WO2021220236A1 - Pharmaceutical compositions for combination therapy - Google Patents

Pharmaceutical compositions for combination therapy Download PDF

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Publication number
WO2021220236A1
WO2021220236A1 PCT/IB2021/053619 IB2021053619W WO2021220236A1 WO 2021220236 A1 WO2021220236 A1 WO 2021220236A1 IB 2021053619 W IB2021053619 W IB 2021053619W WO 2021220236 A1 WO2021220236 A1 WO 2021220236A1
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Prior art keywords
compound
formula
pharmaceutical composition
pharmaceutically acceptable
acid
Prior art date
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PCT/IB2021/053619
Other languages
French (fr)
Inventor
Rajiv Sharma
Mukul Jain
Sanjay Kumar
Brijesh Kumar Srivastava
Suresh GIRI
Ravindra Mittal
Original Assignee
Cadila Healthcare Limited
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Publication of WO2021220236A1 publication Critical patent/WO2021220236A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention describes a pharmaceutical composition
  • a pharmaceutical composition comprising combination of PPAR agonist compound of formula (I) and at least one additional therapeutic agent or pharmaceutically acceptable salts thereof selected from Ezetimibe, ethyl ester of eicopentanoic acid, Nicotinic acid derivative, Bempedoic acid.
  • the pharmaceutical composition comprising, the therapeutically effective amount of PPAR agonist compound of formula (I) and at least one additional therapeutic agent along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient.
  • the present application relates use of pharmaceutical composition for the treatment or prevention of a disease or condition such as metabolic disorder and cardiovascular disease.
  • Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dislipidemia, congestive heart failure and stroke. A need exists for improved treatments for cardiovascular diseases and disorders.
  • Hyperlipidemia has been recognized as the major risk factor in causing cardiovascular diseases due to atherosclerosis.
  • Atherosclerosis and other such peripheral vascular diseases affect the quality of life of a large population in the world.
  • the therapy aims to a reduction in LDL-C levels compared to baseline; increased HDL-C levels compared to baseline; reduced Apo B levels compared to baseline; an increase in apo A-I/apo B ratio compared to baseline; a reduction in total cholesterol reduced triglyceride levels compared to baseline; reduced low density lipoprotein in order to prevent or reduce the risk of occurrence of cardiovascular diseases.
  • WO 91/19702 discloses compounds of the following general formula:
  • WO 03009841 also discloses certain salts including the sodium salt of some of the compounds disclosed therein.
  • WO 2012104869 discloses Magnesium salt of compound of Formula (I) and its being effective in the treatment of lipohypertrophy, lipoatrophy and metabolic abnormalities in HIV patients.
  • WO 20020044361 discloses the pure form of eicosapentaenoic acid (EPA) and WO9508532 discloses the drug product Ezetimibe.
  • WO02058685 also disclosed combination of Ezetimibe with Fenofibrate or Simvastatin.
  • US6818229 and US2843786 discloses the process for the preparation of Nicotinic acid.
  • WO 2004067489 discloses Bempedoic acid.
  • Present invention provides synergistic composition of compound of formula (I) in combination with one or more therapeutic agents as describes herein after.
  • one or more therapeutic agents is cholesterol-absorption inhibitors and selected from Ezetimibe, eicosapentaenoic acid (EPA) and Nicotinic acid derivative (Niacin), Bempedoic acid or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof. It has now surprisingly been found that compound of formula (I) in combination with a Ezetimibe or EPA or Nicotinic acid derivative (Niacin) or Bempadoic acid provides a particularly beneficial effect on cholesterol reduction with no observed adverse effects; such combination is therefore particularly useful for the treatment of metabolic disorder and cardiovascular disease especially hypocholesteremia.
  • the present invention is also based on the surprising finding that combination of compound of formula (I) with ezetimibe or that combination of compound of formula (I) with eicosapentaenoic acid (EPA), or that combination of compound of formula (I) with Nicotinic acid derivative (Niacin) or that combination of compound of formula (I) with Bempadoic acid, a pharmaceutically acceptable ester, derivative, conjugate or salt thereof can be used to treat or prevent metabolic disorder and cardiovascular disease, without increasing the risk for any side effects.
  • EPA eicosapentaenoic acid
  • EPA eicosapentaenoic acid
  • Nicotinic acid derivative Niacin
  • Bempadoic acid a pharmaceutically acceptable ester, derivative, conjugate or salt thereof
  • synergistic combination comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
  • synergistic composition comprising compound of formula (I) with ezetimibe or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with ezetimibe for the treatment of cardiovascular and its associated diseases.
  • a synergistic composition comprising compound of formula (I) with ezetimibe or pharmaceutically acceptable salts thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent.
  • a synergistic composition comprising compound of formula (I) with ezetimibe pharmaceutically acceptable salts thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agents.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agents for the treatment of cardiovascular and its associated diseases.
  • EPA eicosapentaenoic acid
  • statins as an additional therapeutic agents for the treatment of cardiovascular and its associated diseases.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin), pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin), pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
  • synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent.
  • synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe for the treatment of cardiovascular and its associated diseases.
  • a process for the preparation of synergistic composition comprising compound of formula (I) and ezetimibe or eicosapentaenoic acid or nicotinic acid derivative or bempedoic acid.
  • a pharmaceutical composition comprising the compound of formula (I) and Ezetimibe or compound of formula (I) and EPA or compound of formula (I) and Nicotinic acid (Niacin) or compound of formula (I) and bempedoic acid prepared according to the present invention for the treatment of cardiovascular disorder in humans and other mammals in need thereof.
  • a pharmaceutical composition comprising, the therapeutically effective amount of the compound of formula (I) and Ezetimibe or compound of formula (I) and eicosapentaenoic acid (EPA) or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof or compound of formula (I) and Nicotinic acid (Niacin) or compound of formula (I) and bempedoic acid prepared according to the present invention, along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient.
  • the invention provides a method for treatment and/or prevention of a cardiovascular-related disease.
  • cardiovascular-related disease herein refers to any disease or disorder of the heart or blood vessels (i.e. arteries and veins) or any symptom thereof.
  • Non-limiting examples of cardiovascular-related disease and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
  • the term 'pharmaceutically acceptable' use embraces both human and veterinary use.
  • treatment in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder.
  • prevention in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
  • synergistic combination comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
  • composition comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
  • synergistic composition comprising compound of formula (I) with Ezetimibe or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with Ezetimibe and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of Ezetimibe of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 100 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • daily dose amount of compound of Ezetimibe in range of about 0.1 mg to 10mg and amount of compound of formula (I) in range of 4mg to 10 mg.
  • synergistic composition comprising compound of formula (I) with Ezetimibe or pharmaceutically acceptable salts thereof and optionally suitable statins as an additional therapeutic agent.
  • synergistic composition comprising compound of formula (I) with Ezetimibe pharmaceutically acceptable salts thereof and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
  • Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
  • the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
  • a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and ezetimibe.
  • a stable combination is in the form of conjugate or complex of compound of formula (I) and ezetimibe.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • EPA eicosapentaenoic acid
  • a composition for use in methods of the invention comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA.”
  • pharmaceutically acceptable in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.
  • the EPA comprises all-cis eicosa-5, 8, 11 14,17-pentaenoic acid.
  • the EPA comprises an eicosapentaenoic acid ester. In another embodiment, the EPA comprises a C 1- C 5 alkyl ester of eicosapentaenoic acid. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In another embodiment, the EPA comprises In one embodiment, the EPA comprises all-cis eicosa-5, 8, 11,14, 17-pentaenoic acid ethyl ester.
  • the EPA is in the form of ethyl - EPA, lithium EPA, mono-, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA.
  • the EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of EPA or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, or mixtures thereof about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and optionally suitable statins as an additional therapeutic agents.
  • a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and optionally suitable statins as an additional therapeutic agents for the treatment of cardiovascular and its associated diseases.
  • EPA eicosapentaenoic acid
  • Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
  • the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
  • a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and eicosapentaenoic acid (EPA).
  • EPA eicosapentaenoic acid
  • a stable combination is in the form of conjugate or complex of compound of formula (I) and eicosapentaenoic acid (EPA).
  • EPA eicosapentaenoic acid
  • EPA eicosapentaenoic acid
  • EPA eicosapentaenoic acid
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of nicotinic acid derivatives (Niacin) of about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg,
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • nicotinic acid derivatives in range of 1000-2000 mg and amount of compound of formula (I) in range of 4 mg to 10 mg.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and optionally suitable statins as an additional therapeutic agent.
  • a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
  • Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
  • the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
  • a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and Nicotinic acid derivative (Niacin).
