WO2024252410A1 - Composition bioactive synergique pour améliorer l'activité de la voie pink1/parkin - Google Patents

Composition bioactive synergique pour améliorer l'activité de la voie pink1/parkin Download PDF

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WO2024252410A1
WO2024252410A1 PCT/IN2023/051209 IN2023051209W WO2024252410A1 WO 2024252410 A1 WO2024252410 A1 WO 2024252410A1 IN 2023051209 W IN2023051209 W IN 2023051209W WO 2024252410 A1 WO2024252410 A1 WO 2024252410A1
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Rajaram Samant
Manoj Tongra
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Celagenex Research India Pvt Ltd
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Celagenex Research India Pvt Ltd
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    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a synergistic bioactive composition for enhancing activity of PINK 1 /PARKIN pathway.
  • a synergistic bioactive composition comprising a combination of benzo-coumarin compound and at least one cell viability enhancer along with pharmaceutically acceptable excipients.
  • the composition is useful in improving mitochondrial function and cellular metabolism as well as in the treating and managing different disorder such as obesity, diabetes, cancer, liver diseases, sexual dysfunction, neurodegenerative diseases, cardiovascular diseases, osteoarthritis, musculoskeletal diseases, neuromuscular diseases, and kidney diseases.
  • PTEN-induced kinase 1 is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene. It protects cells from stress-induced mitochondrial dysfunction. PINK1 maintains mitochondrial quality control by identifying damaged mitochondria and targeting the same for degradation. Particularly, PINK1 controls mitochondria quality through mitochondrial fission. In the mitochondrial fission, small and round mitochondria are created. Mitochondrial fission promotes the segregation of terminally dysfunctional mitochondria for degradation in the lysosome. Mitochondrial fission is essential for cell growth and division by providing enough new mitochondria and eliminating damaged mitochondria.
  • Parkin is a 465-amino acid protein with a molecular mass of 53kDa that is present in humans and mice, and it is encoded by the PARK2 gene.
  • Parkin is a primarily cytosolic ubiquitin E3 ligase that contains a ubiquitin-like domain.
  • Parkin recognizes proteins on the outer membrane of mitochondria upon cellular insult and facilitates the clearance of damaged mitochondria via proteasomal mechanisms.
  • Parkin also enhances cell survival by suppressing both mitochondria-dependent and -independent apoptosis.
  • Parkin is highly expressed in the heart, testis, brain and skeletal muscle.
  • PINK1 encodes a mitochondrially targeted Ser/Thr kinase and Parkin encodes a ubiquitin-protein ligase which controls the specific elimination of dysfunctional or surplus mitochondria which leads to fine-tuning of mitochondrial network and preserving cellular metabolism.
  • Parkin amplifies a damage detection signal from PINK1 by facilitating the formation of ubiquitin chains, which recruit more Parkin to the mitochondria to exhibit ubiquitination to clear the dysfunctional mitochondria.
  • the main function of the mitochondria is to produce energy. More healthy mitochondria are needed to make more energy for organs such as the heart, muscles, and brain. When mitochondria in the cell are dysfunctional, less energy is produced which results in organ dysfunction. Inadequate mitochondrial activity leads to many health-related conditions such as obesity, fatigue, reduced metabolic rate, metabolic syndrome, diabetes mellitus, impairment of hearing and vision, liver diseases, gastrointestinal diseases, kidney dysfunction, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive disorders, mood disorders, stress, and anxiety disorders.
  • PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) signaling play a key role in mitochondrial motility and size. Mutations in the PINK1/PARKIN signaling pathway disrupt the sensitive homeostatic and quality control processes conducted by mitochondria. PINK1 and PARKIN mutations are responsible for the hereditary neurodegenerative disorder cases, such as Alzheimer, Huntington’s disease, and Parkinson. Further, dysregulation of PINK1/P ARKIN signaling has been associated with neurological disorder, such as amyotrophic lateral sclerosis (ALS) as well as in eye diseases, such as age-related macular degeneration (AMD) which is associated with retinal degeneration.
