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    • 专利摘要:
    Use of a melatonin agonist to induce beige adipocytes in white adipose tissue. The present invention relates to the use of ramelteon for the treatment of diseases or pathological conditions by browning white fat. The induction of beige adipocytes in white adipose tissue is useful for the treatment of diseases or pathological conditions such as obesity, diabetes and diabesity (obesity and diabetes), nephropathy and neuropathic diabetes, metabolic syndrome, neurodegenerative diseases, atherosclerosis, steatosis (fatty liver), so that the invention is also related to the use of ramelteon in the treatment of said diseases and, in general, in the treatment of any disease or pathological condition directly related to weight gain and obesity, and in particular to the central obesity. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2711808A1
    申请号:ES201731282
    申请日:2017-11-02
    公开日:2019-05-07
    发明作者:Abdalla Mhmad Ahmad Agil
    申请人:Universidad de Granada；
    IPC主号:
    专利说明:

    [0001]
    [0002] USE OF A MELATONINE AGONIST TO INDUCE THE INDUCTION OF BEIGE ADIPOCITS IN THE WHITE ADIPOSE TISSUE
    [0003]
    [0004] TECHNICAL SECTOR
    [0005]
    [0006] The present invention fits in general in the medical and pharmaceutical field. Specifically, the invention describes the use of a melatonin agonist, called ramelteon, to induce the differentiation and / or transformation of white adipose tissue into beige-type brown adipose tissue as a treatment against diseases such as obesity and diabetes.
    [0007]
    [0008] STATE OF THE ART
    [0009]
    [0010] Today, obesity is treated with a healthy lifestyle, although this usually does not work for most people. In addition, there are no drugs that are safe and effective, so, generally, doctors recommend reducing energy consumption (diet) and force the expenditure of energy, mainly by doing more physical activity to increase caloric expenditure.
    [0011] The caloric expenditure can be classified into two types: Modifiable and not modifiable
    [0012] The non-modifiable expense is related to the basal metabolism, and refers to the consumption of energy to maintain the vital functions of the organs. This basal metabolic rate can not be modified (it is constitutive) and in the case of sedentary people comes to assume up to 80% of the daily caloric expenditure.
    [0013]
    [0014] On the other hand, the modifiable expense is the caloric expenditure that can be controlled, usually to lose weight, and is composed of three components:
    [0015] 1) The caloric expenditure induced by the intake supposes 10-20% of the caloric expenditure. It has 2 components, the one related to the cellular work of the digestion, absorption and storage of nutrients and the one related to the action of specific components of the diet and to the mere caloric intake to balance a possible excess (adaptive function), partially executed by the thermogenic adipose tissue.
    [0016] 2) The heat expenditure induced by exposure to cold. It is the adaptive or facultative thermogenesis to maintain constant body temperature in homeothermic (or endothermic) animals, such as birds and mammals. It has 2 subcomponents, which operate sequentially, depending on the intensity of the thermal descent. In humans, the moderate decrease of the pericorporal ambient temperature from 22-26 ° C (thermomeutral zone, where the extra metabolism to maintain constant body temperature is zero) to 15 ° C, sets in motion the adaptive thermogenesis to the cold not associated to the trembling that is considered caused by the activation of thermogenic fat. The decrease of the environmental Ta below 10 to 5 ° C triggers, in addition to the activation of thermogenic fat, the involuntary muscular contraction induced by the cold (shivering).
    [0017] 3) The item of heat expenditure induced by voluntary physical activity is the greatest opportunity to increase the caloric expenditure, from 5% of the total caloric expenditure in very sedentary people, reaching up to 2 to 3 times the total expenditure, in trained athletes
    [0018]
    [0019] Thus, while the excess of white adipocytes is stored as triglycerides, and therefore contributes to obesity and consequently to the increase in metabolic risk or cardiovascular diseases, there are other tissues, of darker coloration (coloration due to the increase of mitochondria, cytochrome co to iron) called brown or brown adipose tissue (TAM) and beige adipose tissue, which are considered fat burners to generate heat (thermogenic tissues), since both, brown and beige, selectively express the mitochondrial uncoupling protein ( UCP1, "Uncouplingproteinone" or thermogenin) that causes the tissue to increase the rate of mitochondrial oxidation, which causes a deviation of the chemical energy from the generation of ATP to the production of heat, that is, generating heat by thermogenesis not associated to tremor.
    [0020]
    [0021] The interest in TAM has increased in recent years due to the discovery of a third type of fat cells called "beige" cells (in English "brite", of "brown-in-white"), similar to brown adipocytes, which are present in subcutaneous white adipose tissue, both in animals and humans, which have structural and functional properties similar to those of brown adipocytes [Melatonin and metabolic regulation: a review. M Navarro-Alarcon, Blanca-Herrera MR, Ruiz-Ojeda FJ, Mohamad-Akeel-Serrano M, Acuna Castroviejo D, Fernandez-Vazquez G; Agil A. FoodFunct., 2014. 5 (2806-2832), 2806].