  • a stable combination is in the form of conjugate or complex of compound of formula (I) and Nicotinic acid derivative (Niacin).
  • synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
  • a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose amount of compound of bempedoic acid of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 180 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • daily dose amount of bempedoic acid is in range 4 mg to about 180 mg
  • amount of Ezetimibe is about in range of 0.1 mg to 10mg
  • amount of compound of formula (I) in range of 4mg to 10 mg.
  • synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent.
  • a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of bempedoic acid of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 180 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of Ezetimibe of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 100 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
  • a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
  • daily dose of bempedoic acid is 4 mg to about 180 mg
  • amount of Ezetimibe is about 0.1 mg to 10mg
  • the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
  • a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and bempedoic acid and optionally ezetimibe.
  • a stable combination is in the form of conjugate or complex of compound of formula (I) and bempedoic acid and optionally ezetimibe.
  • a process for the preparation of a stable premix, co-precipitates of compound of formula (I) and bempedoic acid and optionally ezetimibe is provided.
  • Present invention also discloses synergistic composition of bempedoic acid and additional therapeutic agents selected from statins such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like, thyroid hormone beta receptor agonist, cholesterol-absorption inhibitors, FXR agonist semi-synthetic bile acid analogue or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • statins such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like
  • thyroid hormone beta receptor agonist such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like
  • thyroid hormone beta receptor agonist such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like
  • thyroid hormone beta receptor agonist such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like
  • thyroid hormone beta receptor agonist such as Atorvastatin
  • ZYT1 means N-(3,5-dichloro-4-((6-hydroxy-[1,1'-biphenyl]-3- yl)oxy)phenyl)-N-((4-hydroxyphenoxy)carbonyl)glycine and has the chemical formula:
  • Axitirome means 2-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
  • Sobiterome or ‘GC-1’ means 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy) acetic acid and has the chemical formula:
  • KB-141 means 2-(3,5-dichloro-4-(4-hydroxy-3- isopropylphenoxy)phenyl)acetic acid and has the chemical formula:
  • KB-2115 means 3-((3,5-dibromo-4-(4-hydroxy-3- isopropylphenoxy)phenyl)amino)-3-oxopropanoic acid and has the chemical formula:
  • CO-23 means 5-(4-(4-hydroxy-3-isopropylphenoxy)-3,5- diiodobenzyl)imidazolidine-2,4-dione and has the chemical formula:
  • M07811 means (2R,4S)-4-(3-chlorophenyl)-2-((4-(4-hydroxy-3- isopropylbenzyl)-3,5-dimethylphenoxy)methyl)-1,3,2-dioxaphosphinane 2-oxide and has the chemical formula:
  • M07344 means ((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)phosphonate and has the chemical formula:
  • ICI-164384 means N-butyl- 11-((7R,13S,17S)-3,17-dihydroxy-13- methyl-7,8,9, 11 , 12, 13, 14, 15, 16, 17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-N- methylundecanamide and has the chemical formula:
  • GC-24 means 2-(4-(3-benzyl-4-hydroxybenzyl)-3,5- dimethylphenoxy) acetic acid and has the chemical formula:
  • GC-14 means 2-(4-(4-hydroxy-3-isopropyl-5-(3-nitrobenzyl)benzyl)- 3,5-dimethylphenoxy)acetic acid and has the chemical formula:
  • Triac means 2-(4-(4-hydroxy-3-iodophenoxy)-3-iodo-5- methylphenyl)acetic acid and has the chemical formula:
  • SKF-94901 means (S)-2-amino-3-(3,5-dibromo-4-(4-hydroxy-3-((6- oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)phenyl)propanoic acid and has the chemical formula:
  • KAT-681 means 3-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-3-oxopropanoic acid and has the chemical formula:
  • CG23245 means 2-((4-(4-hydroxy-3-isopropylphenoxy)-3,5- dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
  • CG26214 means 2-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
  • Resmetirom or ‘MGL-3196’ means 2-(3,5-dichloro-4-((5-isopropyl-6- oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- carbonitrile and has the chemical formula:
  • the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.
  • the dosages of each particular active agent in any given composition can as required vary within a range of doses known to be required in respect of accepted dosage regimens for that compound. Dosages of each active agent can also be adapted as required to take into account advantageous effects of combining the agents as mentioned herein.
  • compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • composition of the invention is in the form of a unit dose.
  • Unit dosage presentation forms for oral administration may be in tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants and wetting agents.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anesthetic, a preservative and buffering agent can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the active compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
  • binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
  • fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
  • glidants examples include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.
  • disintegrants examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
  • Example of wetting agents include, by way of example and without limitation, poloxamers, gelatin, casein, Glycerol mono-oleate, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, sodium lauryl sulphate, sodium dodecyl sulfate, salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.), cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium do
  • Synergistic pharmaceutical composition described in present invention are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubilizing or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use. No adverse toxicological effects were seen for the compositions or methods of the invention in the above mentioned dosage ranges. Further the composition of the present invention was found suitable for the treatment of diabetes and its associated disorders without increasing the risk for fluid retention, peripheral edema, pulmonary edema, or congestive heart failure.
  • the subject or subject group exhibits one or more of the following outcomes:
  • Reduced low-density lipoprotein In an embodiments a less than 60% increase, a less than 50% increase, a less than 40% increase, a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in LDL-C levels or a reduction in LDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline.
  • compositions or methods of the invention were found suitable for the treatment of diabetes and its associated disorders without increasing the risk for fluid retention, peripheral edema, pulmonary edema, or congestive heart failure
  • HPLC purity was determined by using Agilent 1100 instrument.
  • Wave length UV at 220 nm.
  • composition of Ezetimibe was prepared as provided in WO 2002058732.
  • Niacin composition prepared as per W02007120385 while composition of EPA was adapted from WO 2010127103.
  • the composition of Bempedoic acid was adapted from US 20180338922.
  • the scope of invention is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge, which are within the general understanding of a person skilled in the art. Further the pharmacological studies of the described synergistic composition on various animal models and is undergoing to study effect of various effects of described composition. Other synergistic compositions described in the invention were prepared as per methods provided in literature and known to person skilled in art. Or therapeutic agents were administered to subject independently, parallel or simultaneously.
  • PHARMACOLOGICAL DATA Efficacy of Compound of formula (I) and other therapeutic agent (Bempedoic acid) alone and as combination in Non-Alcoholic Steatohepatitis (NASH) Induced by CDAHFD (Choline Deficient, L-Amino Acid-Defined, High-Fat Diet) in Male C57 Mice.
  • NASH Non-Alcoholic Steatohepatitis
  • Nonalcoholic fatty liver disease is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis, lobular inflammation and progressive pericellular fibrosis in liver.
  • NASH Non-alcoholic steatohepatitis
  • One of the most common animal models used in NASH research is a nutritional model where NASH is induced by feeding a diet deficient in both methionine and choline.
  • the dietary methionine-/choline deficient model in mice can cause severe weight loss and liver atrophy, which are not characteristics of NASH seen in human patients.
  • CDAHFD choline-deficient, L-amino acid-defined, high-fat diet
  • C57BL/6J mice fed with CDAHFD has increase hepatic steatosis due to impaired hepatic VLDL-TG secretive capacity and causes hepatic insulin resistance due to fat accumulation and TNF-a activation in liver.
  • C57BL/6 mice were fed the CDAHFD diet for 8 weeks and were bled for the measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Those animals with elevated serum ALT (> 10-fold) and AST (> 4-fold) levels were enrolled in the study and put on vehicle or test compound and then treatment was given for 8 weeks, as per below table.
  • ALT serum alanine aminotransferase
  • AST aspartate aminotransferase
  • liver lipids (TG) analysis After 8 weeks of treatment (i.e. 16 weeks of diet), 1 h post dose, blood samples were collected for estimation of non-fasted serum ALT and AST levels. All the animals were sacrificed; liver were quickly removed, weighed and fixed in 10 % formalin for histological analysis or snap frozen in liquid nitrogen for other assays like liver lipids (TG) analysis to evaluate the effect on steatosis.
  • TG liver lipids
  • liver tissue Light microscopic examination of liver tissue was performed using standard hematoxylin and eosin (H&E) staining. Hepatic fibrosis was accessed by masson’s trichrome staining method. Liver specific tissue macrophages i.e.kupffer cells was visualized in liver sections stained with the diastase-periodic acid-schiff method. Fat deposition, if any was demonstrated using oil red - O staining technique on 10 % formalin fixed tissue. Specimens were scored as per the scoring method described by Kleiner et al (Hepatology 2005;41:1313-1321) for the NAFLD Activity Score (NAS). Results
  • mice treated with Compound of formula (I) at 0.8 mg/kg, p.o. showed 71% reduction in serum ALT and 64% reduction in serum AST level respectively as compared to vehicle control group.
