composition

专利摘要:
Summary Composition The present invention relates to compositions and methods for controlling glycemia in a mammal in need thereof. The present invention relates to compositions and methods for treating diabetes disease and related disorders. more specifically, the present invention relates to novel therapies or combinatorial therapies for diabetes and related disorders based on compositions that control blood glucose level. 1/1
公开号:BR112015009702A2
申请号:R112015009702
申请日:2013-10-30
公开日:2019-12-17
发明作者:Cohen Daniel；Chumakov Ilya；Hajj Rodolphe；Nabirochkin Serguei
申请人:Pharnext；
IPC主号:

专利说明:

COMPOSITION
FIELD OF THE INVENTION [001] The present invention relates to compositions and methods for controlling glycemia in a mammal that needs them. More specifically, the present invention relates to new therapies or combinatorial therapies for diabetes and related disorders, based on compositions that control the blood glucose level.
BACKGROUND OF THE INVENTION [002] Diabetes mellitus refers to a group of metabolic diseases in which patients have high blood sugar levels. It is a major public health problem due to the high number of affected patients, since 171 million people worldwide, corresponding to 2.8% of the population in 2000, are diabetic. Diabetes is now considered an epidemic: the number of patients is expected to almost double by 2030. There are mainly two types of diabetes. Type 1 diabetes, mainly characterized by insulin-dependent patients, is known to be autoimmune and is sometimes caused by infectious factors. Usually starting in patients under 30 and representing about 5 to 10% of all cases of diabetes [1]. Type 2 diabetes, mainly characterized by insulin independence, has a later onset than type 1 diabetes and is therefore called adult diabetes. It represents about 90 to 95% of all cases of diabetes. Many factors can potentially cause or exacerbate type 2 diabetes. These include hypertension, high cholesterol, metabolic syndrome and overweight / obesity. As an example, approximately 90% of patients with type 2 diabetes
2/96 are overweight / obese [2]. Other forms of diabetes include gestational diabetes, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes and various forms of monogenic diabetes. Current treatments consist of insulin administration for type 1 diabetes and / or glucose-lowering drugs or insulin sensitizers for type 2 diabetes. Insulin is a hormone involved in glucose homeostasis, along with glucagon. In response to high blood glucose levels, insulin is produced by pancreatic beta cells located on the islets of Langerhans. Glucose is then captured from the blood by hepatocytes, muscle cells and adipocytes used as an energy source or for storage, such as glycogen and triglycerides. Insulin also inhibits lipolysis, preventing the release of fatty acid from fatty tissues. In contrast, low blood glucose levels result in both reduced production and insulin release. Together with the action of glucagon, it results in the release of glucose into the bloodstream. In pathological situations, insulin production by beta cells is not sufficient (type 1 diabetes) and / or the cells respond poorly to it (insulin resistance; type 2 diabetes), leading to persistent high blood glucose levels. Precise mechanisms involved in these pathologies are not yet fully understood.
[003] The decrease in insulin production that characterizes type 1 diabetes is due to the destruction of beta cells by an autoimmune process that consists of the production of autoantibodies, activation of autoreactive lymphocytes and infiltration of the pancreas to destroy cells
3/96 beta. Type 2 diabetes mellitus is considered a complex metabolic disorder. It results from the combination of impaired pancreatic insulin secretion due to beta cell dysfunction, insulin resistance, as well as impaired glucagon secretion. The impairment of glucose-stimulated insulin production involves the progressive loss of pancreatic beta cells, as well as a degeneration of islet cell function. Insulin resistance consists, for example, of suppressed or reduced effects of insulin on peripheral organs / tissues (liver, muscles and fatty tissues) or increased lipolysis in adipocytes, resulting in increased circulation of free fatty acids. These cases result in increased endogenous glucose production by the liver, along with decreased glucose uptake due to reduced insulin receptor expression, failures in post insulin receptor actions [3], overproduction of liver glucose or blockage of signaling pathways insulin [4]. Insulin resistance is a characteristic of a more complex syndrome, called metabolic syndrome, which is a group of risk factors for coronary heart disease and diabetes mellitus, including abdominal obesity, elevated triglyceride levels, decreased levels of high-density lipoprotein, high blood pressure and elevated fasting plasma glucose levels [5]. 75% of type 2 diabetes patients have metabolic syndrome.
[004] Persistent high blood glucose levels result in both acute and chronic complications that can be very disabling and even fatal for diabetic patients, such as illness
4/96 cardiac and stroke, which are the most dangerous consequences of diabetes mellitus. Persistent high blood glucose levels damage blood vessels in the long run, leading to microvascular and macrovascular angiopathy, which is responsible for most of the increased morbidity and mortality associated with the disease. Microvascular complications are responsible for diabetic cardiomyopathy, nephropathy, both of which result in organ failure, retinopathy, which can lead to severe loss of vision and neuropathy. Macrovascular complications refer, instead, to cardiovascular disorders that are responsible for coronary artery disease, which ultimately causes angina or myocardial infarction, diabetic myonecrosis, peripheral vascular disease and stroke. Macrovascular complications are more common and up to 80% of patients with type 2 diabetes will develop or die due to a macrovascular disease.
[005] Unfortunately, existing treatments have not been successful in recovering long-term normoglycemia, as beta cell function declines over time [6]. In addition, there is currently no single drug capable of reversing all aspects of the disease.
[006] Glycemic control in type 1 diabetes is almost exclusively achieved with injections of exogenous insulin, as patients no longer produce insulin. Insulin can also be administered to patients with type 2 diabetes, when drugs to lower glucose levels and diet fail to control blood glucose [7]. It is currently administered more frequently to these patients, as it delays the development and progression of
5/96 complications. Insulin use, however, comprises side effects, including hypollolemia when the dosage is not adequate, high risk of developing colorectal cancer [8] and weight gain, which is not recommended for diabetic patients, particularly those who are obese .
[007] The progressive nature of type 2 diabetes suggests that many patients will eventually need a combination of antidiabetics, possibly together with insulin [9]. Antidiabetics were developed in order to neutralize the main mechanisms involved in type 2 diabetes: insulin resistance (biguanides and thiazolidinediones) and insulin secretion (sulfonylureas, glinides, dipeptidyl peptide-4 inhibitors, glucagon-like peptide 1 receptor agonists) , in addition to particular mechanisms that deal with the late absorption of glucose by the gastrointestinal tract. However, it has been shown that most of these drugs have harmful side effects, such as weight gain, peripheral edema or congestive heart failure, and lose efficiency in long-term use [9].
[008] Despite the growing number of therapeutic options related to diabetes, none is able to reverse all aspects of the disease, including the progressive loss of beta cell function and the management of all complications. Thus, there is a need for alternative and improved drugs for the treatment of diabetes and related conditions.
SUMMARY OF THE INVENTION [009] The present invention provides new compositions and methods for treating diabetes and disorders
6/96 related, particularly type 2 diabetes.
[010] The present invention also provides compositions and methods for normalizing blood glucose in a mammalian individual who needs them.
[Oil] The invention also relates to compositions and methods for controlling the blood glucose level in mammalian individuals, particularly in mammalian individuals who have diabetes or a related disorder.
[012] The invention also relates to compositions and methods for increasing or stimulating glucose uptake in adipocytes and / or muscle cells in mammalian individuals, particularly in mammalian individuals who have diabetes or a related disorder.
[013] The invention also relates to compositions and methods for decreasing insulin resistance in mammalian individuals who have type 2 diabetes or a related disorder.
[014] The invention also relates to compositions and methods for decreasing apoptosis of pancreatic beta cells in mammalian individuals, particularly in mammalian individuals who have diabetes or a related disorder.
[015] The present invention features the identification and validation, by the inventors, of drugs that, alone or in combination, effectively affect one or several relevant pathways involved in the control of the blood glucose level and represent new and effective therapies for the treatment of diabetes and related disorders. The invention therefore presents new therapies for diabetes (type 1 or type 2) and related conditions, as well as
7/96 as new drugs and drug combinations that are particularly effective for such conditions. The invention is applicable to any mammal, particularly a human individual. The invention is particularly suitable for treating type 2 diabetes or metabolic syndrome, which are associated with abnormally high blood glucose levels. The treatments according to the invention can be used in combination or alternating with other therapies for such conditions.
[016] An object of the invention relates, more specifically, to a composition comprising at least one, preferably at least two, compound (s) selected from acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbronpheniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendine, diimiline or diprofetidine, idimidine, diimetidine, diprofetidine, dimethyline a related disorder.
[017] In a preferred embodiment, said at least one, preferably at least two, compound (s), is (are) selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene.
[018] In another particular embodiment, the compound (s) is (are) selected (s) from almitrine, azelastine, acamprosate, baclofen, carbetapentane,
8/96 dexbronpheniramine, diethylcarbamazine, D-mannose, ifenprodil, mexiletine, nicergoline or tolperisone.
[019] As illustrated in the examples, the above compounds provide a substantial effect when used individually and are more particularly effective in combinations. The examples show, in fact, that combinatorial therapies are even more preferred to regulate blood glucose levels, in particular, glucose uptake and glucose production, as well as to decrease insulin resistance, and provide clinical benefit more efficient.
[020] Consequently, an additional objective of this invention relates to a composition that comprises at least:
[021] - a first compound selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronfeniramine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tollenone, torolinenic acid, tolfenamic acid, tolfenamic acid, tolfenamic acid, tolfenamic acid and [022] - a second compound, different from the first compound, the second compound being selected from acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedyl, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder.
9/96 [023] Another object of the invention relates to a composition comprising at least two compounds selected from acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine , ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammal that needs the same .
[024] The at least two compounds are, most preferably, selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronpheniramine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicenolin, acid, tinnitus, nicergoline, nicergoline, tolperisone, torasemide or triamterene.
[025] The drug compositions of this invention can also be used in additional combination with other treatments or antidiabetic agents to provide an improved clinical effect and / or to alleviate potential side effects of such drugs or antidiabetic treatments.
[026] Consequently, an additional objective of this invention relates to compositions that comprise:
-a compound selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronpheniramine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolemisone, toremisone, torperisone, toremide, toremisone, toremisone, toremisone, toremide, toremide, toremisone, toremide, toremide; and
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-a compound selected from the group consisting of acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformin, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, dutogliptina, genogliptin, exenatide, genenate, , glibenclamide, glibornuride, glucetanil, gliclazide, glimepiride, glipizide, gliquidone, glisentide, glylopyramide, imidapril, insulin, inulin, lipoic acid, linagliptin, liraglutide, mecobalamin, metformin, miglitone, mitiglinide, mitiglinide, pheniglinide, natiglinide, pyrite repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose;
as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammal that needs it.
[027] An even more preferred objective of this invention relates to compositions comprising a compound selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentan, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene, in combination with metformin, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
[028] The invention also relates to pharmaceutical compositions that comprise a drug combination, as shown above. The pharmaceutical compositions of the invention typically comprise one or more excipients
11/96 or pharmaceutically acceptable carriers. In addition, the compounds in the compositions of the invention can be used as such or in the form of a salt, hydrate, ester, ether, acid, amide, racemate or isomer. They can also be in the form of extended release formulations. Prodrugs or metabolites of the compounds can also be used.
[029] In one embodiment, the invention relates to a composition that comprises a combination selected from:
-ifenprodil and acamprosate,
-ifenprodil and baclofen,
-baclofen and acamprosate,
-mexylethine and cinacalcet,
-mexylethine and torasemide,
-sulfisoxazole and torasemide,
-azelastine and nicergoline,
-idebenone and nicergoline,
-carbetapentane and nicergoline,
-almitrine and nicergoline, -cimetidine and nicergoline, -diethylcarbamazine and nicergoline, -ifenprodil and nicergoline, -azelastine and idebenone, -acamprosate and nicergoline, -azelastine and carbetapentane, -azelastine and almitine, -idebone and carbetaphen, and carbetaphen -triamterene and nicergoline, -D-Mannose and nicergoline,
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-idebenone and diethylcarbamazine,
-ifenprodil and fenspiride, -ifenprodil and tolfenamic acid, -ifenprodil and torasemida, -ifenprodil and triamterene, -fenspiride and torasemida, -fenspiride and triamterene, -fenspiride and tolfenamic acid, -torasemide and tolfenamic acid, -torasemide and triamterene,
-tolfenamic acid and triamterene, or
-D-mannose and baclofen;
as well as the use of such a composition in the treatment of diabetes or a related disorder in a mammal that needs it.
[030] In another embodiment, the invention relates to a combination of metformin with at least one of the combination of compounds above, as well as its use in the treatment of diabetes or a related disorder in a mammal that needs it.
[031] As will be further presented in the present application, the compounds in a composition or combinatorial therapy, according to the invention, can be formulated or administered to the individual together, separately or sequentially, possibly through different routes and protocols. In a preferred embodiment, the compositions of the invention are administered repeatedly to the subject.
[032] The invention also relates to methods for treating diabetes or a related disorder, the methods of which include administering to an individual who
13/96 requires a drug or drug composition (s) thereof, as shown above. In a particular embodiment, the methods further comprise a step of measuring the blood glucose level in a blood sample of the mammalian subject, before or after the administration of drug (s).
[033] An additional object of this invention relates to a method for treating diabetes or a related disorder, the method comprising administering simultaneously, separately or sequentially to an individual who needs a combination of drugs as shown above.