    [0022] [Roman S, Agil A, Peran M, Alvaro-Galue E, Ruiz-Ojeda FG, Marchal JA. Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders. Translational Research. (2015). 165 (4): 464-79]. The white adipose tissue (TAB) regions containing these beige cells (also referred to as "beige adipocytes") are also referred to as "beige deposits" of white adipose tissue.
    [0023] The transformation of white adipose tissue into beige adipose tissue, called " browning", can be induced both in animals and in humans by physiological stimuli such as exposure to cold, which increases adrenergic tone; or by exercise, which selectively increases the passage of white adipose tissue to beige thanks to irisin, a myocin generated during exercise. In addition, strategies that are not based on the practice of physical exercise to stimulate thermogenesis, are having a renewed interest today to treat obesity.
    [0024]
    [0025] The presence and importance of beige fat in adult humans was demonstrated in 2009 in 3 articles from different groups published in The New England Journal of Medicine [Cypess M et al. Identification and importance of BAT in adult humans. NEJM 2009; 360: 1509-1517; Virtanen K. A. et al. N Engl J Med 2009; 360: 1518-25; Virtanen K. A. et al. N Engl J Med 2009; 360: 1518-25]. For this they used high technology, fusion image techniques that achieve the fusion of PET and CT images simultaneously. This technique, CT-PET, provides both functional and precise structural information: computed tomography (CT) provides accurate structural information, while positron emission tomography (PET) provides functional information, using radiotracers such as 18F-fluorodeoxyglucose (18F) -FDG) to measure the metabolic activity of different regions of the body. Thus, by means of CT-PET, the presence of beige fat can be identified in healthy adults, located in the supraclavicular, cervical, paravertebral, perirenal and para-aortic regions. In addition, this fat is functionally active due to exposure to cold (its capacity to absorb glucose is observed using PET 18 Fluor).
    [0026]
    [0027] In these articles it was confirmed that beige cells are the only adipocytes that induce a thermogenic response to exercise, cold and natural components, opening a new range of opportunities to face this problem [Saito M et al. Food Ingredients as Anti-Obesity Agents. Trends Endocrinol Metab. 201526 (11): 585-7].
    [0028]
    [0029] Cypress et al [Cell metabolism, 21, 33-44 6, 2015] describe how pharmacological stimulations by drugs acting on the p3-adrenergic receptor and by prostaglandins can induce the transformation of white adipose tissue in brown, although it has not yet been tested in humans due to the danger of the adverse effects they present.
    [0030] Through the use of vitamin A and its derivatives this induction can be achieved, although it should be noted that vitamin A and its bioactive metabolite, retinoic acid (AR) and the effects of all RA derivatives (ATRA) have shown powerful capacity as Inducers of UCP1 expression in white adipocytes, by their induction of beige adipose tissue and the activation of brown tissue in mouse models, but the induction of the UCP1 gene expression in human adipocytes could not be demonstrated [Murholm et al. . BMC CellBiology 2013, 14:41].
    [0031]
    [0032] Non-pungent capsaicin analogues (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. That is, it only increases energy expenditure in subjects who have brown adipose tissue, so they do not cause this effect in people, such as obese subjects, who do not have brown adipose tissue [Yoneshiro T et al. Am J ClinNutr 2012; 95: 845-50].
    [0033]
    [0034] Use of melatonin to induce the transformation of TAB in TAM
    [0035] It is also described in the state of the art that oral hypnotic drugs containing melatonin convert white inguinal fat into beige fat and cause a weight loss. In addition, our group has previously shown that melatonin has the effect of transforming white fat into beige in a diabetic and obese rat model [Jimenez-Aranda A, Fernandez-Vazquez G, Campos D, Tassi M, Velasco-Perez L, Tan DX , Reiter RJ, Agil A. Melatonin induces browning of inguinal White adipose tissue in Zucker diabetic fatty rats. J Pineal Res. 2013.55 (4): 416-23]. These results show how the administration of a high dose of melatonin by oral route (10 mg / kg of body weight / day for 6 weeks) causes this effect in diabetic and obese rats and also acts as a thermogenic agent (inducing beige cells in white adipose tissue).
    [0036]
    [0037] Although there are several hypnotic drugs used for the treatment of insomnia that are agonists of melatonin receptors (MT1 and MT2), there is still no medication to transform white fat into brown in the pharmaceutical market, so it is useful to provide new drugs or compositions capable of inducing this transformation in order to treat diseases or pathological conditions.
