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WO2016075539A1 - Composition pour le traitement de troubles liés à un poids excessif ou à l'obésité - Google Patents

Composition pour le traitement de troubles liés à un poids excessif ou à l'obésité Download PDF

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Publication number
WO2016075539A1
WO2016075539A1 PCT/IB2015/002263 IB2015002263W WO2016075539A1 WO 2016075539 A1 WO2016075539 A1 WO 2016075539A1 IB 2015002263 W IB2015002263 W IB 2015002263W WO 2016075539 A1 WO2016075539 A1 WO 2016075539A1
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WIPO (PCT)
Prior art keywords
obesity
overweight
metformin
treatment
sibutramine
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Ceased
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PCT/IB2015/002263
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English (en)
Russian (ru)
Inventor
Павел Вячеславович КОРНЕВ
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Promomed Holding Ltd
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Promomed Holding Ltd
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Filing date
Publication date
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Publication of WO2016075539A1 publication Critical patent/WO2016075539A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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 invention relates to medicine, in particular, to a composition for the prevention and treatment of disorders associated with overweight or obesity, containing dipeptidyl peptidase IV (DPP-IV) inhibitors, metformin and sibutramine or their pharmaceutically acceptable salts as active components.
  • DPP-IV dipeptidyl peptidase IV
  • a pharmaceutical composition for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus, and to methods for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus, and regulation of glucose levels blood.
  • tropane derivatives are used, which are reuptake inhibitors of monoamine neurotransmitters such as dopamine, norepinephrine and serotonin (patents RU 2167876, 2348631), with sibutramine and topiramate being preferred .
  • monoamine neurotransmitters such as dopamine, norepinephrine and serotonin (patents RU 2167876, 2348631)
  • sibutramine and topiramate being preferred .
  • Anorexigenic effect is achieved. Reducing the intake of fat from food is achieved through the use of an intestinal lipase inhibitor orlistat.
  • Sibutramine is a prodrug and exerts its effect in vivo due to metabolites (primary and secondary amines) that inhibit the reuptake of monoamines (mainly serotonin and norepinephrine).
  • metabolites primary and secondary amines
  • monoamines mainly serotonin and norepinephrine
  • An increase in the content of neurotransmitters in synapses increases the activity of central 5HT-serotonin and adrenergic receptors, which contributes to an increase in satiety and a decrease in food requirements, as well as an increase in
  • Sibutramine and its metabolites do not affect the release of monoamines, do not inhibit MAO; do not have an affinity for a large number of neurotransmitter receptors, including serotonin (5-HT
  • Metformin is an oral hypoglycemic drug from the biguanide group. Metformin reduces hyperglycemia without leading to development hypoglycemia. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals; increases the sensitivity of peripheral receptors to insulin and glucose utilization by cells, reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis, and delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthetase.
  • metformin the patient’s body weight either remains stable or decreases moderately.
  • metformin as a supplement to the diet in individuals with obesity and type 2 diabetes [Teupe B., Bergis K. Prospective randomized two years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Diabete Metabolisme, 1991, v. 17, p.p. 213-17] allowed metformin to be considered the first choice drug for the hypoglycemic therapy of patients with overweight and obesity.
  • DPP-IV dipeptidyl peptidase IV
  • GLP-1 glucagon-like peptide-1
  • Dipeptidyl peptidase IV - 4 is a membrane-bound
  • non-classical serine aminopeptidase which is localized in a number of tissues (intestines, liver, lungs, kidneys), as well as on blood T-lymphocytes (where the enzyme is known as CD-26). It is responsible for the metabolic cleavage of endogenous peptides (GLP-1 (7-36), glucagon) in vivo and exhibits proteolytic
  • GLP-1 peptide (7-36) having a sequence of 29 amino acids and formed during post-translational processing
  • proglucagon exhibits various in vivo activity, including stimulation of insulin secretion, inhibition of glucagon secretion, and has
  • DPP-IV inhibitors for the treatment of conditions mediated by DPP-IV, such as non-insulin-dependent diabetes mellitus and obesity (WO 98/19998,
  • vildagliptin which is (S) -1- [N- (3-hydroxy-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile with the structural formula
  • condensed cyclopropyl pyrrolidine-based dipeptidyl peptidase IV inhibitors proposed for use in the treatment of diabetes, in particular type II diabetes, as well as hyperglycemia, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related
  • vildagliptin and its pharmaceutically acceptable salts in particular acid addition salts, including acetate, adipate, alginate, 4-aminocalicylate, aspartate, benzoate, carbonate, cinnamate and others, are described in WO 2007/019255.