  • Treatment with bempedoic acid showed 20% and 22% reduction in serum ALT and AST level respectively as compared to vehicle control.
  • When Compound of formula (I) was administered in combination with bempedoic acid the reduction in serum ALT and AST levels were 39% and 37% respectively as compared to vehicle control. (Table 2 and Table 3)
  • Compound of formula (I) treatment for 8 week showed a significant reduction in liver lipid levels which was 72% in liver TG and 77% in liver TC levels.
  • Bempedoic acid showed a 37 and 44% reduction in liver TG and TC levels respectively as compared to vehicle control.
  • the effect in combination group also shows significant decrease in liver lipids levels which was 74% and 78% in liver TG and TC respectively.
  • Dyslipidemia is one of the major pathophysiological conditions commonly associated with the consumption of a calorie -rich western diet, which can, over time, lead to severe health complications including the metabolic syndrome, type2 diabetes, and cardiovascular disease. Cholesterol overconsumption as part of the western diet has been linked to multiple pathological conditions. Addition of dietary cholesterol to a high-fat/high-fructose diet has been shown to exacerbate symptoms of the metabolic syndrome including increased fasting plasma lipids, hepatic steatosis, and insulin resistance.
  • the golden Syrian hamster has been increasingly utilized to do research on lipoprotein metabolism and to investigate the effects of hypolipidemic agents such as PPAR agonists, statins and CETP inhibitors because of its similarity to human in terms of lipid utilization and high susceptibility to dietary cholesterol.
  • HF-HC diet with 10% fructose feeding resulted in 2.8 fold increase in serum total cholesterol level as compared to normal control.
  • Oral administration of Compound (la) for a period of 15 days resulted in 25% reduction in serum total cholesterol level.
  • Treatment with bempedoic acid showed 8% increase in serum total cholesterol level as compared to vehicle control.
  • Combination of Compound (la) with bemepdoic acid showed 34% reduction serum total cholesterol level as compared to vehicle control.
  • Compound 1(a) treatment showed statistically significant, 28% reduction in serum LDLc level.
  • Combination of Compound (la) with bempedoic acid showed 38% reduction in LDLc level. (Table 10).
  • Compound 1(a) showed significant reduction in serum TG ,TC and LDLc levels, but bempedoic acid alone failed to show any significant reduction in serum TG,TC and LDLc.
  • Compound 1(a) was administered in combination with bempedoic acid, a synergistic reduction in the serum level of TG,TC and LDLc was observed.
  • Evaluation of effect on lipid , glucose and atherogenic dyslipidemia (TG/HDL-C) ratio after treatment with Compound (I) co-administration of Compound (I) + Ezetimibe and co-administration of Compound (I) + Eicosapentaenoic acid (EPA) in hCETP/APOB100 DTG mice model.
  • Compounds having hypolipidemic activity need to be screened in hCETP/APOB100 DTG mice as these mice has the lipoprotein cholesterol distribution similar to human so for screening the anti-dyslipidemic activity before human this animal usage is necessary.
  • non-fasting serum lipid profile [Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride] estimated and animals grouped on basis of non-fasting serum LDL-C as primary parameter.
  • Test compounds will be formulated at specified doses in vehicle and animals will be dosed orally, once daily for seven to fourteen days, starting from next day of grouping with vehicle or test compound. The animals will be weighed prior to dosing, and based on these weights; the volume of administration will be calculated. The volume of formulation administered to each mouse will be 10 ml/kg body weight.
  • Serum lipid profile (Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride) analysis performed in Randox Daytona biochemical analyzer.
  • LDL-C Low density cholesterol
  • HDL-C High density cholesterol
  • triglyceride total cholesterol, triglyceride
  • AD insulin resistance
  • IR insulin resistance
  • TG/HDL-C ratio may be used as a surrogate marker for assessing CV risk (Hermans et al. 2010, Cardiovasc Diabetol 9: 88-97; Nicholls et al.2011, J Am Coll Cardiol 57: 153-159).
  • the % change in Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride and TG/HDL-C ratio vs vehicle control group will be calculated using MS Excel software.
  • test compound has been evaluated in high fat diet fed dyslipidemic male C57 mice.
  • the male C57 mice are susceptible to high fat diet induced obesity and show increase lipids and also respond to drugs intended for treatment of hypercholesterolemia. Therefore, this species is preferred for evaluation of their efficacy in lowering circulating lipid levels.
  • Test compounds formulated in appropriate vehicle at specified doses to make the uniform suspension The animals have been dosed orally, once daily for seven days, starting from next day of grouping with vehicle or test compound. The animals were weighed prior to dosing, and based on these weights; the volume of administration will be calculated. The volume of formulation administered to each mouse will be 10 ml/kg body weight. On day 7, one -hr after the dose administration, blood (0.25 ml) will be collected from retro-orbital sinus of the anaesthetized animals. Serum will be separated by centrifugation. Serum lipid profile (Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride) analysis performed in Randox Daytona biochemical analyzer.
  • LDL-C Low density cholesterol
  • HDL-C High density cholesterol
  • triglyceride total cholesterol, triglyceride
  • TG/HDL-C atherogenic dyslipidemia
  • AD cardiovascular risk
  • IR insulin resistance
  • TG/HDL-C ratio may be used as a surrogate marker for assessing CV risk
  • LDL-C Low density cholesterol
  • HDL-C High density cholesterol
  • TG/HDL-C atherogenic dyslipidemia
  • the in-vivo efficacy for antidiabetic activity has been done db/db mice of 13-14 weeks of age.
  • db/db mice Generally obese and diabetic animals are insulin resistant and have abnormalities in glucose and lipid metabolism.
  • diabetes and beta cell dysfunction in these animal models closely parallels the pathophysiology of the disease condition in humans.
  • the db/db mouse exhibits an initial phase of hyperinsulinemia, hyperphagia and obesity. They progressively develop into insulinopenia with age, a feature commonly observed in last stage of type-2 diabetes, when blood sugar levels are insufficiently controlled. Therefore, this genetic model proves to be suitable for predicting the likely therapeutic benefit of novel euglycemic agents in human type-2 diabetes.
  • mice of 13-14 week were divided into 6 groups based on their day 0 serum glucose levels as per Table no.1.
  • Vehicle Control group will be treated with vehicle and other groups with treatment mentioned in Table no.12
  • the treatment has been given oral gavages once daily for 14 days.
  • Oral Glucose Tolerance Test (OGTT): One day before OGTT all animals kept on overnight fasting and on the day of OGTT, day 14 of the treatment each animal dosed with a single dose of vehicle/test compounds administered orally and 60-min post dosing blood will be collected (0 min) and glucose load (1-2gm/kg/10ml) administered per orally. Blood then collected at time points corresponding to 30, 60 and 120 min after glucose load administration. Serum separated and analyzed for glucose using Biotek plate reader and commercial diagnostic kits.
  • the calculation for antidiabetic activity i.e. effect on serum glucose and improvement in glucose Area under Curve (AUC) calculated using the excel sheet and Graph Pad Prism software.
  • the day 0 and day 12 glucose values of vehicle control and treatment will be considered for calculating the effect on serum glucose.
  • the effect on glucose AUC calculated using the OGTT glucose levels at different time points and the improvement in glucose AUC i.e. the reduction in glucose AUC after the treatment estimated.
  • HOMA index calculated from fasting glucose and insulin levels for drug alone and combination groups.
  • NASH Nonalcoholic Fatty Liver Disease
  • NASH nonalcoholic steatohepatitis
  • EPA Eicosapentaenoic acid
  • CDAHFD High-Fat Diet
  • NASH Nonalcoholic Steatohepatitis
  • Nonalcoholic Fatty Liver Disease is the major chronic liver disease affecting over two thirds of the obese population and one third of diabetics in US.
  • NAFLD is characterized by significant lipid deposition (steatosis) in the hepatocytes. Growing body of evidence suggests that steatosis may be playing a role in progression of NAFLD to nonalcoholic steatohepatitis (NASH) and fibrosis.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic steatohepatitis
  • NASH nonalcoholic steatohepatitis
  • Insulin-sensitizing agents such as pioglitazone
  • anti-oxidant agents such as vitamin E
  • CDAHFD choline -deficient, L-amino acid- defined, high-fat diet
  • Test comps formulated in specific vehicle and treatment will be given for 6- 8 weeks.

