WO2001047527A1 - Association of deoxyfructosazine and an antidiabetic of the sulphonylurea family - Google Patents

Association of deoxyfructosazine and an antidiabetic of the sulphonylurea family Download PDF

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Publication number
WO2001047527A1
WO2001047527A1 PCT/FR2000/003603 FR0003603W WO0147527A1 WO 2001047527 A1 WO2001047527 A1 WO 2001047527A1 FR 0003603 W FR0003603 W FR 0003603W WO 0147527 A1 WO0147527 A1 WO 0147527A1
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deoxyfructosazine
association
pharmaceutically acceptable
antidiabetic
acceptable salts
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PCT/FR2000/003603
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French (fr)
Inventor
Michel Evers
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Aventis Pharma S.A.
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Priority to AU26876/01A priority Critical patent/AU2687601A/en
Publication of WO2001047527A1 publication Critical patent/WO2001047527A1/en

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    • 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
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • the present invention relates to the combination of deoxyfructosazine and an antidiabetic of the sulfonylurea family, the pharmaceutical compositions containing this combination and their use in the prevention and / or treatment of type 2 diabetes and its complications.
  • Antidiabetics of the sulfonylurea family are the most used products in the treatment of type 2 diabetes (non-insulin-independent). They are generally used in addition to a diet (G.EMILEN, JM. MALOTEAUX and M. PONCHON; Pha ⁇ nacol. Ther., 81, 37-51 (1999); A. SCHEEN, Drugs, 54, 355-368 (1997 )).
  • glimepiride Amaryl R , Amarel R (EP31058), glyburide or glibenclamide: Diabeta R , Daonil R , Glynase R (US3454635), glipizide: Glibenese R , Minidiab R , Glucotrol R (US3669966 ), gliclazide: Diamicron R (US3501495), chlorpromamide: Diabinese R , Asucrol R (US3349124), tolazamide: Diabewas R , Tolinase R (J. Med. Pharm.
  • the invention relates to combinations of deoxyfructosazine and glimepiride, glyburide or glibenclamide, glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts.
  • the invention relates to combinations of deoxyfructosazine and glimepiride or one of its pharmaceutically acceptable salts, deoxyfructosazine and glipizide or one of its pharmaceutically acceptable salts, deoxyfructosazine and glyburide or one of its pharmaceutically acceptable salts.
  • the activity of the associations can be determined by the methods commonly used by those skilled in the art in the field of diabetes. Among these methods, the following methods can in particular be used:
  • mice Male Wistar rats weighing 180 to 200 g are made diabetic by intravenous injection of 60 mg / kg of streptozotocin. After 72 hours, the blood sugar of the animals is measured on the glucometer. Animals with blood sugar below 2 g / 1 are not used for the study and those with a blood sugar level higher than 2 g / 1 are treated, orally, by gavage using a gastric tube, by a single dose either of deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide. A group of animals receives only the vehicle. Blood sugar levels are measured at 30 minutes
  • mice Male Wistar rats weighing 180 to 200 g are made diabetic by intravenous injection of 60 mg / kg of streptozotocin. After 72 hours, the blood sugar of the animals is measured on the glucometer. Animals with blood sugar below
  • 2 g / 1 are not considered for the study, those with a blood sugar level higher than 2 g / 1 are treated, orally, by gavage using a gastric tube, by a dose per day for 30 days.
  • deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide.
  • a group of animals receives only the vehicle. Blood sugar levels are measured once a day.
  • tests A and B demonstrate that, in the animals receiving the association, the blood sugar levels are much lower than those of the control animals and those of the animals treated with a single antidiabetic.
  • C - preventive activity in mice raised in Madagascar Mice raised in Madagascar are given orally by gavage for 4 days either deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg ) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide.
  • 3 hours after the last treatment 2 g / kg of an aqueous glucose solution are given orally. Blood glucose levels are determined 20 minutes later using a glucometer.