[034] An additional object of this invention relates to the use of the compositions described above for the production of a medication for the treatment of diabetes or a
disturbany human. related.[035] The invention can alsomammal individual particularlyBRIEF DESCRIPTION OF THE FIGURES to beone used inindividual tested [036] For all figures,induce a significant effect the drugsdifferent from
reference (t-test. * p <0.05. ** p <0.01; *** p <0.001)
Figure 1: Effect of pretreatment with D-mannose against apoptosis of beta cells (optical density). Apoptosis is significantly prevented by D-mannose at doses of at least 10 nM (129%).
Figure 2: Effect of short-term pretreatment with triamterene on insulin secretion in INS-1 cells. Insulin secretion is significantly improved by triamterene (+37%).
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Figure 3: Effect of short-term pretreatment with cinacalcet on insulin secretion in INS-1 cells. Insulin secretion is significantly improved by cinacalcet (+55%) at doses of at least 1 μΜ.
Figure 4: Effect of short-term pretreatment with acamprosate on glucose uptake in H-2Kb cells. Glucose uptake is significantly improved by acamprosate (+45%) at doses of at least 0.1 μΜ.
Figure 5: Effect of short-term pretreatment with almitrine on glucose uptake in H-2Kb cells. Glucose uptake is significantly improved by almitrine (+80%) at doses of at least 1 μΜ.
Figure 6: Effect of long-term pretreatment with nicergoline on glucose uptake in H-2Kb cells. Glucose uptake is significantly improved by nicergoline (+28%).
Figure 7: Effect of short-term pretreatment with carbetapentane on glucose uptake in 3T3-L1 cells. Glucose uptake is significantly improved by carbetapentane (+58%) at doses of at least 100 nM.
Figure 8: Effect of long-term pretreatment with almitrine on glucose uptake in 3T3-L1 cells. Glucose uptake is significantly improved by almitrine (+69%) at doses of at least 1 μΜ.
Figure 9: Effect of short-term pretreatment with D-mannose on the production of glucose by liver cells. Glucose production is significantly reduced by D-mannose (-22%).
Figure 10: Effect of long-term pretreatment with ifenprodil on the production of glucose by liver cells.
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Glucose production is significantly reduced by ifenprodil (-22%) at doses of at least 10 nM.
Figure 11: Effect of long-term pretreatment with azelastine on the production of glucose by liver cells. Glucose production is significantly reduced by azelastine (-36%).
Figure 12: Effect of short-term pretreatment with piribedil on glucose uptake in 3T3-L1 cells. Glucose uptake is significantly improved by pyribedyl (+68%) at doses of at least 10 nM.
Figure 13: Effect of pretreatment with torasemide on glucose uptake in primary diabetic human myotubes. Glucose uptake is significantly improved (+24%, +18% and +14%, respectively) at doses of at least 0.01 μΜ, 0.1 μΜ and 1 μΜ.
Figure 14: Effect of pretreatment with fenspiride on glucose uptake in diabetic myotubes from a diabetic patient. Glucose uptake is significantly improved (+ 34%, +30%, +27%, respectively) at doses of at least 0.01 μΜ, 0.1 μΜ and 1 μΜ.
Figure 15: Effect of pretreatment with tolfenamic acid on glucose uptake in primary human myotubes from a diabetic patient. Glucose uptake is significantly improved (+13%, +13% and +12%, respectively) at doses of at least 0.01 μΜ, 0.1 μΜ and 1 μΜ.
Figure 16: Effect of pretreatment with ifenprodil on glucose uptake in primary diabetic human myotubes. Glucose uptake is improved (+48%) in
16/96 doses of at least 0.01 μΜ.
Figure 17: Effect of pretreatment with triamterene on glucose uptake in primary diabetic human myotubes. Glucose uptake is significantly improved (+13%) at doses of at least 0.01 μΜ.
Figure 18: Effect of pretreatment with torasemide on glucose uptake by differentiated adipocytes 3T3L1, under the effect of insulin resistance induced by TNF-α. Glucose uptake is significantly improved (+121%, + 123% and +129%) at doses of at least 0.37 nM, 1 nM and 3.3 nM respectively, compared to untreated insulin resistant cells (TNFa ).
Figure 19: Effect of pretreatment with ifenprodil on glucose uptake by differentiated adipocytes 3T3L1, under the effect of insulin resistance induced by TNF-α. Glucose uptake is significantly improved (+140%) at doses of at least 1 μΜ, compared to untreated insulin resistant cells (TNFa).
Figure 20: Effect of pretreatment with fenspiride on glucose uptake by differentiated adipocytes 3T3L1, under the effect of insulin resistance induced by TNF-α. Glucose uptake is significantly improved (+130%) at a dose of at least 1 nM, compared to untreated insulin resistant cells (TNFa).
Figure 21: Effect of pretreatment with tolfenamic acid on glucose uptake by differentiated adipocytes 3T3L1, under the effect of insulin resistance induced by TNF-α. Glucose uptake is significantly improved (+ 127%) at a dose of at least 10 nM, compared to untreated insulin resistant cells
17/96 (TNFα).
Figure 22: Effect of the baclofen acamprosate combination on the plasma CRP concentration in male ZDF rats after a 4-week treatment. The concentration of CRP is significantly reduced by the combination baclofen acamprosate in treated ZDF rats compared to untreated ZDF rats.
Figure 23: Effect of short-term treatment with D-mannose - baclofen - metformin combination (respectively, 5 mg / kg and 2 mg / kg twice daily and 150 mg / kg once daily) on glucose homeostasis in mice db / db. Fasting glycemia (mg / dl) is significantly decreased in treated db / db mice, compared to untreated db / db mice.
DETAILED DESCRIPTION OF THE INVENTION [037] The present invention provides new therapeutic approaches for controlling the blood glucose level. The invention features new drugs, drug combinations and methods, which allow an effective control of the blood glucose level and can be used for the treatment of patients.
[038] The invention therefore relates to compositions and methods for the treatment of diabetes and related disorders.
Definitions [039] Covered by the context of the invention, the term treatment includes preventive or curative treatment. The term treatment refers, in particular, to the correction, delay or reduction of impaired glucose homeostasis. The blood glucose level fluctuates
18/96 throughout the day. Glucose levels are usually lower in the morning, before the first meal of the day, and increase after meals for a few hours. Consequently, the term treatment includes controlling the blood glucose level by increasing or decreasing the blood glucose level, depending on the condition of the individual mammal and the time of day in order to achieve normal glucose levels. The term treatment includes, more particularly, a temporary or persistent reduction in blood glucose level in an individual who has diabetes or a related disorder. The term treatment also designates an improvement in insulin release (eg, by pancreatic β cells), glucagon release (eg, by pancreatic α cells), glucose utilization and / or uptake (eg, capture of glucose by muscle cells or adipocytes) and / or in hepatic neoglycogenesis.
[040] Covered by the context of the invention, the expressions control blood glucose level or control of blood glucose level refer to the normalization or regulation of the level of glucose in the blood or plasma in an individual mammal that has abnormal levels (that is, levels that are below or above a known reference, mean, or mean value for a corresponding mammalian subject with normal glucose homeostasis).
[041] 0 term diabetes if refers, gift document, to a group of disease metabolic in that the patients feature tall levels in glucose in blood, including Diabetes type 1, Diabetes type 2, diabetes
pregnancy, congenital diabetes, diabetes related to
19/96 cystic fibrosis, steroid diabetes and several forms of monogenic diabetes.
[042] The term related disorder refers to any disease associated with a blood or plasma glucose level outside the normal range, preferably hyperglycemia. Consequently, the term related disorder includes impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome, postprandial hyperglycemia and overweight / obesity. Such related disorders can also be characterized by an abnormal level of insulin in the blood and / or plasma.
[043] Combination or combinatorial therapy or combinatorial treatment means a treatment in which at least two compounds are co-administered to an individual to cause a biological effect. In a combination therapy, according to this invention, the at least two drugs can be administered together or separately, at the same time or sequentially. Simultaneous administration is not required, as long as the drugs have a combined or synergistic effect on the body to improve the patient's conditions. In addition, at least two drugs can be administered through different routes and protocols. As a result, while drugs of a combination can be formulated together, they can also be formulated separately.
[044] Covered by the context of the invention, the terms compound or drug, as identified by their name or CAS number, are intended to designate the chemical compound as specifically named or identified with
20/96 its corresponding CAS number, as well as any salt, hydrate, isomer, racemate, conjugate or derivative of the same pharmaceutically acceptable, of any chemical purity.
[045] The term derivative includes any functional or structurally related compound, such as acid derivatives, amide derivatives, ester derivatives, ether derivatives, prodrugs and metabolites.
[046] The term prodrug, as used herein, refers to any derivative (or precursor) of a compound that, when administered to a biological system (eg, a human organism), generates said compound as a result of, for example, spontaneous chemical reaction (s), enzyme-catalyzed chemical reaction (s) and / or metabolic chemical reaction (s). Prodrugs typically have the X drug structure, where X is a chemical portion of inert carrier and drug is the active compound. Usually, the prodrug is devoid of activity or less active than the drug and the drug is released from the carrier in vivo. Prodrugs are usually inactive or less active than the resulting drug and can be used, for example, to improve the physicochemical properties of the drug, to target the drug to a specific tissue, to improve the pharmacokinetic and pharmacodynamic properties of the drug and / or to reduce unwanted side effects. Some of the common functional groups that are susceptible to prodrug design include, but are not limited to, carboxylic groups, hydroxyl, amine, phosphate / phosphonate and carbonyl. Prodrugs typically produced by modifying these groups include, but are not limited to, esters, carbonates,
21/96 carbamates, amides and phosphates. Specific technical guidelines for the selection of suitable prodrugs are common knowledge [11 to 15]. In addition, the preparation of prodrugs can be carried out by conventional methods known to those skilled in the art. Methods that can be used to synthesize prodrugs are described in several studies on the subject [12; 16 to 21].
[047] The term metabolite of a drug, as used in this document, refers to a molecule that results from the modification (s) (biochemistry (s)) or from the processing of said drug after administration to an organism, usually through specialized enzymatic systems, and that exhibits or retains a biological activity of the drug. The metabolites were shown to be responsible for much of the therapeutic action of the drug with the mother.
[048] The term salt refers to a relatively non-toxic and pharmaceutically acceptable base addition salt or organic or inorganic acid of a compound of the present invention. Pharmaceutical salt formation typically consists of pairing an acidic, basic or zwitterionic drug molecule with a contrion to create a salt version of the drug. A wide variety of chemical species can be used in the neutralization reaction. Although most of the salts of a given active ingredient are bioequivalent, some may have, among others, improved solubility or bioavailability properties. Salt selection is now a common standard operation in the drug development process, as taught by H. Stahl and C.G Wermuth in their manual [22].
22/96 [049] In a preferred embodiment, the designation of a compound is intended to designate the compound per se, as well as any pharmaceutically acceptable salt, hydrate, isomer, racemate, ester or ether.
[050] In a more preferred embodiment, the designation of a compound is intended to designate the compound as specifically designated per se, as well as any pharmaceutically acceptable salt thereof.
[051] In a particular embodiment, an extended release formulation of the compound is used.
Compositions and methods for treating diabetes and related disorders [052] Through a complete integration of experimental data covering results from cellular biological studies, expression evaluation experiments and genetic association studies, the inventors were able to select a small number of drugs which, alone and / or in combination (s), effectively alter relevant pathways for glycemic control and represent new therapeutic approaches to treat diabetes and related disorders. These drugs or combinations can be used to normalize the level of glucose in the blood acting, for example, in the release of insulin, in the release of glucagon, in the use of glucose and / or in the production of glucose, and offer new potent therapies for diabetes and related disorders. As shown in the examples, these drugs and combinations have a strong effect on the relevant functions of diabetes: they are involved in protecting beta cells against apoptosis, in increasing glucose uptake in muscle tissues and in adipocytes, in increasing the secretion of
23/96 insulin by pancreatic β cells and / or in the control of glucose production in liver tissues.
[053] These drugs and combinations therefore represent new therapeutic approaches for controlling the blood glucose level in a mammal that needs them. They also represent new therapeutic approaches for the treatment of diabetes or related disorders in a mammal that needs it.
[054] In that sense, an objective of this invention relates to compositions that comprise at least one compound selected from the group consisting of acamprosate, amlexanox, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone and rilmenidine, for use in the treatment of diabetes or a related disorder in a same mammal.
[055] The invention also relates to the use of at least one compound, as listed above, for the production of a medication to treat diabetes or a related disorder in a mammal that needs it.
[056] The invention also relates to a method for treating diabetes or a related disorder in a mammal that needs the same which comprises administering to the mammal at least one compound as listed above.
[057] Illustrative CAS numbers for each of the selected compounds are provided in Table 1 below:
Table 1
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Drug Name CAS number acamprosate 77337-76-9; 77337-73-6 almitrine 27469-53-0; 29608-49-9 amlexanox 68302-57-8; azelastine 58581-89-8; 79307-93-0 baclofen 1134-47-0; 66514-99-6;69308-37-8; 70206-22-3; 63701-564; 63701-55-3 carbetapentane 77-23-6; 23142-01-0; 1045-21-2 cimetidine 51481-61-9; 70059-30-2 cinacalcet 226256-56-0; 364782-34-3 dexbronpheniramine 86-22-6; 980-71-2; 2391-03-9 diethylcarbamazine 90-89-1; 1642-54-2 diprofilin 479-18-5 D-mannose 10030-80-5; 3458-28-4 fenspiride 5053-06-5; 5053-08-7 fexofenadine 83799-24-0; 138452-21-8; 153439-40-8; 139965-10-9; 139965-11-0 idebenone 58186-27-9 ifenprodil 23210-56-2; 23210-58-4 levosimendana 141505-33-1 mexiletine 5370-01-4; 31828-71-4 nicergoline 27848-84-6 piribedil 3605-01-4 rilmenidine 54187-04-1; 85409-38-7 tolfenamic acid 13710-19-5 tolperisone 728-88-1; 3644-61-9 torasemida 56211-40-6; 72810-59-4 triamterene 396-01-0
[058] As mentioned in the examples, the compounds above, when tested individually, are active in improving glucose levels by altering different important glucose homeostasis pathways.
