to about 8 % by weight of sodium starch glycolate, about 0.1% to about 2.0% by weight of magnesium stearate, and about 85% to about 95% by weight of microcrystalline cellulose.
- obeticholic acid, or a pharmaceutically acceptable salt, or amino acid conjugate thereof, in the pharmaceutical composition is in the form of particles.
- flash dose refers to obeticholic acid formulations that are rapidly dispersing dosage forms.
- immediate release is defined as a release of obeticholic acid from a dosage form in a relatively brief period of time, generally up to about 60 minutes.
- modified release is defined to include delayed release, extended release, and pulsed release.
- pulsed release is defined as a series of releases of drug from a dosage form.
- sustained release or extended release is defined as continuous release of obeticholic acid from a dosage form over a prolonged period.
- a “subject” or “patient” includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like).
- the subject is human.
- the subject is human child (e.g., between about 30 kg to about 70 kg).
- pharmacological effect encompasses effects produced in the subject that achieve the intended purpose of a therapy.
- a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced.
- a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject.
- a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced.
- a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject.
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and
- a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
- antibacterial agents such as benzyl alcohol or methyl parabens
- antioxidants such as ascorbic acid or sodium bisulfite
- chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers
- 257693085 agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the active compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Administration by inhalation may be in the form of an inhaler or a nebulizer.
- the nebulizer and/or inhaler is handheld.
- the nebulizer and/or inhaler can be of different sizes to fit children and/or adults.
- the obeticholic acid or obeticholic acid particles are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the obeticholic acid or obeticholic acid particles is formulated into ointments, salves, gels, or creams as generally known in the art.
- the obeticholic acid or obeticholic acid particles can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- pharmaceutically acceptable carriers such as a controlled release formulation, including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- Liposomal suspensions including liposomes targeted to infected cells with
- 257693085 monoclonal antibodies to viral antigens can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
- a pharmaceutical formulation comprising at least obeticholic acid as described above in a formulation adapted for buccal and/or sublingual, or nasal administration.
- This embodiment provides administration of obeticholic acid in a manner that avoids gastric complications, such as first pass metabolism by the gastric system and/or through the liver.
- This administration route may also reduce adsorption times, providing more rapid onset of therapeutic benefit.
- the compounds of the present application may provide particularly favorable solubility profiles to facilitate sublingual/buccal formulations.
- Such formulations typically require relatively high concentrations of active ingredients to deliver sufficient amounts of active ingredients to the limited surface area of the sublingual/buccal mucosa for the relatively short durations the formulation is in contact with the surface area, to allow the absorption of the active ingredient.
- the very high activity of obeticholic acid combined with its high solubility, facilitates its suitability for sublingual/buccal formulation.
- Obeticholic acid is preferably formulated in a unit dosage form, each dosage containing from about 0.05 mg to about 1500 mg OCA.
- the formulation comprises about 0.05 mg to about 100 mg OCA.
- the formulation comprises about 1 mg to about 100 mg OCA.
- the formulation comprises about 0.05 mg to about 50 mg OCA.
- the formulation comprises about 0.05 mg to about 30 mg OCA.
- the formulation comprises about 0.05 mg to about 20 mg OCA.
- the formulation comprises about 0.5 mg to about 30 mg OCA.
- the formulation comprises about 0.5 mg to about 25 mg OCA.
- the formulation comprises about 1 mg to about 25 mg OCA.
- the formulation comprises about 4 mg to about 26 mg OCA. In another embodiment, the formulation comprises about 5 mg to about 25 mg OCA. In yet another embodiment, the formulation comprises about 0.05 mg to about 2 mg OCA. In another embodiment, the formulation comprises about 1 mg to about 2 mg OCA. In one embodiment, the formulation comprises about 1.2 mg to about 1.8 mg OCA. In one embodiment, the formulation comprises about 1.3 mg to about 1.7 mg OCA. In one embodiment, the formulation comprises about 1.5 mg OCA. In one embodiment, the formulation comprises about 0.05 mg to about 0.5 mg OCA. In another embodiment, the formulation comprises about 0.08 mg to
- the formulation comprises about 0.1 mg to about 0.5 mg OCA. In another embodiment, the formulation comprises about 0.25 mg OCA.