  • Obese Zucker (fa / fa) rats aged 5-6 weeks are treated, orally, in a single gavage, for 7 and 14 days with deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10- 20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide.
  • the control groups are force-fed under the same conditions with the excipient alone.
  • the food intake and the weight of the animals are measured every day during the experiment. After 7 and 14 days, the rats are anesthetized with pentobarbital.
  • a glucose tolerance test (0.5 g / kg) is carried out intravenously and blood samples are taken 5, 10, 15, 20, 25 and 30 minutes after the injection in order to measure blood sugar and insulinemia . The results obtained in this test demonstrate that, in the animals receiving the combination, the responses to the glucose tolerance test are much lower than those of the control animals and those of the animals treated with a single antidiabetic.
  • these associations are therefore useful in the prevention and / or treatment of type 2 diabetes.
  • These associations can also be used in complications of diabetes such as hyperlipemia, disorders of lipid metabolism, dyslipemia, obesity , diabetic cataracts, diabetic neuropathy in its various forms (peripheral polyneuropathies and its manifestations such as paraesthesia, hyperesthesia and pain, mononeuropathies, radiculopathies, autonomic neuropathies, diabetic muscular atrophies), manifestations of diabetic foot (ulcers of the lower extremities and foot ), diabetic nephropathy in both its diffuse and nodular forms.
  • the combination can be used orally, parenterally or rectally either simultaneously or separately or over a period of time.
  • the present invention also relates to pharmaceutical compositions comprising the combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably, glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents and or adjuvants and / or optionally in combination with another pharmaceutically compatible and physiologically active product.
  • the products that make up the association can be administered simultaneously, separately or in a spread over time so as to obtain the maximum effectiveness of the association.
  • compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
  • the active ingredients are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
  • these compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.
  • compositions for oral administration use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
  • These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • the present invention also relates to the method of prevention and / or treatment of type 2 diabetes or its complications in humans which consists in administering to the patient a combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably , glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among the glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, either simultaneously or separately or spread over time.
  • glimepiride glyburide (glibenclamide)
  • glipizide gliclazide
  • chlorpromamide tolazamide
  • glibomuride gliquid
  • the doses depend on the desired effect, the duration of the treatment and the route of administration used and the initial blood sugar level.
  • the doses of the sulfonylurea family antidiabetic will be determined on a case-by-case basis. They may be identical to or less than the doses recommended for single use. Thus, the dose will be 0.5 to 6 mg / day of glimepiride or 2 to 20 mg / day of glipizide or 1 to 10 mg / day of glyburide. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated such as the initial blood sugar level.
  • the present invention also relates to the use of a combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably, glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, for the preparation of a drug useful for the prevention and / or treatment of type 2 diabetes and its complications.
  • glimepiride glyburide (glibenclamide)
  • glipizide gliclazide
  • chlorpromamide tolazamide
  • glibomuride gliquidone
  • glisoxepid

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Abstract

The invention concerns the association of deoxyfructosazine and an antidiabetic of the sulphonylurea family, pharmaceutical compositions containing said association and their use for preventing and/or treating type 2 diabetes and its complications.

Description

ASSOCIATION DE DEOXYFRUCTOSAZINE ET D'UN ANTIDIABETIQUE DE LA FAMILLE DES SULFONYLUREES COMBINATION OF DEOXYFRUCTOSAZINE AND AN ANTIDIABETIC FROM THE SULFONYLUREA FAMILY
La présente invention concerne l'association de déoxyfructosazine et d'un antidiabétique de la famille des sulfonylurées, les compositions pharmaceutiques contenant cette association et leur utilisation dans la prévention et/ou le traitement du diabète de type 2 et ses complications.The present invention relates to the combination of deoxyfructosazine and an antidiabetic of the sulfonylurea family, the pharmaceutical compositions containing this combination and their use in the prevention and / or treatment of type 2 diabetes and its complications.