  • beta-aminotetrahydroimidazo- (1,2-A) pyrazines and tetrahydrotriazolo- (4, 3-A) pyrazines as inhibitors of DPP-IV for the treatment and prevention of diabetes (patent EA 006845), in particular sitagliptin, representing ⁇ ) is described.
  • -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3th] pyrazin-7 (8H) -yl] -1- (2,4 , 5-trifluorophenyl) butan-2-amine with the structural formula
  • Alogliptin which is 2 - ( ⁇ 6 - [(3) -3-aminopiperidin-1-yl] -3-methyl-2,4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl ⁇ methyl) benzonitrile with structural formula
  • Patent EA 013684 describes heterocyclic compounds of boronic acid, including dutogliptin, which is 1- [N- [3 (R) - pyrrolidinyl] glycyl] pyrrolidin-2 (7?) - ilboric acid with a structural formula
  • dutogliptin Methods for producing dutogliptin are described in publications WO / 2005/047297, WO /
  • EAO Patent 12591 describes hemigliptin, which is (35) -3-amino-4- (5,5-difluoro-2-oxopiperidino) -1- [2,4-di (trifluoromethyl) -5,6,7,8 - tetrahydropyrido [3,4-a] pyrimidin-7-y1] butan-1-one with the structural formula
  • DPP-IV used to treat or prevent DPP-IV-dependent diseases, for example type II diabetes mellitus.
  • Melogliptin related to pyrrolidone derivatives and representing (2S, 4S) -l- ⁇ 2 - [(3S, 1 R) -3- (l / - / - 1, 2, 4-triazol-1-ylmethyl) cyclopentylamino] acetyl1 ⁇ -4-fluoropyrrolidin-2-carbonitrile with the structural formula
  • DP4 inhibitors or gliptins can be used in combination with one or more antidiabetic agents other than a DP4 inhibitor, an anti-obesity agent and / or a lipid modulating agent (EA201 101 187,
  • a pharmaceutical combination for inhibiting the enzymatic activity of DPP-IV may include a heterocyclic boronic acid compound and an antidiabetic or antihyperglycemic agent, wherein the weight ratio of the compound to antidiabetic or
  • the antihyperglycemic agent is preferably from about 0.01: 1 to about 100: 1 (patent EA 013684). If the antidiabetic agent is a biguanide, the compounds are used in a weight ratio to the biguanide in the range of about 0.01: 1, about 100: 1, preferably about 0.1: 1, about 5: 1.
  • a serotonin (and dopamine) reuptake inhibitor which optionally can be used in combination with a boronic acid compound, may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and
  • the antidiabetic agent may be an oral antihyperglycemic agent, preferably biguanide such as metformin, preferably metformin HC1.
  • DP4 inhibitors used in weight may be an oral antihyperglycemic agent, preferably biguanide such as metformin, preferably metformin HC1.
  • Metformin in relation to biguanide (metformin), about 0.01: 1-100: 1, preferably about 0.1: 1-5: 1.
  • Metformin or its salt is used in amounts of about 500-2000 mg per day, which can be administered in as a single dose or as
  • Another type of therapeutic agent that, if necessary, can be used with condensed cyclopropylpyrrolidine dipeptidyl peptidase IV inhibitors may be anti-obesity agents, including a serotonin (and dopamine) reuptake inhibitor.