    [0038] BRIEF DESCRIPTION OF THE INVENTION
    [0039]
    [0040] The present invention describes the use of ramelteon, a selective agonist of melatonin receptors (MT1 and MT2), to induce the browning of white adipose tissue.
    [0041]
    [0042] Although the expected technical effects of its administration should be similar to those produced with melatonin, the effects obtained using ramelteon were surprisingly better when using a much lower dose than necessary in the case of melatonin (of order 1: 100). In addition, the administration of ramelteon by the sublingual route has been shown to be more effective in avoiding the effect of the first step, such as hepatic metabolism, with which there is no reduction in the bioavailability of ramelteon.
    [0043]
    [0044] Thus, in a first aspect, the invention relates to the use of ramelteon for the treatment of diseases or pathological conditions by browning of white fat (or transformation of white adipose tissue (TAB) in beige adipose tissue by the induction of beige adipocytes in the TAB.
    [0045]
    [0046] The induction of brown fat is useful for the treatment of diseases or pathological conditions such as obesity, diabetes and diabesity (obesity and diabetes), nephropathy and neuropathic diabetes, metabolic syndrome, neurodegenerative diseases, atherosclerosis, steatosis (fatty liver), so that invention is also related to the use of ramelteon in the treatment of said diseases and, in general, in the treatment of any disease or pathological condition directly related to weight gain and obesity, and in particular to central obesity (also referred to as "Abdominal obesity", "visceral obesity" or "android obesity").
    [0047]
    [0048] In the case of diabetes, the treatment of central obesity may be fundamental for its treatment, since central obesity is related to the excess weight of visceral white fat, which in turn is proinflammatory and may increase resistance to obesity. insulin in the peripheral tissues and the failure of the beta cells that are the origin of diabetes.
    [0049]
    [0050] In a further aspect, the invention describes the use of ramelteon or pharmaceutical compositions comprising it, as a medicament or for the manufacture of a medicament for inducing the browning of white adipose tissue.
    [0051] The invention also describes a pharmaceutical composition, comprising ramelteon, to induce the generation of beige adipose tissue. Also described are preparations or combination compositions comprising ramelteon and another active ingredient to induce the generation of beige adipose tissue.
    [0052]
    [0053] In a further aspect, the invention is related to a method of treating diseases or pathological conditions by induction of the transformation of white adipose tissue into beige adipose tissue comprising the administration of ramelteon to the patient.
    [0054]
    [0055] BRIEF DESCRIPTION OF THE FIGURES
    [0056]
    [0057] Figure 1. Photographs taken with a thermal chamber showing the increase in skin temperature in the inguinal area due to the increase in the thermogenic activity of this tissue after treatment with ramelteon. (Control, 34.4 ± 0.03 ° C (A), ramelteon, 35.1 ± 0.16 ° C (B), P <0.01).
    [0058]
    [0059] Figure 2. Immunocytochemistry with Anti-UCP1 (molecular marker of UCP1 which identifies brown adipocytes and the like). As observed, UCP1 is undetectable in the inguinal areas of the untreated obese ZDF rats (A). Treatment with melatonin clearly induces the expression of UCP1 in these animals (B).
    [0060]
    [0061] Figure 3. Immunocytochemistry with Anti-CITEDI (specific marker of beige adipocytes). As seen, new levels of CITED1 appear in the inguinal areas of the obese treated ZDF rats (B) compared to the untreated rats (A).
    [0062]
    [0063] DETAILED DESCRIPTION OF THE INVENTION
    [0064]
    [0065] Definitions
    [0066]
    [0067] The "adipose cells", "adipocytes" or "lipocytes" are the cells that make up adipose tissue. They are rounded cells, from 10 to 200 microns, with a lipid content (triglycerides) that represents 95% of the cell mass and that forms the constituent element of fat tissue.
    [0068] In the case of the "white adipocytes", adipocytes that form the "white adipose tissue", the fat, formed by triglycerides and cholesterol esters, is grouped forming a large lipid drop that occupies the majority of the cell and displaces to the rest of the organelles (cytoplasm, few mitochondria and a flat nucleus) to its periphery.
    [0069]
    [0070] On the other hand, the "brown adipocytes", which make up the "brown adipose tissue", have a characteristic polygonal shape, and unlike the white adipocytes have a large amount of cytoplasm with dispersed fractions of lipids, their nucleus is round and they do not found in the periphery, and have a large amount of mitochondria, which gives them the color brown. Brown adipocytes, which are constitutive of human tissues and disappear with age.
    [0071]
    [0072] The "beige adipocytes" are a third type of fat cells present in subcutaneous adipose tissue, both in animals and humans, which have structural and functional properties similar to those of brown adipocytes, but, unlike brown adipocytes, beige adipocytes are inducible, which makes the browning of white fat a new opportunity for therapeutic strategies for the treatment of obese and / or diabetic humans or animals.