  • ALS amyotrophic lateral sclerosis
  • AMD age-related macular degeneration
  • WO202 1236981A2 discloses PINK1 and Parkin together protect mitochondria from oxidative stress.
  • PINK1 is translocated into mitochondria via an N-terminal mitochondrial signaling sequence (MTS). Absent mitochondrial stress, PINK1 is proteolytically cleaved within the healthy mitochondria by mitochondrial processing peptidase (MMP) and protease presenilin- associated rhomboid-like protein (PARL).
  • MMP mitochondrial processing peptidase
  • PARL protease presenilin- associated rhomboid-like protein
  • PINK1 fails to fully translocate and instead accumulates at the mitochondrial surface with its transmembrane domain (TMD) embedded in the membrane of the damaged mitochondrial and protected from proteolysis from MMP and PARL.
  • TMD transmembrane domain
  • US 11202795 describes that inhibitors reducing FAS activity can be used for treatment of Parkinson's disease, particularly, the treatment of patients suffering from Parkinson's disease having loss of function mutations in PINK1 or PARKIN genes.
  • US9585945 relates to a composition for preventing or treating an autoimmune disease comprising, as an active ingredient, PTEN-induced kinase 1 (PINK1) protein or polynucleotide encoding the same wherein the autoimmune disease is selected from a group comprised of rheumatoid arthritis, systemic lupus erythematosus, digestive diabetes, atopic dermatitis, autoimmune encephalomyelitis, asthma and Crohn's disease.
  • PINK1 PTEN-induced kinase 1
  • W02007135570A2 provides compositions comprising an agent that mimics the activity of PINK1 in vivo and causes increased parkin expression in PINK1 deficient subjects to reduce mitochondrial related dysfunction.
  • the mitochondrial related dysfunction is evidenced by a phenotype selected from the group consisting of: reduced mitochondrial DNA expression; reduced mitochondrial protein expression; reduced ATP levels in said cell; irregular arrangement of myofibrils; enlarged mitochondria; reduced number of mitochondria organelles in said cell; a decreased anti- tyrosine hydroxylase staining intensity; and a reduced level of dopamine levels.
  • US20220105117 relates to nutritional and medical formulations for treating muscle- related pathological conditions, neurodegenerative diseases, and/or mitochondrial diseases and as dietary supplements, functional foods and beverages, and specialized nutrition or medical foods.
  • EP3278800B 1 relates to use of ellagitannins in the treatment or prevention of a muscle disease, muscle-related pathological condition, a myopathy, a muscular dystrophy, a musculoskeletal disorder, or a neuromuscular disease.
  • PINK 1 -Parkin signaling regulates damage-induced mitochondrial homeostasis.
  • PINKl-Parkin signaling regulates damage-induced mitochondrial homeostasis.
  • PINK1 and PARKIN genes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria. Both proteins act in the same quality control pathway to sense damaged mitochondria and target them for degradation through a specialized form of macro-autophagy, also known as mitophagy. (PLOS ONE, Aaron V. et.al., November 11, 2021).
  • benzo-coumarin compound is a therapeutically active candidate to activate the PINK1/P ARKIN pathway
  • a single dose of benzo-coumarin compound is not much effective for maintaining and improving the mitochondrial function and cellular metabolism.
  • Enhancing cell viability results in the enrichment of the PINK1/P ARKIN pathway, ultimately boosting the activity of this pathway.
  • the primary objective of the present invention is to provide synergistic bioactive compositions for enhancing activity of PINK1/P ARKIN pathway.
  • Another objective of the present invention is to provide bioavailable, safe, non-toxic, rapid acting bioactive composition.
  • Yet another objective of the present invention is to provide synergistic bioactive composition to synergistically activate the PINK1/P ARKIN pathway with no severe adverse effects.
  • Further objective of the present invention is to provide effective composition for oral administration for maintaining and improving the mitochondrial function and cellular metabolism in a therapeutically effective amount for the treatment of diseases associated with the same.