La déoxyfructosazine ou (2-[(lR,2S,3R)(l,2,3,4-tétrahydroxybutyl]-5-Deoxyfructosazine or (2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl] -5-
[2'S,3'R)(2',3',4'-trihydroxybutylpyrazine)] est connue pour ses propriétés antidiabétiques (WO97/28813).[2'S, 3'R) (2 ', 3', 4'-trihydroxybutylpyrazine)] is known for its anti-diabetic properties (WO97 / 28813).
Les antidiabétiques de la famille des sulfonylurées sont les produits les plus utilisés dans le traitement du diabète de type 2 (non insulino-indépendant). Ils sont généralement utilisés en addition à un régime alimentaire (G.EMILEN, JM. MALOTEAUX et M. PONCHON; Phaπnacol. Ther., 81, 37-51 (1999); A. SCHEEN, Drugs, 54, 355-368 (1997)).Antidiabetics of the sulfonylurea family are the most used products in the treatment of type 2 diabetes (non-insulin-independent). They are generally used in addition to a diet (G.EMILEN, JM. MALOTEAUX and M. PONCHON; Phaπnacol. Ther., 81, 37-51 (1999); A. SCHEEN, Drugs, 54, 355-368 (1997 )).
Parmi ces antidiabétiques, on peut notamment citer le glimépiride : AmarylR, AmarelR (EP31058), le glyburide ou glibenclamide : DiabetaR, DaonilR, GlynaseR (US3454635), le glipizide : GlibeneseR, MinidiabR, GlucotrolR (US3669966), le gliclazide : DiamicronR (US3501495), le chlorpromamide : DiabineseR, AsucrolR (US3349124), le tolazamide : DiabewasR, TolinaseR (J. Med. Pharm. Chem., 5, 815 (1962)), le glibornuride : GluboridR, GlutrilR (US3654357), le gliquidone : GlurenormR (US3708486), le glisoxepid : ProdiabanR (US3668215), le glyhexamide : SuboseR (US3097242), l'acétohexamide : DymelorR (UK912789) et leurs sels pharmaceutiquement acceptables. Seuls 60 à 70% des patients peuvent atteindre un bon contrôle glycémique avec ces produits. Par ailleurs, l'efficacité de la thérapie avec ces antidiabétiques diminue dans le temps. Ainsi, environ 10% de patients par an deviennent résistants au traitement. Il est donc recherché des associations permettant de supprimer ces inconvénients.Among these antidiabetics, we can notably cite glimepiride: Amaryl R , Amarel R (EP31058), glyburide or glibenclamide: Diabeta R , Daonil R , Glynase R (US3454635), glipizide: Glibenese R , Minidiab R , Glucotrol R (US3669966 ), gliclazide: Diamicron R (US3501495), chlorpromamide: Diabinese R , Asucrol R (US3349124), tolazamide: Diabewas R , Tolinase R (J. Med. Pharm. Chem., 5, 815 (1962)), le glibornuride: Gluborid R , Glutril R (US3654357), gliquidone: Glurenorm R (US3708486), glisoxepid: Prodiaban R (US3668215), glyhexamide: Subose R (US3097242), acetohexamide: Dymelor R ) pharmaceutically acceptable. Only 60 to 70% of patients can achieve good glycemic control with these products. In addition, the effectiveness of therapy with these anti-diabetic drugs decreases over time. Thus, approximately 10% of patients per year become resistant to the treatment. It is therefore sought associations to eliminate these drawbacks.
II a maintenant été trouvé que l'association d'un antidiabétique de la famille des sulfonylurées et de la déoxyfructosazine présente un effet synergistique dans le traitement du diabète de type 2.It has now been found that the combination of an antidiabetic from the sulfonylurea family and deoxyfructosazine has a synergistic effect in the treatment of type 2 diabetes.
Plus particulièrement, l'invention concerne les associations de déoxyfructosazine et de glimépiride, glyburide ou glibenclamide, glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acétohexamide et leurs sels pharmaceutiquement acceptables.More particularly, the invention relates to combinations of deoxyfructosazine and glimepiride, glyburide or glibenclamide, glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts.