[059] In addition, the inventors surprisingly found that acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicenoline, acid, nicenoline, nicergoline,
25/96 tolperisone, torasemide and triamterene are particularly effective in protecting beta cells against apoptosis, improving glucose uptake by muscle tissues and / or insulin release. Such compounds therefore represent the most preferred embodiment for use in the present invention.
[060] Consequently, the compositions of the invention may comprise 1, 2, 3, 4 or 5 of the above distinct drugs, more preferably, 2, 3 or 4 of the different drugs for combinatorial treatment of diabetes or related disorders in an individual needing the same. In addition, the above drug compositions can also be used in an additional combination with one or more additional drugs or treatments beneficial to individuals suffering from diabetes or a related disorder.
[061] In this regard, a particular objective of the invention relates to a composition for use in the treatment of diabetes or a related disorder, the composition comprising a compound selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene.
[062] The above molecules are preferably used in combination therapies to provide the most effective clinical benefit. Drug combinations are particularly advantageous, as they can reach different pathways and are therefore more effective. In addition, due to their effectiveness and mode of action, drug combinations can be
26/96 used in low dosages, which represents a very substantial additional advantage. Therefore, the most preferred drug compositions comprise 2, 3, 4 or 5 distinct drugs, even more preferably 2, 3 or 4 for combinatorial treatment of diabetes or related disorders in an individual who needs it. In a preferred embodiment, the drugs of the invention are used in combination (s) for combined, separate or sequential administration, in order to provide the most effective effect.
[063] In this regard, a preferred objective of this invention relates to compositions that comprise a combination of at least two compounds chosen from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbromopheniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedyl, levosimendan, cimetidine, diprofilin, idebenone and rilmenidine, as well as the use of such disorders in the treatment of diabetes or in a mammal that needs it.
[064] A more preferred objective of this invention relates to compositions that comprise a combination of at least two compounds selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide and triamterene, as well as the use of such compositions in the treatment of diabetes or a disorder
27/96 related to a mammal that needs them.
[065] An additional object of this invention relates to a composition that comprises:
-at least one compound selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronpheniramine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, torphenone, and tolperone;
-at least one distinct compound that is selected from acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, torethine, torethine, trilin, trilin, trilin, trilin tolfenamic acid, pyribedyl, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder.
[066] Another objective of this invention relates to compositions comprising (i) ifenprodil and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbronfeniramine, diethylcarbamazine, D -Manose, fenspiride, fexofenadine, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such composition in the treatment of diabetes or a related disorder in a mammal that needs it.
[067] An additional objective of this invention is
28/96 refers to compositions comprising (i) acamprosate and (ii) a compound selected from the group consisting of almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedyl, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder in a mammal that needs it.
[068] A particular purpose of this invention relates to compositions comprising (i) azelastine and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D- mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a disorder mammal that needs it.
[069] Another particular objective of this invention relates to compositions comprising (i) torasemide and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronfeniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as
29/96 to the use of such a composition in the treatment of diabetes or a related disorder in a mammal that needs it.
[070] An object of this invention relates to compositions comprising (i) fenspiride and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbronphenphenine, diethylcarbamazine, D -manose, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder in a mammal that needs it.
[071] A particular object of this invention relates to compositions comprising (i) tolfenamic acid and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronfeniramine, diethylcarbamazine , D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder in mammal that needs it.
[072] A particular object of this invention relates to compositions comprising (i) triamterene and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronfeniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine,
30/96 ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder in a mammal that needs it .
[073] Another particular purpose of this invention relates to compositions comprising (i) pyribedyl and (ii) a compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbronfeniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, levosimendan, cimetidine, diprofilin, idebenone or rilmenidine, as well as the use of such a composition in the treatment of diabetes or a related disorder in mammal that needs it.
[074] In a more preferred embodiment, the compositions of this invention comprise at least one of the following drug combinations, for combined, separate or sequential administration:
-ifenprodil and acamprosate,
-ifenprodil and baclofen, -baclofen and acamprosate, -mexylethine and cinacalcet, -mexyletine and torasemide, -sulfisoxazole and torasemide, -azelastine and nicergoline, -idebenone and nicergoline, -carbetapentan and nicergoline, -almitine
31/96
-cimetidine and nicergoline,
-diethylcarbamazine and nicergoline,
-ifenprodil and nicergoline,
-azelastine and idebenone,
-acamprosate and nicergoline,
-azelastine and carbetapentane,
-azelastine and almitrine,
-idebenone and carbetapentane,
-idebenone and almitrine,
-triamterene and nicergoline,
-D-Mannose and nicergoline,
-idebenone and diethylcarbamazine,
-ifenprodil and fenspiride, -ifenprodil and torasemida, -ifenprodil and triamterene, -ifenprodil and tolfenamic acid, -fenspiride and torasemida, -fenspiride and triamterene, -fenspiride and tolfenamic acid, -torasemide and triamterene, -torasemide and tolfenamic acid,
-triamterene and tolfenamic acid, or
-D-mannose and baclofen.
[075] Another objective of this invention relates to the use of a composition, as defined above, to control the level of glucose in the blood or plasma in a mammal that needs it.
[076] An additional objective of this invention relates to the use of a composition, as defined above, for the production of a drug to control the glucose level.
32/96 in the blood or plasma in a mammal that needs it.
[077] An additional object of this invention relates to the use of a composition, as defined above, for the production of a medicament to treat diabetes or a related disorder.
[078] As indicated earlier, in a composition or combination therapy of this invention, the compounds or drugs can be formulated together or separately, and administered together, separately or sequentially.
[079] The invention is particularly adapted to correct dysregulation of glucose levels in human patients suffering from diabetes, pre-diabetes (also known as IGT or IFG), metabolic syndrome, obesity or a cardiovascular disease that implies a predisposition to diabetes.
[080] A further object of the invention is a method for treating diabetes or a related disorder, the method comprising administering simultaneously, separately or sequentially to an individual who requires an effective amount of a drug or combination of drugs as defined above.
[081] In a preferred embodiment, the invention relates to a method for treating diabetes or a related disorder in an individual who needs it, which comprises administering simultaneously, separately or sequentially to the individual an effective amount of at least one of the following combinations of drugs: -ifenprodil and acamprosate, -ifenprodil and baclofen,
33/96
-baclofen and acamprosate,
-mexylethine and cinacalcet,
-mexylethine and torasemide,
-sulfisoxazole and torasemide,
-azelastine and nicergoline,
-idebenone and nicergoline,
-carbetapentane and nicergoline,
-almitrine and nicergoline,
-cimetidine and nicergoline,
-diethylcarbamazine and nicergoline,
-ifenprodil and nicergoline,
-azelastine and idebenone,
-acamprosate and nicergoline,
-azelastine and carbetapentane,
-azelastine and almitrine,
-idebenone and carbetapentane,
-idebenone and almitrine,
-triamterene and nicergoline,
-D-Mannose and nicergoline,
-idebenone and diethylcarbamazine,
-ifenprodil and fenspiride, -ifenprodil and torasemida, -ifenprodil and triamterene, -ifenprodil and tolfenamic acid, -fenspiride and torasemida, -fenspiride and triamterene, -fenspiride and tolfenamic acid, -torasemide and triamterene, -torasemide and tolfenamic acid,
-triamterene and tolfenamic acid, or
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-D-mannose and baclofen.
[082] In a particular embodiment, methods for treating diabetes or a related disorder further comprise a step to measure the blood glucose level in a blood sample from the individual mammal, before and / or after administration of the ) drug (s).
[083] In this sense, an additional objective of the invention is a method to control the level of glucose in the blood, the method comprising the steps of:
1) measure the blood glucose level in a blood sample from an individual mammal,
2) administering to said individual an effective amount of a composition, as shown above.
[084] In the methods of the invention, the step of measuring the level of glucose can be repeated throughout the treatment, for example, to assess or monitor the effectiveness of the treatment and / or to adjust the treatment regimen.
[085] The compositions of the invention typically comprise one or more pharmaceutically acceptable excipients or carriers. In addition, for use in the present invention, drugs or compounds are usually mixed with pharmaceutically acceptable excipients or carriers.
[086] In this regard, an additional objective of this invention is a method for preparing a pharmaceutical composition, wherein the method comprises mixing the above compounds in a suitable excipient or carrier.
[087] According to preferred embodiments of the invention, as indicated above, the compounds are used as such or in the form of a salt, prodrug, metabolite or
35/96 prolonged release formulation of the same pharmaceutically acceptable.
[088] Although they are very effective in vitro and in vivo, depending on the individual or the specific condition, the above combination methods, compositions or therapies can be used additionally together or in combination or in combination with additional drugs or treatments.
[089] Other additional diabetes therapies used in conjunction with drug (s) or drug combination (s) according to the present invention, may comprise one or more drugs that regulate the blood glucose level, a or more drugs used for the treatment of hyperlipidemia or hypercholesterolemia, one or more drugs that could be used, or currently evaluated in clinical trials, to treat diabetes or a related disorder. Preferably, said one or more drugs are selected from acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformine, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, phenylate, dutactoglide, phenylate genfibrozila, gemigliptina, glibenclamide, glibornuride, glicetanil, gliclazida, glimepiride, glipizida, gliquidone, glisentida, gliclopiramide, imidapril, insulin, inulina, lipoico acid, linagliptina, liraglutida, mecobalina, mitobalitida, meclaminina, metlignin, pyridine, metforminamine, metforminamine, metforminine , pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose.
[090] Illustrative CAS numbers for each
36/96 of these compounds are provided in Table 2 below (side effects mainly from Sweetman S (Ed), Martindale: The complete drug reference. London: Pharmaceutical Press. Electronic version, (2011 Edition) and Nathan et al. (2009) [ 9]):
Table 2
Name ofdrug CAS number Side effectspranlintida 196078-30-5 GastrointestinalWeight lossexenatide 141758-74-9 GastrointestinalWeight loss liraglutide 204656-20-2acarbose 56180-94-0 Gastrointestinal miglitol 72432-03-2 voglibose 83480-29-9
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alogliptin 850649-62-6 Upper airway infections berberine 2086-83-1; 633-65-8; 633-6 6- 9 dutogliptin 852329-66-9 gemigliptina 911637-19-9 linagliptin 668270-12-0 saxagliptin 361442-04-8 sitagliptin 654671-78-0 vildagliptin 274901-16-5mitiglinide 145375-43-5 Weight gainCardiovascular complicationsHypolicemia nateglinide 105816-04-4 repaglinide 135062-02-1acetoexamide 968-81-0 Weight gain Cardiovascular complications HypolicemiaLoss of effectiveness with long-term use carbutamide 339-43-5 chlorpropamide 94-20-2 glibenclamide 10238-21-8 glibornuride 26944-48-9 glipizida 29094-61-9 glimepiride 93479-97-1 gliclazide 21187-98-4 gliquidone 33342-05-1 glisentide 32797-92-5 gliclopiramid a 631-27-6 tolbutamide 64-77-7 tolazamide 1156-19-0bezafibrato 41859-67-0 GastrointestinalMyopathy ciprofibrate 52214-84-3 clofibrate 637-07-0; 882-09-7; 3908748-4; 14613- 30-0 fenofibrate 49562-28-9 (fenofibrate);42017-89-0 (acidphenofibric); 856676-23-8
38/96 genf ibrozila | 25812-30-0
39/96
rosiglitazone 122320-73-4; 302543-62-0;155141-29-0; 397263-60-4 Peripheral edema Congestive heart failure pioglitazone 111025-46-8; 112529-15-4buformin 1190-53-0 GastrointestinalLactic acidosis metformin 657-24-9; 1115-70-4 fenformin 834-28-6bromocriptine 22260-51-1 Gastrointestinal complications, hypotension,cardiovascular chromium picolinate 14639-25-9 N / A colesevelam 182815-44-7 Gastrointestinal Hyperchloremic acidosis Increasedconcentrations ofplasma triglyceride dexfenflurami on 3239-44-9 Cardiovascular complications imidapril 89396-94-1 Hypotension Cardiovascular complications Renal impairment Symptoms of the upper respiratory tract Pancreatitis inulin 9005-80-5 N / A lipoic acid 62-46-4 N / A mecobalamin 13422-55-4 N / A orlistat 96829-58-2 Gastrointestinal risk ofliver toxicity
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insulin 9004-10-8; 11070-73-8;12584-58-6; 11061-68-0;8063-29-4; 9004-21-1;68859-20-1; 8049-62-5;53027-39-7; 9004-17-5;116094-23-6; 9004-12-0;51798-72-2; 11091-62-6169148-63-4; 160337-95-1;207748-29-6; 133107-64-9;874442-57-6 Hypolicemia Weight gain
[091] In this sense, an objective of this invention refers to compositions that comprise:
-at least one compound selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbromopheniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, torethine, torethine, trilinone, trilinone, toliletine, torethine, trilinone , tolfenamic acid, pyribedyl, levosimendan, cimetidine, diprofilin, idebenone
and rilmenidine,-fur andleast one compound, selected from the group that cons iste in acarbo if, acetoexamide, alogliptin, berberine, bezafibrato, bromocriptine, buformina, carbutamide, chlorpropamide, picolinate chrome, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, dutogliptin, exenatide, fenofibrate, genfibrozila, gemigliptina, glyburide, glibornuride, glycetanil,
gliclazide, glimepiride, glipizida, gliquidone, glisentide, gliclopyramide, imidapril, insulin, inulin, lipoic acid, linagliptin, liraglutide, mecobalamin, metformin, miglitol, mitiglinide, nateglinide, orlistat, phenformin,
41/96 pioglitazone, pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it. [092] Another preferred objective of this invention relates to compositions comprising (i) a compound selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil , levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, triamterene or torasemide, in combination with (ii) a compound selected from the group consisting of acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformine, carbutamide, chlorpropamide, chlorpropamide chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, dutogliptin, exenatide, fenofibrate, genfibrozila, gemigliptine, glibenclamide, glibornuride, glycetanyl, glylazide, glimepiride, glipizide, glycidine, glycidine, glycidine, glide , liraglutide, mecobalamin, metformin, miglitol, mitiglinide, nateglinide, orl istate, phenformin, pioglitazone, pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
42/96 [093] An even more preferred objective of this invention relates to compositions comprising a compound selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride , ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene, in combination with a compound selected from the group consisting of glibenclamide, repaglinide, metformin and pioglitazone, as well as the use of such compositions in the treatment of diabetes or a related disorder in an individual mammal that needs it.