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Abstract

Present invention describes synergistic composition comprising compound of formula (I) and at least one additional therapeutic agents such as ezetimibe, eicosapentaenoic acid, nicotinic acid derivatives and bempedoic acid derivatives, salt thereof. Invention also describes use of synergistic composition for the treatment or prevention of a disease or condition such as metabolic disorder and cardiovascular diseases.

Description

PHARMACEUTICAL COMPOSITIONS FOR COMBINATION THERAPY
FIELD OF THE INVENTION
The present invention describes a pharmaceutical composition comprising combination of PPAR agonist compound of formula (I) and at least one additional therapeutic agent or pharmaceutically acceptable salts thereof selected from Ezetimibe, ethyl ester of eicopentanoic acid, Nicotinic acid derivative, Bempedoic acid. The pharmaceutical composition comprising, the therapeutically effective amount of PPAR agonist compound of formula (I) and at least one additional therapeutic agent along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient. The present application relates use of pharmaceutical composition for the treatment or prevention of a disease or condition such as metabolic disorder and cardiovascular disease.
BACKGROUND OF THE INVENTION
Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dislipidemia, congestive heart failure and stroke. A need exists for improved treatments for cardiovascular diseases and disorders.
Hyperlipidemia has been recognized as the major risk factor in causing cardiovascular diseases due to atherosclerosis. Atherosclerosis and other such peripheral vascular diseases affect the quality of life of a large population in the world. The therapy aims to a reduction in LDL-C levels compared to baseline; increased HDL-C levels compared to baseline; reduced Apo B levels compared to baseline; an increase in apo A-I/apo B ratio compared to baseline; a reduction in total cholesterol reduced triglyceride levels compared to baseline; reduced low density lipoprotein in order to prevent or reduce the risk of occurrence of cardiovascular diseases.
Hypolipidemic agents which are PPAR modulators have been disclosed in WO 91/19702, WO 94/01420, WO 94/13650, WO 95/03038, WO 95/17394, WO 96/04260, WO 96/04261, WO 96/33998, WO 97/25042, WO 97/36579, WO 98/28534, WO 99/08501, WO 99/16758, WO 99/19313, WO99/20614, WO 00/23417, WO 00/23445, WO 00/23451, WO 01/53257. WO 03009841 discloses compounds of the following general formula:
Figure imgf000003_0001
These compounds are reported to be hypolipidemic agents. WO 03009841 also discloses certain salts including the sodium salt of some of the compounds disclosed therein.
WO 2012104869 discloses Magnesium salt of compound of Formula (I) and its being effective in the treatment of lipohypertrophy, lipoatrophy and metabolic abnormalities in HIV patients. WO 20020044361 discloses the pure form of eicosapentaenoic acid (EPA) and WO9508532 discloses the drug product Ezetimibe. WO02058685 also disclosed combination of Ezetimibe with Fenofibrate or Simvastatin. US6818229 and US2843786 discloses the process for the preparation of Nicotinic acid. WO 2004067489 discloses Bempedoic acid.
Present invention provides synergistic composition of compound of formula (I) in combination with one or more therapeutic agents as describes herein after.
Figure imgf000003_0002
In a preferred embodiment one or more therapeutic agents is cholesterol-absorption inhibitors and selected from Ezetimibe, eicosapentaenoic acid (EPA) and Nicotinic acid derivative (Niacin), Bempedoic acid or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof. It has now surprisingly been found that compound of formula (I) in combination with a Ezetimibe or EPA or Nicotinic acid derivative (Niacin) or Bempadoic acid provides a particularly beneficial effect on cholesterol reduction with no observed adverse effects; such combination is therefore particularly useful for the treatment of metabolic disorder and cardiovascular disease especially hypocholesteremia.
The present invention is also based on the surprising finding that combination of compound of formula (I) with ezetimibe or that combination of compound of formula (I) with eicosapentaenoic acid (EPA), or that combination of compound of formula (I) with Nicotinic acid derivative (Niacin) or that combination of compound of formula (I) with Bempadoic acid, a pharmaceutically acceptable ester, derivative, conjugate or salt thereof can be used to treat or prevent metabolic disorder and cardiovascular disease, without increasing the risk for any side effects.
EMBODIMENTS OF THE INVENTION
In an embodiment of the present invention is provided synergistic combination comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with ezetimibe or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with ezetimibe for the treatment of cardiovascular and its associated diseases.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with ezetimibe or pharmaceutically acceptable salts thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent. In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with ezetimibe pharmaceutically acceptable salts thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agents.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agents for the treatment of cardiovascular and its associated diseases.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients. In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin), pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin), pharmaceutically acceptable excipients and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe for the treatment of cardiovascular and its associated diseases. In another embodiment of the present invention is provided a process for the preparation of synergistic composition comprising compound of formula (I) and ezetimibe or eicosapentaenoic acid or nicotinic acid derivative or bempedoic acid.
In another embodiment is provided a pharmaceutical composition comprising the compound of formula (I) and Ezetimibe or compound of formula (I) and EPA or compound of formula (I) and Nicotinic acid (Niacin) or compound of formula (I) and bempedoic acid prepared according to the present invention for the treatment of cardiovascular disorder in humans and other mammals in need thereof.
In a still further embodiment is provided a pharmaceutical composition comprising, the therapeutically effective amount of the compound of formula (I) and Ezetimibe or compound of formula (I) and eicosapentaenoic acid (EPA) or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof or compound of formula (I) and Nicotinic acid (Niacin) or compound of formula (I) and bempedoic acid prepared according to the present invention, along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention provides a method for treatment and/or prevention of a cardiovascular-related disease. The term "cardiovascular-related disease" herein refers to any disease or disorder of the heart or blood vessels (i.e. arteries and veins) or any symptom thereof. Non-limiting examples of cardiovascular-related disease and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events. As used herein the term 'pharmaceutically acceptable' use embraces both human and veterinary use.
The term "treatment" in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder. The term "prevention" in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
Present invention provides some novel combinations of compound of formula (I).
Figure imgf000008_0001
In an embodiment of the present invention is provided synergistic combination comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
In another embodiment of the present invention is provided pharmaceutical composition comprising compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
In one embodiment of the present invention is provided synergistic combination of compound of formula (I) and Ezetimibe or pharmaceutically acceptable salts thereof.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Ezetimibe or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Ezetimibe and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases. In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of Ezetimibe of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 100 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
In a preferred embodiment daily dose amount of compound of Ezetimibe in range of about 0.1 mg to 10mg and amount of compound of formula (I) in range of 4mg to 10 mg.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Ezetimibe or pharmaceutically acceptable salts thereof and optionally suitable statins as an additional therapeutic agent.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Ezetimibe pharmaceutically acceptable salts thereof and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
In yet another embodiment, the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
In one embodiment of present invention is provided a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and ezetimibe. In another embodiment of the present invention is provided a stable combination is in the form of conjugate or complex of compound of formula (I) and ezetimibe. In another embodiment of the present invention is provided a process for the preparation of a stable premix, co-precipitates of compound of formula (I) and ezetimibe.
In one embodiment of the present invention is provided synergistic combination of compound of formula (I) and eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
In one embodiment, a composition for use in methods of the invention comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA."
The term "pharmaceutically acceptable" in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.
In one embodiment, the EPA comprises all-cis eicosa-5, 8, 11 14,17-pentaenoic acid.
In another embodiment, the EPA comprises an eicosapentaenoic acid ester. In another embodiment, the EPA comprises a C1-C5 alkyl ester of eicosapentaenoic acid. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In another embodiment, the EPA comprises In one embodiment, the EPA comprises all-cis eicosa-5, 8, 11,14, 17-pentaenoic acid ethyl ester. In another embodiment, the EPA is in the form of ethyl - EPA, lithium EPA, mono-, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA. The EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of EPA or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, or mixtures thereof about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about
1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about
1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about
1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about
1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about
1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about
1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about
2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about
2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about
2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
In a preferred embodiment daily dose amount of eicosapentaenoic acid (EPA) of about in range of 1000 mg to 5000mg and amount of compound of formula (I) in range of 4mg to 10 mg. In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and optionally suitable statins as an additional therapeutic agents.
In a still further embodiment of the invention is provided a synergistic composition comprising compound of formula (I) with eicosapentaenoic acid (EPA), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof and optionally suitable statins as an additional therapeutic agents for the treatment of cardiovascular and its associated diseases.
Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
In yet another embodiment, the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
In one embodiment of present invention is provided a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and eicosapentaenoic acid (EPA). In another embodiment of the present invention is provided a stable combination is in the form of conjugate or complex of compound of formula (I) and eicosapentaenoic acid (EPA). In another embodiment of the present invention is provided a process for the preparation of a stable premix, co-precipitates of compound of formula (I) and eicosapentaenoic acid (EPA).
