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EP1853264A1 - Use of rimonabant for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes - Google Patents

Use of rimonabant for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes

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Publication number
EP1853264A1
EP1853264A1 EP06709344A EP06709344A EP1853264A1 EP 1853264 A1 EP1853264 A1 EP 1853264A1 EP 06709344 A EP06709344 A EP 06709344A EP 06709344 A EP06709344 A EP 06709344A EP 1853264 A1 EP1853264 A1 EP 1853264A1
Authority
EP
European Patent Office
Prior art keywords
rimonabant
treatment
diabetes
prevention
use according
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.)
Withdrawn
Application number
EP06709344A
Other languages
German (de)
French (fr)
Inventor
Corinne Hanotin
Pierre Rosenzweig
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.)
Sanofi SA
Original Assignee
Sanofi Aventis France
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
Priority claimed from FR0501861A external-priority patent/FR2882261B1/en
Priority claimed from FR0504942A external-priority patent/FR2882264A1/en
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1853264A1 publication Critical patent/EP1853264A1/en
Withdrawn legal-status Critical Current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
    • A61K31/33—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the present invention relates to the use of rimonabant, for the preparation of drugs useful in the prevention and treatment of type 2 diabetes or non-insulin-dependent diabetes and / or its complications.
  • Type 2 diabetes is characterized by insulin secretion disorders associated with insulin sensitivity or insulin resistance disorders. Insulin resistance is aggravated by hyperglycemia and high levels of circulating free fatty acids and stored triglycerides.
  • Rimonabant is the international nonproprietary name of N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide described in European Patent 656354. Clinical studies conducted with rimonabant have shown that it acts on quantitative and qualitative food intake and reduces the body weight of obese patients (Le Fur, 2003, 35, First European Workshop on Cannabinoid Research,
  • rimonabant can be used for the preparation of medicaments useful for preventing and treating type 2 diabetes and its complications.
  • Diabetes-related complications include:
  • neurological diseases such as diabetic neuropathies, peripheral neuropathies, autonomic cardiac neuropathies;
  • kidney diseases such as diabetic nephropathies, diabetic glomerulopathies
  • ocular diseases such as diabetic retinopathies, macular edema, glaucoma;
  • the subject of the present invention is the use of rimonabant for the prevention and treatment of complications related to diabetes, while particularly, peripheral neuropathies, diabetic neuropathies, diabetic nephropathies, diabetic retinopathies, angiopathies.
  • compositions according to the present invention contain an effective dose of rimonabant as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • the active ingredient may be administered in unit dosage form. in combination with conventional pharmaceutical excipients, animals and humans for the prevention or treatment of type 2 diabetes.
  • Suitable dosage unit forms include oral forms such as tablets, soft or hard capsules , powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, forms of topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • capsules or tablets are preferred. More particularly, capsules or tablets containing rimonabant are preferred at a dose of between 5 and 50 mg, more particularly at doses of 10 to 30 mg, especially the dose of 20 mg.
  • the rimonabant can be associated with another active principle chosen from one of the following therapeutic classes: a lipid-lowering agent or a cholesterol-lowering agent;
  • compositions containing, in combination, a cannabinoid CB 1 receptor antagonist, derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4- bromophenyl) -1- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxanide, and another active ingredient selected from one of the following therapeutic classes:
  • lipid-lowering agent or a cholesterol-lowering agent
  • lipid-lowering or cholesterol-lowering agent a compound chosen from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterin, tiadenol.
  • statins HMG-CoA reductase inhibitors
  • statins HMG-CoA reductase inhibitors
  • antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, methaglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, voglibose.
  • methaglinides such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, glicla
  • the subject of the present invention is a pharmaceutical composition containing, in combination, rimonabant and metformin, or rimonabant and a sulphonylurea such as acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, tolazamide, tolbutamide, for the treatment of type 2 diabetes.
  • a sulphonylurea such as acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, tolazamide, tolbutamide
  • the rimonabant and the other associated active ingredient can be administered simultaneously, separately or spread over time.
  • Extended use over time is understood to mean the sequential administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then, of the second compound of the composition according to the invention, included in a form pharmaceutical industry.
  • the lapse of time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours, it can be higher if one or the other
  • the compounds are presented in a pharmaceutical formulation allowing, for example, a weekly administration.
  • compositions according to the invention comprising either one of the constituent compounds of the composition according to the invention or the combination of the two compounds, which can be used in the various types of use described above, may for example be appropriate for oral, nasal, parenteral or transdermal administration.
  • two different dosage forms may be for the same route of administration or a different route of administration (oral and transdermal). or oral and nasal or parenteral and transdermal etc).
  • the invention therefore also relates to a kit containing the rimonabant and another active ingredient or, where appropriate, two associated active principles in which the rimonabant and said active ingredient or, where appropriate, two associated active ingredients are in separate compartments and in similar or different packages, and are intended to be administered simultaneously, separately or spread over time.