- Obeticholic acid can be administered over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.0001 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
- the formulation comprises about 0.05 mg to about 1500 mg OCA. In another embodiment, the formulation comprises about 0.05 mg to about 100 mg OCA. In yet another embodiment, the formulation comprises about 1 mg to about 100 mg OCA.
- the formulation comprises about 0.05 mg to about 50 mg OCA. In another embodiment, the formulation comprises about 0.05 mg to about 30 mg OCA. In yet another embodiment, the formulation comprises about 0.05 mg to about 20 mg OCA. In yet another embodiment, the formulation comprises about 0.05 mg to about 10 mg OCA.
- the formulation comprises about 1 mg to about 50 mg OCA. In one embodiment, the formulation comprises about 3 mg to about 30 mg OCA. In another embodiment, the formulation comprises about 0.05 mg to about 25 mg OCA. In another embodiment, the formulation comprises about 4 mg to about 25 mg OCA. In another embodiment, the formulation comprises about 5 mg to about 25 mg OCA. In another embodiment, the formulation comprises about 5 mg to about 10 mg OCA. In one embodiment, the formulation comprises about 1 mg to about 2 mg OCA. In one embodiment, the formulation comprises about 1.2 mg to about 1.8 mg OCA. In one embodiment, the formulation comprises about 1.3 mg to about 1.7 mg OCA. In one embodiment, the formulation comprises about 0.05 mg to about 0.5 mg OCA.
- the formulation comprises about 0.08 mg to about 0.8 mg OCA. In yet another embodiment, the formulation comprises about 0.1 mg to about 0.5 mg OCA. In another embodiment, the formulation comprises about 30 mg OCA. In another embodiment, the formulation comprises about 25 mg OCA. In another embodiment, the formulation comprises about 10 mg OCA. In one embodiment, the formulation comprises about 5 mg OCA. In another embodiment, the formulation comprises about 1 mg OCA.
- the amount of obeticholic acid actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the form of obeticholic acid administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the application in any way.
- the above dosage ranges are not intended to limit the scope of the application in any way.
- dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
- Obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered in accordance with a dosing regimen.
- a dosing regimen refers to continual and intermittent administration of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein at one or more of the amounts described herein.
- a dosing regimen can include administration of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein continually for any number of days, weeks, months, or years as set forth herein.
- a dosing regimen can include administration of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein intermittently, where, for example, the composition is administered for one period of time followed by a rest period or off period where obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is not administered.
- Obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same useful in the methods of treatment described herein includes administration of such compositions daily (QD), every other day (Q2D), once a week (QW), twice a week (BID), three times a week (TIW), once a month (QM), or twice a month (Q2M).
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein is administered QD.
- an effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered QD to treat a disease or condition described herein.
- a starting dose described herein can be administered QD during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered QD to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein is administered Q2D.
- 257693085 salt or amino acid conjugate thereof or a composition comprising same described herein can be administered Q2D to treat a disease or condition described herein.
- a starting dose described herein can be administered Q2D during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered Q2D to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is described herein administered QW.
- An effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered QW to treat a disease or condition described herein.
- a starting dose described herein can be administered QW during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered QW to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is described herein administered BID.
- An effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered BID to treat a disease or condition described herein.
- a starting dose described herein can be administered BID during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered BID to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is described herein administered TIW.
- An effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered TIW to treat a disease or condition described herein.
- a starting dose described herein can be administered TIW during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered TIW to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is described herein administered QM.
- An effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered QM to treat a disease or condition described herein.