Encore plus préférentiellement, l'invention concerne les associations de déoxyfructosazine et de glimépiride ou un de ses sels pharmaceutiquement acceptables, de déoxyfructosazine et de glipizide ou un de ses sels pharmaceutiquement acceptables, de déoxyfructosazine et de glyburide ou un de ses sels pharmaceutiquement acceptables.Even more preferably, the invention relates to combinations of deoxyfructosazine and glimepiride or one of its pharmaceutically acceptable salts, deoxyfructosazine and glipizide or one of its pharmaceutically acceptable salts, deoxyfructosazine and glyburide or one of its pharmaceutically acceptable salts.
L'activité des associations peut être déterminée par les méthodes couramment employées par l'homme de l'art dans le domaine du diabète. Parmi ces méthodes on peut en particulier utiliser les méthodes suivantes :The activity of the associations can be determined by the methods commonly used by those skilled in the art in the field of diabetes. Among these methods, the following methods can in particular be used:
A - activité en dose unique, chez le rat traité à la streptozotocineA - single dose activity in rats treated with streptozotocin
Des rats Wistar mâles pesant 180 à 200 g sont rendus diabétiques par injection intraveineuse de 60 mg/kg de streptozotocine. Au bout de 72 heures, la glycémie des animaux est mesurée au glucomètre. Les animaux dont la glycémie est inférieure à 2 g/1 ne sont pas retenus pour l'étude et ceux présentant une glycémie supérieure à 2 g/1 sont traités, par voie orale, par gavage à l'aide d'une sonde gastrique, par une dose unique soit de déoxyfructosazine seule (5-50-100-150 mg/kg) ou de glimépiride seul (0,1-10-20-30 mg/kg) ou de glipizide seul (0,1-10-20-30 mg/kg) ou de glyburide seul (0,1-10-20-30 mg/kg) ou d'une association déoxyfructosazine et glimépiride ou déoxyfructosazine et glipizide ou déoxyfructosazine et glyburide. Un groupe d'animaux ne reçoit que le véhicule. Les taux de glycémie sont mesurés à 30 minutes,Male Wistar rats weighing 180 to 200 g are made diabetic by intravenous injection of 60 mg / kg of streptozotocin. After 72 hours, the blood sugar of the animals is measured on the glucometer. Animals with blood sugar below 2 g / 1 are not used for the study and those with a blood sugar level higher than 2 g / 1 are treated, orally, by gavage using a gastric tube, by a single dose either of deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide. A group of animals receives only the vehicle. Blood sugar levels are measured at 30 minutes,
1 heure puis toutes les heures pendant 8 heures après le traitement par les produits.1 hour then every hour for 8 hours after treatment with the products.
B - activité en dose répétée, chez le rat traité à la streptozotocineB - repeated dose activity in rats treated with streptozotocin
Des rats Wistar mâles pesant 180 à 200 g sont rendus diabétiques par injection intraveineuse de 60 mg/kg de streptozotocine. Au bout de 72 heures, la glycémie des animaux est mesurée au glucomètre. Les animaux dont la glycémie est inférieure àMale Wistar rats weighing 180 to 200 g are made diabetic by intravenous injection of 60 mg / kg of streptozotocin. After 72 hours, the blood sugar of the animals is measured on the glucometer. Animals with blood sugar below
2 g/1 ne sont pas retenus pour l'étude, ceux présentant une glycémie supérieure à 2 g/1 sont traités, par voie orale, par gavage à l'aide d'une sonde gastrique, par une dose par jour pendant 30 jours soit de déoxyfructosazine seule (5-50-100-150 mg/kg) ou de glimépiride seul (0,1-10-20-30 mg/kg) ou de glipizide seul (0,1-10-20-30 mg/kg) ou de glyburide seul (0,1-10-20-30 mg/kg) ou d'une association déoxyfructosazine et glimépiride ou déoxyfructosazine et glipizide ou déoxyfructosazine et glyburide. Un groupe d'animaux ne reçoit que le véhicule. Les taux de glycémie sont mesurés 1 fois par jour.2 g / 1 are not considered for the study, those with a blood sugar level higher than 2 g / 1 are treated, orally, by gavage using a gastric tube, by a dose per day for 30 days. either deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide. A group of animals receives only the vehicle. Blood sugar levels are measured once a day.