  • EXAMPLE 1 Action of rimonabant on overweight or obese type diabetic patients.
  • the Rio-Diabete clinical trial conducted for 12 months in 1045 obese subjects with type 2 diabetes treated with monotherapy (metformin or sulfonylureas) compares the effect of rimonabant to the 20 mg dose versus a placebo product in the reduction of weight; improvement in glycosylated hemoglobin (HbAIc), blood glucose, insulinemia and lipid parameters.
  • a low-calorie diet (deficit of 600 Kcal / day) is prescribed for all patients and is initiated 4 weeks before the start of the treatment period.
  • a decrease in fasting blood glucose of 0.64 ⁇ 1.96 mmol / L was observed in the rimonabant 20 mg group, compared to an increase of 0.33 ⁇ 2.32 mmol / L in the placebo group (p ⁇ 0.001 ).
  • Insulin resistance is evaluated by the Homeostasis Model Assessment (HOMA) test described by Matthew D.R. et al. in Diabetologica, 1985, 28, 412-
  • HOMA Homeostasis Model Assessment
  • Triglycerides were decreased by more than 16.4 ⁇ 3.3% in the treated group compared with the placebo group (p ⁇ 0.001). Following a logistic regression analysis in which weight is introduced as a variable cost, an effect independent of weight loss of approximately 55% for the improvement of PHbAIc and HDL-c and approximately 35%. % for triglycerides is observed in this study.
  • rimonabant induces a significant weight loss: the difference in weight loss compared to the placebo group is 4.3 ⁇ 0.4 kg (p ⁇ 0.001) when rimonabant-metformin combination; it is 3.1 ⁇ 0.5 kg (p ⁇ 0.001) during rimonabant-sulfonylurea combination.
  • the effect of long-term (12 months) treatment with rimonabant was studied in Zucker rats with established obesity.
  • the fa / fa strain of Zucker obese rats is characterized by hyperphagia, obesity, dyslipidemia and type 2 diabetes.
  • the experiment is carried out with the rimonabant administered orally with 3 yes 0 mg / kg.
  • the animals were treated daily from the 7 th day after injection of streptozotocin, for a period of 7 weeks. Sensitivity to a mechanical stimulus is determined by the Von Frey filament
  • anesthesiometer by measuring the threshold of withdrawal of the paw in response to mechanical nociceptive stimulation.
  • a rigid polypropylene tip is used to apply a force to the plantar surface of the paw.
  • the force inducing a withdrawal response is recorded.
  • the test is repeated 3 times at approximately 5 min intervals for each animal and the average value is calculated.
  • VCNS is measured according to the method described by P. De Koning et al. in Peptides: 1987; 8 (3): 415-22.
  • the rats are anesthetized by an injection of 30 mg / kg of pentobarbital, the sciatic and fibular nerves are stimulated successively with the aid of monopolar electrodes, respectively at the notch of the sciatic nerve and the fibular nerve (at the level of ankle). Responses are recorded at the arch by surface electrodes.
  • the VCNS is calculated from the latencies of these responses by subtracting the distal latency from the proximal and the result divided by the distance between the stimulating and receiving electrodes.
  • Diabetic rats develop mechanical hyperalgesia, which is manifest as an approximate 40% reduction in the paw withdrawal threshold in response to mechanical nociceptive stimulation. This deficit is completely repaid (100%) by the treatment with rimonabant at doses of 3 or 10 mg / kg po after 7 weeks of treatment.
  • VCNS was reduced by 22% in diabetic rats compared to control rats; and treatment with rimonabant at 10 mg / kg partially reduced (-12%) the deficits of the VCNS, which correspond to 54.5% of deficit reversion.
  • rimonabant shows efficacy in this model of treatment of diabetic neuropathy.
  • rimonabant is formulated into pharmaceutical compositions which are prepared by wet granulation.
  • Povidone is defined in the European Pharmacopoeia as follows: poly (1- (2-oxo-1-pyrrolidinyl) ethylene) and consists of linear polymers of 1-vinylpyrrolidin-2-one.
  • the tablets are preferably coated using a suitable excipient.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the use of rimonabant, either alone or combined with another active principle, for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes or non-insulin dependent diabetes and/or the complications thereof.

Description

UTILISATION DU RJMONABANT POUR LA PREPARATION DE MEDICAMENTS UTILES DANS LA PREVENTION ET LE TRAITEMENT DU DIABETE DU TYPE 2. USE OF RJMONABANT FOR THE PREPARATION OF MEDICAMENTS USEFUL IN THE PREVENTION AND TREATMENT OF TYPE 2 DIABETES.
La présente invention a pour objet l'utilisation du rimonabant, pour la préparation de médicaments utiles dans la prévention et le traitement du diabète de type 2 ou diabète non insulino-dépendant et/ou de ses complications.The present invention relates to the use of rimonabant, for the preparation of drugs useful in the prevention and treatment of type 2 diabetes or non-insulin-dependent diabetes and / or its complications.
