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WO2008038303A2 - Formulation thérapeutique comprenant une sulfonylurée, une thiazolidinedione, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique - Google Patents

Formulation thérapeutique comprenant une sulfonylurée, une thiazolidinedione, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique Download PDF

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Publication number
WO2008038303A2
WO2008038303A2 PCT/IN2007/000435 IN2007000435W WO2008038303A2 WO 2008038303 A2 WO2008038303 A2 WO 2008038303A2 IN 2007000435 W IN2007000435 W IN 2007000435W WO 2008038303 A2 WO2008038303 A2 WO 2008038303A2
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WIPO (PCT)
Prior art keywords
therapeutic formulation
scavenger
combined
complexated
sulfonylureas
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Ceased
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PCT/IN2007/000435
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English (en)
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WO2008038303A3 (fr
Inventor
Jegannathan Srinivas
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Publication of WO2008038303A3 publication Critical patent/WO2008038303A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • TITLE THERAPEUTIC FORMULATION COMPRISING OF A SULFONYLUREA, THIAZOLIDINEDIONE AND NITRIC OXIDE RELEASING MOIETY COMPLEXATED WITH A NITRIC OXIDE SCAVENGER
  • the present invention belongs to the field of pharmaceutical technology and relates to a pharmaceutical composition that aims at combating secondary complications in diabetes drug intake and optimizes the therapeutic usefulness of Oral Hypoglycemic Agents called Sulfonylureas, which would include Glipizide, Gliclazide, Glibenclamide (Glyburide), Glimepiride and Gliquidone and comprises of the unique advantage of Nitric Oxide Releasing moiety, which is further complexated with a Nitric Oxide Scavenger.
  • the therapeutic edge of this invention would be minimizing the risk of Diabetic Complications due to the Oxidative Cellular Damage produced by Nitric Oxide.
  • Nitric Oxide Scavenger has been complexated to reduce the NO levels and hence enhance the safety profile of the products on a long-term use.
  • the invention can also contain Fixed Dose Combination of Thiazolidinediones (PPAR- ⁇ Agonists) that would include Pioglitazone and Rosiglitazone with each of the above-mentioned Il Generation Sulfonylurea Drugs.
  • PPAR- ⁇ Agonists Fixed Dose Combination of Thiazolidinediones
  • Nitric Oxide one of the most important biological molecules, which is capable of producing several cellular responses, both beneficial as well as detrimental.
  • Metabolic Disorders with an inevitable nexus with Cardiovascular Diseases pose one of the biggest threat to the Scientific Community, contributing to one of the highest number of deaths in populations across the globe.
  • the most important triggering factor appears to be the changes in the lifestyle and dietary pattern, for the onset of the disease in the individuals.
  • the secondary complications are primarily due to factors that are quite unlikely to be noticed. It's precisely because of this reason that Diabetes is often referred to as a "Silent Killer", with a potential damage to the vital organs.
  • Macro- and microvascular diseases are the most common causes of morbidity and mortality in patients with diabetes mellitus.
  • Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction.
  • Hyperglycemic episodes which complicate even well controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications.
  • Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased Superoxide anion formation.
  • nitrosative stress and peroxynitrite interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction.
  • the pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. Thus it would be important to determine the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and evolve novel therapeutic strategies such as neutralization of peroxynitrite and inhibition of PARP
  • This "causal" therapy would also be associated with other promising tools such as LY 333531 , PJ34, and FP15, which block the protein kinase ⁇ isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively.
  • Insulin action is initiated through its binding to the cell surface receptor, initiating a series of signal transduction reactions, which stimulate various effectors to produce its physiological effects. Therefore, impairment of insulin signal transduction results in attenuation of insulin action and leads to insulin resistance resulting in type 2 diabetes mellitus. Because the molecular mechanisms of insulin resistance are still being elucidated, it is indispensable to establish in vitro models of basal and insulin-mediated signal transduction to clarify these mechanisms and suggest treatments where appropriate.
  • nitric oxide can induce insulin resistance in skeletal muscle.
  • the modulatory effects of two NO donors, S-nitroso-N-acetyl D, L-penicillamine (SNAP) and S- nitrosoglutathione (GSNO) were investigated on the early events in insulin signaling in rat skeletal myocytes.
  • Skeletal muscle is responsible for about 75% of whole body glucose metabolism, and insulin resistance is a characteristic feature of individuals with type 11 diabetes mellitus.
  • a number of intracellular defects in insulin action in muscle have been described, including decreased glucose transport and glucose phosphorylation and diminished glycogen synthase activity. A similar effect is observed in rodent model systems.
  • NO nitric oxide
  • Endothelium derived nitric oxide is synthesized from the amino acid L- arginine by the endothelial isoform of nitric oxide synthase (NOS), yielding L-citru!line as a byproduct.
  • NOS nitric oxide synthase
  • Nitric oxide is lab ⁇ e with a short half- life ( ⁇ 4 seconds in biological solutions). It is rapidly oxidised to nitrite and then nitrate by oxygenated haemoglobin before being excreted into the urine.
  • co-factors are required for nitric oxide biosynthesis.
  • nitric oxide diffuses across the endothelial cell membrane and enters the vascular smooth muscle cells where it activates guanylate cyclase, leading to an increase in intracellular cyclic Guanosine-3',5-Monophosphate (cGMP) concentrations4.