    [0073]
    [0074] In this context, and throughout this document, the term " browning" refers to any process that transforms white adipose tissue (or white fat) into beige adipose tissue (or thermogenic fat). to say, any process that induces or causes the appearance of beige adipocytes in white adipose tissues, particularly in subcutaneous white tissue.
    [0075]
    [0076] Melatonin, or N-acetyl-5-methoxytryptamine, is a hormone, or natural compound secreted during the night mainly by pineal gland. Its primordial function is to regulate the circadian cycle of the human body. Its formula is:
    [0077]
    [0078]
    [0079] Melatonin has powerful antioxidant, anti-inflammatory and anti-obesogenic effects. In addition, it is responsible for a molecular mechanism of thermogenensis.
    [0080]
    [0081] On the other hand, ramelteon, also known as TAK-375, is a chemical compound of formula
    [0082]
    [0083]
    [0084]
    [0085]
    [0086] In particular, in this invention the term "ramelteon" can also be extended to salts, prodrugs or solvates of ramelteon.
    [0087]
    [0088] In other equivalent embodiments, the term "ramelteon" can refer to any functional biological equivalent of ramelteon, in particular to a functional biofuel of ramelteon in an equivalent concentration, to induce to induce the appearance of beige adipocytes in white adipose tissue.
    [0089]
    [0090] Ramelteon is a hypnotic agent that binds selectively to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN). It is approved by the US Food and Drug Administration (FDA) for long-term use, and is currently marketed as Rozerem by Takeda Pharmaceuticals.
    [0091]
    [0092] Unlike other hypnotic agents such as melatonin, it shows no appreciable affinity to central nervous system receptors associated with anxiolytic effects, myorelaxants or amnesic receptors such as GABA, dopamine, serotonin or opioid receptors.
    [0093]
    [0094] The term "profarmaco" as used in this description refers to a chemical compound that has undergone a chemical derivation, for example a substitution or addition of an additional chemical group, to modify any of its physical-chemical properties, such as solubility. or bioavailability, but that does not modify the technical characteristics of the original molecule. A prodrug could be, for example, a ester, ether or amide derivative. Bioavailability refers to its availability in a specific biological compartment.
    [0095]
    [0096] The term "solvate" according to this invention is to be understood as that derivative of ramelteon having another molecule, for example a polar solvent, bound by means of a non-covalent bond. Examples of such solvates include hydrates and alcoholates, for example methanolates
    [0097]
    [0098] The preparation of salts, solvates and prodrugs can be carried out by methods known in the state of the art. Non-pharmaceutically acceptable salts, solvates or prodrugs are also within the scope of the invention since they may be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.
    [0099]
    [0100] The term "patient" is used in this document to refer to any animal, preferably mammal, more preferably human, submitted or that is going to undergo treatment.
    [0101]
    [0102] For its part, the term "treatment" or "trataf" in the context of this document refers to the administration of a compound or composition according to the invention to ameliorate or eliminate a disease, pathological condition or one or more symptoms associated with said treatment. disease or condition in a patient. "Treatment" also includes the improvement or elimination of the physiological sequelae of the disease.
    [0103] Specifically, the concept "treat" can be interpreted as:
    [0104] i. Prevent the disease or pathological condition, that is, prevent or delay its appearance;
    [0105] ii. Inhibit the disease or pathological condition, that is, stop its development; iii. Alleviate the disease or the pathological condition, that is, cause the regression of the disease or the pathological condition;
    [0106] iv. Stabilize the disease or the pathological condition.
    [0107]
    [0108] In particular, the term treatment includes the prevention, inhibition, relief or stabilization of diseases or pathological conditions by induction of beige adipocytes in the patient.
    [0109]
    [0110] The term "medication". as used in this description, it refers to any substance used for the treatment of diseases or pathological conditions in man or an animal.
    [0111]
    [0112] The term "functional biological equivalent" or "bioequivalent variable" as used in the present description, refers to a molecule with the same function as the molecule described, which may present slight variations with respect to the molecule described without said variations provide no added technical effect to said molecule. In the present invention, therefore, it refers to variants of ramelteon that have the same function and that present slight variations without these variations contributing any added technical effect to ramelteon.
    [0113]
    [0114] By "concentration that is equivalent" is meant that concentration necessary for the functional biological equivalent of ramelteon that produces the same effect as that described in the present invention.
    [0115]
    [0116] The term "excipient" refers to a substance that aids the absorption of the pharmaceutical composition or medicament of the invention, stabilizes said pharmaceutical composition or assists its preparation in the sense of giving it consistency. Thus, the excipients could have the function of keeping the ingredients together, such as, for example, starches, sugars or celluloses, a drug protection function such as, for example, to isolate it from air and / or humidity.