Le diabète de type 2 se caractérise par des troubles de l'insulino-sécrétion associés à des troubles de la sensibilité à l'insuline ou insulino-résistance. L'insulino-résistance est aggravée par une hyperglycémie et par des taux élevés d'acides gras libres circulants et de triglycérides stockés.Type 2 diabetes is characterized by insulin secretion disorders associated with insulin sensitivity or insulin resistance disorders. Insulin resistance is aggravated by hyperglycemia and high levels of circulating free fatty acids and stored triglycerides.
Rimonabant est la dénomination commune internationale du N-pipéridino-5-(4- chlorophényl)-l-(2,4-dichloroph.ényl)-4-methylpyrazole-3-carboxamide décrit dans le brevet européen 656354. Des études cliniques réalisées avec le rimonabant ont montré qu'il agit sur la prise alimentaire sur le plan quantitatif et qualitatif et réduit le poids corporel de patients obèses (G. Le Fur, 2003, 35, First European Workshop on Cannabinoid Research,Rimonabant is the international nonproprietary name of N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide described in European Patent 656354. Clinical studies conducted with rimonabant have shown that it acts on quantitative and qualitative food intake and reduces the body weight of obese patients (Le Fur, 2003, 35, First European Workshop on Cannabinoid Research,
Madrid, Spain, 4-5 avril 2003 et Heshmati H.M. et al., Obesity Research, 2001, 9Madrid, Spain, 4-5 April 2003 and Heshmati H.M. et al., Obesity Research, 2001, 9
(suppl. 3), 70. II a maintenant été trouvé que le rimonabant présente des propriétés antidiabétiques et agit sur les complications liées au diabète.(Suppl.3), 70. It has now been found that rimonabant has antidiabetic properties and acts on complications related to diabetes.
Ainsi, selon la présente invention, le rimonabant peut être utilisé pour la préparation de médicaments utiles pour prévenir et traiter le diabète de type 2 et ses complications. Par complications liées au diabète, on entend :Thus, according to the present invention, rimonabant can be used for the preparation of medicaments useful for preventing and treating type 2 diabetes and its complications. Diabetes-related complications include:
- les maladies cardiovasculaires liées au diabète ;- cardiovascular diseases related to diabetes;
- les maladies neurologiques telles que les neuropathies diabétiques, les neuropathies périphériques, les neuropathies cardiaques autonomes ;neurological diseases such as diabetic neuropathies, peripheral neuropathies, autonomic cardiac neuropathies;
- les maladies rénales telles que les néphropathies diabétiques, les glomérulopathies diabétiques ;- kidney diseases such as diabetic nephropathies, diabetic glomerulopathies;
- les maladies oculaires telles que les rétinopathies diabétiques, les oedèmes maculaires, le glaucome ;ocular diseases such as diabetic retinopathies, macular edema, glaucoma;
- les angiopathies : les microangiopathies, les macroangiopathies, les coronaropathies, les artériopathies périphériques. Selon l'un de ses aspects, la présente invention a pour objet l'utilisation du rimonabant pour la prévention et le traitement des complications liées au diabète, tout particulièrement, les neuropathies périphériques, les neuropathies diabétiques, les néphropathies diabétiques, les rétinopathies diabétiques, les angiopathies.- angiopathies: microangiopathies, macroangiopathies, coronary heart disease, peripheral arterial diseases. According to one of its aspects, the subject of the present invention is the use of rimonabant for the prevention and treatment of complications related to diabetes, while particularly, peripheral neuropathies, diabetic neuropathies, diabetic nephropathies, diabetic retinopathies, angiopathies.
Les compositions pharmaceutiques selon la présente invention contiennent une dose efficace de rimonabant ainsi qu'au moins un excipient pharmaceutiquement acceptable.The pharmaceutical compositions according to the present invention contain an effective dose of rimonabant as well as at least one pharmaceutically acceptable excipient.
Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus de l'Homme du métier.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra- veineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, le principe actif peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prévention ou le traitement du diabète de type 2. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, on peut utiliser les composés selon l'invention dans des crèmes, gels, pommades ou lotions.In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient may be administered in unit dosage form. in combination with conventional pharmaceutical excipients, animals and humans for the prevention or treatment of type 2 diabetes. Suitable dosage unit forms include oral forms such as tablets, soft or hard capsules , powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, forms of topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.
Les formes pour l'administration orale telles que les gélules ou comprimés sont préférées. Plus particulièrement, on préfère des gélules ou des comprimés contenant le rimonabant à une dose comprise entre 5 et 50 mg, plus particulièrement les doses de 10 à 30 mg, notamment la dose de 20 mg.Forms for oral administration such as capsules or tablets are preferred. More particularly, capsules or tablets containing rimonabant are preferred at a dose of between 5 and 50 mg, more particularly at doses of 10 to 30 mg, especially the dose of 20 mg.