  • Another objective of the present invention is to provide effective composition for the treatment of obesity, diabetes, cancer, liver diseases, sexual dysfunction, neurodegenerative diseases, cardiovascular diseases, osteoarthritis, musculoskeletal diseases, neuromuscular diseases, and kidney diseases.
  • the inventors of the instant invention carried out thorough experiments to establish significant therapeutic effects of the active ingredients or biomolecules or peptides or amino acids or nutrients present in the composition for improving cellular function in a subject in need thereof in safer way.
  • the present invention relates to synergistic compositions comprising therapeutically active ingredients along with pharmaceutically acceptable carriers, diluents or excipients for treating metabolic, neurological, age-related disorders.
  • the present invention provides synergistic composition for enhancing activity of pinkl/parkin pathway, comprising a combination of benzo-coumarin compound or salt thereof and at least one cell viability enhancer or salt thereof which synergistically enhances activity of PINK1/P ARKIN pathway.
  • the composition optionally comprises at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the impairment in activity of PINK1/PARKIN pathway results in diseases such as obesity, diabetes, cancer, liver diseases, sexual dysfunction, neurodegenerative diseases, cardiovascular diseases, osteoarthritis, musculoskeletal diseases, neuromuscular diseases, and kidney diseases.
  • the present invention provides synergistic composition, wherein the benzo-coumarin compound is 3,8-Dihydroxy-6H-dibenzo[b,d]pyran-6-one or its salt thereof.
  • the present invention provides synergistic composition, wherein the at least one cell viability enhancer is selected from the group consisting of N,N,N- trimethylglycine, Oxobutanedioic acid, (R)-2-Amino-3-prop-2-enylsulfanylpropanoic acid, 2- Oxopentanedioic acid, 3-Amino-2-methylpropanoic acid, (3p,5p,7a,12a)-7,12-Dihydroxy-3- (icosanoylamino)cholan-24-oic acid, dileucine, (2Z,4E)-5-[(lS)-l-hydroxy-2,6,6-trimethyl-4- oxocyclohex-2-en-l-yl]-3-methylpenta-2,4-dienoic acid, (2S)-2-[[(2S)-2- hydroxypropanoyl]amino]-3-phenylpropanoic acid, Pentadecanoic
  • the present invention discloses a synergistic composition is useful in improving mitochondrial function and cellular metabolism.
  • PINK1 PTEN-induced kinase 1
  • PTEN Phosphatase and tensin homolog
  • ALS amyotrophic lateral sclerosis
  • AMD age-related macular degeneration
  • MMP mitochondrial processing peptidase
  • PARL protease presenilin- associated rhomboid-like protein
  • TMD transmembrane domain
  • LC3 protein 1 A/ IB -light chain 3
  • P62 ubiquitin-binding protein
  • BNIP3 adenovirus E1B 19 kDa protein-interacting protein 3
  • CRP C-reactive protein
  • MTS N-terminal mitochondrial signaling sequence
  • Fig- 1 illustrates percentage of THP-1 cells in autophagy.
  • Fig- 2 illustrates percentage of PINK 1 expression.
  • the present invention is directed to a cost-effective, non-toxic, safe, and therapeutically bioactive combination of benzo-coumarin compound and the at least one cell viability enhancer or salts thereof wherein both active moieties work synergistically to activate PINK1/P ARKIN pathway with no adverse effect.
  • composition does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.
  • pharmaceutically/ nutraceutically acceptable salt represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds, amino acid salt, sugar-based salt, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.
  • the salts are preferably selected from chloride, bromide, calcium, sodium, hydroxide, aspartate, taurate, threonate, phosphate, acetate, fumarate, lactate, maleate, sulphate, tartrate, citrate, hydrates carbonate, gluconate, mesylate, hydrochloride, hydrobromide and glucosamine.
  • terapéuticaally active is an ⁇ ngredient which is accountable for a therapeutic effect.
  • the present invention provides synergistic bioactive compositions for enhancing activity of PINK1/P ARKIN pathway.
