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WO2007013062A1 - Composition et procede de stabilisation du poids - Google Patents

Composition et procede de stabilisation du poids Download PDF

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Publication number
WO2007013062A1
WO2007013062A1 PCT/IL2006/000853 IL2006000853W WO2007013062A1 WO 2007013062 A1 WO2007013062 A1 WO 2007013062A1 IL 2006000853 W IL2006000853 W IL 2006000853W WO 2007013062 A1 WO2007013062 A1 WO 2007013062A1
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WO
WIPO (PCT)
Prior art keywords
subject
composition
sbs
anyone
weight
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/IL2006/000853
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English (en)
Inventor
Avner Shenfeld
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.)
LEAN-EX Ltd
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LEAN-EX Ltd
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Filing date
Publication date
Application filed by LEAN-EX Ltd filed Critical LEAN-EX Ltd
Publication of WO2007013062A1 publication Critical patent/WO2007013062A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • This invention relates generally to a composition and a method for weight maintenance for individuals with a past history of obesity or for those at risk at becoming obese.
  • the first corresponds to the dietary consumption of fats (mostly triglycerides), which after a brief processing in the liver are integrated into lipoproteins and transported through the blood stream to the various sites of deposition.
  • the main physiological task of this process is to clear excess of serum lipids and store them in the fat tissue (i.e. adipose tissue) as energy reservoir.
  • the second physiological mechanism corresponds to conversion of carbohydrate metabolites to fatty acids (i.e. lipogenesis) in the liver.
  • the synthesized fatty acids then integrate into triglycerides, phospholipids and cholesterol esters and join the parallel dietary lipids in their transport by blood lipoproteins.
  • the lipogenesis mechanism involves a complicated enzymatic network where acetyl-CoA carboxylase and fatty acid synthetase are the rate determining enzymes. It is of great importance that both enzymes are inhibited by free fatty acids and their CoA conjugates thus providing a negative feedback loop between the lipid consumption pathway and the lipogenesis machinery. Thus, upon excess fat consumption the relatively high level of released free fatty acids can transiently shut-off the lipogenesis channel.
  • GAD2 GAD2
  • PPAR- ⁇ membranal peroxisome proliferator-activated receptor- alpha
  • the presently available drugs may be divided into three groups: noradrenergic, serotonergic and lipid absorption inhibitors.
  • the first two classes are ⁇ -phenethylaminic derivatives, acting centrally by inhibiting the reuptake of the neurotransmitters dopamine, noradrenaline and serotonin. This mode of action suppresses appetite, promotes satiety and induces a peripheral thermogenic effect.
  • this mechanism is also responsible for cardiovascular adverse events, which were serious enough to cause the withdrawal from the market of two compounds: fenfluramine and dexfenfluramine, due to induction of valvulopathy.
  • the most effective compound in this series was a compound having a C16 chain, and abbreviated MEDICA 16.
  • the compound was found not only to reduce the net synthesis of triglycerides but also to increase their burning as immediate energy source and to reduce the biosynthesis of cholesterol esters. This induced a reduction in the level of blood LDL and VLDL through a marked decrease in apolipoprotein C-III, with a parallel increase in HDL.
  • the prevention of catabolism has endowed this highly stable compound with long term toxic effects due to accumulation and deposition on essential body tissues like blood vessels. This characteristic has prevented, so far, the development of MEDICA 16 into an ethical drug.
  • US Patent No. 5,602,164 to Shinitzky et al discloses a method for treatment of obesity which involves administering to an obese individual an effective amount of an ⁇ , ⁇ dicarboxylic acid derivative.
  • the present invention is based on the surprising finding that linear ⁇ , ⁇ dicarboxylic acids derivatives such as sebacoyl bis sarcosine (SBS) are effective not only in stopping weight gain but most importantly may be used as agents for maintaining a subject's weight.
  • SBS sebacoyl bis sarcosine
  • This invention is further based on the observation that the exhibited prophylactic activity does not require special dietary behavior. This allows the subject to return to normal dietary behavior (namely, not such which to an average person would seem abnormal in nature) without fearing a rebound effect, e.g. return to abnormal eating regimen.
  • the present invention provides a method for weight maintenance in a subject, comprising administering to said subject an effective amount of sebacoyl bis- sarcosine (SBS).
  • SBS sebacoyl bis- sarcosine
  • the subject has a history of obesity. In another embodiment, the subject has a risk of becoming obese.
  • the present invention further provides a method for weight maintenance in a subject with a history of obesity or having a risk of becoming obese, comprising repeatedly administering to said subject an effective amount of sebacoyl bis-sarcosine (SBS).
  • SBS sebacoyl bis-sarcosine
  • the methods according to the present invention may or may not be associated with any prior or on-going weight loss modality.
  • an association between the method of the present application and an on-going weight-loss modality e.g. a low calorie diet
  • an on-going weight-loss modality e.g. a low calorie diet
  • the type of association namely the nature of the accompanying treatment or modality, e.g. dietary therapies, physical activity and behavior therapy, that would be administered or executed simultaneously with the method of the present invention, may differ based on the individual's age, health condition, psychological state, history of obesity, degree of risk of returning to the obese state and other factors which a medical personnel familiar with the individual will consider.
  • the methods of the present invention may be used by individuals having a history of obesity or who are at risk at being obese, who are at the time of treatment considered lean or who are at the time of treatment pleased with their weight.
  • the methods of the present invention may also be used by such individuals who are naturally lean, or who have achieved a goal of weight loss, being it after a dietary regimen or as a result of other personal circumstances and who wish to maintain that weight without needing to adhere to strict modalities of weight loss therapy.
  • the invention further provides a method for weight maintenance in a subject, comprising repeatedly administering to said subject an effective amount of sebacoyl bis- sarcosine (SBS), wherein said administration does not cause the subject to reduce food consumption, i.e. the subject substantially continues to eat according to his everyday habits.
  • SBS sebacoyl bis- sarcosine
  • the invention also provides for the use of SBS for the preparation of a composition for weight maintenance.
  • composition comprises SBS and a pharmaceutically acceptable carrier, diluent or excipient and may also comprise at least one other agent selected from a variety of amino acids, vitamins, natural salts, natural extracts, and/or metabolic stimulates.
  • a pharmaceutically acceptable carrier diluent or excipient