  • cGMP mediates many of the biological effects of nitric oxide including the control of vascular tone and platelet function.
  • nitric oxide has other molecular targets, which include haern, or other iron centred proteins, DNA, and thiols. These additional reactions may mediate changes in functions of certain key enzymes or ion channels. Nitric oxide also interacts with enzymes of the respiratory chain including complex I and II, and aconitase, and through these effects alters tissue mitochondrial respiration. Interaction of nitric oxide with superoxide anion can attenuate physiological responses mediated by nitric oxide and produce irreversible inhibitory effects on mitochondrial function as a result of the formation of peroxynitrite (ONOO-), a powerful oxidant species.
  • ONOO- peroxynitrite
  • NOSs are the only enzymes known to simultaneously require five bound cofactors/prosthetic groups: FAD, FMN, haem, tetrahydrobiopterin (BH4) and Ca2+-calmodulin (CaM).
  • FAD fluorescence deficiency deficiency
  • FMN adenosine-phosphate
  • BH4 tetrahydrobiopterin
  • CaM Ca2+-calmodulin
  • three distinct genes encode NOS isozymes: neuronal (nNOS or N0S1), cytokine inducible (iNOS or NOS2) and endothelial (eNOS or NOS3).
  • NO donor drugs are used in the treatment of hypotension and angina where abnormalities in the L- arginine-nitric oxide pathway have been implicated.
  • NO is produced by a group of enzymes, the nitric oxide synthases.
  • Selective inhibition of the inducible isoform is one approach to the treatment of diseases where there is an overproduction of NO; an alternative approach is to scavenge or remove excess NO.
  • a number of NO scavenger molecules have demonstrated pharmacological activity in disease models, particularly models of septic shock.
  • PTIO pyridoxalated haemoglobin polyoxyethylene conjugate
  • PPP pyridoxalated haemoglobin polyoxyethylene conjugate
  • iron compounds of diethylenetriaminepentaacetic acid and diethyldithiocarbamate ruthenium polyaminocarboxylate complexes.
  • An Objective of this invention is to treat Diabetes and prevent its complications by providing the Oral Hypoglycemic Agents, commonly known as, " Sulfonylureas".
  • Sulfonylureas commonly known as, " Sulfonylureas".
  • the Invention embodies in itself the Claim for separate and individual Sulfonylureas, such as include Glipizide, Gliclazide, Glibenclamide (Glybuhde), Glimepiride and Gliquidone as separate entities and separate set of inventions
  • Another Objective of this invention is to prevent the Diabetic complications produced due to excessive nitrosative stress by mitigating the deleterious effects of NO, with the combination/complexation of the Antidiabeti drugs with the NO scavengers, which would include PTIO, PHP, low molecular weight iron compounds of diethylenetriaminepentaacetic acid, diethyldithiocarbamate or ruthenium polyaminocarboxylate complexes or any other suitable NO scavenger
  • Another objective of this invention is to develop useful and convenient dosage levels and forms of such a combination therapeutic.
  • Another objective of this invention is to enhance individual effects of the components of this composition by their combination.
  • Yet another Objective of the invention is to provide long-term dosage convenience to patients on combinational therapy of Sulfonylureas and Thiazolidinediones (PPAR- ⁇ Agonists) that would include Pioglitazone and Rosiglitazone.
  • PPAR- ⁇ Agonists Thiazolidinediones
  • the Fixed Dose combination of Sulfonylureas with Thiazolidinediones has a strong medical and scientific rationale as it serves the dual purpose of a) Enhance insulin secretion from the pancreatic Beta cells and thereby achieve control of Hyperglycemia b) Reduce Glycogenolysis as well as Gluconeogenesis c) Improve Insulin sensitivity and d) Decrease Insulin Resistance and e) Promoting peripheral utilization of Glucose by activating the GLUT.
  • the invention embodies in itself 5 separate entities, each belonging to the class of drugs known as "Sulfonylureas or Insulin secretagogues". Further, each active ingredient from the said class has been combined or complexated with NO Scavenger to prevent Diabetic Complications arising out of Nitrosative stress
  • the active ingredients are Sulfonylureas that are synthetic Oral Hypoglycemic Agents.
  • the active ingredients further contain Thiazolidinediones.
  • the inactive ingredients are more or less the same for each of the compound: microcrystalline cellulose or hydroxypropyl methylcellulose, lactose, glycolate, Magnesium stearate, Sodium, Starch, PEG and other appropriate agents.
  • the inactive ingredients particularly for Gliquidone would include Betacyclodextrin to enhance its hydrophillicity.
  • the Sulfonylurea drugs act by inhibiting ATP-sensitive potassium channels in pancreatic beta cells. This inhibition causes cell membrane depolarization, opening of voltage-dependent calcium channels, thus triggering an increase in intracellular calcium into the beta cell which stimulates insulin release. Almost all the Sulfonylureas share some common attributes, though some of the drugs (Glimepiride) have extra- pancreatic effects as well.
  • Thiazolidinediones act by binding to PPARs (peroxisome proliferator- activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARy (gamma).
  • PPARs peroxisome proliferator- activated receptors
  • the normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.
  • compositions are as follows:
  • Glibenclamide (Glyburide) from a dosage range of 1.25 to 10 mg per day in combination or complexated with NO-Scavenger
  • Glipizide from a dosage range of 2.5 to 10 mg per day in combination or complexated with NO-Scavenger 4.
  • Glimepiride from a dosage range of 1 to 4 mg per day in combination or complexated with NO-Scavenger 5.
  • Gliquidone from a dosage range of 30 mg per day in combination or complexated with NO-Scavenger
  • the invention also embodies Fixed Dose Combination of Thiazolidinediones (PPAR- ⁇ Agonists) that would include Pioglitazone 15 to 45 mg and Rosiglitazone 2 to 8 mg with each of the active ingredients above

