WO2014138426A2 - Procédés et compositions pour la réduction de la graisse corporelle et des adipocytes - Google Patents

Procédés et compositions pour la réduction de la graisse corporelle et des adipocytes Download PDF

Info

Publication number
WO2014138426A2
WO2014138426A2 PCT/US2014/021288 US2014021288W WO2014138426A2 WO 2014138426 A2 WO2014138426 A2 WO 2014138426A2 US 2014021288 W US2014021288 W US 2014021288W WO 2014138426 A2 WO2014138426 A2 WO 2014138426A2
Authority
WO
WIPO (PCT)
Prior art keywords
subject
compound
prodrug
stereoisomer
polymorph
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/021288
Other languages
English (en)
Other versions
WO2014138426A3 (fr
Inventor
Murat V. Kalayoglu
Michael S. Singer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Topokine Therapeutics Inc
Original Assignee
Topokine Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Topokine Therapeutics Inc filed Critical Topokine Therapeutics Inc
Publication of WO2014138426A2 publication Critical patent/WO2014138426A2/fr
Publication of WO2014138426A3 publication Critical patent/WO2014138426A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/489—Sophora, e.g. necklacepod or mamani
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/074—Ganoderma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to methods and compositions for reducing fat and/or adipocytes in the body of a subject. More specifically, body fat and/or adipocytes, by administering to a subject compounds and/or compositions as described herein.
  • obesity is responsible for much of the morbidity and health care costs. It is a risk factor for a wide array of diseases, for example, type 2 diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, breast and colon cancer, sleep apnea, gall bladder disease, gastroesophogeal reflux disease, fatty liver, gout, and thromboembolism. Blood pressure, blood sugar, serum cholesterol, and serum uric acid are usually higher in obese people than in those of normal weight. Despite increased awareness of these health risks, the prevalence of obesity has risen steadily for decades in many industrialized nations. As a result, there has been considerable interest in methods to reduce obesity.
  • adipose tissue This tissue and its principal cell type, the adipocyte, have been implicated in a wide array of diseases, for example, metabolic syndrome, type 2 diabetes, atherosclerosis, fatty liver, hepatic fibrosis, breast cancer, inflammation, depression, and dementia.
  • the causative role of adipose tissue in these diseases appears to involve mediators such as adiponectin, resistin, tumor necrosis factor alpha (TNF-cc), interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and/or C-terminal binding protein (CtBP).
  • TNF-cc tumor necrosis factor alpha
  • IL-6 interleukin-6
  • CRP C-reactive protein
  • PAI-1 plasminogen activator inhibitor-1
  • CtBP C-terminal binding protein
  • a number of medical conditions are considered to be causes of excess body fat. Examples include drug-induced obesity, hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, growth hormone resistance, and leptin deficiency or resistance.
  • Disfiguring excess regional fat deposits may be found in conditions such as HIV-associated lipodystrophy syndrome, Cushing syndrome and pseudo-Cushing syndrome (i.e., characteristic syndrome of excess body fat and other findings due to excessive endogenous or exogenous corticosteroid levels), other acquired lipodystrophies, familial lipodystrophies, lipoma, lipomatosis, and Madelung disease.
  • concentration of fat on particular parts of the body e.g., dorsocervical fat ("buffalo hump"), facial fat (“moon fades”), visceral fat, and/or lipoma, can make local therapy a preferred option.
  • Lipomatosis is any condition characterized by the formation of multiple lipomas on the body, e.g., familial multiple lipomatosis, adiposis dolorosis (Dercum's disease), pelvic lipomatosis, etc.
  • Medications known to cause obesity or local excesses of body fat include
  • Cortisol and analogs other corticosteroids, megace, sulfonylureas, antiretrovirals, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin, risperidone, clozapine, and thiazolidinediones.
  • a subject may have cosmetic or other concerns about body fat. These can usually be attributed to constitutional or hereditary factors, developmental history, age, gender, diet, alcohol use, or other aspects of lifestyle.
  • Extractive methods such as lipoplasty (e.g., liposuction) or local excision, are methods whereby fat is physically removed from areas of interest. Such methods are costly and may involve scars, postsurgical deformity or regression, discomfort, infection, and other adverse reactions.
  • metabolic methods which include medications, nutritional supplements, devices, and exercise or other body treatment, seek to modify the subject's metabolism (e.g., whether caloric consumption, expenditure, or both) such that the subject incurs a net loss of fat.
  • a disadvantage is potential concomitant loss of water, carbohydrates, protein, vitamins, minerals, and other nutrients.
  • traditional diet medications may have undesired side effects, for example palpitations, tremor, insomnia, and/or irritability in a subject who uses stimulants as appetite suppressants.
  • the traditional metabolic methods of diet and exercise are not practical for everybody.
  • Adipolytic methods aim to cause breakdown of adipocytes and/or their lipid contents.
  • fat deposits can be reduced by exposure to cold temperature or to deoxycholate, a solubilizer which lyses cell membranes and results in local necrosis.
  • Drawbacks of these methods can include poor discrimination between adipose and other nearby tissues, barriers to delivery that require hypodermic needles or special equipment, and adverse effects such as necrosis, inflammation, and pain.
  • AMP- activated protein kinase (AMPK or AMP kinase) is a heterotrimeric intracellular enzyme that serves as a master regulator of cellular metabolic homeostasis.
  • AMPK When AMPK is activated, e.g. by phosphorylation of threonine 172, it phosphorylates downstream substrates to exert myriad effects, e.g., regulation of energy homeostasis, autophagy, cell polarity, cell growth and differentiation, and mitochondrial biogenesis and disposal. See, e.g., Hardie, Genes Dev. 2011, 25, 1895-1908. Endogenous physiological activators of AMPK include adenosine monophosphate (AMP), adenosine diphosphate (ADP), and some cytokines and hormones.
  • AMP adenosine monophosphate
  • ADP adenosine diphosphate
  • a primary function of AMPK is energy sensing and homeostasis. See, e.g.,
  • AMPK can be activated by an increase in the AMP:ATP or ADP:ATP ratio, reflects metabolic stress.
  • metabolic stressors can be classified as those that interfere with ATP generation (e.g., glucose deprivation, hypoxia, ischemia, or metabolic poisons) and those that increase ATP consumption (e.g., muscle contraction).
  • AMPK activation can restore energy homeostasis by phosphorylating certain substrates, for example, acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2), SREBP lc, HMG-CoA reductase, and hormone- sensitive lipase. See, e.g., Hardie, supra.
  • Phosphorylation of these substrates in skeletal muscle, liver, and adipose tissue down-regulates anabolic pathways, e.g. by inhibiting fatty acid synthesis, protein synthesis, lipogenic gene expression, and gluconeogenic gene expression. See, e.g., Hardie, supra.
  • AMPK can also be activated by Thr 172 phosphorylation by the
  • Ca2+/calmodulin-dependent protein kinase CaMKK providing a Ca2+-activated pathway to switch on AMPK. See, e.g., Hardie, supra.
  • the phenomenon can occur without an increase in the AMP: ATP or ADP: ATP ratio.
  • AMPK regulates cell division, as well as normal growth and development.