  • the present invention provides a synergistic bioactive composition for enhancing activity of pinkl/parkin pathway, wherein the composition comprises: bioactive benzo-coumarin compound or salt thereof; at least one cell viability enhancer(s) or salt thereof; and at least one pharmaceutically acceptable excipient.
  • the compound 3,8-Dihydroxy-6H-dibenzo[b,d]pyran-6-one belongs to the class of benzo-coumarins or dibenzo-a-pyrones. These are polycyclic aromatic compounds containing a 1-benzopyran moiety with a ketone group at the C2 carbon atom (l-benzopyran-2-one). 3,8- Dihydroxy-6H-dibenzo[b,d]pyran-6-one is a metabolite resulting from ellagitannins.
  • 3,8-Dihydroxy-6H-dibenzo[b,d]pyran-6-one activates PINKl-Parkin- mediated pathway by stabilizing the kinase PINK1. Parkin is then recruited to PINK1 and ubiquitinates mitochondrial proteins. Ubiquitin chains are in turn phosphorylated by PINK1 which lead accumulation of7rabic71o-ubiquitinated mitochondrial proteins. These serve as docking sites for adapter proteins, such as optineurin and p62, which then bind LC3.
  • This compound also activates a PINK 1 -Parkin-independent pathway by increasing mitochondrial BNIP3 levels.
  • BNIP3 recruits LC3 independently of Parkin and other docking proteins.
  • LC3 allows the formation of a phagosome membrane around the mitochondria. The deriving mitophagosome fuses with lysosomes. Low pH and hydrolytic enzymes from lysosomes finally breakdown the mitochondria.
  • the present invention relates to synergistic bioactive composition
  • synergistic bioactive composition comprising combination of benzo-coumarin compound and at least one cell viability enhancer and salts thereof along with pharmaceutically acceptable excipients.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising a therapeutically effective amount of benzo-coumarin compound or pharmaceutically acceptable salts thereof, wherein benzo-coumarin compound is present in a range of 1-1000 mg of the total composition.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising a therapeutically effective amount of at least one cell viability enhancer or pharmaceutically acceptable salts thereof, wherein at least one cell viability enhancer(s) is present in a range of 0.1-1000 mg of the total composition.
  • the present composition provides at least one cell viability enhancer, wherein the cell viability enhancer is selected from the group consisting of N,N,N- trimethylglycine, Oxobutanedioic acid,®)-2-Amino-3-prop-2-enylsulfanylpropanoic acid, 2- Oxopentanedioic acid, 3-Amino-2-methylpropanoic acid, (3p,5p,7a,12a)-7,12-Dihydroxy-3- (icosanoylamino)cholan-24-oic acid, dileucine, (2Z,4E)-5-[(lS)-l-hydroxy-2,6,6-trimethyl-4- oxocyclohex-2-en-l-yl]-3-methylpenta-2,4-dienoic acid, (2S)-2-[[(2S)-2- hydroxypropanoyl]amino]-3-phenylpropanoic acid, Pentadecanoic acid,
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising synergistic exogenous blend of 3,8-Dihydroxy-6H- dibenzo[b,d]pyran-6-one and at least one cell viability enhancer, wherein the at least one cell viability enhancer is selected from the group consisting of N,N,N-trimethylglycine, Oxobutanedioic ac® (R)-2-Amino-3-prop-2-enylsulfanylpropanoic acid, 2-Oxopentanedioic acid, 3-Amino-2-methylpropanoic acid, (3p,5p,7a,12a)-7,12-Dihydroxy-3- (icosanoylamino)cholan-24-oic acid, dileucine, (2Z,4E)-5-[(lS)-l-hydroxy-2,6,6-trimethyl-4- oxocyclohex-2-en-l-yl]-3-
  • the present biologically active composition is composed of synergistic combination of 3,8-Dihydroxy-6H-dibenzo[b,d]pyran-6-one and at least one cell viability enhancer, wherein the at least one cell viability enhancer is selected from the group consisting of N,N,N- trimethylglycine, OxobutanedioicOid, (R)-2-Amino-3-prop-2-enylsulfanylpropanoic acid, 2- Oxopentanedioic acid, 3-Amino-2-methylpropanoic acid, (3p,5p,7a,12a)-7,12-Dihydroxy-3- (icosanoylamino)cholan-24-oic acid, dileucine, (2Z,4E)-5-[(lS)-l-hydroxy-2,6,6-trimethyl-4- oxocyclohex-2-en-l-yl]-3-methylpenta-2,4-dienoic acid, (2S)-2-[[
  • the synergistic combination of benzo-coumarin compound and at least one cell viability enhancer enhances activity of PINK1/P ARKIN pathway which is required for the improvement in autophagy.