In one embodiment of the present invention is provided synergistic combination of compound of formula (I) and Nicotinic acid (niacin), or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients. In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of nicotinic acid derivatives (Niacin) of about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about
1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about
1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about
1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about
1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about
1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about
1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about
2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about
2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about
2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
In a preferred embodiment daily dose amount of nicotinic acid derivatives (Niacin) of in range of 1000-2000 mg and amount of compound of formula (I) in range of 4 mg to 10 mg. In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and optionally suitable statins as an additional therapeutic agent.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with Nicotinic acid derivative (Niacin) and optionally suitable statins as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
Suitable statin used is selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like.
In yet another embodiment, the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
In one embodiment of present invention is provided a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and Nicotinic acid derivative (Niacin). In another embodiment of the present invention is provided a stable combination is in the form of conjugate or complex of compound of formula (I) and Nicotinic acid derivative (Niacin). In another embodiment of the present invention is provided a process for the preparation of a stable premix, co-precipitates of compound of formula (I) and Nicotinic acid derivative (Niacin).
In an embodiment there is provided a combination of synergistic compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof and pharmaceutically acceptable excipients for the treatment of cardiovascular and its associated diseases. In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose amount of compound of bempedoic acid of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 180 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
In a preferred embodiment daily dose amount of bempedoic acid is in range 4 mg to about 180 mg , amount of Ezetimibe is about in range of 0.1 mg to 10mg and amount of compound of formula (I) in range of 4mg to 10 mg.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent.
In one embodiment of the present invention is provided a synergistic composition comprising compound of formula (I) with bempedoic acid or a pharmaceutically acceptable ester derivative, conjugate or salt thereof, pharmaceutically acceptable excipients and optionally ezetimibe as an additional therapeutic agent for the treatment of cardiovascular and its associated diseases.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of bempedoic acid of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 180 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg. In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of Ezetimibe of about 1 mg to about 500 mg, 2 mg about 400 mg, about 3 to about 250 mg, about 4 mg to about 100 mg, or about 5 mg to about 50 mg and 10 mg to about 25 mg.
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of compound of formula (I) of about 0.1 mg to about 100 mg, 1 mg about 50 mg, about 2 to about 25 mg, about 4 mg to about 10 mg.
In a preferred embodiment daily dose of bempedoic acid is 4 mg to about 180 mg , amount of Ezetimibe is about 0.1 mg to 10mg and amount of compound of formula (I) of about 4mg to 10 mg.
In yet another embodiment, the pharmaceutically acceptable excipients generally are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
In one embodiment of present invention is provided a stable combination is in the form of premix or co-precipitates or of compound of formula (I) and bempedoic acid and optionally ezetimibe. In another embodiment of the present invention is provided a stable combination is in the form of conjugate or complex of compound of formula (I) and bempedoic acid and optionally ezetimibe. In another embodiment of the present invention is provided a process for the preparation of a stable premix, co-precipitates of compound of formula (I) and bempedoic acid and optionally ezetimibe.
Present invention also discloses synergistic composition of bempedoic acid and additional therapeutic agents selected from statins such as Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin and the like, thyroid hormone beta receptor agonist, cholesterol-absorption inhibitors, FXR agonist semi-synthetic bile acid analogue or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. Additional therapeutic agents selected from thyroid hormone beta receptor agonist, cholesterol- absorption inhibitors, FXR agonist semi-synthetic bile acid analogue are as described below:
As herein used the term ZYT1 means N-(3,5-dichloro-4-((6-hydroxy-[1,1'-biphenyl]-3- yl)oxy)phenyl)-N-((4-hydroxyphenoxy)carbonyl)glycine and has the chemical formula:
Figure imgf000017_0001
As herein used the term ‘Axitirome’ means 2-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
Figure imgf000017_0002
As herein used the term ‘Sobiterome’ or ‘GC-1’ means 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy) acetic acid and has the chemical formula:
Figure imgf000017_0003
As herein used the term ‘KB-141’ means 2-(3,5-dichloro-4-(4-hydroxy-3- isopropylphenoxy)phenyl)acetic acid and has the chemical formula:
Figure imgf000017_0004
As herein used the term ‘Eprotirome’ or KB-2115 means 3-((3,5-dibromo-4-(4-hydroxy-3- isopropylphenoxy)phenyl)amino)-3-oxopropanoic acid and has the chemical formula:
Figure imgf000018_0001
As herein used the term ‘CO-23’ means 5-(4-(4-hydroxy-3-isopropylphenoxy)-3,5- diiodobenzyl)imidazolidine-2,4-dione and has the chemical formula:
Figure imgf000018_0002
As herein used the term ‘MB07811' means (2R,4S)-4-(3-chlorophenyl)-2-((4-(4-hydroxy-3- isopropylbenzyl)-3,5-dimethylphenoxy)methyl)-1,3,2-dioxaphosphinane 2-oxide and has the chemical formula:
Figure imgf000018_0003
As herein used the term ‘MB07344’ means ((4-(4-hydroxy-3-isopropylbenzyl)-3,5- dimethylphenoxy)methyl)phosphonate and has the chemical formula:
Figure imgf000018_0004
As herein used the term ‘ICI-164384’ means N-butyl- 11-((7R,13S,17S)-3,17-dihydroxy-13- methyl-7,8,9, 11 , 12, 13, 14, 15, 16, 17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-N- methylundecanamide and has the chemical formula:
Figure imgf000018_0005
As herein used the term ‘GC-24’ means 2-(4-(3-benzyl-4-hydroxybenzyl)-3,5- dimethylphenoxy) acetic acid and has the chemical formula:
Figure imgf000019_0001
As herein used the term ‘GC-14’ means 2-(4-(4-hydroxy-3-isopropyl-5-(3-nitrobenzyl)benzyl)- 3,5-dimethylphenoxy)acetic acid and has the chemical formula:
Figure imgf000019_0002
As herein used the term ‘Triac’ means 2-(4-(4-hydroxy-3-iodophenoxy)-3-iodo-5- methylphenyl)acetic acid and has the chemical formula:
Figure imgf000019_0003
As herein used the term ‘SKF-94901’ means (S)-2-amino-3-(3,5-dibromo-4-(4-hydroxy-3-((6- oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)phenyl)propanoic acid and has the chemical formula:
Figure imgf000019_0004
As herein used the term ‘KAT-681' means 3-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-3-oxopropanoic acid and has the chemical formula:
Figure imgf000020_0001
As herein used the term ‘CG23245’ means 2-((4-(4-hydroxy-3-isopropylphenoxy)-3,5- dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
Figure imgf000020_0002
As herein used the term ‘CG26214’ means 2-((4-(3-((4-fluorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)-3,5-dimethylphenyl)amino)-2-oxoacetic acid and has the chemical formula:
Figure imgf000020_0003
As herein used the term ‘Resmetirom’ or ‘MGL-3196’ means 2-(3,5-dichloro-4-((5-isopropyl-6- oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- carbonitrile and has the chemical formula:
Figure imgf000020_0004
In a related embodiment, upon treatment in accordance with the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week. In the treatment, the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day. Also, the dosages of each particular active agent in any given composition can as required vary within a range of doses known to be required in respect of accepted dosage regimens for that compound. Dosages of each active agent can also be adapted as required to take into account advantageous effects of combining the agents as mentioned herein.
Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dosage presentation forms for oral administration may be in tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants and wetting agents.
The solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, a preservative and buffering agent can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the active compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
Examples of binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
Examples of fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
Examples of lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
Examples of glidants include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.
Examples of disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
Example of wetting agents include, by way of example and without limitation, poloxamers, gelatin, casein, Glycerol mono-oleate, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, sodium lauryl sulphate, sodium dodecyl sulfate, salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.), cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxy methylcellulose sodium, methyl cellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxy propyl methyl cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and poly vinyl pyrrolidone (PVP) & their suitable combinations and other such materials known to those of ordinary skill in the art. Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent which may be used.
Synergistic pharmaceutical composition described in present invention are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubilizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances. In some aspects the solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use. No adverse toxicological effects were seen for the compositions or methods of the invention in the above mentioned dosage ranges. Further the composition of the present invention was found suitable for the treatment of diabetes and its associated disorders without increasing the risk for fluid retention, peripheral edema, pulmonary edema, or congestive heart failure.