Pour l'utilisation selon la présente invention, le rimonabant peut être associé à un autre principe actif choisi parmi l'une des classes thérapeutiques suivantes : - un hypolipémiant ou un hypocholestérolémiant ;For the use according to the present invention, the rimonabant can be associated with another active principle chosen from one of the following therapeutic classes: a lipid-lowering agent or a cholesterol-lowering agent;
- un autre antidiabétique ;- another antidiabetic agent;
- un autre agent anti-obésité.another anti-obesity agent.
Ainsi, la présente invention a également pour objet des compositions pharmaceutiques contenant en association un antagoniste des récepteurs CB i aux cannabinoïdes, dérivé du pyrazole, choisi parmi le rimonabant et le N-pipéridino-5-(4- bromophényl)-l-(2,4-dichlorophényl)-4-éthylpyrazole-3-carboxaniide, et un autre principe actif choisi parmi l'une des classes thérapeutiques suivantes :Thus, the subject of the present invention is also pharmaceutical compositions containing, in combination, a cannabinoid CB 1 receptor antagonist, derived from pyrazole, chosen from rimonabant and N-piperidino-5- (4- bromophenyl) -1- (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxanide, and another active ingredient selected from one of the following therapeutic classes:
- un hypolipémiant ou un hypocholestérolémiant ;a lipid-lowering agent or a cholesterol-lowering agent;
- un autre antidiabétique. Par hypolipémiant ou hypocholestérolémiant, on entend un composé choisi parmi les fibrates tels que alufibrate, béclobrate, bézafibrate, ciprofibrate, clinofibrate, clofibrate, étofibrate, fénofibrate ; les statines (inhibiteurs de HMG-CoA reductase), telles que atorvastatine, fluvastatine sodium, lovastatine, pravastatine, rosuvastatine, simvastatine, ou un composé tel que acipimox, aluminum nicotinate, azacostérol, cholestyramine, dextrothyroxine, méglutol, nicéritrol, nicoclonate, acide nicotinique, béta-sitosterin, tiadénol.- another antidiabetic. By lipid-lowering or cholesterol-lowering agent, is meant a compound chosen from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterin, tiadenol.
Par autre antidiabétique, on entend un composé appartenant à l'une des classes suivantes : les sulfonylurées, les biguanidines, les inhibiteurs d'alpha glucosidase, les thiazolidinedione, les métiglinides, tel que acarbose, acétohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimépiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, métahexamide, metformine, miglitol, natéglinide, pioglitazone, répaglinide, rosiglitazone, tolazamide, tolbutamide, voglibose.By other antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, methaglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, voglibose.
Selon un autre mode de réalisation particulier, la présente invention a pour objet une composition pharmaceutique contenant en association le rimonabant et la metformine, ou le rimonabant et une sulfonylurée telle que acétohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimépiride, glipizide, tolazamide, tolbutamide, pour le traitement du diabète de type 2.According to another particular embodiment, the subject of the present invention is a pharmaceutical composition containing, in combination, rimonabant and metformin, or rimonabant and a sulphonylurea such as acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, tolazamide, tolbutamide, for the treatment of type 2 diabetes.
Selon un autre aspect de l'invention, le rimonabant et l'autre principe actif associé peuvent être administrés de manière simultanée, séparée ou étalée dans le temps.According to another aspect of the invention, the rimonabant and the other associated active ingredient can be administered simultaneously, separately or spread over time.
On entend par "utilisation séparée" l'administration, en même temps, des deux composés de la composition selon l'invention, chacun compris dans une forme pharmaceutique distincte.By "separate use" is meant the administration, at the same time, of the two compounds of the composition according to the invention, each comprised in a separate pharmaceutical form.
On entend par "utilisation étalée dans le temps", l'administration successive, du premier composé de la composition selon l'invention, compris dans une forme pharmaceutique, puis, du deuxième composé de la composition selon l'invention, compris dans une forme pharmaceutique distincte."Extended use over time" is understood to mean the sequential administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then, of the second compound of the composition according to the invention, included in a form pharmaceutical industry.
Dans le cas de cette "utilisation étalée dans le temps", le laps de temps écoulé entre l'administration du premier composé de la composition selon l'invention et l'administration du deuxième composé de la même composition selon l'invention n'excède généralement pas 24 heures, il peut être supérieur si l'un ou l'autre des composés est présenté dans une formulation pharmaceutique permettant, par exemple, une administration hebdomadaire.In the case of this "use spread over time", the lapse of time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours, it can be higher if one or the other The compounds are presented in a pharmaceutical formulation allowing, for example, a weekly administration.
Les formes pharmaceutiques, comprenant soit un seul des composés constitutifs de la composition selon l'invention soit l'association des deux composés, qui peuvent être mises en œuvre dans les différents types d'utilisations décrites ci-dessus, peuvent par exemple être appropriées à l'administration orale, nasale, parentérale ou transdermique.The pharmaceutical forms, comprising either one of the constituent compounds of the composition according to the invention or the combination of the two compounds, which can be used in the various types of use described above, may for example be appropriate for oral, nasal, parenteral or transdermal administration.