- 257693085 described herein can be administered QM during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered QM to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same is described herein administered Q2M.
- An effective amount of obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered Q2M to treat a disease or condition described herein.
- a starting dose described herein can be administered Q2M during the course of a titration period described herein to treat a disease or condition described herein.
- An adjusted dose described herein can be administered Q2M to treat a disease or condition described herein.
- obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof or a composition comprising same described herein can be administered in a frequency provided above in an amount of 5 mg, 10 mg, 25 mg, 30 mg, or 50 mg.
- the formulation can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
- additional active compounds include, but are not limited to antiviral drugs such as Remdesivir and Molnupiravir, corticosteroids (e.g., dexamethasone, prednisone, or methylprednisone), anti coagulation drugs (e.g., heparin or enoxaparin), janus kinase inhibitors (e.g.
- Vitamin C e.g., aminobutylcholine
- Vitamin D e.g., aminobutylcholine
- anti-inflammatory antibodies e.g., an anti-IL-ip antibody, an anti -IL-6 antibody (e.g.
- anti-TNFa antibodies e.g., Humira or Remicade
- anti-CD20 antibodies e.g., Rituximab or Rituxan
- anti-IFNy antibodies e.g., Gamifant or emapalumab
- anti-Granulocyte-Macrophage Colony- Stimulating Factor antibodies anti-GM-CSF antibody; e.g., GSK3196165
- an anti-CD3 antibodies e.g., Foralumab.
- Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications.
- the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
- an agent that enhances its function such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
- Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
- Obeticholic acid or a or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof will generally be employed to treat, alleviate, and/or prevent a disease or pathology associated with coronavirus infection in a subject.
- a therapeutic regimen is carried out by identifying a subject, e.g., a human patient suffering from (or at risk of developing) coronavirus infection, using standard methods.
- the subject is a human subject.
- the subject has or is suspected of having a coronavirus infection.
- the subject has been or thought to have been exposed to a coronavirus and has not yet developed symptoms of a coronavirus infection.
- the coronavirus is, for example, the virus that causes COVID-19, SARS, or MERS. Signs and symptoms of a coronavirus infection can be, for example, fever, cough, and shortness of breath.
- the dose should be sufficient to result in slowing the replication of the coronavirus within the host and also preferably prevent or reduce the symptoms of a coronavirus-related disease (e.g. COVID-19, SARS, or MERS).
- a coronavirus-related disease e.g. COVID-19, SARS, or MERS.
- the dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects (e.g., mucositis or anaphylactic shock).
- the state of the disease condition e.g., SERS, MERS, or CO VID-19
- the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
- An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, slowing the replication of the coronavirus may be detected using PCR amplification assay to detect coronavirus nucleotides. Efficacy is also indicated by reduction in symptoms such as dry cough, pneumonia-like symptoms, or fever,
- compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
- the dosage regimen utilizing the therapeutic compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient.
- the dosage regimen can selected from those described herein, including daily administration (e.g., every 24 hours) of a therapeutic compound of the disclosure.
- the dosage regimen can be daily administration for consecutive days, for example, at least two, at least three, at least four, at least five, at least six or at least seven consecutive days. Dosing can be more than one time daily, for example, twice, three times or four times daily (per a 24 hour period).
- the dosing regimen can be a daily administration followed by at least one day, at least two days, at least three days, at least four days, at least five days, or at
- a therapeutic compound of the disclosure is administered at least once in a 24 hour period, then a compound of the disclosure is not administered for at least six days, then a therapeutic compound of the disclosure is administered to a subject in need.
- the dosing regimen can once or twice over a period of 1, 2, or 3 weeks.
- anti-inflammatory agent includes, without limitation, pentoxifylline and nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen.
- NSAIDs nonsteroidal anti-inflammatory drugs
- antioxidant includes, without limitation, vitamin C, retinoic acid (e.g., all trans-retinoic acid), amifostine, and N-acetyl cysteine.