[094] A very preferred objective of this invention relates to compositions comprising a compound selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan , mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene, in combination with metformin, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
[095] A more preferred objective of this invention relates to compositions comprising (i) at least two compounds selected from the group consisting of acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbromopheniramine, diethylcarbamazine, D- mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedyl, levosimendan,
43/96 cimetidine, diprofilin, idebenone and rilmenidine, and a compound selected from the group consisting of acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformine, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate, clofibrate. dexfenfluramine, dutogliptin, exenatide, fenofibrate, genfibrozil, gemigliptin, glibenclamide, glibornuride, glycetanyl, gliclazide, glimepiride, glipizide, gliquidone, glisentide, glylopyramide, imidapril, insulin, linuline, inulin, insulin, lignin, insulin, linuline, inulin, glucamine , nateglinide, orlistat, phenformin, pioglitazone, pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammal that needs the same mammal .
[096] A more preferred objective of this invention relates to compositions that comprise:
-at least two compounds selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentan, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, torolinone, tolemone, tolsenidone, tolemone, tollenone, tolemone triamterene,
-in combination with a compound selected from the group consisting of acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformin, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, dutogliptine, fenogliptin, exoglide, fenogliptina, exoglycida, fenogliptina, genfibrozila,
44/96 gemigliptin, glibenclamide, glibornuride, glucetanil, gliclazide, glimepiride, glipizide, gliquidone, glisentide, glycopiramide, imidapril, insulin, inulin, lipoic acid, linagliptin, liraglutide, mecobalamin, metformin, mitinigol, mitinitol, miglinitol, mitinitol, metformin, miglinitol, mitinitol, metformin, mitinigolide pioglitazone, pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
[097] An even more preferred objective of this invention relates to compositions comprising at least two compounds selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentan, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide or triamterene, in combination with a compound selected from the group consisting of glibenclamide, repaglinide, metformin and pioglitazone, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it. Another preferred object of this invention relates to compositions comprising at least two compounds selected from the group consisting of acamprosate, almitrine, azelastine, baclofen, carbetapentan, cinacalcet, dexbronpheniramine, diethylcarbamazine, D-mannose, fenspiride, ifenprodiline, levosimendan, mexilet , nicergoline, tolfenamic acid,
45/96 tolperisone, torasemide or triamterene, in combination with a compound selected from the group consisting of bezafibrate, ciprofibrate, clofibrate, genfibrozil, fenofibrate, orlistat, as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
[098] Another preferred objective of this invention relates to compositions comprising baclofen and acamprosate, in combination with a compound selected from the group consisting of pioglitazone, rosiglitazone, bezafibrate, ciprofibrate, clofibrate, fenofibrate, genfibrozil, buformine, colesevelam, orlistate , as well as the use of such compositions in the treatment of diabetes or a related disorder in a mammalian individual who needs it.
[099] A more preferred purpose of this invention relates to compositions comprising metformin in combination with at least one compound from the following combination of compounds: -ifenprodil and acamprosate, -ifenprodil and baclofen, -baclofen and acamprosate, -mexiletine and cinacalcet, -mexylethine and torasemide, -sulfisoxazole and torasemide, -azelastine and nicergoline, -idebenone and nicergoline, -carbetapentan and nicergoline, -almitrine and nicergoline, -cimetidine and nicergoline,
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-diethylcarbamazine and nicergoline,
-ifenprodil and nicergoline,
-azelastine and idebenone,
-acamprosate and nicergoline,
-azelastine and carbetapentane,
-azelastine and almitrine,
-idebenone and carbetapentane,
-idebenone and almitrine,
-triamterene and nicergoline,
-D-Mannose and nicergoline,
-idebenone and diethylcarbamazine,
-ifenprodil and fenspiride, -ifenprodil and torasemida, -ifenprodil and triamterene, -ifenprodil and tolfenamic acid, -fenspiride and torasemida, -fenspiride and triamterene, -fenspiride and tolfenamic acid, -torasemide and triamterene, -torasemide and tolfenamic acid,
-triamterene and tolfenamic acid, or -D-mannose and baclofen.
[0100] Another more preferred objective of this invention concerns the use of such compositions in the treatment of diabetes or a related disorder in an individual
mammal what needs of same. At combinations above that understand one or more drugs gives invention and a drug known listed in the table 2, or an combination of the same, allow an decrease gives dosage of these drugs for the
diabetes treatment. This decrease allows to avoid or
47/96 delay the appearance of known disadvantages of these drugs (Table 2; for example, resistance to treatment that increases over time, weight gain, peripheral edema, renal toxicity due to lactic acidosis).
[0101] As already mentioned, in the combinatory therapies mentioned above, drugs can be administered together or separately, at the same time or sequentially, depending on the specific pharmacokinetic characteristics of each drug in order to produce a combined or synergistic effect in the body.
[0102] The above combinations can also be used in conjunction with any other therapy used to regulate the blood glucose level; such therapy may be, more particularly, the well-known diabetes-specific diet (rich in dietary fiber, low in fat, low in sugar), natural supplementation such as extracts or part of Cinnamonum cassia, moringa, ginseng, gymnema, aloe vera , walnut leaf, myrcia, garlic, leafy Grifola, Reishi, Agaricus blazei, Agrocibe cylindracea, Cordyceps, agrimony, alfalfa, coriander, eucalyptus, juniper, as well as trace elements such as chromium, vanadium, magnesium or zinc.
[0103] The therapy, according to the invention, can be provided at home, in the doctor's office, in a clinic, in a hospital outpatient clinic or in a hospital, so that it is possible to observe the effects of therapy up close and do any adjustments that are needed as a function of the measured blood glucose level.
[0104] The duration of therapy depends on the stage of the disease being treated, the age and condition of the patient and how the patient responds to treatment. Dosage,
The frequency and mode of administration of the drugs or each component of the drug combinations of the invention can be controlled independently. For example, a drug of a combination can be administered orally, while the second drug can be administered intramuscularly or at different times throughout the day. Drugs can also be formulated together in such a way that one administration releases all drugs.
[0105] The treatment of the invention can be administered during particular periods of the day, for example, at the moment or before or just after the moment when the glucose concentration reaches its peak in the plasma. Blood glucose can be easily determined, even by the patients themselves, with the use of different commercially available glucometers. The timing and dosage of treatment can therefore be adapted as a function of the measured blood glucose. If there is a sequential administration, the administration may be dependent on the concentration of glucose in the blood, for example, the first active ingredient is administered before the peak of glucose, while the other is administered after the peak of glucose. Usually, the glucose concentration reaches its peak in an individual's plasma after meals.
[010 6] The administration of each drug in the combination can occur by any suitable means that results in a concentration of the drug that, combined with another component, is capable of controlling blood glucose levels.
[0107] Although it is possible that the drug or drugs in the combination are administered as an element
49/96 pure chemical, it is preferable to present them as a pharmaceutical composition, also called, in this context, as a pharmaceutical formulation. Possible compositions include those suitable for oral, rectal, topical (including transdermal, buccal and sublingual), or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
[0108] Most commonly, these pharmaceutical formulations are prescribed to the patient in patient kits containing several unit doses or other means for administering unit doses measured for use during a different treatment period in a single package, usually a portfolio of pills from blister type. Patient kits have an advantage over traditional prescriptions, in which a pharmacist divides a patient's reserve from a pharmaceutical element from a batch reserve, a sense that the patient always has access to the package insert contained in the patient kit, which is normally absent in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the doctor's instructions. Thus, the invention also includes a pharmaceutical formulation, as in the present document described above, in combination with packaging material suitable for said formulations. In such a patient kit, the intended use of a formulation for the combination treatment can be inferred from the instructions, facilities, provisions, adaptations and / or other means to assist in using the formulation in the most appropriate way possible for the treatment. Such measures make a patient kit specifically suitable and adapted for use for the
50/96 treatment with the compositions of the present invention.
[0109] The drug can be contained, in any suitable amount, in any suitable carrier substance. The drug can be present in an amount of up to 99% by weight of the total weight of the composition. The composition can be supplied in a pharmaceutical form that is suitable for oral, parenteral (for example, intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalation, dermatological (patch) or ocular administration. Thus, the composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels, including hydrogels, pastes, ointments, creams, plasters, splashes, osmotic release device, suppositories, enemas, injectables, implants, sprays or aerosols.
[0110] The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington. The Science and Practice of Pharmacy (20th ed), ed AR Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia. of Pharmaceutical Technology, eds J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).
[0111] Pharmaceutical compositions, according to the invention, can be formulated to release the active drug substantially immediately upon administration or at any predetermined time or period of time after administration.
[0112] Controlled release formulations include (i) formulations that create a substantially constant concentration of the drug (s) in the body throughout
51/96 of an extended period of time; (ii) formulations that, after a predetermined time variability, create a substantially constant concentration of the drug (s) in the body over an extended period of time; (iii) formulations that prolong the action of the drug (s) for a predetermined period of time maintaining a relatively constant effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the substance the active drug; (iv) formulations that localize the action of the drug (s) by, for example, spatial positioning of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that direct the action of the drug (s) with the use of carriers or chemical derivatives to release the drug to a particular type of target cell.
[0113] The administration of drugs in the form of a controlled release formulation is especially preferred in cases where the drug has (i) a narrow therapeutic index (ie, the difference between the plasma concentration that results in harmful side effects or toxic reactions and the plasma concentration that results in a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio between the median lethal dose (LD50) and the median effective dose (ED50)); (ii) a narrow absorption window in the gastrointestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to keep the plasma level at a therapeutic level.
[0114] Any one among several strategies
52/96 can be performed in order to obtain controlled release in which the rate of release exceeds the rate of metabolism of the drug in question. Controlled release can be achieved by the proper selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings. Then, the drug is formulated with suitable excipients in a pharmaceutical composition that, upon administration, releases the drug in a controlled manner (single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, adhesives and liposomes).
Solid dosage form for oral use [0115] Formulations for oral use include tablets containing the composition of the invention in a mixture with non-toxic pharmaceutically acceptable excipients. Such excipients can be, for example, inert diluents or fillers (for example, sucrose, microcrystalline cellulose, starches, including potato starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (for example, cellulose derivatives, including microcrystalline cellulose, starches, including potato starch, croscarmellose sodium, alginates or alginic acid); binding agents (for example, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricating, sliding and anti-adhesive agents (eg acid
53/96 stearic, silica or talc). Other pharmaceutically acceptable excipients can be dyes, flavoring agents, plasticizers, humectants, buffering agents and the like.
[0116] The tablets may be uncoated or may be coated by known techniques, optionally to slow down disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. The coating can be adapted to release the active drug substance in a predetermined pattern (for example, to achieve a controlled release formulation) or it can be adapted to not release the active drug substance until after it has passed through the stomach (coating enteric). The coating may be a sugar coating, a film coating (for example, based on hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and / or polyvinylpyrrolidone), or an enteric coating (for example, based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, shellac and / or ethyl cellulose). A retarding material, such as glyceryl monostearate or glyceryl distearate, can be employed.
[0117] Solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (eg degradation
54/96 chemical prior to the release of the active drug substance). The coating can be applied in solid pharmaceutical form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology.
[0118] Drugs can be mixed in the tablet or can be divided. For example, a first drug is contained within the tablet and a second drug is outside it, such that a substantial portion of the second drug is released before the first drug is released.
[0119] Formulations for oral use can also be presented as chewable tablets or as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (eg potato starch, microcrystalline cellulose, calcium carbonate, phosphate calcium or kaolin), or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, for example, liquid paraffin or olive oil. Powders and granules can be prepared using the ingredients mentioned above in tablets and capsules in a conventional manner.
[0120] Controlled-release compositions for oral use can, for example, be constructed to release the active drug by controlling the dissolution and / or diffusion of the active drug substance.
[0121] Controlled release from dissolution or diffusion can be achieved by adequately coating a drug formulation in a tablet, capsule, pellet or granulate, or by incorporating the drug in a suitable matrix. A controlled release coating can
55/96 include one or more of the coating substances mentioned above and / or, for example, shellac, beeswax, glucose wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate glycerol, glycerol palmitostearate, ethylcellulose, acrylic resins, di-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethylacrylate, hydrogels, 1,3 , ethylene glycol methacrylate and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material can also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride , polyethylene and / or halogenated fluorocarbon.