  • composition of the present invention increases cell viability and thus improves mitochondrial function and cell health with enhanced bioavailability, solubility, and therapeutic efficacy.
  • the present invention provides synergistic bioactive compositions for inducing or promoting mitochondrial health comprising exogenous blend or combination of effective amount of 3,8-Dihydroxy-6H-dibenzo[b,d]pyran-6-one and at least one cell viability enhancer, wherein the at least one cell viability enhancer is selected from the group consisting of N,N,N-trimethylglycine, Oxobutanedi® acid, (R)-2-Amino-3-prop-2- enylsulfanylpropanoic acid, 2-Oxopentanedioic acid, 3-Amino-2-methylpropanoic acid, (3p,5p,7a,12a)-7,12-Dihydroxy-3-(icosanoylamino)cholan-24-oic acid, dileucine, (2Z,4E)-5- [(lS)-l-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-l-yl]-3-
  • the present invention relates to synergistic bioactive composition, which is useful for improving or inducing autophagy, lysosomal biogenesis, mitophagy, and/or lipophagy.
  • subject in need thereof pertains to subject preferably mammal, more preferably human suffering or suspected with dysregulation of PINK 1 /PARKIN pathway.
  • the present synergistic composition is non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects.
  • the present medicinal composition is also used as preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.
  • Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the present invention are formulated in geometric or, enantiomeric or stereoisomeric forms.
  • Excipients also include antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, waters of hydration, or salts.
  • the present invention relates to a synergistic bioactive composition prepared in a manner well known in the pharmaceutical art, and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • the preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal, or oral.
  • the present synergistic bioactive composition is administered to a subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transm
  • the synergistic composition of the present invention is nontoxic, cost effective, enriched with bioactive ingredients, and provides treatment against dysregulation of PINK 1 /PARKIN pathway.
  • the composition provides therapeutic approach in the treatment of neurodegenerative diseases [including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease], myopathy, muscular dystrophy, liver diseases, muscle diseases, cerebral ischemia, amyotrophic lateral sclerosis (ALS), psychiatric disorders, cardiac diseases, cancer, age- related disorders, Infection, Immunity, and Inflammatory diseases, pregnancy complications, neonatal neurological disorders, fetal and infant brain development.
  • neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease
  • myopathy muscular dystrophy
  • liver diseases including muscle diseases, cerebral ischemia, amyotrophic lateral sclerosis (ALS), psychiatric disorders, cardiac diseases, cancer, age- related disorders, Infection, Immunity, and Inflammatory diseases, pregnancy complications, neonatal neurological disorders, fetal and infant
  • the diluents are selected from a group comprising starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulphate, cellulose acetate, com starch, pregelatinized starch, dextrin, P-cyclodextrin, methylated-P-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain t
  • the diluent in the composition/formulation is present in a range of 1% to 30% by weight of the total compo sition/formulation .
  • the binder is selected from a group comprising disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxy methylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, com starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum,
  • disaccharides such as
  • the antioxidant is selected from a group comprising tocopherol (vitamin E), sesamol, guaiac resin, methionine, beta-carotene, lycopene, lutein, zeaxanthin, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium metabisulfite (SMB), 1-carnosine, propyl gallate (PG), tertiary butyl hydroquinone, cysteine (CYS), citric acid, tartaric acid, phosphoric acid and ascorbic acid or any combination thereof.