    [0117]
    [0118] The term "advvant" refers to any substance that enhances the response of an active principle. In the present invention refers to any substance that enhances the effects of the composition of the invention, can refer to any adjuvant known to the person skilled in the art.
    [0119] The term "pharmaceutically acceptable" refers to the fact that the compound referred to is permitted and evaluated so as not to cause damage to the organisms to which it is administered.
    [0120]
    [0121] A "pharmaceutically acceptable vehicle", or pharmaceutically acceptable vehicle , refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes, but is not limited to, solids, liquids, solvents or surfactants. The vehicle can be an inert substance or of an analogous action to any of the compounds of the present invention. The function of the vehicle is to facilitate the incorporation of the expression product of the invention as well as other compounds, to allow a better dosage and administration or to give consistency and form to the pharmaceutical composition.
    [0122]
    [0123] Use of ramelteon for the induction of beige adipocytes in white adipose tissue
    [0124]
    [0125] In a first aspect, the present invention describes the use of ramelteon, a selective agonist of melatonin receptors (MT1 and MT2), to induce the browning of white adipose tissue, that is, to induce the appearance of beige adipocytes in adipose tissue. white, particularly in white subcutaneous tissue.
    [0126]
    [0127] The browning of white adipose tissue is useful for the treatment of diseases or pathological conditions such as obesity (high levels of white adipose tissue), diabetes, diabesity (obesity and diabetes), nephropathy, neuropathic diabetes, metabolic syndrome, atherosclerosis, neurodegenerative diseases such as dementia and Parkinson's, steatosis (fatty liver), and cancer, so the invention also refers to the use of ramelteon in the treatment of said diseases and, in general, in the treatment of any disease or condition that can be treated by the induction of beige adopocytes in white adipose tissue. Thus, the present also aims at ramelteon to treat pathological conditions or diseases associated with pathological scenarios caused by obesity, such as diabetes mellitus type 2, hepatic steatosis (fatty liver), alterations of hyperlipoproteinemias, such as hyperocholesterol (increased low-density lipoprotein or LDL cholesterol) and hypertrigeridemia (low levels of high-density lipoprotein or HDL cholesterol).
    [0128]
    [0129] Preferably, the invention relates to ramelteon for the treatment of obesity, more preferably central obesity; diabesity, neuropathic diabetes and diseases associated with pathological scenarios caused by obesity, such as diabetes mellitus type 2, hepatic steatosis, hyperocholesterolemia and hypertryglycemia.
    [0130]
    [0131] In a particular embodiment, the administration of ramelteon is carried out orally, preferably sublingually.
    [0132]
    [0133] The dosage to obtain a therapeutically effective amount depends on a variety of factors, such as, for example, the patient type, preferably mammary and more preferably human. Thus, in another particular embodiment, the daily dose of ramelteon used in the treatment method is between 0.005 and 0.5 mg / kg of body weight, preferably between 0.01 and 0.5 mg / kg, more preferably between 0 , 01 and 0.1 mg / kg of body weight of the patient, and even more preferably 0.01 mg / kg of body weight. The administration of the daily dose can be done in one or more doses.
    [0134]
    [0135] In an even more preferred embodiment, the daily dose used sublingually is 0.01 mg per kg of body weight.
    [0136]
    [0137] In another particular embodiment, the administration is carried out parenterally, preferably intraarterially, intravenously, subcutaneously or intraperitoneally.
    [0138]
    [0139] In a preferred embodiment, the administration of ramelteon to induce the appearance of beige adipocytes in the white adipose tissue is prolonged for a time of at least 6 weeks, preferably at least 12 weeks.
    [0140]
    [0141] In another aspect, the present invention relates to the use of ramelteon as a medicament or to the manufacture of a medicament for treating it in the treatment of any disease or pathological condition susceptible to be treated by the induction of beige adopocytes in the white adipose tissue, preferably to treat obesity, more preferably central obesity, diabesity, neuropathic diabetes and diseases associated with scenarios pathologies caused by obesity, such as diabetes mellitus type 2, hepatic steatosis, hyperocholesterolemia and hypertriglyceridemia.