[0122] A controlled-release composition containing one or more of the drugs in the claimed combinations may also be in the form of a floating tablet or capsule (i.e., a tablet or capsule that, upon oral administration, floats on top of the gastric contents for a certain period of time). A floating tablet formulation of the drug (s) can be prepared by granulating a mixture of the drug (s) with excipients and 20 to 75% w / w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. The granules obtained can then be compressed into tablets. Upon contact with gastric juice, the tablet forms a gel barrier substantially
56/96 water impermeable around its surface. This gel barrier participates in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in gastric juice.
Liquids for oral administration [0123] Powders, dispersible powders or granules suitable for preparing an aqueous suspension by adding water are convenient dosage forms for oral administration. The formulation as a suspension provides the active ingredient in a mixture with a wetting or dispersing agent, suspending agent and one or more preservatives. Suitable suspending agents are, for example, sodium carboxymethyl cellulose, methyl cellulose, sodium alginate and the like.
Parenteral compositions [0124] The pharmaceutical composition can also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous or similar) in dosage forms, formulations or by means of suitable delivery devices or implants containing carriers and adjuvants conventional non-toxic pharmaceutically acceptable. The formulation and preparation of such compositions are well known to those skilled in the pharmaceutical formulation art.
[0125] Compositions for parenteral use can be supplied in unit dosage forms (for example, in single dose ampoules) or in vials containing several doses and in which a suitable preservative can be added (see below). The composition can be in the form of a solution, a suspension, an emulsion, a
57/96 infusion or a delivery device for implantation or may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. In addition to the active drug (s), the composition may include suitable parenterally acceptable carriers and / or excipients. The active drug (s) can be incorporated into microspheres, microcapsules, nanoparticles, liposomes or the like for controlled release. The composition can include suspending, solubilizing, stabilizing, pH adjusting and / or dispersing agents.
[0126] The pharmaceutical compositions according to the invention can be in the form suitable for sterile injection. To prepare such a composition, the appropriate active drug (s) is (are) dissolved or suspended in a parenterally acceptable liquid carrier. Among these acceptable vehicles and solvents that can be used are water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic solution of sodium chloride. The aqueous formulation can also contain one or more preservatives (for example, methyl, ethyl or n-propyl phydroxybenzoate). In cases where one of the drugs is only sparingly or slightly soluble in water, a dissolution enhancing or solubilizing agent may be added, or the solvent may include 10 to 60% w / w propylene glycol or the like.
[0127] Parenteral controlled-release compositions may be in the form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions or emulsions. So
58/96 alternative, the active drug (s) can be incorporated in biocompatible carriers, liposomes, nanoparticles, implants or infusion devices. Materials for use in the preparation of microspheres and / or microcapsules are, for example, biodegradable / bioerodible polymers, such as polygalactin, poly (isobutyl cyanoacrylate), poly- (2-hydroxyethyl-Lglutamine). The biocompatible carriers that can be used when formulating a controlled release parenteral formulation are carbohydrates (eg, dextrans), proteins (eg, albumin), lipoproteins or antibodies. Materials for use in implants can be non-biodegradable (for example, polydimethyl siloxane) or biodegradable (for example, poly (caprolactone), poly (glycolic acid) or poly (orthoesters)).
Alternative routes [0128] Although less preferred and less convenient, other routes of administration and, therefore, other formulations can be contemplated. Accordingly, for rectal application, dosage forms suitable for a composition include suppositories (emulsion or suspension type) and rectal gelatin capsules (solutions or suspensions). In a typical suppository formulation, the active drug (s) is (are) combined with a suitable pharmaceutically acceptable suppository base, such as cocoa butter, esterified fatty acids, glycerin gelatin and various bases dispersible or soluble in water, such as polyethylene glycols. Various additives, enhancers or surfactants can be incorporated.
[0129] Pharmaceutical compositions can also
59/96 be administered topically to the skin for percutaneous absorption in dosage forms or formulations that conventionally contain non-toxic pharmaceutically acceptable carriers and excipients, including microspheres and liposomes. The formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters and other types of transdermal drug delivery systems. Pharmaceutically acceptable excipients or carriers can include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes and skin protecting agents.
[0130] Preservatives, humectants and penetration enhancers can be parabens, such as methyl or propyl phydroxybenzoate and benzalkonium chloride, glycerin, propylene glycol, urea, etc.
[0131] The pharmaceutical compositions described above for topical administration to the skin can also be used in conjunction with topical administration on or near the part of the body that is to be treated. The compositions can be adapted for direct application or for application by means of special drug delivery devices, such as dressings or, alternatively, plasters, pads, sponges, strips or other forms of suitable flexible material. Dosages and duration of treatment [0132] The composition, according to the invention, is administered to an individual orally or by subcutaneous, intravenous or intramuscular injections, in different
60/96 times of the day, to change the blood glucose level. When carrying out this process, in which it is desired to modify, regulate or normalize a mammal's blood glucose level, to treat diabetes or a related disorder, or both, the composition of the invention is administered in a dosage amount sufficient to alter , regulate or normalize the individual's blood glucose level. The composition of the invention can be administered to a mammal, particularly a human being, who has an abnormal blood glucose level, at a particular time of day, for example, at the moment or just before or just after the moment when the glucose concentration reaches its peak in plasma. The blood glucose level of the mammal depends on the time of day and is cyclical. The blood glucose level rises and falls at different times of the day, preferably depending on the timing of meals and physical activities / exercises. Usually, the glucose concentration reaches its peak in the plasma of an individual after meals, therefore, the composition of the invention can, for example, preferably be administered from 2 hours before meals to 2 hours after meals, more preferably, from one hour before meals to one hour after meals and, even more preferably, during meals to achieve maximum therapeutic effectiveness.
[0133] It will be appreciated that the drugs in the combination can be administered concomitantly, in the same pharmaceutical formulation or in a different pharmaceutical formulation or sequentially. A minimum requirement for a combination, according to this description, is that the combination must be intended for use combined with the
61/96 benefit from the effective effect of the combination of the active ingredients. The intended use of a combination can be inferred by facilities, provisions, adaptations and / or other means to assist in the use of the combination, according to the invention.
[0134] Therapeutically effective amounts of drugs in a combination of this invention include, for example, amounts that are effective in controlling blood or plasma glucose levels.
[0135] Administration can occur from one to several times a day for several days to several years and can occur even for the entire life of the patient. Chronic or at least periodically repeated long-term administration is indicated in most cases.
[0136] The term unitary dosage form refers to physically discrete units (such as loaded capsules, tablets or syringe cylinders) suitable as unitary dosages for human subjects, each unit containing a predetermined amount of the active material or materials calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
[0137] The amount of each drug in a preferred unit dosage composition depends on several factors, including the method of administration, the patient's body weight and age, the stage of the disease, the risk of potential side effects considering the general health status of the person to be treated. Additionally, pharmacogenomic information (the effect of the genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapy) about a particular patient can affect the dosage
62/96 used.
[0138] Except when it is necessary to respond to specially compromised glucose levels, where higher dosages may be required, the preferred dosage of each drug in the combination will usually be in the dose range not exceeding the dosage usually prescribed for long-term maintenance treatment. or that has been proven to be safe in phase 3 of clinical studies.
[0139] A notable advantage of the invention is that each compound can be used in low doses in a combination therapy, while producing, in combination, a substantial clinical benefit for the patient. Combination therapy may, in fact, be effective at doses where the compounds individually have a low or no effect. Consequently, a particular advantage of the invention relates to the ability to use sub-ideal doses of each compound, that is, doses that are lower than the therapeutic doses usually prescribed, preferably 1/2 of the therapeutic doses, more preferably, 1/3, 1 / 4, 1/5, or, even more preferably, 1/10 of the therapeutic doses. In particular examples, doses of at least 1/20, 1/30, 1/50, 1/100, or even lower, therapeutic doses are used.
[0140] At such subtherapeutic dosages, the compounds would exhibit no or less side effects, while the combinations, according to the invention, are fully effective in controlling blood or plasma glucose levels.
[0141] A preferred dosage corresponds to quantities of 1% to 50% of those usually prescribed
63/96 for long-term maintenance treatment.
[0142] The most preferred dosage can correspond to the amounts of 1% up to 10% of those usually prescribed for long-term maintenance treatment.
[0143] Specific examples of drug dosages for use in the invention are provided below:
- Acamprosate orally from about 9 to 200 mg per day,
- Almitrine orally of about 0.5 to 10 mg per day,
- Amlexanox orally from about 0.75 to 15 mg per day,
- Azelastine orally from about 0.04 to 0.4 mg per day,
- Baclofen orally from about 0.15 to 50 mg per day,
- Carbetapentane orally from about 0.6 to 18 mg per day,
- Cimetidine orally from about 4 to 160 mg per day,
- Cinacalcet orally from about 0.3 to 36 mg per day,
- D-mannose orally from 0.01 to 1.6 g per day,
- Dexbronpheniramine orally from about 0.06 to 1.2 mg per day,
- Diethylcarbamazine orally from about 0.6 to 600 mg per day,
- Diprofilin orally from about 9 to 320 mg daily
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- Fenspiride orally from 1.6 to 24 mg per day,
- Fexofenadine orally from 1.2 to 18 mg daily,
- Idebenone orally from about 4.5 mg to 225 mg per day,
- Ifenprodil orally from about 0.4 to 6 mg per day,
- Levosimendan orally from about 0.05 to 4 mg daily,
- Metformin orally from about 1 mg to 2.5 mg per day,
- Mexiletine orally from about 6 to 120 mg per day,
- Nicergoline orally from about 0.6 to 6 mg per day,
- Piribedil orally from about 0.8 to 25 mg per day,
- Rilmenidine orally from about 10 to 200 pg per day,
- Tolperisone orally of about 1.5 to 4.5 mg per day,
- Tolfenamic acid orally of about 3 to 60 mg per day,
- Torasemide orally from about 0.05 to 4 mg per day,
- Triamterene orally from about 1.5 to 25 mg per day, [0144] In combinations of the invention, the molar ratio between drugs can vary, for example, from 0.001 to 1000. In addition, the ratio of the drug (s) ( s) and excipient in a composition of the invention advantageously vary between 0.001 and
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1000.
[0145] It will be understood that the amount of the drug actually administered will be determined by a doctor, in the light of the relevant circumstances, including the condition or conditions to be treated, the exact composition to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the chosen route of administration. Therefore, the above dosage ranges are intended to provide general guidance and support for the teachings of this document, however, they are not intended to limit the scope of the invention.
[0146] The following examples are given for illustrative purposes and not for limitation.
EXAMPLES [0147] Diabetes is a metabolic disease that profoundly affects energy homeostasis and the high plasma glucose level seen in patients can have multiple causes. Type 1 diabetes is characterized by the destruction of β cells in the islets of Langerhans. Type 2 diabetes is characterized, in part, by a decrease in insulin production by pancreatic β cells, a progressive death of β cells, resistance to insulin (that is, less glucose capture by muscle cells and adipocytes), or an increase in abnormal hepatic gluconeogenesis. Thus, the determination of the effectiveness of candidate compounds is based on several in vitro and in vivo studies in order to solve most of the metabolic and physiological impairments that characterize this complex pathology. The drugs were first tested individually, then by tests of their action
6/96 combinatory. The activity of the drug is determined in several models that illustrate different physiological characteristics representative of an abnormal blood glucose level, such as those involved in diabetes or related disorders. 1. IN VITRO STUDIES
1.1 Prevention of beta cell apoptosis [0148] The drugs of the invention have been tested for their effectiveness in protecting beta cells from apoptosis. Such an activity would be considered useful for type 1 diabetes as well as type 2 diabetes. Cell culture and medium [0149] Pancreatic beta cells INS-1 were selected for this study. The cells are cultured in complete medium, RPMI 1640 with 10 mM glucose, supplemented with 1 mM sodium pyruvate, 50 μΜ of 2-mercaptoethanol, 2 mM glutamine, 10 mM HEPES, 100 lU / ml penicillin, 100 pg / ml streptomycin and 10% heat-inactivated fetal bovine serum (FCS), as described by Asfari et al. (23). INS-1 cells are plated (4.5 x 10 ⁴ cells / well) on 96-well poly-ornithine coated plates and cultured at 37 ° C in a humidified atmosphere of 95% air / 5% CO2. The next day, the cells are pre-incubated with the tested molecules for 1 hour. Then, after a change of medium, the cells are cultured for 24 hours in a medium containing the tested molecules and 30 mM glucose, 0.05 mM mistyric acid, INF 25 ng / ml, TNF 25 ng / ml and IL 5 ng / ml.
Quantification of apoptosis [0150] The effectiveness of compounds to prevent apoptosis is then assessed by the apoptosis detection kit
67/96 highly specific to Chemicon (Ref. APT225). This procedure is based on the detection of single-stranded DNA (ssDNA), which is a specific marker of apoptotic cells (24).
[0151] Results are expressed in arbitrary optical density unit (OD) and% reduction in apoptosis induced by apoptotic condition. After a Dunnett t test, all compounds that show a significant decrease in% of apoptotic cells compared to the apoptotic control condition are considered to be active. Results [0152] The results are shown in figure 1 and table 3 and demonstrate that the drugs of the invention, when tested by themselves, induce a substantial protective effect against apoptosis of beta cells. In figure 1, D-mannose induces significant and complete protection of beta cells against apoptosis compared to an untreated cell under apoptotic conditions. D-mannose provides more than 129% protection against apoptosis. Similarly, Table 3 shows the percentage of protection afforded by the drugs of the invention.