  • the present invention arises from the observation that local administration of certain AMPK activators to the skin or subcutaneous fat of a subject causes local reduction of body fat and adipocytes in the subject.
  • U.S. Patent 7,666,912 contemplates that local administration (e.g., topical, subcutaneous, intralesional) of certain prostaglandins, e.g., latanoprost and travoprost, would locally reduce fat in a subject at the site of administration.
  • the present inventor(s) have verified this experimentally. Furthermore, the inventor(s) have discovered that this effect, i.e., local reduction of subcutaneous fat and adipocytes, is mediated by local activation of AMPK. Based on this observation, the inventors now contemplate that other AMPK activators can be administered locally (e.g., topically to the skin) to reduce fat or adipocytes in the body of a subject.
  • local administration has particular advantages over systemic administration (e.g., the ability to treat particular part(s) of the body without systemic exposure or systemic side effects).
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject a direct or indirect activator of AMPK.
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject one or more compounds of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), and
  • the compound for use in the present invention is of the Formula (I):
  • metformin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (II):
  • phenformin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (III):
  • fhifenamic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (IV):
  • AICAR also described herein as AICAR, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (V):
  • resveratrol or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VI):
  • combretastatin A4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VII):
  • chlorogenic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VIII):
  • caffeic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (IX):
  • o/t/iocoumaric acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (X):
  • ferulic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XI):
  • pipeline also described herein as pipeline, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XII):
  • cinnamaldehyde or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XIII):
  • methyl cinnamate or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XIV):
  • gallic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XV):
  • quercetin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XVI):
  • kaempferol or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XVII):
  • apigenin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XVIII): (XViii) also described herein as naringin, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XIX):
  • the compound for use in the present invention is of the Formula (XX):
  • epigallocatechin-3-gallate or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXI):
  • the compound for use in the present invention is of the Formula (XXII):
  • curcumin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXIII
  • ginsenoside Rh2 also described herein as ginsenoside Rh2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXIV):
  • maslinic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXV):
  • berberine or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXVI):
  • cc-lipoic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXVII):
  • the compound for use in the present invention is of the Formula (XXVI
  • the compound for use in the present invention is of the Formula (XXIX):
  • fucoxanthin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXX):
  • methyl-methionine sulphonium chloride or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject a composition comprising one of more natural product extracts, as described herein.
  • the natural product extract for use in the present invention is obtained from a mushroom of the genus Ganoderma, e.g., Ganoderma lucidum or Ganoderma tsugae.
  • the natural product extract for use in the present invention is obtained from Coix lacryma-jobi, e.g., from the grains thereof.
  • the natural product extract for use in the present invention is obtained from Boesenbergia pandurata, e.g., from the roots thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Mangifera, e.g., Mangifera indica, e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Combretum, e.g., Combretum caffrum or Combretum molle, e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from Flor sophorae, e.g., from the flowers or stems thereof.
  • the natural product extract for use in the present invention is obtained from Lysimachia foenum-graecum, e.g., from the flowers, stems, and/or leaves thereof.
  • administering locally can comprise administering to the skin, administering percutaneously, administering topically,
  • administering subcutaneously, administering by injection (e.g., to a visceral fat deposit), and administering intralesionally (e.g., within a lipoma).
  • the compound or composition is administered to the skin in a dosage form of a cream, gel, ointment, or lotion. In certain embodiments, the compound or composition is administered to the skin as a percutaneous patch. In certain embodiments, the compound or composition is administered to an adipose depot or lesion as an aqueous injection. In certain embodiments, the compound or composition is administered as a sustained-release injectable form comprising, e.g., biodegradable microspheres.
  • the compound or composition can be administered in a sustained-release formulation.
  • the method of reducing fat comprises reducing adipocytes.
  • the subject suffers from a disease or condition characterized in part by a local excess of body fat.
  • the disease or condition is selected from the group consisting of HIV-associated lipodystrophy syndrome, Cushing syndrome, pseudo-Cushing syndrome, a familial lipodystrophy (e.g. , familial partial lipodystrophy), lipoma, lipomatosis, Madelung disease, and excess visceral fat.
  • the subject also suffers from or is likely to suffer from an adipocyte-related disease.
  • the adipocyte-related disease is selected from the group consisting of metabolic syndrome, excess body fat (e.g., being overweight, obesity), dyslipidemia, hypercholesterolemia, hypertriglyceridemia, diabetes (e.g., type 2 diabetes), atherosclerosis, vascular disease, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease, fatty liver, hepatic fibrosis, pancreatitis, cancer (e.g., breast cancer, uterine cancer, colon cancer, colorectal cancer, kidney cancer, esophageal cancer), inflammation or inflammatory disease, depression, and dementia.
  • metabolic syndrome e.g., being overweight, obesity
  • dyslipidemia e.g., hypercholesterolemia, hypertriglyceridemia
  • diabetes e.g., type 2 diabetes
  • atherosclerosis vascular disease
  • coronary artery disease CAD
  • stroke cerebrovascular disease
  • salts As used herein, the terms “salt”, “acceptable salt”, or “pharmaceutically acceptable salt” refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • prodrug means a biologically active derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the pharmacologically active compound.
  • the "prodrug” is a compound administered to a subject, and the pharmacologically active compound is the "active metabolite thereof.”
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The advantage of a prodrug can lie in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from across the skin, or it may enhance drug stability for long-term storage.
  • polymorph refers to a compound having more than one crystal structure, e.g., resulting from differences in molecular packing and/or molecular conformation of the compound in the solid state.