    [0142]
    [0143] Composition of the invention
    [0144]
    [0145] In another aspect, the present invention relates to a pharmaceutical composition, hereinafter "composition of the invention", for inducing the appearance of beige adipocytes in white adipose tissue, particularly in subcutaneous white tissue, comprising a therapeutically effective amount of ramelteon
    [0146]
    [0147] In the sense used in this description, the term "therapeutically effective amount" refers to that amount of a compound of the invention that when administered to a mammal, preferably humans, is sufficient to produce the treatment of a disease or pathological condition of interest in mammals, preferably humans. The amount of ramelteon, metabolite, salt, solvate or prodrug which constitutes a therapeutically effective amount will vary, for example, according to the activity of the specific compound employed; the metabolic stability and duration of the action of the compound; the species (preferably human), the type of tumor, the age, the body weight, the general state of health, the sex and the diet of the patient; the route of administration; the mode and time of administration; the rate of excretion, the combination of drugs; the severity of the particular disorder or pathological condition; and the subject who undergoes therapy, but can be determined by a specialist in the art according to his own knowledge and that description.
    [0148]
    [0149] In particular, the composition of the invention is useful for treating any disease or pathological condition susceptible to be treated by induction of beige adopocytes in white adipose tissue, preferably to treat obesity, more preferably central obesity, diabesity, neuropathic diabetes and diseases associated with pathological scenarios caused by obesity, such as diabetes mellitus type 2, hepatic steatosis, hyperocholesterolemia and hypertryglycemia.
    [0150]
    [0151] In a particular embodiment, the composition of the invention is suitable for oral administration, preferably sublingual administration. Preferably, the composition is a pharmaceutical form suitable for sublingual administration as tablets can be rapid dissolution with adequate water solubility so that they disintegrate in contact with the sublingual moist medium or fast dissolving capsules. Ramelteon is freely soluble in organic solvents, such as methanol, ethanol and dimethylsulfoxide; soluble in 1-octanol and acetonitrile; and very slightly soluble in water and in aqueous buffers from pH 3 to pH 11.
    [0152]
    [0153] In another particular embodiment, the composition of the invention comprises at least 75%, preferably at least 85%, more preferably at least 90%, and even more preferably at least 99% ralmelteon.
    [0154]
    [0155] In a preferred embodiment the composition consists of ramelteon and an excipient suitable for sublingual administration. Suitable excipients for this composition are, for example, lactose monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000 or black synthetic iron oxide. In a more preferred embodiment the composition employed consists of rameteon, lactose monohydrate, starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, copovidone, titanium dioxide, yellow ferric oxide, polyethylene glycol 8000, shellac and black synthetic iron oxide.
    [0156]
    [0157] In another particular embodiment, the composition is suitable for parenteral administration, preferably by intraarterial, intravenous, subcutaneous or intraperitoneal route.
    [0158]
    [0159] The composition of the invention may contain any other active ingredient in the treatment of the aforementioned diseases or be characterized as containing only ramelteon as active ingredient.
    [0160]
    [0161] Thus, another preferred embodiment refers to a composition that also comprises at least one other active ingredient. As used herein, the terms "active ingredient", "active substance", "pharmaceutically active substance", "active ingredient" or " pharmaceutically active ingredient" refers to any component that potentially provides a pharmacological activity or other different effect in the diagnosis , cure, mitigation, treatment or prevention of a disease, or that affects the structure or function of the body of the human being or other animals.
    [0162] The compositions of the invention may also contain excipients or pharmaceutically acceptable adjuvants.
    [0163]
    [0164] The excipients and vehicles used must be pharmaceutically and pharmacologically tolerable, so that they can be combined with other components of the formulation or preparation and do not exert adverse effects on the treated organism.
    [0165]
    [0166] The compositions of the invention are prepared using standard methods such as those described or referenced in the Spanish and US Pharmacopoeias and similar reference texts.
    [0167]
    [0168] The composition of the invention of the invention can also be referred to a composition comprising a functional biological equivalent of ramelteon in a concentration that is equivalent to that described in the compositions of the invention.
    [0169]
    [0170] Combined preparations
    [0171]
    [0172] The term " combined preparation " or also referred to as "vuxtaposition", in this specification, means that the components of the combined preparation do not need to be present as a union, for example in a true composition, in order to be available for their combined, separate or sequential. In this way, the expression "vuxtapuesta" implies that it is not necessarily a true combination, in view of the physical separation of the components.
    [0173]
    [0174] Thus, in another aspect, the invention relates to a composition, preparation or pharmaceutical form, hereinafter "combined preparation of the invention", comprising:
    [0175] a) a therapeutically effective amount of ramelteon, and
    [0176] b) a second active principle for the treatment of the previously mentioned diseases.
    [0177]
    [0178] In a particular embodiment, the second active ingredient is melatonin.
    [0179]
    [0180] Preferably, the combined preparation of the invention is used to treat obesity, more preferably central obesity, diabesity, neuropathic diabetes and diseases associated with pathological scenarios caused by obesity, such as diabetes mellitus type 2, hepatic steatosis, hyperocholesterolemia and hypertriglyceridemia
    [0181]
    [0182] Kit of the invention
    [0183]
    [0184] In another aspect, the present invention relates to a kit ( "kit-of-parts", the English "kit of parts") for the preparation of the composition or the combined preparation of the invention.