Table 3
Drugs Percentage of apoptosis reduction D-mannose 129% Mexiletine 74% Tolperisone 78% Baclofen 84% Cinacalcet 167% Dexbronpheniramine 76%
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Diethylcarbamazine 44% Nicergolina 112% Torasemida 67% Trianterene 64% Almitrina 103% Azelastine 81% Acamprosate 49% Carbetapentane 103% Ifenprodil 54% Levosimendana 118%
1.2 Insulin secretion in response to glucose stimulus
Cell culture and medium [0153] Pancreatic INS-1 beta cells were selected because they are insulin secretion profiles in response to glucose and other physiological or pharmacological insulin secretagogues, such as sulfonylureas and GLP-1. The cells are cultured in complete medium, RPMI 1640 with 10 mM glucose, supplemented with 1 mM sodium pyruvate, 50 μΜ of 2-mercaptoethanol, 2 mM glutamine, 10 mM HEPES, 100 lU / ml penicillin, 100 pg / ml streptomycin and 10% heat-inactivated fetal bovine serum (FCS), as described by Asfari et al. (23). For the insulin secretion assay, INS-1 cells are plated (4.5 x 10 ⁴ cells / well) and cultured on 96-well poly-ornithine coated plates. After 3 days of culture at 37 ° C in a humidified atmosphere of 95% air / 5% CO2, the medium is removed and the cells are cultured for 16 hours in a medium containing 5 mM glucose, 1% FCS ( and the drugs tested for
9/96 long-term evaluation).
[0154] On the day of the insulin secretion test, cells are washed with Krebs-Ringer Bicarbonate buffer with HEPES (KRBH; pH 7.4) at 0.1% Bovine Serum Albumin (BSA) and pre-incubated for 30 minutes at 37 ° C in KRBH 0.1% BSA containing 2.8 mM glucose.
[0155] The cells are washed again with KRBH and are incubated for 1 hour in KRBH 0.1% BSA containing 3.5 mM glucose and the tested molecules. Supernatants are collected for insulin determination and measurement of lactate dehydrogenase (LDH) activity.
Insulin quantification [0156] Insulin concentration in collected supernatants is measured by an ELISA kit according to the manufacturer's recommendations and using an anti-rat insulin antibody (Alpco Long Range Rat Insulin ELISA, Category No. 80-INSRTH-E10). Very briefly, mouse monoclonal antibodies specific for insulin are immobilized on 96-well plates. Standards, samples and controls are added to the appropriate wells with a monoclonal antibody labeled with horseradish peroxidase (Conjugate). After incubation, the microplates are washed to remove unbound conjugate and a TMB Substrate solution is added to react with the bound conjugate. Finally, after adding a stop solution, the optical density is measured at 450 nm using a reference wavelength of 620 nm. The intensity of the yellow color is directly proportional to the amount of insulin in the samples.
[0157]
The effectiveness of drugs is demonstrated
70/96 by assessing the amount of insulin (expressed in pmol / 1) secreted in the absence or presence of drugs of the invention in the medium.
Results [0158] The drugs of the invention induce an insulin secretion in response to the glucose stimulus. For example, figures 2 and 3 show that triamterene (10 μΜ, + 37%) and cinacalcet (1 μΜ, +55%), respectively, can significantly improve insulin secretion in response to glucose stimulation after a short-term or long-term incubation, respectively.
1.3 Uptake of glucose in muscles or adipocytes
1.3.1 Glucose uptake in mouse muscle cells [0159] The drugs of the invention were tested in several models for insulin resistance. The glucose uptake enhancement capabilities of compositions of the invention were measured in muscle cells and in adipocytes under normal or pathological conditions. Depending on the culture conditions, muscle cells exhibit continuous mitosis or, alternatively, present terminal differentiation in myotubes.
Media and cell culture [0160] H-2Kb mouse muscle cells are cultured for 4 days in 24-well plates coated with matrigel at a density of 0.8 x 10 cells / well spb permissive conditions (33 ° C in a humidified atmosphere) hoisted 95% air / 10% CO2; DMEM with glucose 5.5 mM supplemented with 20% FCS, 10% horse serum, 2% glutamine, 0.5% chicken embryo, 20
71/96 mU / ml mouse INFy, 100 U / ml penicillin and 100 pg / ml streptomycin), as previously described by Fryer et al. (25). For differentiation into myoblasts, cells are switched to non-permissive culture conditions (37 ° C in a humidified atmosphere of 95% air / 5% CO2; DMEM with 5.5 mM D-glucose supplemented with 2% FCS, 10% horse serum, 2% glutamine, 1% chicken embryo, 100 U / ml penicillin and 100 pg / ml streptomycin).
Glucose uptake [0161] For the long-term effect assessment, the day before the glucose uptake assay, cells are incubated in DMEM with 5.5 mM D-glucose supplemented with 10% horse serum, 2% SVF, 1% chicken embryo, 2% glutamine in the presence of the tested molecules for 16 hours. The next day, and before the test, the cells are washed and incubated in the presence of the tested molecules for an additional 4 hours, in a serum-free medium (DMEM) containing 5.5 mM D-glucose.
[0162] For the short-term effect assessment, 4 hours before the glucose test, the cells are washed and incubated in a serum-free medium (DMEM) containing 5.5 mM D-glucose and the tested molecules. Glucose uptake is then measured by incubating the cells for 5 to 10 minutes with radiolabelled 2-deoxy-D- [1,2 ³ H] -glucose in Krebs-Ringer buffer with HEPES (KRBH; pH 7.4) fraction V of 0.1% Bovine Serum Albumin (BSA) (Sigma_ A-4503). The uptake of glucose is interrupted by two washing steps in cold 0.9% NaCl. Then, the cells are solubilized in 0.1 N NaOH for 30 minutes. The radioactivity associated with the cell is then counted and the protein quantification is
72/96 determined using the Lowry colorimetric method. Glucose uptake is estimated by measuring the radioactivity incorporated into the cells by a MicroBeta counter after adding 600 μΐ per scintillant well (Optiphase SuperMix3).
[0163] Protein quantification is performed by a colorimetric assay derived from the Lowry method.
[0164] Results are expressed in nmol of incorporated glucose / 5 m / mg protein and in% of baseline or control condition (100%). Results [0165] The drugs of the invention, tested by themselves, can enhance glucose uptake in muscle cells. For example, Figures 4, 5 and 6 show that glucose uptake by H-2Kb muscle cells is significantly improved after short-term incubation with acamprosate (0.1 μΜ, +45%) and almitrine (1 μΜ, +80 %) or after long-term incubation with nicergoline (10 μΜ, +28%), respectively, compared to untreated muscle cells.
1.3.2 Glucose uptake in primary cultures of human diabetic myotubes [0166] In order to obtain a model that better reflects diabetic pathological conditions, the efficiency of drugs in improving glucose uptake in diabetic myotubes was tested. In fact, it has been shown that the diabetic phenotype is conserved in myotubes established from diabetic individuals. Media and cell culture [0167] The myotubes of a diabetic patient
73/96 were grown in HAM's FIO-based media (Sigma, ref. N6908) supplemented with 15% fetal bovine serum, 1 mM glutamine.
[0168]
The myoblast was seeded at 380000 cells / well in 12-well plates. After 2 days of proliferation, the cells were placed in reduced serum conditions (2% horse serum) to induce differentiation. Myotubes were used after 5 days of differentiation.
[0169]
Eagle-based media modified by
Dulbecco (DMEM) (Gibco, ref. 31053-028) was supplemented with 2% heat-inactivated horse serum, 2% Glutamax (Gibco, 35050) and washed for glucose uptake assays. The compounds were dissolved in DMSO to achieve the desired final concentration before use.
[0170]
Differentiated myotubes were treated for 24 hours with the compositions of the invention, before testing.
Glucose uptake assay [0171]
Before the initiation of glucose uptake, the cells were devoid of serum and glucose. A deprivation was first performed in DMEM media that contain reduced glucose (1 g / 1) and no serum. After adding the compounds in the desired concentrations, the cells were incubated at 37 ° C for 2h30. Insulin control allows measurement of glucose uptake induction via the insulin pathway. Insulin treatment (100 nM) was carried out for 30 minutes at 37 ° C. A subsequent deprivation of glucose and serum was performed in HBS buffer at 37 ° C for 2 hours. The cells were treated with a
74/96 mixture of 2- [ ³ H] 10 Ci / mM deoxyglucose + 10 μΜ 2-deoxy-D-glucose for 30 minutes. The cells were rinsed twice with 1 ml of cold PBS. Lysis was carried out in 500 µl of 0.05 N NaOH for 20 minutes. Cell Uses were transferred to scintillation vials for radioactivity measurement with a MicroBeta counter.
Results [0172] The compositions of the invention can improve glucose uptake in human primary myotubes. For example, figures 13, 14, 15, 16 and 17 show that glucose uptake in diabetic myotubes is improved after pre-incubation with torasemide (+24%, 18%, respectively, at 0.01 μΜ and 0, 1 μΜ p <0.01; and +14% to 1 pM p <0.05), fenspiride (+34%, +30%, respectively, to 0.01 pM and 0.1 μΜ p <0.01; and +27% at 1 μΜ, p <0.05), tolfenamic acid (+13%, +13% and +12%, respectively, at 0.01 μΜ, 0.1 μΜ and 1 μΜ, p <0, 05), ifenprodil (+48% at 0.01 μΜ, p = 0.07; and improves at 0.1 pM and 1 μΜ) and triamterene (0.01 μΜ, +13%, p <0.05).
1.3.3 Glucose uptake in 3T3-L1 adipocyte cells [0173] 3T3-L1 cells are fibroblasts that, under suitable conditions, differentiate into adipocyte-like cells. These cells are used to show that compositions of the invention increase glucose uptake in adipocytes, compared to controls.
Differentiation and cell culture [0174] 3T3-L1 pre-adipocyte cells were cultured in DMEM containing 1% penicillin-streptomycin (PS) and 10% fetal bovine serum at 37 ° C in an atmosphere of 5% CO ₂ . To induce differentiation,
75/96 2-day post-confluent pre-adipocytes were cultured in MDI differentiating medium I (DMEM containing 1% PS, 10% FBS, 0.5 mM IBMX, 1 μΜ dexamethasone, 0.5 pg / ml insulin) for 2 days. Differentiation, as measured by the expression of adipogenic markers and the appearance of lipid droplets, usually reaches a conclusion between days 4 and 8.
Glucose uptake assay [0175] Glucose uptake activity was analyzed by measuring radiolabeled uptake of glucose. Differentiated 3T3-L1 adipocytes grown in 12-well plates were washed twice with serum-free DMEM and incubated for 2 hours at 37 ° C with 1 ml of DMEM containing 0.1% BSA. The cells were washed three times with Krebs-Ringer-HEPES (KRH) buffer (20 mM HEPES, pH 7.4, 136 mM NaCl, 4.7 mM KCl, 1.2 5 mM MgSO4, 1.25 mM CaC12, 2 mg / ml of bovine serum albumin) and incubated at 37 ° C for 30 minutes with 0.9 ml of KRH buffer.
[0176] The cells were then incubated with or without drugs for different durations in order to evaluate their short-term and long-term effects.
[0177] In order to evaluate their short-term effect, the cells were incubated with drugs of the invention for 4 hours at 37 ° C. To assess the long-term effect of the drugs of the invention, the day before the test, the cells were pre-incubated with or without drugs for 16 hours. The next day, and before the test, the cells were washed and incubated in the presence of the tested molecules for an additional 4 hours.
[0178]
Glucose uptake was initiated by
76/96 addition of 0.1 ml of KRH buffer containing 2-deoxy-D- [ ³ H] glucose (37 MBq / 1) and glucose (1 mM). After 20 minutes, glucose uptake was completed by washing the cells three times with cold PBS. The cells were used by incubation for 20 minutes at 37 ° C with 0.7 ml of Triton X100. The level of radioactivity in the cell's Users was determined using a scintillation counter.
[0179] Protein quantification was performed by a colorimetric assay derived from the LOWRY method.
[0180] The results are expressed in nmol of glucose incorporated / 5 m / mg of protein and in% of baseline or control condition (100%).
Results [0181] The drugs of the invention can improve glucose uptake in adipocytes. For example, figures 7, 12 and 8 show that glucose uptake by differentiated 3T3-L1 adipocyte cells can be improved after short-term incubation with carbetapentan (0.1 μΜ, +58%) and pyribedyl (10 nM, +68%) or after long-term incubation with almitrine (1 μΜ, +69%), respectively.
1.3.4 Glucose uptake in differentiated insulin-resistant 3T3-L1 adipocytes induced by TNFa [0182] In order to assess the capabilities of the drugs of the invention to improve glucose uptake by adipocytes under insulin resistant conditions, the cells were pre- treated by TNF-α. Upon exposure to TNF-a, a decrease in glucose uptake in response to insulin is expected. In contrast, an increase in glucose uptake in response to insulin is expected after treatment of 3T3-L1 cells with TNF-α and acetylsalicylic acid (control
77/96 positive).