- the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject.
- the therapeutically effective amount can be estimated initially either in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or pigs.
- the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
- Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., EDso (the dose therapeutically effective in 50% of the population) and LDso (the dose lethal to 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
- Compositions that exhibit large therapeutic indices are preferred.
- the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
- the application also comprehends isotopically-labeled obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof, which is identical to those recited in the formulae of the application and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
- isotopes that can be incorporated into obeticholic acid (or a pharmaceutically acceptable salt or an amino acid
- 257693085 conjugate of obeti cholic acid include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, U C, 14 C and 18 F.
- [OHl] Obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof that contains the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present application.
- Isotopically-labeled obeticholic acid (or a pharmaceutically acceptable salt or amino acid conjugate thereof), for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, is useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
- Isotopically labeled obeticholic acid can generally be prepared by carrying out the known procedures, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one embodiment, obeticholic acid (or a pharmaceutically acceptable salt or amino acid conjugate thereof) is not isotopically labeled.
- obeticholic acid (or a pharmaceutically acceptable salt or amino acid conjugate thereof) is radiolabeled.
- deuterated obeticholic acid (or deuterated salt or deuterated amino acid conjugate thereof) is useful for bioanalytical assays.
- deuterated obeticholic acid (or deuterated salt or deuterated amino acid conjugate thereof) is useful as an active pharmaceutical ingredient in composition and methods described herein.
- Coronavirus particles e.g., SARS-Cov-2
- OCA a serial dilution of OCA
- the cells and the culture media are collected.
- a viral titer assay is performed to measure the viral replication in the absence or presence of OCA treatment.
- Example 257693085 Example 2. Inhibition of Coronavirus Production by OCA In Animal Model [0113] Healthy experimental animals susceptible to coronavirus infection are exposed to coronavirus. One group of animals is administered OCA, while the control group of animals is not. After an infection period of 7-14 days, the number of live animals in each group is counted. For the live animals, lung tissues are collected to measure tissue damages, such as fibrosis, caused by the infection, through histological analysis. In addition, blood and lung cell samples are collected to assess the level of pro-inflammatory cytokines through biochemical analysis.
Abstract
La présente invention concerne des méthodes de traitement, de prévention ou de soulagement d'une infection à coronavirus ou d'un état ou d'un symptôme associés à l'infection, à l'aide d'acide obéticholique.
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---|---|---|---|---|
US20160220586A1 (en) * | 2013-09-11 | 2016-08-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of hepatitis b virus infection |
US20170035784A1 (en) * | 2015-04-27 | 2017-02-09 | Intercept Pharmaceuticals, Inc. | Compositions of obeticholic acid and methods of use |
WO2021237193A1 (fr) * | 2020-05-22 | 2021-11-25 | Georgetown University | Utilisation de précurseurs de nad+, d'inhibiteurs de sting et d'agonistes de fxr permettant d'inhiber la libération de cytokine induite par sars-cov-2 (covid-19) |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160220586A1 (en) * | 2013-09-11 | 2016-08-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of hepatitis b virus infection |
US20170035784A1 (en) * | 2015-04-27 | 2017-02-09 | Intercept Pharmaceuticals, Inc. | Compositions of obeticholic acid and methods of use |
WO2021237193A1 (fr) * | 2020-05-22 | 2021-11-25 | Georgetown University | Utilisation de précurseurs de nad+, d'inhibiteurs de sting et d'agonistes de fxr permettant d'inhiber la libération de cytokine induite par sars-cov-2 (covid-19) |
Non-Patent Citations (1)
Title |
---|
ADRIANA CARINO ET AL.: "Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region", BIORXIV, 11 June 2020 (2020-06-11), pages 1 - 26, XP055737369, Retrieved from the Internet <URL:https://www.biorxiv.org/content/10.1101/2020.06.10.144964v1.full.pdf> DOI: 10.1101/2020.06.10.144964 * |
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