Les résultats obtenus dans les tests A et B démontrent que, chez les animaux recevant l'association, les taux de glycémie sont nettement inférieurs à ceux des animaux témoins et à ceux des animaux traités par un seul antidiabétique.The results obtained in tests A and B demonstrate that, in the animals receiving the association, the blood sugar levels are much lower than those of the control animals and those of the animals treated with a single antidiabetic.
C - activité préventive chez la souris élevée à Madagascar A des souris élevées à Madagascar, on donne par voie orale par gavage pendant 4 jours soit la déoxyfructosazine seule (5-50-100-150 mg/kg) ou le glimépiride seul (0,1-10-20-30 mg/kg) ou le glipizide seul (0,1-10-20-30 mg/kg) ou le glyburide seul (0,1-10-20-30 mg/kg) ou d'une association déoxyfructosazine et glimépiride ou déoxyfructosazine et glipizide ou déoxyfructosazine et glyburide. Trois heures après le dernier traitement, on donne par voie orale 2 g/kg d'une solution aqueuse de glucose. Les concentrations de glucose dans le sang sont déterminées, 20 minutes plus tard, au moyen d'un glucomètre.C - preventive activity in mice raised in Madagascar Mice raised in Madagascar are given orally by gavage for 4 days either deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg ) or glipizide alone (0.1-10-20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide. Three hours after the last treatment, 2 g / kg of an aqueous glucose solution are given orally. Blood glucose levels are determined 20 minutes later using a glucometer.
Dans ce test, les résultats obtenus démontrent que, chez les animaux recevant l'association, l'accroissement de la concentration de glucose sanguin est nettement diminué par rapport à celui des animaux non traités et à celui des animaux traités par un seul antidiabétique.In this test, the results obtained demonstrate that, in the animals receiving the combination, the increase in the blood glucose concentration is markedly reduced compared with that of the untreated animals and that of the animals treated with a single antidiabetic.
D - activité chez le rat Zucker (fa/fa)D - activity in the Zucker rat (fa / fa)
Des rats obèses Zucker (fa/fa) âgés de 5-6 semaines sont traités, par voie orale, en un seul gavage, pendant 7 et 14 jours par la déoxyfructosazine seule (5-50-100- 150 mg/kg) ou le glimépiride seul (0,1-10-20-30 mg/kg) ou le glipizide seul (0,1-10- 20-30 mg/kg) ou le glyburide seul (0,1-10-20-30 mg/kg) ou d'une association déoxyfructosazine et glimépiride ou déoxyfructosazine et glipizide ou déoxyfructosazine et glyburide. Les groupes contrôles sont gavés dans les mêmes conditions avec l'excipient seul. La prise alimentaire et le poids des animaux sont mesurés chaque jour au cours de l'expérience. Au bout de 7 et 14 jours, les rats sont anesthésiés au pentobarbital. Un test de tolérance au glucose (0,5g/kg) est effectué par voie intraveineuse et des échantillons de sang sont prélevés 5, 10, 15, 20, 25 et 30 minutes après l'injection afin de mesurer la glycémie et l'insulinémie. Les résultats obtenus dans ce test démontrent que, chez les animaux recevant l'association, les réponses au test de tolérance au glucose sont nettement inférieures à celles des animaux témoins et à celles des animaux traités par un seul antidiabétique.Obese Zucker (fa / fa) rats aged 5-6 weeks are treated, orally, in a single gavage, for 7 and 14 days with deoxyfructosazine alone (5-50-100-150 mg / kg) or glimepiride alone (0.1-10-20-30 mg / kg) or glipizide alone (0.1-10- 20-30 mg / kg) or glyburide alone (0.1-10-20-30 mg / kg) or a combination of deoxyfructosazine and glimepiride or deoxyfructosazine and glipizide or deoxyfructosazine and glyburide. The control groups are force-fed under the same conditions with the excipient alone. The food intake and the weight of the animals are measured every day during the experiment. After 7 and 14 days, the rats are anesthetized with pentobarbital. A glucose tolerance test (0.5 g / kg) is carried out intravenously and blood samples are taken 5, 10, 15, 20, 25 and 30 minutes after the injection in order to measure blood sugar and insulinemia . The results obtained in this test demonstrate that, in the animals receiving the combination, the responses to the glucose tolerance test are much lower than those of the control animals and those of the animals treated with a single antidiabetic.