Aussi, dans le cas d'une "utilisation séparée" et d'une "utilisation étalée dans le temps", deux formes pharmaceutiques distinctes peuvent être destinées à la même voie d'administration ou à une voie d'administration différente (orale et transdermique ou orale et nasale ou parentérale et transdermique etc).Also, in the case of "separate use" and "spread use over time", two different dosage forms may be for the same route of administration or a different route of administration (oral and transdermal). or oral and nasal or parenteral and transdermal etc).
L'invention concerne donc également une trousse contenant le rimonabant et un autre principe actif ou, le cas échéant, deux principes actifs associés dans laquelle le rimonabant et ledit principe actif ou, le cas échéant, deux principes actifs associés sont dans des compartiments distincts et dans des conditionnements semblables ou différents, et sont destinés à être administrés de manière simultanée, séparée ou étalée dans le temps.The invention therefore also relates to a kit containing the rimonabant and another active ingredient or, where appropriate, two associated active principles in which the rimonabant and said active ingredient or, where appropriate, two associated active ingredients are in separate compartments and in similar or different packages, and are intended to be administered simultaneously, separately or spread over time.
EXEMPLE 1 : Action du rimonabant sur des patients diabétiques de type en surpoids ou obèses. L'étude clinique Rio-Diabete, menée pendant 12 mois chez 1045 sujets obèses présentant un diabète de type 2 traité par monothérapie (metformine ou sulfonylurées) compare l'effet du rimonabant à la dose de 20 mg versus un produit placebo dans la réduction du poids ; l'amélioration de l'hémoglobine glycosylée (HbAIc), de la glycémie, de l'insulinémie ainsi que des paramètres lipidiques. Un régime alimentaire hypocalorique (déficit de 600 Kcal/jour) est prescrit à tous les patients et est instauré 4 semaines avant le début de la période de traitement.EXAMPLE 1: Action of rimonabant on overweight or obese type diabetic patients. The Rio-Diabete clinical trial, conducted for 12 months in 1045 obese subjects with type 2 diabetes treated with monotherapy (metformin or sulfonylureas) compares the effect of rimonabant to the 20 mg dose versus a placebo product in the reduction of weight; improvement in glycosylated hemoglobin (HbAIc), blood glucose, insulinemia and lipid parameters. A low-calorie diet (deficit of 600 Kcal / day) is prescribed for all patients and is initiated 4 weeks before the start of the treatment period.
Les sujets traités par le rimonabant à la dose de 20 mg pendant 12 mois présentent une perte de poids supérieure de 4,2 + 0,4 kg à celle observé dans le groupe placeboSubjects treated with rimonabant at a dose of 20 mg for 12 months had a greater weight loss of 4.2 + 0.4 kg compared to the placebo group
(p ≤ 0,001). Sous rimonabant 20 mg, une différence de 0,7 ± 0,1% est observée dans la réduction du taux d'HbAlc par rapport au placebo (p < 0,001). Cette diminution est maximum à 9 mois et ensuite maintenue jusqu'à 12 mois, alors que la perte de poids apparaît stabilisée après 6 mois.(p ≤ 0.001). Under rimonabant 20 mg, a difference of 0.7 ± 0.1% was observed in the reduction of HbAlc compared to placebo (p <0.001). This decrease is maximum at 9 months and then maintained until 12 months, while weight loss appears stabilized after 6 months.
Une baisse de la glycémie à jeun de 0,64 ±_1,96 mmol/L est observée dans le groupe rimonabant 20 mg, comparée à une augmentation de 0,33 ± 2,32 mmol/L dans le groupe placebo (p < 0,001). Pour l'insulinémie à jeun on observe une diminution de 0,7 ± 9,9 μUI/mL sous rimonabant 20 mg comparée à une augmentation de 0,4 + 14,8 μUI/mL dans le groupe placebo (p = 0,247).A decrease in fasting blood glucose of 0.64 ± 1.96 mmol / L was observed in the rimonabant 20 mg group, compared to an increase of 0.33 ± 2.32 mmol / L in the placebo group (p <0.001 ). For fasting insulinemia, a decrease of 0.7 ± 9.9 μIU / mL was observed with rimonabant 20 mg compared to an increase of 0.4 + 14.8 μIU / mL in the placebo group (p = 0.247).
L'insulino-résistance est évaluée par le test HOMA (de l'anglais Homeostasis Model Assessment) décrit par Matthew D.R. et al. dans Diabetologica, 1985, 28, 412-Insulin resistance is evaluated by the Homeostasis Model Assessment (HOMA) test described by Matthew D.R. et al. in Diabetologica, 1985, 28, 412-
419.419.