    [0185]
    [0186] The term "kit", as used herein, refers to a combination of a set of components suitable for obtaining the composition or the combined preparation of the invention, which may or may not be packaged together, together with its containers and appropriate containers for commercial sale, etc.
    [0187]
    [0188] In the present invention, "suitable component for obtaining the composition or the combined preparation of the invention" is understood as any compound that can be used for the preparation thereof, and includes, without limitation, aqueous solutions, prepared solids, tampons, syrups, preservation solutions, flavorings, pH correctors, thickeners, etc.
    [0189]
    [0190] The components of the kit can be provided in separate vials (in the form of "kit-de-parted") or in a single vial In addition, it is understood that the kit of the present invention is intended for the preparation of the composition or of the combined preparation or of the pharmaceutical form of the invention Preferably, the kit components of the present invention are ready to be used to prepare the composition or the combined preparation or the pharmaceutical form of the present invention. how to prepare the composition or the combined preparation or the pharmaceutical form of the present invention The instructions can be provided to the users in electronic or paper form.
    [0191]
    [0192] Therefore, the invention provides a kit for the preparation of the composition of the invention or of the combined preparation of the invention a container comprising a container with ramelteon in any pharmaceutically acceptable formulation, together with suitable components for obtaining the composition or of the combined preparation of the invention.
    [0193] In particular, the kit of the invention also comprises a package with any pharmaceutically acceptable formulation.
    [0194]
    [0195] Treatment method
    [0196]
    [0197] In another particular embodiment, the invention relates to a method of treating the aforementioned diseases comprising the induction of the appearance of beige adipocytes in white adipose tissue, particularly in subcutaneous white tissue, by the administration of ramelteon, of a medicament comprising it and / or of the composition, and / or the combined preparation and / or the kit of the invention.
    [0198]
    [0199] In particular, the method comprises the administration of ramelteon, ramelteon, a medicament comprising it and / or the composition, and / or the combined preparation and / or the kit of the invention, to a patient to treat one or more of the diseases mentioned.
    [0200]
    [0201] In a particular embodiment, the administration is carried out orally, preferably sublingually.
    [0202]
    [0203] In another preferred embodiment, the administration is carried out parenterally, preferably intraarterially, subcutaneously, intravenously or intraperitoneally.
    [0204]
    [0205] The amount administered will depend on the patient, the disease or pathological condition to be treated, its degree or severity, and the route of administration.
    [0206]
    [0207] Thus, in another particular embodiment, the daily dose of ramelteon used in the treatment method is between 0.005 and 0.5 mg / kg of body weight, preferably between 0.01 and 0.5 mg / kg, more preferably between 0 , 01 and 0.1 mg / kg of body weight of the patient, and even more preferably 0.01 mg / kg of body weight. The administration of the daily dose can be done in one or more doses.
    [0208]
    [0209] In another preferred embodiment, the treatment method has a duration of at least 6 weeks, preferably at least 12 weeks.
    [0210] MODES OF REALIZATION
    [0211]
    [0212] Materials and methods
    [0213]
    [0214] We identified brown adipose tissue induced within the white fat of the inguinal area as beige adipocytes in response to the selective administration of ramelteon sublingual (rozerem) with a daily dose of 0.1 mg per kg body weight for 6 weeks to obese diabetic rats of Zucker (Zucker dibatetic fatty rats or ZDF), starting at the age of six weeks up to 12 weeks. For this purpose, the following were used:
    [0215] 1. - IR - Thermography
    [0216] 2. - Immunocytochemistry for the thermogenic molecular signature, UCP1.
    [0217] 3. - Immunocytochemistry for the molecular specific marker of beige adipocytes, that is, CITED1 (transactivator 1 that interacts with Cbp / p300).
    [0218]
    [0219] The present work demonstrated that the treatment with ramelteon increased the thermogenic activity of this tissue, as indicated by an increase in the temperature of the inguinal skin and also of the thermal chamber records.
    [0220]
    [0221] Chronic treatment with ramelteon increased inguinal temperature in obese rats (control, 34.4 ± 0.03 ° C (Figure 1B), ramelteon, 35.1 ± 0.16 ° C (Figure 1B), P <0.01). Immunocytochemistry with Anti-UCP1 (molecular signature of UCP1: identifies brown adipocytes and the like) and Anti-CITED1 (specific marker of beige adipocytes) shows positive confirmation of the appearance of beige adipocytes in the inguinal area of ZDF rats after treatment with ramelteon (UCP1 was not detectable in the inguinal fat of obese untreated ZDF rats (Fig. 2 and 3, A). The treatment with melatonin clearly induced the expression of UCP1 in these animals (Figures 2 and 3, B). ).