En thérapeutique, ces associations sont donc utiles dans la prévention et/ou le traitement du diabète de type 2. Ces associations peuvent être utilisées également dans les complications du diabète telles que les hyperlipémies, les troubles du métabolisme lipidique, les dyslipémies, l'obésité, la cataracte diabétique, la neuropathie diabétique dans ses diverses formes (polyneuropathies périphériques et ses manifestations telles que paresthésies, hyperesthésies et douleurs, mononeuropathies, radiculopathies, neuropathies autonomes, amyotrophies diabétiques), les manifestations du pied diabétique (ulcères des extrémités inférieures et du pied), la néphropathie diabétique dans ses deux formes diffuse et nodulaire.In therapy, these associations are therefore useful in the prevention and / or treatment of type 2 diabetes. These associations can also be used in complications of diabetes such as hyperlipemia, disorders of lipid metabolism, dyslipemia, obesity , diabetic cataracts, diabetic neuropathy in its various forms (peripheral polyneuropathies and its manifestations such as paraesthesia, hyperesthesia and pain, mononeuropathies, radiculopathies, autonomic neuropathies, diabetic muscular atrophies), manifestations of diabetic foot (ulcers of the lower extremities and foot ), diabetic nephropathy in both its diffuse and nodular forms.
L'association peut être employée par voie orale, parentérale ou rectale soit simultanément soit séparément soit de manière étalée dans le temps.The combination can be used orally, parenterally or rectally either simultaneously or separately or over a period of time.
La présente invention concerne également les compositions pharmaceutiques comprenant l'association de déoxyfructosazine et d'un antidiabétique de la famille des sulfonylurées et, de préférence, le glimépiride, le glyburide (glibenclamide), le glipizide, le gliclazide, le chlorpromamide, le tolazamide, le glibomuride, le gliquidone, le glisoxepid, le glyhexamide, l'acétohexamide et leurs sels pharmaceutiquement acceptables, et, plus particulièrement, parmi le glimépiride, le glyburide (glibenclamide), le glipizide et leurs sels pharmaceutiquement acceptables, à l'état pur ou sous forme d'une association avec un ou plusieurs diluants et ou adjuvants compatibles et pharmaceutiquement acceptables et/ou éventuellement en association avec un autre produit pharmaceutiquement compatible et physiologiquement actif. Les produits qui constituent l'association peuvent être administrés simultanément, séparément ou d'une manière étalée dans le temps de façon à obtenir le maximum d'efficacité de l'association.The present invention also relates to pharmaceutical compositions comprising the combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably, glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents and or adjuvants and / or optionally in combination with another pharmaceutically compatible and physiologically active product. The products that make up the association can be administered simultaneously, separately or in a spread over time so as to obtain the maximum effectiveness of the association.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimés, des pilules, des poudres (capsules de gélatine, cachets) ou des granulés. Dans ces compositions, les principes actifs sont mélangés à un ou plusieurs diluants inertes, tels que amidon, cellulose, saccharose, lactose ou silice, sous courant d'argon. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple un ou plusieurs lubrifiants tels que le stéarate de magnésium ou le talc, un colorant, un enrobage (dragées) ou un vernis.As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active ingredients are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des émulsions, des sirops et des élixirs pharmaceutiquement acceptables contenant des diluants inertes tels que l'eau, l'éthanol, le glycérol, les huiles végétales ou l'huile de paraffine. Ces compositions peuvent comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants, épaississants, aromatisants ou stabilisants.As liquid compositions for oral administration, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Les compositions stériles pour administration parentérale, peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'éthyle ou d'autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, isotonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorporant à la composition des agents stérilisants, par irradiation ou par chauffage. Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable.The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Les compositions pour administration rectale sont les suppositoires ou les capsules rectales qui contiennent, outre le produit actif, des excipients tels que le beurre de cacao, des glycérides semisynthétiques ou des polyéthylèneglycols.The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