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

Abstract

L'invention concerne une formulation thérapeutique comprenant des sulfonylurées en tant que principes actifs, tels que le glibenclamide, le gliclazide, le glimépiride, le glipizide et la gliquidone. Cette invention est caractérisée en ce que lesdites sulfonylurées sont combinées avec des thiazolidinediones, et sont combinées ou complexées avec un capteur de l'oxyde nitrique pour empêcher la survenue de complications diabétiques liées à un stress nitrosatif.
PCT/IN2007/000435 2006-09-26 2007-09-26 Formulation thérapeutique comprenant une sulfonylurée, une thiazolidinedione, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique Ceased WO2008038303A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1760/CHE/2006 2006-09-26
IN1760CH2006 2006-09-26

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WO2008038303A2 true WO2008038303A2 (fr) 2008-04-03
WO2008038303A3 WO2008038303A3 (fr) 2008-05-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104127423A (zh) * 2014-07-30 2014-11-05 沈阳药科大学 格列喹酮衍生物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030181495A1 (en) * 1998-06-23 2003-09-25 Medinox, Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104127423A (zh) * 2014-07-30 2014-11-05 沈阳药科大学 格列喹酮衍生物及其制备方法和应用

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Publication number Publication date
WO2008038303A3 (fr) 2008-05-15

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