The subject or subject group exhibits one or more of the following outcomes:
1. A reduction in LDL-C levels compared to baseline;
2. Increased HDL-C levels compared to baseline;
3. Reduced Apo B levels compared to baseline;
4. An increase in apo A-I/apo B ratio compared to baseline;
5. A reduction in total cholesterol
6. Reduced triglyceride levels compared to baseline;
7. Reduced low-density lipoprotein In an embodiments a less than 60% increase, a less than 50% increase, a less than 40% increase, a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in LDL-C levels or a reduction in LDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline.
In an embodiments substantially no change in HDL-C levels, no change in HDL-C levels, or an increase in HDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline.
In an embodiments a decrease in Apo B levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline.
In an embodiments an increase in apo A-I levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline. An increase in apo A-I/apo B ratio of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline.
In an embodiments a reduction in total cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline. In an embodiments a reduction in triglyceride level of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline.
No adverse toxicological effects were seen for the compositions or methods of the invention in the above mentioned dosage ranges. Further the composition of the present invention was found suitable for the treatment of diabetes and its associated disorders without increasing the risk for fluid retention, peripheral edema, pulmonary edema, or congestive heart failure
Instrument details
Mass spectrum was recorded on LC-MS 2010- A Shimadzu.
HPLC purity was determined by using Agilent 1100 instrument.
HPLC Column: YMC J Sphere C18 (150X4.6 mm) x 4m Mobile phase: 0.05 % TFA in water: ACN gradient.
Flow rate: 1.0 mL/min.
Wave length: UV at 220 nm.
UPFC was determined on Acquity Ultra performance instrument.
UPFC Column: BEHC18 (2.1x100 mm) xl.7 m Mobile phase: 0.05 % TFA in water: ACN gradient.
Flow rate: 0.04 ml/min
NMR spectrum: Bruker Avanc 400 mHz
Composition of Ezetimibe was prepared as provided in WO 2002058732. Niacin composition prepared as per W02007120385 while composition of EPA was adapted from WO 2010127103. The composition of Bempedoic acid was adapted from US 20180338922. The scope of invention is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge, which are within the general understanding of a person skilled in the art. Further the pharmacological studies of the described synergistic composition on various animal models and is undergoing to study effect of various effects of described composition. Other synergistic compositions described in the invention were prepared as per methods provided in literature and known to person skilled in art. Or therapeutic agents were administered to subject independently, parallel or simultaneously.
PHARMACOLOGICAL DATA Efficacy of Compound of formula (I) and other therapeutic agent (Bempedoic acid) alone and as combination in Non-Alcoholic Steatohepatitis (NASH) Induced by CDAHFD (Choline Deficient, L-Amino Acid-Defined, High-Fat Diet) in Male C57 Mice.
Nonalcoholic fatty liver disease (NAFLD) is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis, lobular inflammation and progressive pericellular fibrosis in liver. Non-alcoholic steatohepatitis (NASH) is a progressive fibrotic disease, the pathogenesis of which has not been fully elucidated. One of the most common animal models used in NASH research is a nutritional model where NASH is induced by feeding a diet deficient in both methionine and choline. However, the dietary methionine-/choline deficient model in mice can cause severe weight loss and liver atrophy, which are not characteristics of NASH seen in human patients. The CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) model overcomes these problems to study the development of NASH-induced fibrosis, and this model has been demonstrated to mimic human NASH in both mice and rats by sequentially producing steatohepatitis, liver fibrosis and liver cancer without any loss of body weight mice . C57BL/6J mice fed with CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) has increase hepatic steatosis due to impaired hepatic VLDL-TG secretive capacity and causes hepatic insulin resistance due to fat accumulation and TNF-a activation in liver. It was reported that, 6-8 weeks CDAHFD feeding develops NASH in C57 mice (Matsumoto et al., 2013, I nr. J. Exp. Path.) which was confirmed in our in-house studies also. To study the effect of Compound I (a) and its combination, we used intervention study protocol which will be relevant to the treatment of NASH in human. In this study we established the NASH by feeding CDAHFD for 8 weeks.
Methods
C57BL/6 mice were fed the CDAHFD diet for 8 weeks and were bled for the measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Those animals with elevated serum ALT (> 10-fold) and AST (> 4-fold) levels were enrolled in the study and put on vehicle or test compound and then treatment was given for 8 weeks, as per below table.
Table no.l: Treatment groups and dose levels
Figure imgf000028_0001
After 8 weeks of treatment (i.e. 16 weeks of diet), 1 h post dose, blood samples were collected for estimation of non-fasted serum ALT and AST levels. All the animals were sacrificed; liver were quickly removed, weighed and fixed in 10 % formalin for histological analysis or snap frozen in liquid nitrogen for other assays like liver lipids (TG) analysis to evaluate the effect on steatosis.
Light microscopic examination of liver tissue was performed using standard hematoxylin and eosin (H&E) staining. Hepatic fibrosis was accessed by masson’s trichrome staining method. Liver specific tissue macrophages i.e.kupffer cells was visualized in liver sections stained with the diastase-periodic acid-schiff method. Fat deposition, if any was demonstrated using oil red - O staining technique on 10 % formalin fixed tissue. Specimens were scored as per the scoring method described by Kleiner et al (Hepatology 2005;41:1313-1321) for the NAFLD Activity Score (NAS). Results
At the end of 16 weeks, the disease control animals that are fed only CDAHFD exhibited significant 14 fold and 5 fold increases in serum ALT, AST levels, compared with animals fed a normal control diet respectively. These changes was accompanied with 6 fold increase in intrahepatic triglyceride and 7 fold increase in hepatic cholesterol levels accumulation and presence of NASH histologically.
The mice treated with Compound of formula (I) at 0.8 mg/kg, p.o. showed 71% reduction in serum ALT and 64% reduction in serum AST level respectively as compared to vehicle control group. Treatment with bempedoic acid showed 20% and 22% reduction in serum ALT and AST level respectively as compared to vehicle control. When Compound of formula (I) was administered in combination with bempedoic acid the reduction in serum ALT and AST levels were 39% and 37% respectively as compared to vehicle control. (Table 2 and Table 3)
Compound of formula (I) treatment for 8 week showed a significant reduction in liver lipid levels which was 72% in liver TG and 77% in liver TC levels. Bempedoic acid showed a 37 and 44% reduction in liver TG and TC levels respectively as compared to vehicle control. The effect in combination group also shows significant decrease in liver lipids levels which was 74% and 78% in liver TG and TC respectively. (Table 4 and Table 5)
Liver histology showed a total NASH score of 9.4 in the vehicle control group. Compound of formula (I) treatment for a period of 8 week resulted in 44% reduction in the total NASH score vs vehicle control whereas bempedoic acid showed a 2% rise in total NASH score. Combination of Compound I (a) with bempedoic acid showed 52% reduction in the total NASH score as compared to vehicle control. (Table 6)
Table 2: Effect on serum ALT
Figure imgf000029_0001
Figure imgf000030_0001
Table 3: Effect on serum AST
Figure imgf000030_0002
Table 4: Effect on liver triglyceride
Figure imgf000030_0003
Figure imgf000031_0002
Table 5: Effect on liver total cholesterol
Figure imgf000031_0001
Table 6: Effect on liver histology
Figure imgf000031_0003
Conclusion:
Treatment with Compound of formula (I) as well as bempedoic acid showed improvement in the NASH serum and liver biomarkers. Similar effect was observed with their combination. When the liver histology was considered, compound of formula I showed a significant reduction in total NASH score while bempedoic acid alone failed to show any improvement in total NASH score. Combination of Compound of formula I with bempedoic acid showed synergistic reduction in the total NASH score. Evaluation of effect on lipid , glucose and atherogenic dyslipidemia (TG/HDL-C) ratio after treatment with Compound (I), co -administration of Compound (I) + Bempedoic acid in Syrian Golden Hamsters
Dyslipidemia is one of the major pathophysiological conditions commonly associated with the consumption of a calorie -rich western diet, which can, over time, lead to severe health complications including the metabolic syndrome, type2 diabetes, and cardiovascular disease. Cholesterol overconsumption as part of the western diet has been linked to multiple pathological conditions. Addition of dietary cholesterol to a high-fat/high-fructose diet has been shown to exacerbate symptoms of the metabolic syndrome including increased fasting plasma lipids, hepatic steatosis, and insulin resistance. The golden Syrian hamster has been increasingly utilized to do research on lipoprotein metabolism and to investigate the effects of hypolipidemic agents such as PPAR agonists, statins and CETP inhibitors because of its similarity to human in terms of lipid utilization and high susceptibility to dietary cholesterol.