    [0222]
    [0223] Results
    [0224]
    [0225] Animals and experimental protocols
    [0226] A group of male ZDF rats (fa / fa n = 8) and a group of lele (male lean littermates) used as control, ZL (fa / - n = 8) were used with an age of 4 weeks. This study was carried out in accordance with the guidelines of the European Union for the care and protection of animals. The animals were kept with the rat feed Purina 5008 (protein 23%, fat 6.5%, carbohydrates 58.5%, fiber 4% and ash 8%, Charles River) and were housed two in two in transparent plastic cages, controlled by climpatizer in a room at 28- 30 ° C and 30-40% relative humidity, with a dark / light cycle of 12 hours (lights at 07:00 h). In the first week after arrival, the animals were acclimated to the conditions of the room and the water intake was recorded. Then, the ZDF rats were subdivided into two groups: animals treated for 6 weeks with ramelteon via sc, (R-ZDF) and controls (C-ZDF). Water intake and body weight (BW ) were recorded twice a week. The fresh ramelteon solutions were prepared twice a week, and the ramelteon dose was adjusted to the BW throughout the study period. The water bottles were covered with aluminum foil to protect from light, and the drinking liquid was changed twice a week.
    [0227]
    [0228] Immunohistochemistry
    [0229]
    [0230] The embedded paraffin sections were cut into 7 mm sections. Before being had, deparaffinized (inclusions in xylene and alcohol). They were subjected to a citrate-based recovery as an antigen using a solution recovered from Citra antigen (Biogenex) and incubated for 1 hour at room temperature with a polyclonal rabbit paraffin antibody. The paraffin blocks were incubated for 1 hour at room temperature with a mouse monoclonal antibody against CITED1 at a dilution of 1: 1000 (Sigma Aldrich) or a rabbit monoclonal antibody against UCP1 at a dilution of 1: 1000 (Sigma Aldrich) or IgG as a negative control. Secondary detection was performed for 1 hour at room temperature using anti-mouse Alexa 488 and anti-rabbit Alexa 594 (Invitrogen). The blocks were labeled with DAPI. The images were captured using an Olympus IX2 microscope.
    权利要求:
    Claims (10)
    [1]
    1. - Ramelteon for use in the treatment of pathological conditions or diseases susceptible to be treated by induction of beige adopocytes in white adipose tissue.
    [2]
    2. Ramelteon, according to previous claim, for use in the treatment of diseases or pathological conditions related to an excess of white adipose tissue by the induction of beige adipocytes in the white adipose tissue.
    [3]
    3. - Ramelteon, according to previous claim in which the disease is selected from the group consisting of diabetes mellitus type 2, hepatic steatosis, hyperocholesterolemia and hypertriglyceridemia.
    [4]
    4. Ramelteon according to any of the preceding claims, characterized in that the treatment is carried out by the daily administration of ramelteon used in the treatment method is between 0.005 and 0.5 mg / kg of body weight, preferably between 0, 01 and 0.5 mg / kg, more preferably between 0.01 and 0.1 mg / kg of the patient's body weight, and even more preferably 0.01 mg / kg of body weight.
    [5]
    5. - Pharmaceutically acceptable composition comprising ramelteon as described in any of the preceding claims.
    [6]
    6. - Composition, according to previous claim, suitable for oral administration.
    [7]
    7. - Composition, according to previous claim, suitable for sublingual administration.
    [8]
    8. - Composition, according to claim 5, suitable for parenteral administration.
    [9]
    9. - Pharmaceutically acceptable composition, comprising:
    a) a therapeutically effective amount of ramelteon as described in claims 1 to 4, and
    b) a second active principle for the treatment of the previously mentioned diseases.
    [10]
    10.- Composition, according to previous revindication, characterized in that the second active principle is melatonin.
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    同族专利:
    公开号 | 公开日
    WO2019086744A1|2019-05-09|
    ES2711808B2|2020-03-13|
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    ES201731282A|ES2711808B2|2017-11-02|2017-11-02|USE OF A MELATONIN AGONIST TO INDUCE LA TO INDUCE BEIGE ADIPOCITS IN WHITE ADIPOSE TISSUE|ES201731282A| ES2711808B2|2017-11-02|2017-11-02|USE OF A MELATONIN AGONIST TO INDUCE LA TO INDUCE BEIGE ADIPOCITS IN WHITE ADIPOSE TISSUE|
    PCT/ES2018/070708| WO2019086744A1|2017-11-02|2018-11-02|Use of a melatonin agonist to induce beige adipocytes in white adipose tissue|
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