La présente invention concerne également la méthode de prévention et/ou de traitement du diabète de type 2 ou ses complications chez l'homme qui consiste à administrer au patient une association de déoxyfructosazine et d'un antidiabétique de la famille des sulfonylurées et, de préférence, le glimépiride, le glyburide (glibenclamide), le glipizide, le gliclazide, le chlorpromamide, le tolazamide, le glibomuride, le gliquidone, le glisoxepid, le glyhexamide, l'acétohexamide et leurs sels pharmaceutiquement acceptables, et, plus particulièrement, parmi le glimépiride, le glyburide (glibenclamide), le glipizide et leurs sels pharmaceutiquement acceptables soit simultanément soit séparément soit de manière étalée dans le temps.The present invention also relates to the method of prevention and / or treatment of type 2 diabetes or its complications in humans which consists in administering to the patient a combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably , glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among the glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, either simultaneously or separately or spread over time.
Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée et du taux de glycémie initial.The doses depend on the desired effect, the duration of the treatment and the route of administration used and the initial blood sugar level.
Elles sont généralement, chez l'homme adulte, de 50 à 600 mg par jour de déoxyfructosazine, par voie orale, en une ou plusieurs prises, la dose de l'antidiabétique de la famille des sulfonylurées étant ajustée pour obtenir un taux de glycémie normal.They are generally, in adult men, from 50 to 600 mg per day of deoxyfructosazine, orally, in one or more doses, the dose of the anti-diabetic of the sulfonylurea family being adjusted to obtain a normal blood sugar level. .
Les doses de l'antidiabétique de la famille des sulfonylurées seront déterminées au cas par cas. Elles pourront être identiques ou inférieures aux doses préconisées en utilisation unique. Ainsi, la dose sera de 0,5 à 6 mg/jour de glimépiride ou de 2 à 20 mg/jour de glipizide ou de 1 à 10 mg/jour de glyburide. D'une façon générale, le médecin déterminera la posologie appropriée en fonction de l'âge, du poids et de tous les autres facteurs propres au sujet à traiter tel que le taux de glycémie initial.The doses of the sulfonylurea family antidiabetic will be determined on a case-by-case basis. They may be identical to or less than the doses recommended for single use. Thus, the dose will be 0.5 to 6 mg / day of glimepiride or 2 to 20 mg / day of glipizide or 1 to 10 mg / day of glyburide. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated such as the initial blood sugar level.
La présente invention concerne également l'utilisation d'une association de déoxyfructosazine et d'un antidiabétique de la famille des sulfonylurées et, de préférence, le glimépiride, le glyburide (glibenclamide), le glipizide, le gliclazide, le chlorpromamide, le tolazamide, le glibomuride, le gliquidone, le glisoxepid, le glyhexamide, l'acétohexamide et leurs sels pharmaceutiquement acceptables, et, plus particulièrement, parmi le glimépiride, le glyburide (glibenclamide), le glipizide et leurs sels pharmaceutiquement acceptables, pour la préparation d'un médicament utile pour la prévention et/ou le traitement du diabète de type 2 et ses complications. The present invention also relates to the use of a combination of deoxyfructosazine and an antidiabetic of the family of sulfonylureas and, preferably, glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide, acetohexamide and their pharmaceutically acceptable salts, and, more particularly, among glimepiride, glyburide (glibenclamide), glipizide and their pharmaceutically acceptable salts, for the preparation of a drug useful for the prevention and / or treatment of type 2 diabetes and its complications.