  • vitamin E tocopherol
  • sesamol guaiac resin
  • methionine beta-carotene
  • beta-carotene beta-carotene
  • lycopene lycopene
  • lutein zeaxanthin
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxytoluen
  • the amount of antioxidant in the composition/formulation is present in the range of 0.1 to 10% by wt. of the composition/ formulation.
  • the lubricant is selected from a group comprising magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, and sodium benzoate or any combination thereof.
  • the lubricant in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total compo sition/formulation .
  • the solubilizing agent/surfactant is selected from a group comprising polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin ml3rabicl311ose hl3rabicl311ose hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone
  • the amount of solubilizing agent or surfactant in the composition/formulation ranges from 0.1% to 10% by weight of the compo sition/formulation .
  • the glidant is selected from a group comprising colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate and silicon dioxide or any combination thereof.
  • the glidant in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total compo sition/formulation .
  • the stabilizer is selected from a group comprising alginate, agar, carrageen, gelatin, gl4rabicm, gum arabic, locust bean gum, pectin, starch, xanthan gum and trehalose or any combination thereof.
  • the stabilizer in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/ formulation.
  • the plasticizer added to coating of the formulation is selected from a group comprising propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, acetylated monoglycerides, castor oil and mineral oil or any combination thereof.
  • the plasticizer in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/ formulation.
  • the solvent is selected from a group comprising water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water- miscible solvents, organic polar or non-polar solvents or any combination/mixtures thereof.
  • the solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/formulation 100% by weight.
  • Additional additives that may be present in the composition of the present invention include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients.
  • the powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.
  • the additives are used in a range of 0.1 to 10% w/w of unit dose.
  • the present invention provides the composition/formulation comprising a therapeutic blend of benzo-coumarin compound or salts thereof and at least one cell viability enhancer or salts thereof along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer, an antioxidant, a plasticizer or mixtures thereof.
  • the present invention provides the composition/formulation wherein the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.
  • the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to
  • compositions containing compounds of the present invention can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 5000 mg per day, preferably from about 10 mg per day to about 1500 mg per day.
  • the present invention provides the oral composition wherein the effective unit dose for an oral administration is formulated in solid form which is present in a range of 1 to 3000 mg, preferably 10 to 1000 mg.
  • administration of effective dose is useful for treating obesity, diabetes, cancer, liver diseases, sexual dysfunction, neurodegenerative diseases, cardiovascular diseases, osteoarthritis, musculoskeletal diseases, neuromuscular diseases, and kidney diseases.
  • the present composition can be used as adult as well as infant formula by varying the concentration of active ingredients. Further, it is noted that the dietician or nutritionist or certified physician, medical practitioner knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.
  • Example 1 Various compositions/formulations i.
  • Composition 1 Tablet / Capsule ii.
  • Composition 2 Tablet / Capsule iii.
  • Composition 3 Tablet / Capsule iv.
  • Composition 4 Tablet / Capsule v.
  • Composition 5 Tablet / Capsule vi.
  • Composition 6 Tablet / Capsule vii.
  • Composition 7 Tablet / Capsule viii.
  • Composition 8 Tablet / Capsule ix.
  • Composition 9 Tablet / Capsule x.
  • Composition 10 Tablet / Capsule xi.
  • Composition 11 Tablet / Capsule xii.
  • Composition 12 Tablet / Capsule xii.
  • Composition 13 Tablet / Capsule xiv.
  • Composition 14 Tablet / Capsule xv.
  • Composition 15 Tablet / Capsule xvi.
  • Composition 16 Tablet / Capsule xvii.
  • Composition 17 Tablet / Capsule xviii.
  • Composition 18 Tablet / Capsule xix.
  • Composition 19 Tablet / Capsule xx.
  • Composition 21 Tablet / Capsule xxii.