Differentiation and cell culture [0183] The 3T3L1 fibroblasts were maintained in DMEM, with 4.5 g / l glucose, supplemented with 5% fetal serum donor, 5% newborn calf serum, 100 U / ml penicillin and 100 pg / ml streptomycin at 37 ° C in an atmosphere of 10% CO2. The cells were grown in 24-well plates at a density of 2560 cells / well in 0.5 ml growth medium (DMEM with 4.5 g / l glucose supplemented with 10% FCS, 100 U / ml penicillin and 100 pg / ml streptomycin). Five days after plating (90% confluence), induction of adipocyte differentiation was performed in DMEM, with 4.5 g / l glucose, which contains 10% FBS, IBMX 100 μΜ, dexamethasone 0.25 μΜ and 170 nM insulin. Two days later, the induction medium was removed and changed by DMEM, with 4.5 g / l of glucose, which contains 10% FBS and 170 nM insulin. The fresh medium was replaced after two days. Three days later, the adipocytes were incubated overnight in a fasting medium (DMEM, with 4.5 g / l glucose, containing 0.2 SVF, 100 U / ml penicillin, 100 pg / ml of The cells were then treated with H2O or 5 ng / ml of mouse TNF-α (Peprotech, 400-14) for 48 hours in DMEM, with 4.5 g / l of glucose, which contains 10% FBS The medium was refreshed each day Glucose uptake was tested in different conditions: adipocytes were treated for an additional 24 hours with 0ml% DMSO with or without 5 ng / ml TNF-α, or with 5 ng / ml TNF-α and 5 mM acetylsalicylic acid, or with 5 ng / ml TNF-α and 100 nM insulin, or compounds tested with 5 ng / ml TNF-α in the presence or absence of insulin (100 nM), as described below.
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Glucose uptake assay [0184] Glucose uptake was measured by incorporated radiolabelled glucose quantification, after an incubation step with 2-deoxy-D [1,2 ³ H] -glucose for 5 minutes. Glucose uptake was interrupted by two washing steps in ice-cold PBS IX. Then, they were solubilized in 0.1 N NaOH for 30 minutes. The radioactivity associated with the cell was counted, then, using a MicroBeta counter after adding 600 μΐ per well of scintillant (Optiphase SuperMix3).
[0185] In parallel, protein quantification was determined by a colorimetric assay derived from the LOWRY method. The results are expressed in nmol of glucose incorporated / 5 m / mg of protein and in% of baseline or control condition (100%).
[0186] In order to assess cell viability, a measurement of LDH activity was performed on supernatants using a UV method with the commercial kit (ABS for LDH IFCC CP, ref. A11A01871). Very briefly, LDH reduces NAD + to NADH by oxidation of lactate to pyruvate. The produced NADH were evaluated by measuring the absorbance at 340 nm. The amount of NADH produced is proportional to the amount of LDH released into the culture medium as a result of cytotoxicity. Cell viability results are expressed as% of baseline or control (100%).
Results [0187] The drugs of the invention, tested by themselves, improve glucose uptake in adipocytes under conditions that mimic insulin resistance. For example, figures 18, 19, 20 and 21 show that glucose uptake
79/96 by TNF-α induced insulin-resistant 3T3-L1 adipocytes is significantly improved after long-term incubation with torasemide (+121% to 0.37 nM, p <0.05; +123% and +129% , respectively, at 1 nM and 3.3 nM, p <0.01), ifenprodil (+ 140% at 1 μΜ, p <0.01; and improves at 10 nM and 100 nM, not shown), fenspiride (+ 130% at 1 nM, p <0.01; and improves at 0.37 nM and 3.3 nM, not shown) and tolfenamic acid (+127% at 10 nM, p <0.01; and improves at 100 nM and 1 μΜ, not shown).
[0188] The results in section 1.3 show that the drugs of the invention are efficient in improving glucose uptake in normal muscle cells and adipocytes, as well as in conditions that mimic insulin resistance.
1.4 Glucose production by liver cells Differentiation and cell culture [0189] Hepatocytes are isolated from male Wistar rats for 24 hours (200 to 250 g of body weight) by ex situ liver perfusion in the presence of collagenase. Cell viability is validated by an trypan blue exclusion test. The cells are then suspended in William's medium supplemented with insulin and seeded in six well plates (8 10 ⁵ cells / well) and incubated at 37 ° C in a humidified atmosphere of 95% air / 5% CO2. After plating, the medium is removed and the cells are cultured for 16 hours in RPMI medium without glucose (supplemented with the drugs tested for long-term evaluation). The next day, the liver glucose production test is evaluated in Krebs-Ringer Bicarbonate buffer with HEPES (KRBH; pH 7.4) in the presence of neoglycogenic substrates (10 mM lactate and 1 mM pyruvate) and the molecules are tested for 4 hours (short term).
80/96
Glucose quantification [0190] Supernatants are collected and glucose concentrations are determined using a Glucose Oxidase kit (Instrumentation Laboratory 0018250840). In parallel, protein quantification is performed using the Colorimetric Lowry method.
[0191] Results are expressed in nmol of glucose / mg of protein and% of control condition (KLP: KRBH containing lactate and pyruvate).
Results [0192] The drugs of the invention, tested by themselves, can decrease the production of glucose by liver cells. For example, Figures 9, 10 and 11 show that glucose production by hepatocytes is significantly reduced after a short-term treatment with D-mannose (10 μΜ, -22%) or after a long-term treatment with ifenprodil (0 , 01 μΜ, -22%) or Azelastine (10 μΜ, -36%).
1.5 Isolated organs
1.5.1 Insulin and glucagon secretion in isolated Langerhans islets [0193] Isolated islets incubated with a range of glucose concentrations show a dose-dependent pattern of insulin release. Thus, the use of isolated islets is a physiological way of investigating the effects of candidate compounds as initiators and enhancers of insulin secretion.
Tissue preparation [0194] The rats are anesthetized by intraperitoneal (ip) ketamine / xilasin injection. The peritoneal cavity is exposed and the main pancreatic duct for the intestine is
81/96 arrested. The pancreas is then cannulated through the common bile duct, distended with collagenase and removed. The islets are extracted, washed and passed through a sterile stainless steel screen before being centrifuged. The islets are then cleaned and placed in CMRL medium containing 2 mM glutamine, 10% fetal bovine serum and 1% antibiotic / antimycotic solution and placed in a culture chamber at 37 ° C containing 5% CO2. Islet perfusion [0195] The islets are pre-incubated for 90 minutes in RPMI 1640 medium containing 10% FBS and 3 mM glucose at 37 ° C with 5% CO2. The islets of treated and control groups are then incubated in the glucose perfusion system with a constant flow rate (500 μΙ / m) at 37 ° C for 90 minutes. They are placed for 30 minutes at baseline (3 mM glucose), for 30 minutes in a concentrated medium with a high glucose content (20 mM) and finally for 30 minutes again at baseline (3 mM glucose). Throughout the perfusion, the medium samples are collected from the outlet fraction and frozen at -80 ° C. At the end of the infusion, the islets are collected and frozen at -80 ° C. The total protein in the islets is extracted with acid ethanol (0.18 M HCI in 95% ethanol). Quantifications of intracellular insulin and glucagon or released in the collected output fractions are performed by ELISA.
1.5.2 Glucose uptake in isolated muscles Muscle incubation procedure [0196] The removed epitrochlear muscles are incubated at 29 ° C for 50 minutes in 3 ml of continuously aerated pre-incubation medium (95% O2, 5% CO2),
82/96 which consists of Krebs-Henselheit bicarbonate buffer (KHB), 8 mM glucose, 32 mM mannitol and 0.1% bovine serum albumin (BSA). After pre-incubation, the muscle is transferred to another flask and incubated at 29 ° C for 10 minutes in 3 ml of continuously aerated washing medium, which consists of KHB, 2 mM pyruvate, 38 mM and 0.1 mannitol % BSA.
[0197] Finally, the muscle is incubated at 29 ° C for 20 minutes in 3 ml of uptake medium, which consists of KHB, 2 mM pyruvate, 6 mM glucose and 32 mM mannitol, 0.1% BSA, with or without 280 pCi / mmol of [ ³ H] 2-deoxyglucose (2-DG) and 10 pCi / mmol [ ¹⁴ C] -manitol and the desired treatment.
[0198] Immediately after incubation, the muscles are briefly stained in gauze moistened with 0.9% saline and subjected to rapid freeze (freeze clamp) in liquid nitrogen.
Glucose uptake measurements by muscle [0199] Glucose uptake is calculated from the rate of incorporation of 2-DG into muscle fibers during the 20 minutes of incubation in the uptake medium. The frozen muscle samples are digested in 1 ml of 1M KOH at 60 ° C for 20 minutes. The muscle homogenates are neutralized with 1 ml of 1 M HCI and 300 μΐ are added in a scintillation cocktail. Duplicate samples are counted to ³ H and ¹⁴ C on an LS-6000 liquid scintillation spectrophotometer.
[0200] The uptake of 2-DG by the muscle is calculated as the difference between total 2-DG in the muscle and 2DG in the extracellular space. The concentration of 2-DG in the extracellular space is determined by the amount of [ ¹⁴ C] -manitol in the tissue.
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1.5.3 Isolated perfused liver glucose production [0201] The model of the isolated perfused rat model allows the study of direct effects on the intact organ without the influence of extrahepatic hormones and other systemic changes in metabolic flows.
Tissue preparation [0202] Rats are anesthetized by ip injection of thiopental (50 mg / kg). The hemoglobin-free non-recirculating infusion is performed. After cannulation of the portal and vena cava veins, the liver is placed in a Plexiglass chamber. The perfusion fluid is a Krebs / Henseleit-bicarbonate buffer (pH 7.4), saturated with a mixture of oxygen and carbon dioxide (95: 5) by means of a membrane oxygenator with simultaneous temperature adjustment at 37 ° C . The flow, provided by a peristaltic pump, is between 30 and 33 ml / m. Candidate compounds or the vehicle are added to the perfusion fluid after supplementing the Krebs / Henseleitbicarbonate buffer with fatty acid free bovine serum albumin to ensure the total dissolution of the drugs. For all drug concentrations, the molar ratio of albumin / drug was 2.4.
[0203] The cell viability of the perfused liver is judged both from the rates of oxygen uptake and from the leakage of perfusion fluid from its surface. Livers are discarded when the oxygen uptake drops to 0.7 pmol min ¹ g ¹ or when the surface fluid leakage exceeds 2.5% of the portal flow. The samples of the effluent perfusion fluid are collected and analyzed for their metabolite content. The
84/96 following compounds are tested using standard enzyme procedures: glucose, lactate and pyruvate. The oxygen concentration in the effluxing perfusate is continuously monitored, using a Teflon-protected platinum electrode properly positioned in a Plexiglass chamber at the perfusate outlet. Metabolic rates are calculated from differences in input-output and total flow rates and refer to the wet weight of the liver.
1.6 Summary of results [0204] Table 4 joins the results that were obtained in all models previously described (see points 1.1 to 1.5 above). A value is assigned to each candidate compound depending on its effect on different in vitro models compared to the vehicle. The results are normalized and weighted in order to generate a relative performance value for each candidate compound. A high value reflects the high potential of the compound for normalizing the glucose level and, therefore, a significant efficacy for controlling glucose levels and / or for the treatment of diabetes or related disorders.
Table 4
Drug Name Relative performance value acamprosate 15 almitrine 38 azelastine 30 baclofen 16 carbetapentane 33 cimetidine 31 cinacalcet 32
85/96
Drug Name Relative performance value dexbromopheniramine 21 diethylcarbamazine 32 diprofilin 11 D-mannose 18 idebenone 53 ifenprodil 28 levosimendana 20 mexiletine 10 nicergoline 40 piribedil 24 tolfenamic acid 9 tolperisone 19 torasemida 16 triamterene 18 rilmenidine 16
[0205] The effectiveness of drug combinations of the invention is also evaluated in the above in vitro models. The protocol used in these tests is the same as that described in section 1 above. The drug combinations listed in Table 5 below show a particularly high relative performance value (determined as above).
Results:
[0206] All drug combinations detailed in Table 5 have resulted in an overall positive effect for normalizing the blood glucose level, and are therefore considered to be effective in the treatment of diabetes.
Table 5
86/96
Drug combinations with high relative value Effectiveness in diabetes Ifenprodil and acamprosate + Ifenprodil and baclofen + baclofen and acamprosate + mexiletine and cinacalcet + mexiletine and torasemide + sulfisoxazole and torasemide + azelastine and nicergoline + idebenone and nicergoline + carbetapentane and nicergoline + almitrine and nicergoline + cimetidine and nicergoline + diethylcarbamazine and nicergoline + ifenprodil and nicergoline + azelastine and idebenone + acamprosate and nicergoline + azelastine and carbetapentane + azelastine and almitrine + idebenone and carbetapentane + idebenone and almitrine + triamterene and nicergoline + D-mannose and nicergoline + idebenone and diethylcarbamazine + baclofen and D-mannose + baclofen and metformin + D-mannose and metformin + baclofen and D-mannose and metformin + ifenprodil and fenspiride + ifenprodil and torasemide +
87/96
ifenprodil and triamterene + ifenprodil and tolfenamic acid + fenspiride and torasemide + fenspiride and triamterene + fenspiride and tolfenamic acid + torasemide and triamterene + torasemide and tolfenamic acid + triamterene and tolfenamic acid + metformin and ifenprodil and fenspiride + metformin and ifenprodil and torasemide + metformin and ifenprodil and triamterene + metformin and ifenprodil and tolfenamic acid + metformin and fenspiride and torasemide + metformin and fenspiride and triamterene + metformin and fenspiride and tolfenamic acid + metformin and torasemide and triamterene + metformin and torasemide and tolfenamic acid + metformin and triamterene and tolfenamic acid +
. IN VIVO STUDIES
2.1 Anti-inflammatory effect of combinations in
88/96 Zucker Obese and Diabetic (ZDF) mouse model [0207] The efficacy of drug compositions of the invention comprising the compound (s) of Tables 4 and 5 is confirmed in the Zucker Obese and Diabetic mouse model ( ZDF). The Obese and Diabetic Zucker Rat (ZDF) is an accurate model for type 2 diabetes based on impaired glucose tolerance caused by the inherited obesity genetic mutation that leads to insulin resistance. The fa mutation, which occurs in ZDF mice, results in a shortened leptin receptor protein, which does not interact effectively with leptin. This mutation is phenotypically expressed as obesity with high levels of normal leptin in the blood.