  • Such may be for example, without being limited thereto, vitamins A, B-I, B-2, B-6, B-12, C, D, E, K, biotin, folic acid, inositol, calcium slats, phosphorus salts, magnesium salts, selenium, iron, iodine and others.
  • the SBS may be administered to the subject alone or as part of a composition which comprises other active agents, excepients, dilutents, or carriers.
  • the pharmaceutical composition of the present invention for weight maintenance, comprises an effective amount of sebacoyl bis-sarcosine (SBS) and a pharmaceutically acceptable carrier, excipient, or a diluent. It may be administered to a subject who has a history of obesity or to a subject who has a risk of becoming obese, as detailed hereinbefore.
  • excipient diluent
  • carrier diluent
  • Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of SBS dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of SBS, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodiumk talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • compositions of the present invention may be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations may be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the SBS can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxy- ethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopriopionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
  • Suitable preservatives and buffers can be used in such pharmaceutical compositions.
  • such compositions may contain one or more nonionic surfactants having a hydrophile- lipophile balance (HLB) of from about 12 to about 17.
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • composition of the present invention may be administered to the individual in combination with other weight maintenance agents.
  • weight maintenance refers to the continuous preservation of one's weight at or about a substantially constant starting weight.
  • the term "repeated administration” refers to a regimen according to which the SBS or a composition comprising thereof is administered on a regular basis over a period of time for the duration of the weight maintenance term. Such administration may for example involve a once-daily administration, administration after or before every meal, once-weekly etc, based on the professional judgment of the medical personnel prescribing the composition.
  • the term "effective amount” refers to an amount of SBS or a composition containing thereof which is sufficient to significantly induce a maintenance of weight at a relatively constant weight while avoiding side effects within the scope of sound medical judgment.
  • the amount of the compound or the composition comprising it will vary with the particular condition, the age and physical condition of the individual being treated, the nature of the condition, the particular carrier, diluent or excipient used and other factors known to a member of the medical personnel.
  • histoiy of obesity refers to a period of time preceding the beginning of the weight maintenance period during which the individual was considered obese. Such period may be several years, months, weeks, days, hours, or minutes before commencement of said weight maintenance period.
  • Such risk may arise from a genetic tendency which runs in the family, to a certain health disorder, to a certain psychological disorder which causes the subject to become obese and the like.
  • the term "obese” refers to individuals having a BMI greater or equal to 30, or greater or equal to 27 in the case of coexisting complications. Individuals having a BMI 25-30 are considered overweight and those having a BMI up to 25 are considered of normal weight. Morbid obese individuals are those having a BMI greater than 40.
  • the SBS or the composition comprising thereof is administered to a subject having a BMI greater or equal to 27.
  • the method is utilized by a subject having a BMI between 27-25.
  • the method is utilized by a subject having a BMI up to 25.
  • Weight loss modality refers to any therapy directed at weight loss. Such may be dietary therapies, physical activity and behavior therapy.
  • Figs. IA and IB demonstrate the efficiency of SBS in stopping weight gain in normal mature and old rats and mice, as compared to control animals. Effect of SBS given by the "mixed-in-food" regiment (200mg/Kg): in Fig. IA middle age (6-month old) and in Fig. IB old male mice (12-month old).
  • Fig. 2 depicts the effects of SBS given by oral gavages on body weight in middle age rats under food restriction regiment (animals treated with SBS received the same amount of food as the controls).
  • Fig. 3 is a depiction of results of an experiment during which SBS was given by oral gavages twice daily to diet induced rats, which were fed high calorie fat diet without any restriction.
  • PCG-I ⁇ is a novel co-activator of PPAR- ⁇ , the over-expression of which in transgenic mice increases energy expenditure and blocks weight increase, probably by burning fat in the face of increased energy demands.
  • PCG-I ⁇ is part of a larger family of transcriptional co-activators, such as PCG- l ⁇ , which is induced in brown fat and controls its thermogenesis.
  • PCG- l ⁇ transcriptional co-activators
  • Sprague-Dowley Rats were fed continuously a highly fattening diet ad libidum, divided into 3 groups, treated by SBS, olestat, or sibutramin respectively, for comparison.
  • Preliminary results have shown a 300% difference in weight after 25 days in the group of animals treated with 150mg/kg SBS and weighing >450g, and having maintained a constant weight on the above diet, while the controls continued to add weight (Fig. 3).
  • Two groups of 8 beagle dogs each (4 Males and 4 Females) were fed gelatin capsules, containing a single dose of 700mg/kg SBS (16-19 fold the human clinical dose), in the treated group, and empty capsules in the control one, during a period of 14 days.
  • the main findings were related to gastrointestinal side-effects, mainly diarrhea, which did not cause any mortality or biochemical disturbances. This was probably due to the high osmolarity resulting from the high local concentration of the drug upon the emptying of the capsules.
  • This assay was to evaluate the potential of SBS to induce potentially damaging mutations in the DNA, which may be carcinogenic or cause cell death.
  • Five strains of Salmonella typhimurium bacteria were used in 2 experiments. All the data showed that SBS did not induce an increase in revertant colony numbers and gene mutations by base pair changes or frame shifts in the bacterial genome.
  • Example 6 mammalian chromosome aberration test
  • V79 cells of the Chinese Hamster were used in 2 experiments. No decrease in the relative mitotic index or in cell density was observed.
  • a randomized, double-blind, placebo-controlled, oral multiple-dose escalation trial was performed in 18 male human healthy volunteers. The purpose was to evaluate the safety, tolerability and pharmacokinetics of SBS. This trial was performed after a preliminary study, in which single oral doses of 0.5, 1.0, 2.0 and 4.Og of SBS were administered to 4 groups of 8 male volunteers in each group, showing no deleterious effects on vital signs, 12-lead ECG and laboratory safety tests. In this stuffy, oral doses of 1.0, 2.0 and 4.0 grams were administered during 7 consecutive days to 3 groups of 6 volunteers each, one participant in each group being assigned randomly to placebo. Thus, 18 subjects were included, 16 of which concluded the study, two having been withdrawn due to adverse events (AE) not related to SBS.
  • AE adverse events