To study the effect of Compound of formula (I) and its combination, we used intervention study protocol which will be relevant to the treatment of hyperlipidemia in human. In this study we established the hyperlipidemia in hamsters by feeding high fat -high cholesterol and high fructose diet for 2 weeks.
Methods
Syrian golden hamsters at the age of 21 to 23 weeks were used. Animals were fed with high-fat, high-cholesterol (0.5%) with 10% fructose diet for 2 weeks. After two weeks of diet, body weight of animals was recorded and blood collection was performed from retro orbital plexus under isoflurane anesthesia for serum triglyceride (TG), total cholesterol (TC), and LDLc levels. Those animals with elevated (> 2-fold vs normal control) serum TC and LDLc levels were enrolled in the study and administered vehicle or test compound as per table no.l Treatment was given by oral gavage once a day daily for 15 days along with diet.
Table no. 7: Treatment groups and dose levels
Figure imgf000033_0001
After 15 days of treatment, 1 -h post dose, blood samples were collected for estimation of non- fasted serum TC,TG and LDLc levels and compared with the vehicle control.
Results
At the end of 15 days, the vehicle control animals exhibited significant 2.9 fold increases in serum TG levels, compared with normal control. The animals treated with Compound (la) at 1 mg/kg, p.o. showed 35% reduction in serum TG but no reduction in serum TG was observed in bempedoic acid treatment group. Group treated with Compound (la) and bempedoic acid combination showed 54% reduction in serum TG level as compared to vehicle control. (Table 8)
HF-HC diet with 10% fructose feeding resulted in 2.8 fold increase in serum total cholesterol level as compared to normal control. Oral administration of Compound (la) for a period of 15 days resulted in 25% reduction in serum total cholesterol level. Treatment with bempedoic acid showed 8% increase in serum total cholesterol level as compared to vehicle control. Combination of Compound (la) with bemepdoic acid showed 34% reduction serum total cholesterol level as compared to vehicle control. (Table 9). Compound 1(a) treatment showed statistically significant, 28% reduction in serum LDLc level. Combination of Compound (la) with bempedoic acid showed 38% reduction in LDLc level. (Table 10).
Table 8: Effect on serum Triglyceride
Figure imgf000034_0001
Table 9: Effect on serum Total cholesterol
Figure imgf000034_0002
Figure imgf000035_0001
Table 10: Effect on serum LDLc level
Figure imgf000035_0002
Conclusion:
Oral administration of Compound 1(a) showed significant reduction in serum TG ,TC and LDLc levels, but bempedoic acid alone failed to show any significant reduction in serum TG,TC and LDLc. When Compound 1(a) was administered in combination with bempedoic acid, a synergistic reduction in the serum level of TG,TC and LDLc was observed. Evaluation of effect on lipid , glucose and atherogenic dyslipidemia (TG/HDL-C) ratio after treatment with Compound (I), co-administration of Compound (I) + Ezetimibe and co-administration of Compound (I) + Eicosapentaenoic acid (EPA) in hCETP/APOB100 DTG mice model. Compounds having hypolipidemic activity need to be screened in hCETP/APOB100 DTG mice as these mice has the lipoprotein cholesterol distribution similar to human so for screening the anti-dyslipidemic activity before human this animal usage is necessary.
In this experiment, 6 to 12 week old male/ female hCETP/APOB100 dtg mice will be issued and kept on chow fed diet. On day 0 body weight of animals will be recorded, non-fasting serum lipid profile [Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride] estimated and animals grouped on basis of non-fasting serum LDL-C as primary parameter.
Table No. 11
Figure imgf000036_0001
Test compounds will be formulated at specified doses in vehicle and animals will be dosed orally, once daily for seven to fourteen days, starting from next day of grouping with vehicle or test compound. The animals will be weighed prior to dosing, and based on these weights; the volume of administration will be calculated. The volume of formulation administered to each mouse will be 10 ml/kg body weight.
On day 7 and day- 14 one -hr after the dose administration, blood (0.25 ml) will be collected from retro-orbital sinus of the anaesthetized animals. Serum will be separated by centrifugation. Serum lipid profile (Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride) analysis performed in Randox Daytona biochemical analyzer. We will evaluate various lipid parameters along with atherogenic dyslipidemia (TG/HDL-C) ratio.lt is also known that atherogenic dyslipidemia (AD) which poses a cardiovascular risk (CV) risk due to elevated TG levels and accompanied by low HDL-C. AD is associated with insulin resistance (IR), and confers a marked increasein residual vascular risk, even when LDL-C is low (Hermans et al. 2010, Cardiovasc Diabetol 9: 88-97). It has been reported that TG/HDL-C ratio may be used as a surrogate marker for assessing CV risk (Hermans et al. 2010, Cardiovasc Diabetol 9: 88-97; Nicholls et al.2011, J Am Coll Cardiol 57: 153-159). The % change in Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride and TG/HDL-C ratio vs vehicle control group will be calculated using MS Excel software. Evaluation of effect on lipid , glucose and atherogenic dyslipidemia (TG/HDL-C) ratio after treatment with Compound (I), co-administration of Compound (I) + Ezetimibe and co-administration of Compound (I) + Eicosapentaenoic acid (EPA) in high fat diet induced dyslipidemic male C57 mice model.
The in-vivo efficacy of test compound have been evaluated in high fat diet fed dyslipidemic male C57 mice. The male C57 mice are susceptible to high fat diet induced obesity and show increase lipids and also respond to drugs intended for treatment of hypercholesterolemia. Therefore, this species is preferred for evaluation of their efficacy in lowering circulating lipid levels.
In this experiment, seven to nine week old male C57 mice issued and kept for 8 to 12- weeks of high fat diet (60 Kcal%, D12492, Research Diet Inc.). On day 0 body weight of animals recorded, non-fasting serum lipid profile [Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol and triglyceride] estimated and animals grouped on basis of non-fasting serum LDL-C as primary parameter.
Table no. 12- Treatment groups and dose levels
Figure imgf000037_0001
Figure imgf000038_0001
Test compounds formulated in appropriate vehicle at specified doses to make the uniform suspension. The animals have been dosed orally, once daily for seven days, starting from next day of grouping with vehicle or test compound. The animals were weighed prior to dosing, and based on these weights; the volume of administration will be calculated. The volume of formulation administered to each mouse will be 10 ml/kg body weight. On day 7, one -hr after the dose administration, blood (0.25 ml) will be collected from retro-orbital sinus of the anaesthetized animals. Serum will be separated by centrifugation. Serum lipid profile (Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride) analysis performed in Randox Daytona biochemical analyzer.
Various lipid parameters along with atherogenic dyslipidemia (TG/HDL-C) ratio would be evaluated .It is also known that atherogenic dyslipidemia (AD) which poses a cardiovascular risk (CV) risk due to elevated TG levels and accompanied by low HDL-C. AD is associated with insulin resistance (IR), and confers a marked increase in residual vascular risk, even when LDL- C is low (Hermans et al. 2010, Cardiovasc Diabetol 9: 88-97). It has been reported that TG/HDL-C ratio may be used as a surrogate marker for assessing CV risk (Hermans et al. 2010, Cardiovasc Diabetol 9: 88-97; Nicholls et al.2011, J Am Coll Cardiol 57: 153-159). The % change in Low density cholesterol (LDL-C), High density cholesterol (HDL-C), total cholesterol, triglyceride and atherogenic dyslipidemia (TG/HDL-C) ratio vs vehicle control group will be calculated using MS Excel software. Antidiabetic activity of Compound (I), co-administration of Compound (I) + Ezetimibe and co-administration of Compound (I) + Eicosapentaenoic acid (EPA) in db/db mice model
The in-vivo efficacy for antidiabetic activity has been done db/db mice of 13-14 weeks of age. Generally obese and diabetic animals are insulin resistant and have abnormalities in glucose and lipid metabolism. The development of diabetes and beta cell dysfunction in these animal models closely parallels the pathophysiology of the disease condition in humans. The db/db mouse exhibits an initial phase of hyperinsulinemia, hyperphagia and obesity. They progressively develop into insulinopenia with age, a feature commonly observed in last stage of type-2 diabetes, when blood sugar levels are insufficiently controlled. Therefore, this genetic model proves to be suitable for predicting the likely therapeutic benefit of novel euglycemic agents in human type-2 diabetes.
In this experiment, male/ female db/db mice of 13-14 week were divided into 6 groups based on their day 0 serum glucose levels as per Table no.1. Vehicle Control group will be treated with vehicle and other groups with treatment mentioned in Table no.12 The treatment has been given oral gavages once daily for 14 days.