  • hydrate refers to a compound non-covalently associated with one or more molecules of water.
  • solvate refers to a compound non-covalently associated with one or more molecules of an organic solvent.
  • stereoisomer as used herein includes geometric isomers, enantiomers, diastereomers, mixtures thereof. A stereoisomer which is provided in excess of one or more other stereoisomers is referred to as "optically enriched.”
  • the compound of the present invention is made up of at least about 90% by weight of a stereoisomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a stereoisomer.
  • Preferred stereisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et ah, Enantiomers,
  • tautomer includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.
  • isotopically labeled derivatives of a compound refer to derivatives of the compound wherein at least one atom of the compound is enriched for an isotope that is higher or lower in molecular weight than the most abundant isotope of the atom found in nature.
  • an "individual” or “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., child, adolescent) or adult subject (e.g., young adult, middle- aged adult or senior adult)), other primates (e.g., cynomolgus monkeys, rhesus monkeys) and commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., child, adolescent) or adult subject (e.g., young adult, middle- aged adult or senior adult)
  • other primates e.g., cynomolgus monkeys, rhesus monkeys
  • commercially relevant mammals such as cattle, pigs, horses, sheep,
  • a “therapeutically effective amount” means the level, amount or concentration of the compound needed to treat a disease, disorder or condition, or to reduce or lower a particular parameter (e.g., adipocytes and/or body fat) in the body of a subject, without causing significant negative or adverse side effects to body or the treated tissue.
  • a particular parameter e.g., adipocytes and/or body fat
  • therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutically active agent.
  • lowering means to diminish or lessen the volume, size, mass, bulk, density, amount, and/or quantity of a substance (e.g., body fat, adipocytes, adipose tissue, lipid concentration) in the body of a subject.
  • a substance e.g., body fat, adipocytes, adipose tissue, lipid concentration
  • the term “eliminate” means to completely remove any unwanted or undesired volume, size, mass, bulk, density, amount, and/or quantity of a substance (e.g., excess body fat, excess adipocytes, excess adipose tissue) in the body of a subject.
  • “suffer”, “suffers” or “suffering from” refers to a subject having a particular disease, disorder, or condition.
  • “likely to suffer” refers to a subject who has not been diagnosed with a particular disease, disorder, or condition by a medical practitioner, but has a predisposition (e.g., genetic and/or physiologic predisposition), or exhibits signs or symptoms of the disease, disorder, or condition.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition.
  • prevent contemplate an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition, which inhibits or reduces the severity of the disease, disorder, or condition.
  • local administration or “administering locally” or “local effect” means administration/application of the active ingredient or active metabolite thereof directly, or in proximity to, a part of the body, tissue, or lesion where said active substance is intended to exert its action. This may include, for example, topical administration to a part of the skin or injection directly into a tissue or lesion where treatment is needed.
  • natural product or “natural product extract” means any substance or chemical compound obtained from a living organism.
  • Figures 2A-2D depicts photomicrographs of immunostained rat skin and subcutaneous adipocytes, as more fully explained in Example 2.
  • the immunohistochemistry used an antibody specific for activated (phosphorylated) AMPK.
  • Figure 2A untreated side of a control (vehicle-treated) animal.
  • Figure 2B treated side of same animal.
  • Figure 2C untreated side of an animal treated with topical latanoprost.
  • the present invention arises from the observation that local administration of certain AMPK activators to the skin or a fat deposit of a subject causes local reduction of body fat and adipocytes in the subject.
  • the present invention contemplates therapy in mature adipose tissue in the body of a subject, it is to be distinguished from the effects of some AMPK activators on the differentiation of pre-adipocyte fibroblasts in cell culture.
  • some AMPK activators on the differentiation of pre-adipocyte fibroblasts in cell culture.
  • Habinowski and Witters Biochem Biophys Res Comm (2001) 286:852-856; Ha et al., Bioorg Med Chem Lett (2010) 20:6076-6081; Ha et al; J Med Food (2010) 13: 1331-1339; Huang et al; J Agric Food Chem (2011) 59: 3666-3673; Zhang et al, J Agric Food Chem (2011) 59: 11526-11533; Lee et al, Int J Mol Med (2011) 28:65-71; Chen et al, J Agric Food Chem (2012) 60:955- 963; Lai et al, J Agric Food Chem (2012) 60: 1094-1101; Seo
  • U.S. Patent 7,666,912 contemplates that local administration ⁇ e.g., topical, subcutaneous, intralesional) of certain prostaglandins, e.g., latanoprost and travoprost, would locally reduce fat in a subject at the site of administration.
  • the present inventors have verified this experimentally. Furthermore, the inventor(s) have discovered that this effect, i.e., local reduction of subcutaneous fat and adipocytes, is mediated by local activation of AMPK. Based on this observation, the inventors now contemplate that other AMPK activators can be administered locally to reduce fat or adipocytes in the body of a subject. For certain uses as described herein, local administration has particular advantages over systemic administration.
  • AMPK activators e.g., latanoprost and travoprost
  • treatment can be directed to particular affected areas of the body of the subject.
  • Local administration to visceral fat e.g., central abdominal fat, could nevertheless have benefits for a systemic condition, e.g., metabolic syndrome,
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject a direct or indirect activator of AMPK.
  • administration of the compounds disclosed herein may include reducing the number of fat cells, reducing the volume of one or more fat cells, reducing maturation of one or more fat cells, and/or dedifferentiating one or more fat cells.
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject one or more compounds of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), and
  • Each of these compounds is a direct or indirect activator of AMPK.
  • the compound for use in the present invention is of the Formula (I):
  • metformin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (II):
  • phenformin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (III):
  • flufenamic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (IV):
  • AICAR also described herein as AICAR, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (V):
  • resveratrol or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VI):
  • combretastatin A4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VII):
  • chlorogenic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (VIII):
  • caffeic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (IX):
  • o/t/iocoumaric acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (X):
  • ferulic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XI):
  • pipeline also described herein as pipeline, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XII):
  • cinnamaldehyde or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XIII): also described herein as methyl cinnamate, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XIV):
  • gallic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XV):