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Child & Adolescent Psychology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (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)

Abstract

L'invention concerne une composition et un procédé de stabilisation du poids. Plus particulièrement, cette composition, qui renferme de la bis-sarcosine de sébacoyle (SBS), est utilisée pour stabiliser le poids chez des sujets qui présentent un historique d'obésité ou un risque d'obésité.
PCT/IL2006/000853 2005-07-25 2006-07-24 Composition et procede de stabilisation du poids Ceased WO2007013062A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70198105P 2005-07-25 2005-07-25
US60/701,981 2005-07-25

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WO2007013062A1 true WO2007013062A1 (fr) 2007-02-01

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PCT/IL2006/000853 Ceased WO2007013062A1 (fr) 2005-07-25 2006-07-24 Composition et procede de stabilisation du poids

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119326742A (zh) * 2024-12-20 2025-01-21 四川大学华西医院 肌氨酸作为唯一活性成分在制备防治肥胖和/或高血脂症的药物中的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021913A1 (fr) * 1992-04-28 1993-11-11 Senyorina Ltd. Medicaments contre l'obesite
WO2003045370A1 (fr) * 2001-11-26 2003-06-05 Lean-Ex Ltd. Composition pharmaceutique pour traiter l'obésité

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021913A1 (fr) * 1992-04-28 1993-11-11 Senyorina Ltd. Medicaments contre l'obesite
WO2003045370A1 (fr) * 2001-11-26 2003-06-05 Lean-Ex Ltd. Composition pharmaceutique pour traiter l'obésité

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119326742A (zh) * 2024-12-20 2025-01-21 四川大学华西医院 肌氨酸作为唯一活性成分在制备防治肥胖和/或高血脂症的药物中的用途

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