Table No. 12
Figure imgf000039_0001
The blood collected by retro-orbital sinus puncture method under isoflurane anesthesia on day 0 (pretreatment) and on day 12 for non-fasting glucose analysis. Oral glucose tolerance test (OGTT) performed on day 14 of the treatment in fasting condition. After blood collection serum separated and analyzed glucose analysis using Biotek and commercial diagnostic kits. The OGTT procedure followed is as given below-
Oral Glucose Tolerance Test (OGTT): One day before OGTT all animals kept on overnight fasting and on the day of OGTT, day 14 of the treatment each animal dosed with a single dose of vehicle/test compounds administered orally and 60-min post dosing blood will be collected (0 min) and glucose load (1-2gm/kg/10ml) administered per orally. Blood then collected at time points corresponding to 30, 60 and 120 min after glucose load administration. Serum separated and analyzed for glucose using Biotek plate reader and commercial diagnostic kits.
The calculation for antidiabetic activity i.e. effect on serum glucose and improvement in glucose Area under Curve (AUC) calculated using the excel sheet and Graph Pad Prism software. The day 0 and day 12 glucose values of vehicle control and treatment will be considered for calculating the effect on serum glucose. The effect on glucose AUC calculated using the OGTT glucose levels at different time points and the improvement in glucose AUC i.e. the reduction in glucose AUC after the treatment estimated. HOMA index calculated from fasting glucose and insulin levels for drug alone and combination groups. Evaluation of effect on Nonalcoholic Fatty Liver Disease (NAFLD) nonalcoholic steatohepatitis (NASH) after treatment with Compound (I), coadministration of Compound (I) + Ezetimibe and co-administration of Compound (I) + Eicosapentaenoic acid (EPA) in Choline-deficient, L-Amino Acid- Defined, High-Fat Diet (CDAHFD) induced NASH in C57/BL6 Mice.
Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease affecting over two thirds of the obese population and one third of diabetics in US. NAFLD is characterized by significant lipid deposition (steatosis) in the hepatocytes. Growing body of evidence suggests that steatosis may be playing a role in progression of NAFLD to nonalcoholic steatohepatitis (NASH) and fibrosis. NAFLD is mostly accompanied by central obesity and/or diabetes. Several pharmacological agents have been studied with the aim of improving insulin sensitivity and reducing the pro-inflammatory mediators potentially involved in the development and progression of NASH. Insulin-sensitizing agents, such as pioglitazone, and anti-oxidant agents, such as vitamin E, have shown some promise in improving liver histology in patients with NASH. Unfortunately, they did not show efficacy in large randomized clinical trials. Although number of therapeutic options has been explored for management of NAFLD/NASH, no pharmacological treatment is yet approved. Methods
NASH induced in C57BL/6 male mice by feeding them a choline -deficient, L-amino acid- defined, high-fat diet (CDAHFD) at the age of 6 to 8 weeks. After 8 weeks of CDAHFD diet and treatment, blood collection performed for serum ALT, AST and, TG and on the basis serum ALT level animals divided in to following groups-
Table No. 13
Figure imgf000041_0001
Test comps formulated in specific vehicle and treatment will be given for 6- 8 weeks.
After 6-8 weeks of dose administration along with diet, blood collection performed after 1 hour of dosing under isoflorane anesthesia for the measurement of serum ALT, AST and TG using Randox Daytona biochemical analyzer.
We evaluated the effects on various liver injury and inflammation makers (serum ALT , AST and liver lipid and collagen levels ) by biochemical and histological analysis. The % change in ALT, AST, TG and liver lipid levels and collagen levels vs vehicle control group has been calculated using MS Excel software. While the present invention has been described in terms of a few specific aspects, modifications and equivalents thereof, in light of teaching and disclosure of the present invention, which are apparent of the skilled artisan, are to be construed as included within the scope of the invention.

Claims

We claim:
1. Synergistic combination comprising compound of formula (I)
Figure imgf000042_0001
and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid.
2. Pharmaceutical composition comprising synergistic combination of compound of formula (I) and Ezetimibe or eicosapentaenoic acid (EPA) or Nicotinic acid (Niacin) or bempedoic acid as claimed in claim 1 and pharmaceutically acceptable excipients.
3. Pharmaceutical composition as claimed in claim 2 comprising synergistic combination of compound of formula (I), Ezetimibe, optionally suitable additional therapeutic agent and pharmaceutically acceptable excipients.
4. Pharmaceutical composition as claimed in claim 3 wherein amount of Ezetimibe is in range of 0.1 mg to 10mg and compound of formula (I) in range of 4mg to 10mg.
5. Pharmaceutical composition as claimed in claim 3 wherein suitable additional therapeutic agent is statins selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin.
6. Pharmaceutical composition as claimed in claim 3 wherein pharmaceutically acceptable excipients are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
7. Pharmaceutical composition as claimed in claim 3 is for the treatment of cardiovascular and its associated diseases.
8. Pharmaceutical composition as claimed in claim 2 comprising synergistic combination of compound of formula (I), eicosapentaenoic acid (EPA), optionally suitable additional therapeutic agent and pharmaceutically acceptable excipients.
9. Pharmaceutical composition as claimed in claim 8 wherein amount of eicosapentaenoic acid (EPA) is in range of 1000 mg to 5000mg and amount of compound of formula (I) in range of 4mg to 10 mg.
10. Pharmaceutical composition as claimed in claim 8 wherein suitable additional therapeutic agent is statins selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin.
11. Pharmaceutical composition as claimed in claim 8 wherein pharmaceutically acceptable excipients are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
12. Pharmaceutical composition as claimed in claim 8 is for the treatment of cardiovascular and its associated diseases.
13. Pharmaceutical composition as claimed in claim 2 comprising synergistic combination of compound of formula (I), Nicotinic acid (Niacin) and optionally suitable additional therapeutic agent and pharmaceutically acceptable excipients .
14. Pharmaceutical composition as claimed in claim 13, wherein amount of nicotinic acid (Niacin) is in range of 1000-2000 mg and amount of compound of formula (I) in range of 4 mg to 10 mg.
15. Pharmaceutical composition as claimed in claim 13 wherein suitable additional therapeutic agent is statins selected from Atorvastatin, Simvastatin, Rosuvastatin, Pimvastatin.
16. Pharmaceutical composition as claimed in claim 13 wherein pharmaceutically acceptable excipients are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
17. Pharmaceutical composition as claimed in claim 13 is for the treatment of cardiovascular and its associated diseases.
18. Pharmaceutical composition as claimed in claim 2 comprising synergistic combination of compound of formula (I), bempedoic acid, optionally suitable additional therapeutic agent and pharmaceutically acceptable excipients.
19. Pharmaceutical composition as claimed in claim 18 wherein additional therapeutic agent is Ezetimibe.
20. Pharmaceutical composition as claimed in claim 18 wherein amount of bempedoic acid is in range of 4 mg to about 180 mg , amount of Ezetimibe in range of 0.1 mg to 10mg and amount of compound of formula (I) in range of 4mg to 10 mg.
21. Pharmaceutical composition as claimed in claim 18 wherein pharmaceutically acceptable excipients are selected from binding agents, fillers, lubricants, glidants, disintegrants, wetting agents and the like.
22. Pharmaceutical composition as claimed in claim 18 is for the treatment of cardiovascular and its associated diseases.
23. Pharmaceutical composition as claimed in any of preceding claims further comprise pharmaceutically acceptable excipients selected from carrier, diluents, vehicle, wetting agents, disintegrants, glidants, lubricants, fillers, binding agents or excipient.
24. Pharmaceutical composition as claimed in any of preceding claims is in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, suitable for oral administration.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009841A1 (en) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
WO2009074286A2 (en) * 2007-12-10 2009-06-18 Ratiopharm Gmbh Pharmaceutical formulation comprising ezetimibe
AU2009290542A2 (en) * 2008-09-10 2011-03-31 Pronova Biopharma Norge As A polysaccharide capsule enclosing a fatty acid oil-containing emulsion
WO2018218147A1 (en) * 2017-05-26 2018-11-29 Esperion Therapeutics, Inc. Fixed dose formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003009841A1 (en) * 2001-07-26 2003-02-06 Cadila Healthcare Limited Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
WO2009074286A2 (en) * 2007-12-10 2009-06-18 Ratiopharm Gmbh Pharmaceutical formulation comprising ezetimibe
AU2009290542A2 (en) * 2008-09-10 2011-03-31 Pronova Biopharma Norge As A polysaccharide capsule enclosing a fatty acid oil-containing emulsion
WO2018218147A1 (en) * 2017-05-26 2018-11-29 Esperion Therapeutics, Inc. Fixed dose formulations

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