  • quercetin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XVI):
  • the compound for use in the present invention is of the Formula (XVII):
  • apigenin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XVIII):
  • the compound for use in the present invention is of the Formula (XIX):
  • the compound for use in the present invention is of the Formula (XX):
  • epigallocatechin-3-gallate or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXI):
  • the compound for use in the present invention is of the Formula (XXII):
  • curcumin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXIII): (XXIII) also described herein as ginsenoside Rh2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXIV):
  • maslinic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXV):
  • berberine or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXVI):
  • cc-lipoic acid or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXVII):
  • A769662 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXVI
  • the compound for use in the present invention is of the Formula (XXIX):
  • fucoxanthin or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the compound for use in the present invention is of the Formula (XXX):
  • methyl-methionine sulphonium chloride or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject a composition comprising one of more natural product extracts, as described herein.
  • the natural product extract for use in the present invention is obtained from a mushroom of the genus Ganoderma, e.g., Ganoderma lucidum or Ganoderma tsugae.
  • the natural product extract for use in the present invention is obtained from Coix lacryma-jobi, e.g., from the grains thereof.
  • the natural product extract for use in the present invention is obtained from Boesenbergia pandurata, e.g., from the roots thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Mangifera, e.g., Mangifera indica, e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Combretum, e.g., Combretum caff rum or
  • Combretum molle e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from Flor sophorae, e.g., from the flowers thereof.
  • the natural product extract for use in the present invention is obtained from Lysimachia foenum-graecum, e.g., from the flowers, stems, and/or leaves thereof.
  • the present invention provides pharmaceutical compositions and formulations for use in any of the inventive methods, described herein, e.g., comprising a direct or indirect activator of AMPK.
  • the inventive methods described herein, e.g., comprising a direct or indirect activator of AMPK.
  • the present invention provides pharmaceutical compositions and formulations for use in any of the inventive methods, described herein, e.g., comprising a direct or indirect activator of AMPK.
  • the inventive methods described herein, e.g., comprising a direct or indirect activator of AMPK.
  • composition comprises a natural product extract as described herein and/or one or more compounds of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXIII), (XIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), and (XXX) (collectively referred to herein as the "active ingredient”) and, optionally, a pharmaceutically acceptable excipient.
  • active ingredient a pharmaceutically acceptable excipient
  • compositions agents include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • solvents diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the active ingredient into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc. , and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc. , and combinations thereof.
  • cross-linked poly(vinyl-pyrrolidone) crospovidone
  • sodium carboxymethyl starch sodium starch glyco
  • Exemplary surface active agents and/or emulsifiers include lipids/natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl
  • lipids/natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,
  • carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate
  • polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • starch e.g. cornstarch and starch paste
  • gelatin e.g. cornstarch and starch paste
  • sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. acacia
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc. , and combinations thereof.
  • Exemplary oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Liquid dosage forms for parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents (e.g.
  • solubilizing agents such as alcohols (e.g., ethyl alcohol, isopropyl alcohol, tetrahydrofurfuryl alcohol, benzyl alcohol, glycerol and glycols (e.g., 1,3-butylene glycol, propylene glycol,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the active ingredient is mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer' s solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Time release formulations including but not limited to, sustained-release
  • Time-release formulations refer to solid dosage forms useful in releasing an active ingredient at a predetermined rate by maintaining a constant level of the active ingredient or active metabolite thereof in the bloodstream for a specific period of time with minimum side effect.
  • Time-release formulations may comprise imbedding the active ingredient in a matrix of insoluble particles, micro-encapsulation, use of liposomes and/or use of hydrogels.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the active ingredient with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Dosage forms for topical and/or transdermal administration of an active ingredient may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof.
  • Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Patents 5,480,381; 5,599,302; 5,334,144;
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.
  • compositions and/or kits may comprise a provided composition and a container (e.g. , a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g. , a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a suitable aqueous carrier for dilution or suspension of the provided composition for preparation of administration to a subject.
  • contents of provided formulation container and solvent container combine to form at least one unit dosage form.
  • the active ingredient can be administered using any amount and any route of administration effective for treatment.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular composition, its mode of administration, its mode of activity, and the like.
  • the active ingredient is typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the exact amount of the active ingredient required to achieve a therapeutically effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g. , two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • daily administration to the subject can be adequate (but not necessarily preferable) to achieve the desired effect.
  • a daily administration schedule is considered convenient for human use.
  • the active ingredient may be administered by the subject to himself or herself repeatedly and without special equipment or training, although a medical professional also can also administer the active ingredient to the subject.
  • a therapeutically effective amount of the active ingredient for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of the active ingredient per unit dosage form.
  • a therapeutically effective concentration may comprise between about 0.0001% to about 5.0% (w/v) in liquid or semisolid formulations.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the active ingredient can be administered in combination with one or more additional therapeutically active agents ("agents” or “active agents”).
  • agents or “active agents”
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional agents.