Claims

REVENDICATIONS
1 - Association de déoxyfructosazine et d'un antidiabétique de la famille des sulfonylurées ou un de leurs sels pharmaceutiquement acceptables.1 - Association of deoxyfructosazine and an antidiabetic of the family of sulfonylureas or one of their pharmaceutically acceptable salts.
2 - Association selon la revendication 1 dans laquelle l'antidiabétique de la famille des sulfonylurées est le glimépiride, le glyburide (glibenclamide), le glipizide, le gliclazide, le chlorpromamide, le tolazamide, le glibomuride, le gliquidone, le glisoxepid, le glyhexamide ou l'acétohexamide et leurs sels pharmaceutiquement acceptables.2 - Association according to claim 1 wherein the antidiabetic of the family of sulfonylureas is glimepiride, glyburide (glibenclamide), glipizide, gliclazide, chlorpromamide, tolazamide, glibomuride, gliquidone, glisoxepid, glyhexamide or acetohexamide and their pharmaceutically acceptable salts.
3 - Association de déoxyfructosazine et de glimépiride ou un de ses sels pharmaceutiquement acceptables.3 - Association of deoxyfructosazine and glimepiride or one of its pharmaceutically acceptable salts.
4 - Association de déoxyfructosazine et de glipizide ou un de ses sels pharmaceutiquement acceptables.4 - Association of deoxyfructosazine and glipizide or one of its pharmaceutically acceptable salts.
5 - Association de déoxyfructosazine et de glyburide ou un de ses sels pharmaceutiquement acceptables.5 - Association of deoxyfructosazine and glyburide or one of its pharmaceutically acceptable salts.
6 - Association selon l'une des revendications 1 à 5 pour une utilisation simultanée, séparée ou étalée dans le temps.6 - Association according to one of claims 1 to 5 for simultaneous, separate or spread over time.
7 - Composition pharmaceutique contenant une association selon l'une des revendications 1 à 6.7 - Pharmaceutical composition containing an association according to one of claims 1 to 6.
8 - Utilisation d'une association selon l'une des revendications 1 à 6 pour la préparation d'un médicament utile pour la prévention et/ou le traitement du diabète de type 2 et ses complications. 8 - Use of a combination according to one of claims 1 to 6 for the preparation of a medicament useful for the prevention and / or treatment of type 2 diabetes and its complications.
PCT/FR2000/003603 1999-12-23 2000-12-20 Association of deoxyfructosazine and an antidiabetic of the sulphonylurea family WO2001047527A1 (en)

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FR9916358A FR2802814B1 (en) 1999-12-23 1999-12-23 COMBINATION OF DEOXYFRUCTOSAZINE AND AN ANTIDIABETIC FROM THE SULFONYLUREA FAMILY
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FR2826278B1 (en) * 2001-06-20 2005-03-25 Lipha USE OF ANTIDIABETIC AGENTS FOR MANUFACTURING A MEDICAMENT HAVING A HEALING EFFECT
DK1397124T3 (en) * 2001-06-20 2007-04-02 Merck Sante Sas Use of diabetic agents for the manufacture of a medicament having a healing effect

Citations (2)

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WO1997028813A1 (en) * 1996-02-06 1997-08-14 Institut Malgache De Recherches Appliquees Mixtures derived from grains of eugenia jambolana lamarck, preparation and use of said mixtures and some of their constituents as medicaments
US5859037A (en) * 1997-02-19 1999-01-12 Warner-Lambert Company Sulfonylurea-glitazone combinations for diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028813A1 (en) * 1996-02-06 1997-08-14 Institut Malgache De Recherches Appliquees Mixtures derived from grains of eugenia jambolana lamarck, preparation and use of said mixtures and some of their constituents as medicaments
US5859037A (en) * 1997-02-19 1999-01-12 Warner-Lambert Company Sulfonylurea-glitazone combinations for diabetes

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