  • Inhibitor may be anti-obesity agents, including a serotonin (and dopamine) reuptake inhibitor.
  • Anti-obesity substances can be used in the same dosage form as gliptin or in various dosage forms.
  • the adult gliptin dose is preferably about 10-1000 mg per day, this amount can be administered as a single dose or in divided doses 1-4 times a day.
  • Antidiabetic drugs containing a DPP-4 inhibitor in particular, linagliptin
  • a DPP-4 inhibitor in particular, linagliptin
  • agents that can be used to treat or prevent one or more conditions selected from the group including, but not limited to, type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia are described in application EA 201 101 187.
  • compositions containing dipeptidyl peptidase IV inhibitors are known, an additional antidiabetic agent other than a DP4 inhibitor, wherein the antidiabetic agent may be an oral antihyperglycemic agent, preferably biguanide such as metformin and an anti-obesity substance, including sibutramine, but not any synergistic effect is mentioned
  • metmorphine and sibutramine compared with monotherapy with each of
  • the authors of the present invention proposed a pharmaceutical composition containing as active components a dipeptidyl peptidase inhibitor.
  • IV which is vildagliptin, melogliptin or dutogliptin or their pharmaceutically acceptable salts, in combination with metmorphine and sibutramine with a ratio of gliptin: metformin: sibutramine, comprising 0.1: 2-5: 25-0.05: 0.2.
  • the pharmaceutical composition proposed in accordance with the present invention is an effective tool for weight loss and is suitable in the treatment of disorders associated with overweight or obesity, including diabetes mellitus type P.
  • composition has a pronounced synergistic effect, which manifests itself in a more effective weight loss with overweight or obesity, in particular with diabetes mellitus, with the combined use of dipeptidyl peptidase IV inhibitor, metmorphine and sibutramine or their pharmaceutically acceptable salts in the composition in the ratio of gliptin: metformin : sibutramine, comprising 0.1: 2-5: 25-0.05: 0.2 by
  • dipeptidyl peptidases IV, metmorphine and sibutramine or their pharmaceutically acceptable salts can enhance their therapeutic effect, reduce side effects and, thus, provide preventive protection and optimize the treatment of patients with overweight or obesity, including diabetes.
  • Another aspect of the invention relates to a kit containing
  • Another object of the invention is the use of the pharmaceutical composition and kit according to the invention for the prevention or treatment of disorders associated with overweight or obesity, including type II diabetes mellitus, and regulation of blood glucose levels.
  • Another object of the invention is a method for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus, comprising administering to a patient a pharmaceutical composition or kit according to the invention in a therapeutically effective amount.
  • the present invention provides a pharmaceutical composition exhibiting weight loss activity and comprising, as active components, a dipeptidyl peptidase IV inhibitor, metmorphine and sibutramine, or pharmaceutically acceptable salts thereof, in a ratio
  • dipeptidyl peptidase IV inhibitor metformin: sibutramine, comprising 0.1: 2-5: 25-0.05: 0.2.
  • the dipeptidyl peptidase IV inhibitor is vildagliptin, dutogliptin or melogliptin.
  • the composition has a pronounced synergistic effect.
  • composition according to the invention containing a dipeptidyl peptidase IV inhibitor, metmorphine and sibutramine with a ratio of gliptin: metformin: sibutramine of 0.1: 2-5: 25-0.05 : 0.2 with respect to monotherapy with a dipeptidyl peptidase IV inhibitor, metmorphine and sibutramine.
  • vildagliptin is preferably from 10 to 100 mg, most
  • dutogliptin is 100 to 200 mg
  • melogliptin is 50 to 200 mg
  • metformin is 500 to 2500 mg
  • sibutramine is 5 to 20 mg.
  • composition in accordance with the present invention may be any composition in accordance with the present invention.