  • the active ingredient and each additional active agent will be administered at a dose and/or on a time schedule determined for the ingredient and agent.
  • the active ingredient and active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the active ingredient with the active agent and/or the desired therapeutic effect to be achieved.
  • additional active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually.
  • the active ingredient can be administered in combination with active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that therapy employed may achieve a desired effect for the same disorder (for example, an active ingredient can be administered in combination with an anti-inflammatory and/or anti- depressive agent, etc.), and/or it may achieve different effects (e.g., control of adverse side- effects).
  • Exemplary active agents include, but are not limited to, antibiotics, anti- obesity agents, anesthetics, anti-coagulants, steroidal agents, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agents, antihistamines, immunosuppressant agents, antigens, vaccines, antibodies, opioids, pain-relieving agents, analgesics, hormones, prostaglandins, progestational agents, anti-glaucoma agents, ophthalmic agents, anticholinergics, anti-depressants, anti-psychotics, hypnotics, tranquilizers, anti- convulsants/anti-epileptics (e.g., Neurontin, Lyrica, valproates (e.g., Depacon), and other neuro stabilizing agents), muscle relaxants, anti-spasmodics, muscle contractants, channel blockers, miotic agents, anti-secretory agents, anti-thrombotic agents, anticoagulants, anticholinergics, ⁇ -adrene,
  • Active agents include small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drugs Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides,
  • oligosaccharides polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • the invention provides a method for reducing body fat and/or adipocytes in a subject in need thereof, the method comprising administering locally to the subject a direct or indirect activator of AMPK.
  • the method comprising administering locally to the subject one or more natural product extracts and/or one or more compounds of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), and (XXX), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically
  • the natural product extract for use in the present invention is obtained from a mushroom of the genus Ganoderma, e.g., Ganoderma lucidum or Ganoderma tsugae.
  • the natural product extract for use in the present invention is obtained from Coix lacryma-jobi, e.g., from the grains thereof.
  • the natural product extract for use in the present invention is obtained from Boesenbergia pandurata, e.g., from the roots thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Mangifera, e.g., Mangifera indica, e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from a tree of the genus Combretum, e.g., Combretum caffrum or
  • Combretum molle e.g., from the leaves, fruit, stems, and/or twigs thereof.
  • the natural product extract for use in the present invention is obtained from Flor sophorae, e.g., from the flowers thereof.
  • the natural product extract for use in the present invention is obtained from Lysimachia foenum-graecum, e.g., from the flowers, stems, and/or leaves thereof.
  • Fat reduction can include reducing fat as measured by at least one of volume, size, mass, bulk, density, amount, and/or quantity.
  • the present invention is expected to reduce fat by greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 25%, greater than or equal to 20%, greater than or equal to 15%, greater than or equal to 10%, or greater than or equal to 5%.
  • fat reduction can also include reducing fat cell amount (for example, fat cell number), reducing fat cell volume, reducing fat cell maturation, and/or dedifferentiating a fat cell.
  • the present method encompasses administering one or more inventive compounds and/or natural product extracts to a subject by any suitable local route (e.g., topically, dermally, subcutaneously, intralesionally), in an amount sufficient to reduce body fat in a subject.
  • any suitable local route e.g., topically, dermally, subcutaneously, intralesionally
  • the subject has excess body fat.
  • body fat As used herein,
  • Excess body fat refers to any unwanted fatty tissue on the subject's body, and encompasses a subject who is not overweight but has excess body fat, or a subject who is overweight. [00185] In certain embodiments, the subject is overweight. "Overweight” is a medical condition, and is defined by the subject' s body mass index (BMI). Any subject with a BMI of greater than or equal to 25 is considered overweight. An overweight subject encompasses pre-obese subjects (e.g. , having a BMI of between 25 and 30) and obese subjects (e.g., having a BMI of greater than or equal to 30).
  • BMI body mass index
  • the overweight subject is obese and suffers from obesity.
  • Any subject with a BMI of between 35 and 40, inclusive is considered “severely obese” and suffers from “super obesity”.
  • Any subject with a BMI between 40 and 45 is considered “morbidly obese” and suffers from “morbid obesity”.
  • Any subject with a BMI greater than or equal to 45 is considered “super obese” and suffers from "super obesity”.
  • the subject has excess body fat as a side effect of medication (e.g. , for example, Cortisol and analogs, corticosteroids, megace, sulfonylureas, anti-retrovirals, antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin or a form of insulin, risperidone, clozapine, and thiazolidinediones).
  • medication e.g. , for example, Cortisol and analogs, corticosteroids, megace, sulfonylureas, anti-retrovirals, antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin or a form of insulin, risperidone, clozapine, and thiazolidinediones.
  • the subject has excess body fat due to changes in hormonal status (e.g. , as a result of physiologic changes such as pregnancy or menopause).
  • the subject with excess body fat is undergoing or has recently undergone smoking cessation.
  • the subject has excess body fat due to immobility or disuse of an extremity.
  • the subject suffers from obesity, drug-induced obesity, HIV-associated lipodystrophy syndrome, hypothyroidism,
  • pseudohypoparathyroidism hypothalamic obesity, polycystic ovarian disease, depression, binge eating, postpartum obesity, obesity associated with smoking cessation, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, growth hormone resistance, leptin deficiency or resistance, Cushing syndrome, pseudo-Cushing syndrome, dorsocervical fat hypertrophy ("buffalo hump"), moon facies, HIV lipodystrophy, other acquired lipodystrophy, familial
  • lipodystrophy lipoma, lipomatosis, or Madelung disease
  • the subject is not overweight.
  • the method of reducing body fat in a subject is useful for not only treating obesity in a subject, but also useful in treating subjects who are not overweight, but still desire to increase the proportion of lean body mass to total body mass.
  • the methods of the present invention are useful in increasing the proportion of lean body mass to total body mass in a subject.
  • This aspect of invention may also be useful as an adjunct to any of various kinds of surgery, whether used in the pre-operative, peri-operative, or post-operative period.
  • the invention further contemplates uses preceding abdominal, thoracic, oncologic, endocrine, neurologic, transplant, and dermatologic surgery, whereby surgical exposure may be improved; and preceding or following orthopedic procedures, whereby surgical exposure as well as post-operative recovery may be improved.
  • methods and compositions of the present invention are useful for local reduction of orbital fat in Graves disease (thyroid-related orbitopathy), whereby the orbital contents can be decompressed and exophthalmos treated by reduction in the overall volume of orbital contents.
