Compositions and methods for regulating body metabolism

Abstract

The present invention relates to a composition comprising regulators / modulators of T1R2 / T1R3, T1R1 / T1R3, CaSR and GPRC6A affecting body metabolism. Moreover, the composition can assists in promoting early satiety sensation and optimizing insulin section during and / or after meals.

Description

COMPOSITIONS AND METHODS FOR REGULATING BODY METABOLISMFIELD OF THE INVENTION

[0001] The present invention is in the field of compositions for regulating / modulating body metabolism.BACKGROUND OF THE INVENTION

[0002] Pancreatic 0-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in 0-cells, is a critical regulator of metabolism. Insulin is secreted primarily in response to glucose. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide- 1 also regulate insulin secretion. Notably, GLP-1 and GIP act as incretin hormones, amplifying insulin secretion following oral glucose administration (Creutzfeldt M.W. The incretin concept today. Diabetologia. 1979;16:75-85. Elrick H., et al. Plasma insulin response to oral and intravenous glucose administration). These hormones account for 50-70% of total postprandial insulin secretion.

[0003] Thus, the 0-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion (Zhuo Fu et al. Curr Diabetes Rev. 2013 Jan 1; 9(1): 25-53).

[0004] Luminal nutrient sensing by G-protein-coupled receptors (GPCR) expressed on the apical domain of enteroendocrine cells activates intracellular pathways leading to secretion of gut hormones that control vital physiological processes such as digestion, absorption, food intake and glucose homeostasis. The taste 1 receptor (T1R) family of GPCR consists of three members: T1R1; T1R2; T1R3. Expression of T1R1, T1R2 and T1R3 at mRNA and protein levels has been demonstrated in the intestinal tissue of various species. It has been shown thatT1R2-T1R3, in association with G-protein Gustducin, is expressed in intestinal K and L endocrine cells, where it acts as the intestinal glucose (sweet) sensor. A number of studies have demonstrated that activation of T1R2-T1R3 by natural sugars and artificial sweeteners leads to secretion of glucagon-like peptides 1&2 (GLP-1 and GLP-2) and glucose dependent insulinotropic peptide (GIP). GLP-1 and GIP enhance insulin secretion; GLP-2 increases intestinal growth and glucose absorption. T1R1-T1R3 combination co-expressed on the apical domain of cholecystokinin (CCK) expressing cells is a luminal sensor for a number of L-amino acids; with amino acid-activation of the receptor eliciting CCK secretion. Satiation is the sense of feeling full during a meal, which induces meal termination. Satiety signals can be thought of as occurring in a sequence. In addition to sensory-specific satiety, which involves reduced activity in cortical areas, further temporally overlapping signals include gastric distension, duodenal chemosensory signals, glucose utilization, and hormonal (including leptin) signals.

[0005] Due to the consistent rise in the numbers of incidents of obesity and diabetes worldwide, there is a need in simple and reliable solutions that assist in regulating weight in a subject.SUMMARY

[0006] The invention may have several aspects.

[0007] In one aspect, the invention provides a composition comprising: component A and component B, wherein component A being formulated in an immediate release form and comprising at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator as a major active ingredient and at least one first T1R2 / T1R3 modulator as a minor active ingredient; component B being formulated in a delayed release form and comprising at least one second T1R2 / T1R3 modulator as a major ingredient and at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator as a minor ingredient;wherein the at least one first and second T1R1 / T1R3 - CaSR - GPRC6A modulators, each comprise, at least one modulator independently selected from the group consisting of a T1R1 / T1R3 modulator, a CaSR modulator and a GPRC6A modulator.

[0008] In one aspect, the invention provides a composition comprising component A and component B, wherein component A is formulated in an immediate release form and component B is formulated in a delayed release form, wherein component A primarily increases satiety sensation or decreases hunger sensation and further affects insulin secretion and component B primarily affects or optimizes insulin secretion and further affects long lasting satiety sensation.

[0009] In one or more embodiments, the composition comprises component A and component B, wherein component A is formulated in an immediate release form and component B is formulated in a delayed release form, wherein component A includes as a major active ingredient at least one of an umami compound and as a minor active ingredient at least one of a sweetener agent, and component B includes as a major active ingredient at least one of a sweetener and as a minor active ingredient at least one of an umami compound.

[0010] In one or more embodiments, the composition is a pharmaceutical composition.

[0011] In one or more embodiments, the composition is a nutritional or nutraceutical composition.

[0012] In one or more embodiments, component A and component B are formulated as one single tablet.

[0013] In one or more embodiments, component A and component B are formulated as two separate tablets.

[0014] In one or more embodiments, the composition is useful for treating at least one of type 2 diabetes and obesity.