[0208] Inflammation is known to play a role in the etiology of type 2 diabetes and metabolic syndrome. High abnormal plasma levels of C-reactive protein (CRP) are associated with diabetes and metabolic syndrome. ZDF mice were used to study the effect of compositions of the invention on inflammatory components of type 2 diabetes. ZDF mice show an increased plasma CRP level.
Chronic management and treatment [0209] The rats were housed individually and maintained at 22 +/- 2 ° C in a 12-hour light / dark cycle. The animals had access to food (Purina 5008) and water ad libitum. While one group received the vehicle, the other groups were treated with the candidate compounds listed in tables 5 and 6 for 4 weeks. The administrations were carried out twice a day orally.
Blood samples [0210] Blood samples were obtained from
89/96 from the topically anesthetized tails of fasting rats overnight in all groups.
Plasma CRP level measurement [0211] The plasma CRP concentration of all mice (standard mice, vehicle and baclofen-acamprosate-treated ZDF mice) was measured by an ELISA kit according to the manufacturer's recommendations (ref. Millipore CYT294). The Mouse C-Reactive Protein (CRP) kit is a polyclonal antibody double sandwich (EIA) enzyme immunoassay, which measures the mouse CRP. Standards, quality controls and plasma samples were incubated for 30 minutes in microtiter wells coated with polyclonal anti-rat CRP antibody. After a thorough wash, the horseradish peroxidase-labeled anti-rat CRP antibody (HRP) was added to the wells and incubated for 30 minutes with the immobilized antibody-CRP complex. After another washing step, the remaining HRP-conjugated antibody was allowed to react with the substrate and with tetramethylbenzidine (TMB). The reaction (5 to 10 minutes) was stopped by adding an acid solution, and the absorbance of the resulting yellow product was measured spectrophotometrically at 450 nm. The absorbance is proportional to the concentration of CRP. A standard curve was constructed by plotting absorbance values versus standard CRP concentrations, and concentrations of unknown samples were determined using this standard curve.
Results [0212] The compositions of the invention are efficient in reducing the concentration of CRP in the plasma of ZDF rats. Per
90/96 example, figure 22 shows that the CRP concentration is significantly reduced by treatment with acamprosate and baclofen (7.5 mg / kg and 0.5 mg / kg, respectively) compared to vehicle-treated ZDF rats, and reaches the CRP level of standard mice. Those results suggest a systemic anti-inflammatory effect of combinations of the invention.
2.2 Glucose homeostasis control in a db / db mouse model [0213] The mouse of the db / db strain, deficient in leptin receptor, is a well-known and characterized mouse model used to evaluate compounds targeting diabetes. The db / + heterozygous mouse was used as a control.
Acclimation and pre-study periods [0214] 85 mice (8 weeks old, 75 db / db and 10 db / +) were obtained from Janvier (France). The animals were housed in 28 ventilated cages (530 cm ² x 20 cm) throughout the experimental phase. The animals' beds were renewed twice a week. Small devices were placed in the cages to enrich the environment (mouse housings and cellulose plugs). The mice were housed in groups of 2 animals with a normal 12-hour light cycle (the lights are turned off at 7 pm), 22 ± 2 ° C and 55 ± 10% relative humidity. The mice had at least 14 days of acclimatization during which the mice were fed a standard feed R04 diet (SAFE Augy, France) and had free access to water.
[0215] After 12 days of acclimatization and 2 days (OD) before the start of treatments, all mice were
91/96 weighed and fasted for 6 hours from 8 am to 2 pm. Subsequently, body weight was measured daily throughout the study.
[0216] Blood (200 μΙ / EDTA) was collected from the retrobulbar sinus under anesthesia with isoflurane. Plasma glucose and plasma insulin were quantified using enzymatic and immunoenzymatic methods respectively in order to randomize the animals into homogeneous groups.
[0217] On Day 0, just before gavage, a drop of blood was collected from the tail vein to measure blood glucose without fasting using a glucometer (SmartCheck®).
Test groups [0218] The mice were allocated to groups according to their body weight and fasting blood glucose (N = 8 mice / group):
-Standard controls (db / + mice) treated with vehicle (per os, twice daily).
- Obese negative controls (db / db mice) treated with vehicle (per os, twice a day).
- Positive obese controls (db / db mice) treated with metformin at 300 mg / kg (per os, once daily).
-Obese animals (db / db mice) treated with compounds or compositions of the invention.
Treatment [0219] The duration of the treatment study was 6 weeks. The mice were treated twice a day at 8 am and at 4 pm by gavage with vehicle, reference compound or PXT compounds in relation to the following ratio: 10 ml / kg of
92/96 dosage (up to 20 ml / kg / day max).
[0220] The gavage volumes were individually adjusted to the body weight recorded in the morning.
[0221] During the treatment period, food and water consumption was monitored and recorded. Food intake was measured and recorded daily (difference between two consecutive days). The average food intake expressed as grams of food consumed per animal per day was attributed to all mice in the cage considered. Water intake was assessed twice a week using the same method.
[0222] Once a week, on Days D7, D13, D21, D27, D35 and D41, just before the gavage, a drop of blood was collected from the tail vein to measure blood glucose without fasting with use glucometer (SmartCheck®).
[0223] On Days D14, D28 and D42, the food was removed at 8 am. Blood (200 μΙ / EDTA) was collected from the retrobulbar sinus under anesthesia at 14 h (after 6 hours of fasting) to measure fasting plasma glucose.
Glucose quantification [0224] The plasma glucose concentration was determined by a colorimetric method based on the enzymatic oxidation of glucose in the presence of glucose oxidase. The hydrogen peroxide produced reacts with phenol and 4amophenazone in a reaction catalyzed by peroxidase to form a red-violet quinoneimine dye as an indicator. The final color intensity is directly proportional to the glucose concentration and was measured at 505 nm.
Results
93/96 [0225] The compositions of the invention reduce the plasma glucose of db / db mice as soon as the treatment D28 arrives (not shown). Figure 23 shows that at D42, the glucose concentration is significantly reduced by administering a combination of D-mannose (5 mg / kg), (RS) -baclofen (6 mg / kg) and metformin (150 mg / kg ) compared to animals that received the vehicle (p <0.001).
[0226] Notably, drugs, when used alone, do not induce any significant decrease in blood glucose. Most notably, the compounds of the invention can be considered as potent enhancers
of treatments currently known to diabetes, thus allowing the dosage reduction and so, a decrease in Side effects.REFERENCESvan Belle, T.L., K.T. Coppieters, and M.G. von
Herrath, Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev, 2011. 91 (1): p. 79 to
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4. Boden, G., Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes, 1997. 46 (1): p. 3 to 10.
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6/9 6 immunosorbent assay (ELISA) for the specific detection of apoptotic cells and its application to rapid drug screening. J Immunol Methods 253: 133 to 144 (2001)
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权利要求:
Claims (5)
[1]
1. COMPOSITION characterized by comprising ifenprodil or fenspiride, or salt (s), prodrug (s), derivative (s) or prolonged release formulation (s), for use in the treatment of diabetes or a selected related disorder from impaired glucose tolerance, impaired fasting glucose, insulin resistance, metabolic syndrome, post-pandrial hyperglycemia and overweight / obesity in a mammalian individual who needs it.
[2]
2. COMPOSITION for use, according to claim 1, characterized in that said composition additionally comprises at least one distinct compound selected from acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentan, cinacalcet, dexbromopheniramine, diethylcarbamazine, D-mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, pyribedil, levosimendan, cimetidine, diprofilin, idebenone and rilmenidine, or salt (is), prodrug (s), or derivative (s), or derivative prolonged release (s).
[3]
3. COMPOSITION for use according to claim 2, characterized in that at least one distinct compound is selected from acamprosate, almitrine, azelastine, baclofen, carbetapentane, cinacalcet, dexbronphenphenine, diethylcarbamazine, D-mannose, fenspiride, ifenprodil, levosimendan, levosimendan , mexiletine, nicergoline, tolfenamic acid, tolperisone, torasemide and triamterene, or salt (s), prodrug (s), derivative (s) or prolonged release formulation (s).
2/5
4. The composition for use in accordance with any one of re Claims 1 to 2, characterized by said compositioncombinationsor comprise at least one of the following compounds:ifenprodil and acamprosate,ifenprodil and baclofen,ifenprodil and nicergoline,ifenprodil and fenspiride,ifenprodil and torasemide,fenspiride and triamterene,fenspiride and tolfenamic acid,torasemide and torasemide,fenspiride and triamterene,fenspiride and tolfenamic acid,salt (s), prodrug (s), derivative (s) or
prolonged release formulation (s).
COMPOSITION for use according to any one of claims 1 to 4, characterized in that it additionally comprises at least one antidiabetic agent.
6. COMPOSITION for use, according to claim 5, characterized in that at least one additional antidiabetic agent is selected from acarbose, acetoexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformin, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramina, dutogliptina, exenatide, fenofibrato, genfibrozila, gemigliptina, glibenclamide, glibornuride, glyetanil, gliclazide, glimepiride, glipizida, gliquidone, glisentide, glycyridine, acid, lipid, insulin, lipopride, lime, acid
3/5 metformin, miglitol, mitiglinide, nateglinide, orlistat, phenformin, pioglitazone, pranlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin or voglibose, or (s), derivative (s), s (), s or prolonged release formulation (s).
7. COMPOSITION for use, according to claim 5, characterized in that at least one additional antidiabetic agent is metformin or salt (s), prodrug (s), derivative (s) or prolonged release formulation (s) thereof.
8. COMPOSITION for use according to claim 7, characterized in that said composition comprises at least one of the following combinations of compounds:
- ifenprodil and metformin,
- fenspiride and metformin,
- ifenprodil and acamprosate and metformin,
- ifenprodil and baclofen and metformin,
- ifenprodil and nicergoline and metformin,
- ifenprodil and fenspiride and metformin,
- ifenprodil and torasemide and metformin,
- ifenprodil and triamterene and metformin,
- ifenprodil and tolfenamic acid and metformin,
- fenspiride and torasemide and metformin,
- fenspiride and triamterene and metformin,
- fenspiride and tolfenamic acid and metformin, or salt (s), prodrug (s), derivative (s) or prolonged release formulation (s).
9. COMPOSITION for use, according to any
[4]
4/5 of claims 1 to 8, characterized in that it is for controlling the blood glucose level in a mammalian individual who needs it.
10. COMPOSITION according to claim 9, characterized by the individual mammal suffering from diabetes or a related disorder selected from impaired glucose tolerance, impaired fasting glucose, insulin resistance, metabolic syndrome, post-pandrial hyperglycemia and overweight /obesity
11. COMPOSITION for use according to any one of claims 1 to 10, characterized in that the compound (s) increase (s) or stimulate (s) glucose uptake in adipocytes and / or muscle cells in said individual mammal.
12. COMPOSITION for use according to any one of claims 1 to 10, characterized in that the compound (s) increase (s) or stimulate (s) glucose uptake in adipocytes and / or muscle cells in said individual mammal.
13. COMPOSITION for use according to any one of claims 1 to 8, characterized in that it is for decreasing insulin resistance in an individual mammal that needs it.
14. COMPOSITION for use, according to claims 1, 9 and 13, characterized by the individual suffering from type 2 diabetes.
COMPOSITION for use according to any one of claims 1 to 14, characterized in that it further comprises a pharmaceutically acceptable carrier or excipient.
[5]
5/5
16. COMPOSITION for use according to any one of claims 1 to 15, characterized in that the compounds in said composition are formulated or administered together, separately or sequentially.
17. COMPOSITION for use according to any one of claims 1 to 16, characterized in that said composition is administered repeatedly to the individual.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-02-12| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2019-12-03| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

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2019-12-17| B11N| Dismissal: publication cancelled [chapter 11.14 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 11.2 NA RPI NO 2552 DE 03/12/2019 POR TER SIDO INDEVIDA. |

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2019-12-24| B15I| Others concerning applications: loss of priority|Free format text: PERDA DA PRIORIDADE US61/720,156, DE 30/10/2012, REIVINDICADA NO PCT/EP2013/072728, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9279, DE 14/05/1996 (LPI), ART. 16,7O. ESTA PERDA SE DEU PELO FATO DE O DEPOSITANTE CONSTANTE DA PETICAO DE REQUERIMENTO DO REFERIDO PEDIDO PCT SER DISTINTO DAQUELE QUE DEPOSITOU A PRIORIDADE REIVINDICADA, NAO TER SIDO APRESENTADO DOCUMENTO COMPROBATORIO DE CESSAO, NEM TER ENCAMINHADO RESPOSTA A EXIGENCIA PUBLICADA NA RPI 2542, DE 24/09/2019, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9279 DE 14/05/1996 (LPI), ART. 16,6O, ITEM 27, E NO ART. 2 DA RESOLUCAO INPI-PR 179/2017. |

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2020-09-15| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-10| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 7A ANUIDADE. |

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2021-01-05| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

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2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201261720156P| true| 2012-10-30|2012-10-30|

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EP12306354.7A|EP2727587A1|2012-10-30|2012-10-30|Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level|

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PCT/EP2013/072728|WO2014068007A1|2012-10-30|2013-10-30|Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level|

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