Une amélioration de l'insulino-résistance, évaluée par le test HOMA, est objectivée sous rimonabant 20 mg (-0,5 ± 5,7%) alors que le groupe placebo induit une détérioration de cette msulino-résistance. En ce qui concerne le profil lipidique, une augmentation du taux d'HDL-c supérieure de 8,4 ± 1,2 % est observée avec le rimonabant 20 mg par rapport au placebo (p < 0,001).An improvement of the insulin resistance, evaluated by the HOMA test, is objectified under rimonabant 20 mg (-0.5 ± 5.7%) whereas the placebo group induces a deterioration of this msulino-resistance. Regarding the lipid profile, an increase in the HDL-c level of 8.4 ± 1.2% was observed with rimonabant 20 mg compared to placebo (p <0.001).
Les triglycérides sont diminués de plus de 16,4 ± 3,3 % dans le groupe traité par rapport au groupe placebo (p < 0,001). Suite à une analyse de type régression logistique dans laquelle le poids est introduit comme une co variable, un effet indépendant de la perte de poids d'environ 55% pour l'amélioration de PHbAIc et de l'HDL-c et d'environ 35% pour les triglycérides est observé dans cette étude.Triglycerides were decreased by more than 16.4 ± 3.3% in the treated group compared with the placebo group (p <0.001). Following a logistic regression analysis in which weight is introduced as a variable cost, an effect independent of weight loss of approximately 55% for the improvement of PHbAIc and HDL-c and approximately 35%. % for triglycerides is observed in this study.
De plus, chez les patients traités par le rimonabant à la dose de 20 mg, on constate une diminution de la pression artérielle systolique de 0,8 ± 12,8 mmHg (p=0,020) et de la pression artérielle diastolique de 1,9 ± 8,2 mmHg (p = 0,060).In patients treated with 20 mg rimonabant, systolic blood pressure decreased by 0.8 ± 12.8 mmHg (p = 0.020) and diastolic blood pressure by 1.9 ± 8.2 mmHg (p = 0.060).
Ainsi chez les sujets traités par le rimonabant l'amélioration de paramètres métaboliques tels que l'HbAIc, l'HDL-c et les triglycérides n'est pas seulement liée à la perte de poids mais aussi à un effet direct du produit. On constate que quelque soit le traitement antidiabétique reçu pendant l'étude, le rimonabant induit une perte de poids significative : la différence de perte de poids par rapport au groupe placebo est de 4,3 ± 0,4 kg (p < 0,001) lors de l'association rimonabant-metformine ; elle est de 3,1 ± 0,5 kg (p < 0,001) lors de l'association rimonabant-sulfonylurée. On constate également que les résultats sur PHbAIc sont similaires avec une différence observée par rapport au placebo de 0,7 ± 0,1% (p<0,001) que le rimonabant soit en association avec la metformine ou avec une sulfonylurée EXEMPLE 2 : Action du rimonabant sur la protection du pancréas chez le rat obèse.Thus in subjects treated with rimonabant the improvement of metabolic parameters such as HbAIc, HDL-c and triglycerides is not only related to weight loss but also to a direct effect of the product. It is observed that whatever the antidiabetic treatment received during the study, rimonabant induces a significant weight loss: the difference in weight loss compared to the placebo group is 4.3 ± 0.4 kg (p <0.001) when rimonabant-metformin combination; it is 3.1 ± 0.5 kg (p <0.001) during rimonabant-sulfonylurea combination. It is also found that the results on PHbAIc are similar with an observed difference compared to placebo of 0.7 ± 0.1% (p <0.001) that rimonabant is in combination with metformin or with a sulfonylurea. EXAMPLE 2 rimonabant on the protection of the pancreas in obese rats.
On a étudié l'effet d'un traitement à long terme (12 mois) par le rimonabant, chez les rats Zucker ayant une obésité établie. La souche fa/fa de rats obèses Zucker est caractérisée par une hyperphagie, l'obésité, une dyslipidémie et un diabète de type 2.The effect of long-term (12 months) treatment with rimonabant was studied in Zucker rats with established obesity. The fa / fa strain of Zucker obese rats is characterized by hyperphagia, obesity, dyslipidemia and type 2 diabetes.
Après 12 mois, les rats obèses Zucker fa/fa traités par le véhicule montrent une hypertrophie marquée du pancréas (+ 38 %, p < 0,05). Cette hypertrophie est reversée de façon dose dépendante par l'administration du rimonabant de façon dose dépendante : respectivement + 17 % et + l % à 3 mg/kg/jour et à 10 mg/kg/jour (p < 0,05).After 12 months, vehicle-treated Zucker fa / fa obese rats showed marked pancreatic hypertrophy (+ 38%, p <0.05). This hypertrophy is dose-dependently reversed by administration of rimonabant in a dose-dependent manner: respectively + 17% and + 1% at 3 mg / kg / day and at 10 mg / kg / day (p <0.05).