  • Composition 22 Tablet / Capsule
  • the purpose of this study is to assess autophagy inducing potential of test substances in Human Monocytes (THP-1) cell line.
  • test substances were evaluated for its in vitro potency to induce autophagy in THP- 1 cell line.
  • treatments with the test substance and their combination among all the groups tested have shown considerable increase in autophagic activity.
  • G14-G35 with the combination of two ingredients exhibited the highest percentage of autophagic activity when analysed by CYTO-ID® Autophagy Detection Kit.
  • THP-1 Human Monocyte cells
  • FBS Fetal Bovine Serum
  • penicillin 100 lU/mL
  • streptomycin 100 pg/mL
  • amphotericin B 5 pg/mL
  • the cell count was adjusted to 1.5-2 x 10 5 cells/mL using RPMI-1640 containing 10% FBS.
  • 2 mL of the diluted cell suspension was added to each well of the 6 well plates.
  • ImL of different test concentrations and combinations of test substances were added.
  • the plate was then incubated at 37°C for 24 h in a 5% CO2 atmosphere, and microscopic examination was carried out and observations were noted after 24 h time.
  • Table 1 Percentage of THP-1 cells in autophagy analysed by CYTO-ID® Autophagy
  • test compound and groups of the test formulations screened could be a good autophagy modulating agent which improves mitochondrial quality via enhancing activity of pinkl/parkin pathway.
  • PINKl/Parkin pathway mediated autophagy could effectively eliminate damaged mitochondria and improves overall cell health (cell viability) in the combination of test sample as compared with the individual test sample.

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Abstract

La présente invention concerne une composition synergique pour améliorer l'activité de la voie PINK1/PARKIN. En particulier, la présente invention concerne une composition bioactive synergique comprenant une combinaison de composé de benzo-coumarine et d'au moins un activateur de viabilité cellulaire conjointement avec des excipients pharmaceutiquement acceptables. La composition est utile dans le traitement de l'obésité, du diabète, du cancer, de maladies hépatiques, d'une dysfonction sexuelle, de maladies neurodégénératives, de maladies cardiovasculaires, de l'arthrose, de maladies musculo-squelettiques, de maladies neuromusculaires et de maladies rénales.
PCT/IN2023/051209 2023-06-09 2023-12-21 Composition bioactive synergique pour améliorer l'activité de la voie pink1/parkin Pending WO2024252410A1 (fr)

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IN202321039605 2023-06-09

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180256539A1 (en) * 2017-03-08 2018-09-13 Amazentis Sa Method for improving mitophagy in subjects
US20190240181A1 (en) * 2016-12-29 2019-08-08 The United States Of America As Represented By The Secretary Of The Navy Compositions for Diagnosis and Treatment of Inflammation
WO2019222146A1 (fr) * 2018-05-15 2019-11-21 University Of Louisville Research Foundation, Inc. Urolithine a et ses dérivés destinés à être utilisés en thérapie
CN115887392A (zh) * 2021-09-30 2023-04-04 大连五音方科技有限公司 一种尿石素a分散片药物组合物及其3d打印制备方法
US20230115416A1 (en) * 2021-10-07 2023-04-13 Todd Ewing Compositions and methods for promoting cellular metabolic fitness

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190240181A1 (en) * 2016-12-29 2019-08-08 The United States Of America As Represented By The Secretary Of The Navy Compositions for Diagnosis and Treatment of Inflammation
US20180256539A1 (en) * 2017-03-08 2018-09-13 Amazentis Sa Method for improving mitophagy in subjects
WO2019222146A1 (fr) * 2018-05-15 2019-11-21 University Of Louisville Research Foundation, Inc. Urolithine a et ses dérivés destinés à être utilisés en thérapie
CN115887392A (zh) * 2021-09-30 2023-04-04 大连五音方科技有限公司 一种尿石素a分散片药物组合物及其3d打印制备方法
US20230115416A1 (en) * 2021-10-07 2023-04-13 Todd Ewing Compositions and methods for promoting cellular metabolic fitness

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