  • Graves disease thyroid-related orbitopathy
  • Reducing adipocytes in a subject includes, but is not limited to, reducing fat cell amount (e.g., for example, fat cell number), reducing fat cell volume, reducing fat cell formation, reducing fat cell maturation, dedifferentiating a fat cell, and/or inducing the death of a fat cell (e.g., for example, by apoptosis) as measured by at least one of volume, size, mass, bulk, density, amount, and/or quantity.
  • reducing fat cell amount e.g., for example, fat cell number
  • reducing fat cell volume e.g., for example, reducing fat cell formation
  • reducing fat cell maturation e.g., reducing fat cell maturation
  • dedifferentiating a fat cell e.g., by apoptosis
  • the method of reducing adipocytes comprises reducing the fat cell amount, reducing fat cell volume, reducing fat cell formation, or reducing fat cell maturation, in a subject by greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 25%, greater than or equal to 20%, greater than or equal to 15%, greater than or equal to 10%, or greater than or equal to 5%.
  • the active ingredient can be administered by any suitable local route, parenteral (e.g., subcutaneous, intradermal, intralesional, e.g., as in a lipoma), and topical administration (e.g. , transdermal, transmucosal, ophthalmic).
  • parenteral e.g., subcutaneous, intradermal, intralesional, e.g., as in a lipoma
  • topical administration e.g. , transdermal, transmucosal, ophthalmic.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the part of body where it is administered), the condition of the subject (e.g., whether the subject is able to tolerate subcutaneous administration), etc.
  • treatment of an adipocyte-related disease can be accomplished by reduction of adipocytes that is microscopic rather than macroscopic, or diffuse rather than focal.
  • the present invention also contemplates a method of treating an adipocyte-related disease, comprising administering locally to a subject in need thereof one or more of the compounds and/or natural product extracts described herein within the scope of the invention.
  • adipocyte-related disease means a disease: (i) wherein reduction of adipocytes treats the disease, disorder, or condition from which the subject is suffering; or (ii) whose mechanism comprises an adipocyte and/or its molecular products, e.g., secreted proteins, e.g., adiponectin, resistin, tumor necrosis factor alpha (TNF-cc), interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor- 1 (PAI-1), and/or C-terminal binding protein (CtBP).
  • TNF-cc tumor necrosis factor alpha
  • IL-6 interleukin-6
  • CRP C-reactive protein
  • PAI-1 plasminogen activator inhibitor- 1
  • CtBP C-terminal binding protein
  • Exemplary adipocyte-related diseases include, but are not limited to, metabolic syndrome, excess body fat (e.g., being overweight, obesity), dyslipidemia, hypercholesterolemia, hypertriglyceridemia, diabetes (e.g., type 2 diabetes), atherosclerosis, vascular disease, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease, fatty liver, hepatic fibrosis, pancreatitis, cancer (e.g., breast cancer, uterine cancer, colon cancer, colorectal cancer, kidney cancer, esophageal cancer), inflammation or inflammatory disease, depression, and dementia.
  • metabolic syndrome e.g., being overweight, obesity
  • dyslipidemia e.g., hypercholesterolemia, hypertriglyceridemia
  • diabetes e.g., type 2 diabetes
  • atherosclerosis vascular disease
  • coronary artery disease CAD
  • stroke cerebrovascular disease
  • peripheral vascular disease fatty liver
  • pancreatitis e.g., breast cancer
  • the adipocyte- related disease is selected from the group consisting of metabolic syndrome, diabetes (e.g., type 2 diabetes), liver disease, atherosclerosis, fatty liver, hepatic fibrosis, breast cancer, colon cancer, inflammation or inflammatory disease, depression, and dementia.
  • diabetes e.g., type 2 diabetes
  • liver disease e.g., atherosclerosis
  • fatty liver e.g., hepatic fibrosis
  • breast cancer e.g., colon cancer
  • inflammation or inflammatory disease e.g., depression, and dementia.
  • Rats [00203] A randomized controlled trial was conducted on Zucker Diabetic Fatty Rats, which are defective for the leptin receptor (Charles River Laboratories). These rats are hyperphagic and consequently obese, hyperglycemic, and hyperlipidemic. Rats
  • FIGS 1A-1C show hematoxylin and eosin-stained histologic sections from the aforementioned samples.
  • Latanoprost 0.005% (Group 2) was associated with local reduction of the subcutaneous adipose layer and adipocyte size at the treatment site but not on the contralateral, untreated flank.
  • Figures 2A-2D show histologic sections from the aforementioned samples stained with a monoclonal antibody specific for activated AMPK (phosphorylated threonine 172): untreated flank of control animal (treated with vehicle only) (A); treated flank of same control animal (B); untreated flank of animal treated with latanoprost 0.5% with faint immunoreactivity for phosphorylated AMPK in subcutaneous tissues, indicative of a mild systemic effect (C); and treated flank of same animal shows cutaneous and subcutaneous immunoreactivity for phosphorylated AMPK, indicative of a strong local effect (D).
  • mice are housed under identical conditions and fed ab libitum. Animals are weight daily. Following 28 consecutive days of treatment, mice are sacrificed and samples of skin and adjacent fat from the treated flanks are taken for histologic examination.
  • the vehicle is, for example, Lipoderm® (PCCA, Houston, Texas).
  • the final concentration of each active ingredient is, for example, 5 millimolar.
  • Unit-dose syringes (for example, 0.5 ml per syringe) are furnished to subjects by a study pharmacist; syringes are unlabeled as to the presence of an active ingredient or vehicle.
  • USB Serial ultrasound
  • CT computed tomography
  • AMPK activator e.g., AICAR, flufenamic acid, piperine, berberine, or A769662
  • a 56-year-old female flight attendant is troubled by prominent fat deposits on her hips and thighs, which interfere with her work and lower her self-esteem.
  • Her physician recommends diet and exercise. The woman loses 7 pounds, but there is no noticeable reduction in the fat deposits. She is referred to a plastic surgeon but declines lipoplasty due to potential adverse effects.
  • the plastic surgeon prescribes a daily application of an AMPK activator solution, e.g., caffeic acid 0.3% in a dimethyl sulfoxide vehicle, to the hips and thighs as treatment for the fat deposits. After a period of time, for example from a few days to several months, the fatty deposits on the woman's hips and/or thighs are reduced.
  • an AMPK activator solution e.g., caffeic acid 0.3% in a dimethyl sulfoxide vehicle
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention may also consist essentially of, or consist of, the recited components, and that the processes of the present invention may also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable.
  • any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Engineering & Computer Science (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne des procédés et des compositions pour la réduction de la graisse corporelle et/ou des adipocytes chez un sujet, comprenant l'administration d'un composé et/ou d'un extrait de produit naturel qui est un activateur de la kinase activée par l'adénosine monophosphate (AMPK).
PCT/US2014/021288 2013-03-07 2014-03-06 Procédés et compositions pour la réduction de la graisse corporelle et des adipocytes Ceased WO2014138426A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361773942P 2013-03-07 2013-03-07
US61/773,942 2013-03-07