EXEMPLE 3 : Action du rimonabant sur un modèle de neuropathie diabétique chez le rat. Le diabète est induit par une injection intraveineuse d'une solution de streptozotocine (55 mg/kg) dans un tampon citrate 0.1 M citrate pH 4,5 selon B. Rudas, Arzneimittelforschung 1972 ;22 :830-61. Cinq jours après, du sang est prélevé dans le sinus retro-orbitaire puis centrifugé ; pour chaque animal, on mesure la concentration de glucose dans le plasma. La sensibilité mécanique et la vitesse de conduction nerveuse sensitive (VCNS) sont évalués 8 semaines après induction du diabète et la glycémie est re-mesurée à la fin de l'étude.EXAMPLE 3 Action of Rimonabant on a Model of Diabetic Neuropathy in the Rat Diabetes is induced by intravenous injection of a solution of streptozotocin (55 mg / kg) in 0.1 M citrate citrate buffer pH 4.5 according to B. Rudas, Arzneimittelforschung 1972; 22: 830-61. Five days later, blood is taken from the retro-orbital sinus and centrifuged; for each animal, the concentration of glucose in the plasma is measured. Mechanical sensitivity and sensory nerve conduction velocity (RSV) are evaluated at 8 weeks after induction of diabetes and blood glucose is re-measured at the end of the study.
L'expérience est réalisée avec le rimonabant administré par voie orale à 3 oui 0 mg/kg. Les animaux sont traités quotidiennement à partir du 7eme jour après injection de streptozotocine, pendant une durée de 7 semaines. La sensibilité à un stimulus mécanique est déterminée par le filament de Von FreyThe experiment is carried out with the rimonabant administered orally with 3 yes 0 mg / kg. The animals were treated daily from the 7 th day after injection of streptozotocin, for a period of 7 weeks. Sensitivity to a mechanical stimulus is determined by the Von Frey filament
(anesthesiomètre) par mesure du seuil de retrait de la patte en réponse à une stimulation nociceptive mécanique. Un embout en polypropylène rigide est utilisé pour appliquer une force à la surface plantaire de la patte. La force induisant une réponse de retrait est enregistrée. Le test est répété 3 fois à environ 5 min d'intervalle pour chaque animal et la valeur moyenne est calculée.(anesthesiometer) by measuring the threshold of withdrawal of the paw in response to mechanical nociceptive stimulation. A rigid polypropylene tip is used to apply a force to the plantar surface of the paw. The force inducing a withdrawal response is recorded. The test is repeated 3 times at approximately 5 min intervals for each animal and the average value is calculated.
La VCNS est mesurée selon la méthode décrite par P. De Koning et al. dans Peptides :1987;8(3):415-22. Les rats sont anesthésiés par une injection de 30 mg/kg de pentobarbital, les nerfs sciatique et péroné sont stimulés successivement à l'aide d'électrodes monopolaires, respectivement au niveau de l'encoche du nerf sciatique et du nerf péroné (au niveau de la cheville). Les réponses sont enregistrées au niveau de la voûte plantaire par des électrodes de surface. La VCNS est calculée à partir des latences de ces réponses en soustrayant la latence distale de la proximale et le résultat est divisé par la distance entre les électrodes stimulatrice et réceptrice.VCNS is measured according to the method described by P. De Koning et al. in Peptides: 1987; 8 (3): 415-22. The rats are anesthetized by an injection of 30 mg / kg of pentobarbital, the sciatic and fibular nerves are stimulated successively with the aid of monopolar electrodes, respectively at the notch of the sciatic nerve and the fibular nerve (at the level of ankle). Responses are recorded at the arch by surface electrodes. The VCNS is calculated from the latencies of these responses by subtracting the distal latency from the proximal and the result divided by the distance between the stimulating and receiving electrodes.
Les rats diabétiques développent une hyperalgésie mécanique qui se manifeste par une réduction approximative de 40 % du seuil de retrait de la patte en réponse à une stimulation nociceptive mécanique. Ce déficit est complètement reversé (100%) par le traitement avec le rimonabant aux doses de 3 ou 10 mg/kg po après 7 semaines de traitement.Diabetic rats develop mechanical hyperalgesia, which is manifest as an approximate 40% reduction in the paw withdrawal threshold in response to mechanical nociceptive stimulation. This deficit is completely repaid (100%) by the treatment with rimonabant at doses of 3 or 10 mg / kg po after 7 weeks of treatment.
A la même période, la VCNS est réduite de 22 % chez les rats diabétiques comparé aux rats témoins ; et le traitement par le rimonabant à 10 mg/kg réduit de façon partielle (-12%) les déficits de la VCNS, ce qui correspont à 54,5% de reversion des déficits.At the same time, VCNS was reduced by 22% in diabetic rats compared to control rats; and treatment with rimonabant at 10 mg / kg partially reduced (-12%) the deficits of the VCNS, which correspond to 54.5% of deficit reversion.