  • composition may be in the form of drops or a solution for oral administration, or in the form of a nasal spray or nasal drops, a sublingual or oral aerosol, or in the form of a powder, or in the form of a lyophilizate for preparing the finished product
  • compositions are prepared by known methods.
  • the composition is preferably prescribed for patients in need of prophylaxis or treatment.
  • oral and / or parenteral administration e.g., intravenously,
  • the pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders. Tablets containing various excipients, for example,
  • microcrystalline cellulose, sodium citrate, calcium carbonate and calcium phosphate, or any other pharmaceutically acceptable excipients may also include various disintegrants, for example, starch, preferably
  • binders for example, polyvinylpyrrolidone, sucrose, gelatin, gum arabic and any other pharmaceutically acceptable binders.
  • moving agents such as magnesium stearate are often used,
  • compositions of the invention may also be soft or hard gelatin capsules; preferred capsules in this case include, for example, lactose or milk sugar, and high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, the claimed compositions may be combined with various sweeteners to improve taste and smell, tinting agents, emulsifying agents and / or
  • suspending agents as well as solvents such as water, ethanol, propyl glycol, glycerin and various combinations thereof.
  • solvents such as water, ethanol, propyl glycol, glycerin and various combinations thereof.
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be used, as well as sterile aqueous solutions
  • aqueous solutions may be buffered, if necessary, and the aqueous solvent is first isotonized with a sufficient amount of a salt or glucose solution.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and
  • kits comprising individually metformin or a pharmaceutically acceptable salt thereof and tezofenzin or a pharmaceutically acceptable salt thereof in oral form.
  • the kit also contains instructions for use.
  • excipients are used as excipients, most preferably calcium stearate.
  • the oral form according to the invention is a solid
  • dosage form including powders, tablets, pills, dragees,
  • Capsules represent special dosage capsules
  • powdered, granular active substances according to the invention can be gelatinous or starchy. Tablets represent a solid dosage unit form obtained by compression. Jelly beans
  • any pharmaceutically acceptable salts are used, such as, for example, metformin hydrochloride and.
  • the invention also relates to the use of the above composition and kit for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus. These disorders include overweight, obesity, repeated weight gain after a previous decrease, for example, after a diet, a change in the component composition of the body, including diabetes, with the ineffectiveness of diet therapy and physical activity.
  • Another object of the invention is a method for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus, comprising administering to the patient a composition according to the invention in a therapeutically effective amount.
  • the regimen and dose of the pharmaceutical composition according to the invention depend on the stage of the disease and the patient's condition.
  • the daily dose depends on the severity of the disease, the weight of the patient and the desired effect.
  • the dose is set individually depending on tolerance and clinical efficacy.
  • the daily dose of vildagliptin is preferably from 10 to 100 mg, most preferably 50 mg;
  • dutogliptin is from 100 to 200 mg; melogliptin - from 10 to 300 mg, most preferably from 50 to 200 mg; metformin - from 500 to 2500 mg, and sibutramine - from 5 to 20 mg.
  • Example 1 The effect of gliptin (vildagliptin, dutogliptin or melogliptin), metformin and sibutramine in the pharmaceutical composition according to the invention on weight loss
  • Body mass index is defined as the weight of a person (in kilograms) divided by his height (in meters) squared.
  • a BMI equal to or greater than 28 corresponds to obesity, and a BMI from 28 to 35 indicates mild or moderate obesity, and a BMI from 35 to 40 corresponds to severe obesity.
  • the effectiveness of the drug was evaluated by the dynamics of weight loss.
  • the invention and its effect on the cardiovascular system regularly measured blood pressure and heart rate.
  • the effect of the pharmaceutical composition on the change in body weight was studied with enhanced nutrition: men received 3600-4000 kcal per day, women - 2800-3200 kcal per day. Patients received a pharmaceutical composition in the form of a set of capsules or tablets.
  • n 410 .
  • vildagliptin in the form of monotherapy or in combination with metformin does not significantly affect body weight.