Publications (2)

Publication Number Publication Date
WO2014138426A2 true WO2014138426A2 (fr) 2014-09-12
WO2014138426A3 WO2014138426A3 (fr) 2014-10-30

Family

ID=51492097

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/021288 Ceased WO2014138426A2 (fr) 2013-03-07 2014-03-06 Procédés et compositions pour la réduction de la graisse corporelle et des adipocytes

Country Status (1)

Country Link
WO (1) WO2014138426A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3009138A3 (fr) * 2014-09-01 2016-07-13 Shyam Prasad Kodimule Composition à base d'herbes pour la gestion de l'obésité et/ou du poids
EP3124047A1 (fr) * 2015-07-28 2017-02-01 Merz Pharma GmbH & Co. KGaA Triterpénoïdes pentacycliques pour lipolyse par injection
WO2017068069A1 (fr) * 2015-10-20 2017-04-27 Valbiotis Composition comprenant un melange de molecules particulieres et utilisation pour agir sur le metabolisme glucidique et/ou lipidique
WO2017037594A3 (fr) * 2015-08-28 2018-08-23 康霈生技股份有限公司 Composition pharmaceutique utilisée pour réduire la graisse localisée et utilisation de la composition pharmaceutique
CN109640969A (zh) * 2016-08-26 2019-04-16 康霈生技股份有限公司 用于減少体重的皮下注射剂及其用途
US10369179B2 (en) 2015-09-13 2019-08-06 Vidya Herbs, Inc. Composition of Mangifera indica
WO2021236128A1 (fr) * 2020-05-21 2021-11-25 Peregrine Ophthalmic PTE LTD. Procédés et compositions pour réduire le nombre d'adipocytes
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US20230372378A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat
US11896600B2 (en) 2019-09-21 2024-02-13 Vidya Herbs, Inc. Composition and method of using eicosanoyl-5-hydroxytryptamide for treating neurodegenerative disorders

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696063B1 (en) * 1998-12-30 2004-02-24 Applied Research Systems Ars Holding N.V. Treatment of HIV-associated dysmorphia/dysmetabolic syndrome (HADDS) with or without lipodystrophy
US20030212014A1 (en) * 2000-08-09 2003-11-13 Neil Ruderman Methods fo treating conditions associated with insulin resistance with aicar, (5-amino-4-imidazole carboxamide riboside) and related compounds
US20020136785A1 (en) * 2000-11-07 2002-09-26 Chun-Su Yuan Ginseng berry extracts and pharmaceutical compositions from ginseng berry for the treatment of type 2 diabetes and obesity
JP4301940B2 (ja) * 2001-07-31 2009-07-22 日清オイリオグループ株式会社 抗肥満剤およびその原料
EP1708689A2 (fr) * 2003-12-29 2006-10-11 The President and Fellows of Harvard College Compositions pour traiter ou prevenir l'obesite et les troubles de resistance a l'insuline
WO2005113069A2 (fr) * 2004-05-14 2005-12-01 Research Development Foundation Utilisation de curcumine et d'analogues de curcumine comme inhibiteurs de l'acc2
EP2015763A2 (fr) * 2006-01-05 2009-01-21 Deviris Inc. Composes et derives pour le traitement d etats medicaux par modulation de l activite de la lipase hormono-sensible
US20100152275A1 (en) * 2008-12-11 2010-06-17 Kaloness, Inc. Drug or Supplement Combination with Conjugated Linoleic Acid for Fat Loss in Mammals
WO2011152692A2 (fr) * 2010-06-03 2011-12-08 주식회사 리스토어랩스 Composition de crème anti-obésité contenant de la fucoxanthine
TWI442920B (zh) * 2011-01-25 2014-07-01 Univ Nat Cheng Kung 香椿萃取物於減少體重或以降低體脂肪之藥物上之用途