Ces résultats montrent que l' administration orale de rimonabant, reverse complètement les symptômes de douleur associés au diabète et réduit significativement les déficits de la VCNS dans le nerf sciatique chez le rat 8 semaines après induction du diabète.These results show that the oral administration of rimonabant completely reverses the pain symptoms associated with diabetes and significantly reduces the deficits of the VCNS in the sciatic nerve in the rat 8 weeks after induction of diabetes.
Ainsi, le rimonabant montre une efficacité dans ce modèle de traitement de la neuropathie diabétique. EXEMPLE 4 : Composition pharmaceutique.Thus, rimonabant shows efficacy in this model of treatment of diabetic neuropathy. EXAMPLE 4 Pharmaceutical Composition
Pour radministration aux patients, le rimonabant est formulé dans des compositions pharmaceutiques qui sont préparées par granulation humide.For administration to patients, rimonabant is formulated into pharmaceutical compositions which are prepared by wet granulation.
* La Povidone est définie dans la Pharmacopée Européenne comme suit : poly(l-(2- oxo-l-pyrrolidinyl)éthylène) et est constituée de polymères linéaires de 1- vinylpyrrolidin-2-one.* Povidone is defined in the European Pharmacopoeia as follows: poly (1- (2-oxo-1-pyrrolidinyl) ethylene) and consists of linear polymers of 1-vinylpyrrolidin-2-one.
Les comprimés sont préférentiellement enrobés en utilisant un excipient approprié. The tablets are preferably coated using a suitable excipient.

Claims

REVENDICATIONS
I . Utilisation du rimonabant pour la préparation de médicaments utiles dans le traitement et la prévention du diabète de type 2 et/ou de ses complications. I. Use of rimonabant for the preparation of medicaments useful in the treatment and prevention of type 2 diabetes and / or its complications.
2. Utilisation selon la revendication 1 pour la prévention et le traitement du diabète de type 2.2. Use according to claim 1 for the prevention and treatment of type 2 diabetes.
3. Utilisation selon la revendication 1 pour la prévention et le traitement des complications du diabète de type 2.3. Use according to claim 1 for the prevention and treatment of complications of type 2 diabetes.
4. Utilisation selon la revendication 1 pour la prévention et le traitement des neuropathies diabétiques.4. Use according to claim 1 for the prevention and treatment of diabetic neuropathies.
5. Utilisation selon la revendication 1 pour la prévention et le traitement des rétinopathies diabétiques.5. Use according to claim 1 for the prevention and treatment of diabetic retinopathies.
6. Utilisation selon la revendication 1 pour la prévention et le traitement des angiopathies. 6. Use according to claim 1 for the prevention and treatment of angiopathies.
7. Utilisation selon l'une quelconque des revendications 1 à 6 dans laquelle le rimonabant est associé à un autre principe actif choisi parmi l'une des classes thérapeutiques suivantes :7. Use according to any one of claims 1 to 6 wherein the rimonabant is associated with another active ingredient selected from one of the following therapeutic classes:
- un hypolipémiant ou un hypocholestérolémiant ;a lipid-lowering agent or a cholesterol-lowering agent;
- un antidiabétique. - an antidiabetic.
8. Utilisation selon l'une quelconque des revendications 1 à 7 dans laquelle le rimonabant est utilisé à une dose comprise entre 5 mg et 50 mg.8. Use according to any one of claims 1 to 7 wherein the rimonabant is used at a dose of between 5 mg and 50 mg.
9. Utilisation selon la revendication 7 dans laquelle le rimonabant est associé à la metformine.9. Use according to claim 7 wherein the rimonabant is associated with metformin.
10. Utilisation selon la revendication 7 dans laquelle le rimonabant est associé à une sulfonylurée.10. Use according to claim 7 wherein the rimonabant is associated with a sulfonylurea.
I 1. Composition pharmaceutique contenant en association le rimonabant et un autre principe actif choisi parmi la metformine, une sulfonylurée. 1. A pharmaceutical composition containing in combination rimonabant and another active ingredient selected from metformin, a sulfonylurea.
EP06709344A 2005-02-21 2006-02-20 Use of rimonabant for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes Withdrawn EP1853264A1 (en)

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FR0501861A FR2882261B1 (en) 2005-02-21 2005-02-21 USE OF A PYRAZOLE DERIVATIVE FOR THE PREPARATION OF MEDICAMENTS USEFUL IN THE PREVENTION AND TREATMENT OF TYPE 2 DIABETES
FR0504942A FR2882264A1 (en) 2005-02-21 2005-05-12 Use of rimonabant and N-peperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, having cannabinoids receptor antagonistic activity, to treat and prevent type-II diabetes
FR0505228A FR2882265B1 (en) 2005-02-21 2005-05-23 USE OF A PYRAZOLE DERIVATIVE FOR THE PREPARATION OF MEDICAMENTS USEFUL IN THE PREVENTION AND TREATMENT OF TYPE 2 DIABETES.
PCT/FR2006/000376 WO2006087481A1 (en) 2005-02-21 2006-02-20 Use of rimonabant for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes

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