  • metformin another sugar-lowering drug
  • a significant decrease in body weight is observed in patients taking a composition containing dutogliptin or
  • melogliptin in combination with metformin and sibutramine melogliptin in combination with metformin and sibutramine.
  • sibutramine are from the digestive system — loss of appetite, constipation, nausea; from the nervous system and sensory organs - dry mouth, insomnia, headache, dizziness.
  • vildagliptin 50 and 100 mg Unlike control (monotherapy with vildagliptin, metformin and sibutramine), when using the composition according to the invention at a daily dose of vildagliptin 50 and 100 mg, dutogliptin - 100 mg and 200 mg, or melogliptin - 50 and 200 mg, in combination with metformin in a daily dose - 500 and 2000 mg, and sibutramine - 10 and 15 mg, these side effects were not noted.
  • Example 2 The effect of a composition containing vildagliptin, dutogliptin or meloglptin in combination with metformin and sibutramine.
  • vildagliptin 50 and 100 mg dutogliptin - 100 mg and 200 mg, or melogliptin - 50 and 200 mg, in combination with metformin in a daily dose - 500 and 2000 mg, and sibutramine - 10 and 15 mg to regulate blood glucose
  • vildagliptin, dutogliptin, or melogliptin in combination with metformin showed a significant decrease in GKN by an average of 3.52 mmol / L.
  • vildagliptin from 50 to 100 mg
  • dutogliptin from 100 mg to 200 mg
  • melogliptin from 50 to 200 mg in combination with metformin in a daily dose of 500 to 2500 mg
  • sibutramine - from 10 to 15 mg.

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Abstract

On propose une composition et un ensemble pour la prévention et le traitement de troubles liés à un poids excessif ou à l'obésité comprenant la tésofensine et de metformine en tant que principes actifs dans des quantité entre 0,1 et 2 mg de tésofensine et de 500 à 3000 mg de metformine. L'invention concerne aussi l'utilisation de la composition pharmaceutique et un ensemble pour la prévention ou le traitement des troubles liés à un poids excessif ou à une obésité, y compris en cas de diabète sucré, et des méthodes de prévention et de traitement des troubles liés à un poids excessif ou à une obésité, y compris en cas de diabète sucré. La composition possède un effet de synergie bien exprimé qui se manifeste en une réduction considérable de poids et d'effets secondaires lors de l'utilisation conjointe dans la composition de tésofensine et de metformine en cas de troubles liés à un poids excessif ou à une obésité, y compris en cas de diabète sucré.
PCT/IB2015/002263 2014-11-10 2015-11-09 Composition pour le traitement de troubles liés à un poids excessif ou à l'obésité Ceased WO2016075539A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2014001133 2014-11-10
EA201401133 2014-11-10

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WO2016075539A1 true WO2016075539A1 (fr) 2016-05-19

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151565A2 (fr) * 2009-06-26 2010-12-29 Metabolous Pharmaceuticals, Inc. Multithérapies pour le traitement de l'obésité
WO2011009115A2 (fr) * 2009-07-17 2011-01-20 Metabolous Pharmaceuticals, Inc. Thérapies combinées destinées à traiter l'obésité
WO2014008374A2 (fr) * 2012-07-06 2014-01-09 Thetis Pharmaceuticals Llc Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151565A2 (fr) * 2009-06-26 2010-12-29 Metabolous Pharmaceuticals, Inc. Multithérapies pour le traitement de l'obésité
WO2011009115A2 (fr) * 2009-07-17 2011-01-20 Metabolous Pharmaceuticals, Inc. Thérapies combinées destinées à traiter l'obésité
WO2014008374A2 (fr) * 2012-07-06 2014-01-09 Thetis Pharmaceuticals Llc Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAILEY C J ET AL: "Anti-obesity fixed-dose combinations", BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 2012 SAGE PUBLICATIONS LTD GBR, vol. 12, no. 1, January 2012 (2012-01-01), pages 2 - 5, XP002755444, ISSN: 1474-6514 *

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