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3009138A3 (fr) * 2014-09-01 2016-07-13 Shyam Prasad Kodimule Composition à base d'herbes pour la gestion de l'obésité et/ou du poids
EP3124047A1 (fr) * 2015-07-28 2017-02-01 Merz Pharma GmbH & Co. KGaA Triterpénoïdes pentacycliques pour lipolyse par injection
US10610496B2 (en) 2015-08-28 2020-04-07 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
JP2020143091A (ja) * 2015-08-28 2020-09-10 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪の減少に用いる医薬組成物およびその用途
WO2017037593A3 (fr) * 2015-08-28 2018-08-23 康霈生技股份有限公司 Composition pharmaceutique utilisée pour réduire la graisse localisée et utilisation de la composition pharmaceutique
CN108697668A (zh) * 2015-08-28 2018-10-23 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
JP2018531220A (ja) * 2015-08-28 2018-10-25 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪減少に用いられる医薬組成物及びその用途
JP2018533545A (ja) * 2015-08-28 2018-11-15 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪の減少に用いる医薬組成物およびその用途
JP2020128404A (ja) * 2015-08-28 2020-08-27 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪減少に用いられる医薬組成物及びその用途
AU2016314545B2 (en) * 2015-08-28 2019-07-11 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
CN108697668B (zh) * 2015-08-28 2022-11-04 康霈生技股份有限公司 用于减少局部脂肪的医药组成物及其用途
AU2016314546B2 (en) * 2015-08-28 2019-09-12 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
WO2017037594A3 (fr) * 2015-08-28 2018-08-23 康霈生技股份有限公司 Composition pharmaceutique utilisée pour réduire la graisse localisée et utilisation de la composition pharmaceutique
IL257784B1 (en) * 2015-08-28 2023-07-01 Caliway Biopharmaceuticals Co Ltd Methods and compositions for reducing fat
IL257784B2 (en) * 2015-08-28 2023-11-01 Caliway Biopharmaceuticals Co Ltd Methods and compositions for reducing fat
AU2016314546C1 (en) * 2015-08-28 2021-07-22 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
AU2016314545C1 (en) * 2015-08-28 2021-09-23 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition used for reducing localised fat and use of pharmaceutical composition
US12357588B2 (en) 2015-08-28 2025-07-15 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
AU2021202349B2 (en) * 2015-08-28 2022-12-08 Caliway Biopharmaceuticals Co., Ltd. A pharmaceutical composition for reducing localized fat and uses thereof
JP7054540B2 (ja) 2015-08-28 2022-04-14 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪の減少に用いる医薬組成物およびその用途
US11318110B2 (en) 2015-08-28 2022-05-03 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
JP7063804B2 (ja) 2015-08-28 2022-05-09 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪減少に用いられる医薬組成物及びその用途
JP7063803B2 (ja) 2015-08-28 2022-05-09 カリウェイ バイオファーマシューティカルズ カンパニー リミテッド 局所脂肪の減少に用いる医薬組成物およびその用途
US11433034B2 (en) 2015-08-28 2022-09-06 Caliway Biopharmaceuticals Co., Ltd. Pharmaceutical composition for reducing local fat and uses thereof
US10369179B2 (en) 2015-09-13 2019-08-06 Vidya Herbs, Inc. Composition of Mangifera indica
WO2017068069A1 (fr) * 2015-10-20 2017-04-27 Valbiotis Composition comprenant un melange de molecules particulieres et utilisation pour agir sur le metabolisme glucidique et/ou lipidique
CN109640969A (zh) * 2016-08-26 2019-04-16 康霈生技股份有限公司 用于減少体重的皮下注射剂及其用途
US11896600B2 (en) 2019-09-21 2024-02-13 Vidya Herbs, Inc. Composition and method of using eicosanoyl-5-hydroxytryptamide for treating neurodegenerative disorders
US11452703B2 (en) 2020-05-21 2022-09-27 Peregrine Ophthalmic PTE LTD. Methods and compositions for reducing adipocyte numbers
JP2023528759A (ja) * 2020-05-21 2023-07-06 ペレグリン オフサルミク ピーティーイー リミテッド 脂肪細胞数を減少させる方法及び組成物
CN113694025A (zh) * 2020-05-21 2021-11-26 佩雷格林眼科私人有限公司 减少脂肪细胞数量的方法及组合物
WO2021236128A1 (fr) * 2020-05-21 2021-11-25 Peregrine Ophthalmic PTE LTD. Procédés et compositions pour réduire le nombre d'adipocytes
AU2020448839B2 (en) * 2020-05-21 2026-07-09 Peregrine Ophthalmic PTE LTD. Methods and compositions for reducing adipocyte numbers
US20230372378A1 (en) * 2022-05-16 2023-11-23 Caliway Biopharmaceuticals Co., Ltd. Compositions and methods for alleviating conditions caused by abnormal subcutaneous deposit of adipose tissue or fat

Also Published As

Publication number Publication date
WO2014138426A3 (fr) 2014-10-30

Similar Documents

Publication Publication Date Title
EP2982373B1 (fr) Procédés et compositions pour la réduction de la graisse corporelle
EP2863886B1 (fr) Compositions et procédés permettant une administration topique de prostaglandines à la graisse sous-cutanée
EP2793895B1 (fr) Procédés et compositions pour la réduction de la graisse corporelle et des adipocytes
AU2001264011B2 (en) Use of biguanide derivatives for making a medicine having a wound healing effect
KR101330889B1 (ko) 탈모 방지 또는 육모 촉진을 위한 조성물
EP4093393A1 (fr) Compositions et procédés pour le traitement d'états inflammatoires et de maladies de la peau
US20020192241A1 (en) Methods of using kavalactone compositions
EP2854784A1 (fr) Méthode de traitement de maladies inflammatoires de la peau
US20180055838A1 (en) Methods and compositions for treatment of dermal and epidermal wounds
JP7406192B2 (ja) 線維症治療薬
KR20070059079A (ko) 경피 페로스피론 투여용 의약적 조성물
WO2012083397A1 (fr) Composé contenant du guanabenz pour le traitement de l'amyloïdose cutanée primaire
HK1220912B (en) Methods and compositions for reducing body fat
HK1190936B (en) Methods and compositions for treating metabolic syndrome
HK1233926B (en) Compositions and methods for topical delivery of prostaglandins to subcutaneous fat
KR20240167400A (ko) 염증성 피부 질환의 예방 또는 치료용 조성물
WO2015034947A2 (fr) Agonistes non peptidiques du récepteur b2 de la bk pour la croissance capillaire
US7989008B2 (en) Cosmetic preparations designed to reduce unsightly cellulite
CA2880399C (fr) Utilisation d'acide libre de bimatoprost administre sur la peau en vue de reduire les tissus adipeux
CA2575842A1 (fr) Composition contenant un derive de la thio-uree destinee a prevenir ou a traiter des maladies de la peau prurigineuses ou irritantes
WO2020101977A1 (fr) Composés d'amine éther lipidique pour le traitement topique de maladies cutanées
JPH0826993A (ja) 鎮痒剤
KR20160044214A (ko) Abh 항원의 발현을 조절하는 물질을 포함하는 모공 축소용 조성물
PL203478B1 (pl) Zastosowanie pochodnych biguanidu i ich soli do wytwarzania leku do bliznowacenia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14759616

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 14759616

Country of ref document: EP

Kind code of ref document: A2