[0015] In one or more embodiments, the composition is useful after bariatric surgeries, to aid and optionally complement the surgery as an adjuvant therapy. In one or more embodiments, theat least one first and second T1R1 / T1R3 - CaSR - GPRC6A modulators can be same or different and the at least one first and second T1R2 / T1R3 modulators can be same or different.

[0016] In one or more embodiments, the molar ratio between the at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator and the at least one first T1R2 / T1R3 modulator of component A is bigger than 1, and wherein the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator.

[0017] In one or more embodiments, the molar ratio between the at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator and the at least one second T1R1 / T1R3 modulator of component B is smaller than 1, and wherein the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator.

[0018] In one or more embodiments, the at least one T1R1 / T1R3 modulator is independently selected from at least one umami agent.

[0019] In one or more embodiments, the umami agent is selected from the group consisting of glutamate, glutamic acid and a salt thereof, 5-guanosine monophosphate (5-GMP), 5- inosine monophosphate (5-IMP), aspartic acid, theanine, Ac-Glu, lactoyl-Glu, succinoyl-glu, a-glu- ala, y-glu-ala, fruvtosyl-pryroglutamic acid, (S)-morelid, (R)-strombine, L-AP4, NMDA, ibotenic acid, y-glu-cys-gly, y-glu-val-gly, y-glutamyl, and tricholomic acid.

[0020] In one or more embodiments, the molar ratio of the at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator is at least 0.6, 0.7, 0.8, or 0.9 of the total concentration of component A.

[0021] In one or more embodiments, the molar ratio of the at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator is less than 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 of the total concentration of component B.

[0022] In one or more embodiments, the delayed release formulation is adapted to release the second component in at least one of the duodenum, jejunum, ileum, and / or colon or at a pH environment of between 5.5 and 7.5, or below.

[0023] In one or more embodiments, the CaSR modulator is selected from at least one non-branched neutral or negatively charged amino acid.

[0024] In one or more embodiments, the CaSR modulator is selected from at least one of L-histidine, L-phenyalanine, L-trytophan, L-pheynyalanine, L-Alanine, L-serine, L-proline, L-glutamic acid, L-aspartic acid, and L-isoleuucine. Further contemplated CaSR modulators are Glutamyl peptides, such as S-Methylglutathione, y-glu-val-gly, Glutathione, y-glu-cys. Additionally, Polyamines such as Spermine, Spermidine, and Putrescine.

[0025] In one or more embodiments, component A comprises Ca2+, or Ca2+, Mg+source, or an amino acid other than a branched chained positively charged amino acid.

[0026] In one or more embodiments, the GPRC6A modulator is saccharin.

[0027] In one or more embodiments, the T1R2 / T1R3 modulator is a sweetener or an oligofructose enriched inulin.

[0028] In one or more embodiments, the composition further comprising probiotics.

[0029] In one or more embodiments, the sweetener is characterized as at least one of a natural sweetener, artificial sweetener, high intensity sweetener, a low caloric sweetener, a non-caloric sweetener or combination thereof.

[0030] In one or more embodiments, the sweetener is selected from at least one of sugar, a sugar alcohol and a modified sugar.

[0031] In one or more embodiments, the sweetener is at least one of fructose, glucose, stevia (various steviol glycosides that may be extracted from the plant Stevia rebaudiana and mainly comprise stevioside and rebaudioside), erythritol, xylitol, sucralose, saccharine, faspartame, olgifructose, advantame, acesulfame potassium (Ace-K), neotame, Luo Han Guo fruit extracts, (Siraitia grasvenorii) , swingle fruit extract (SGFE), saccharine, and a combination thereof.

[0032] In one or more embodiments, component A comprises Glutamic acid, IMP and 5’-GMP.

[0033] In one or more embodiments, component A comprises: Glutamic acid, glutamine, IMP, 5’- GMP, calcium salt, at least one of L-histidine or L-phenylalanine, saccharine and sucralose; and component B comprises: sucralose, L-glutamic acid or salt thereof, glutamine, L-arginine and L-lysine.

[0034] In a further aspect, the present invention provides a method for treating diabetes comprising administering to a subject in need thereof a first composition before or with a meal and a second composition after the meal, wherein the first composition comprising a major ingredient and a minor ingredient, the major ingredient being a first T1R1 / T1R3 - CaSR - GPRC6A modulator mixture and the minor ingredient being a first T1R2 / T1R3 modulator; the second composition comprising a major ingredient and a minor ingredient, the major ingredient being a second T1R2 / T1R3 modulator and the minor ingredient being a second T1R1 / T1R3 - CaSR - GPRC6A modulator mixture wherein the first and second T1R1 / T1R3 - CaSR - GPRC6A modulator mixtures comprise at least one modulator independently selected from the group consisting of a T1R1 / T1R3 modulator, a CaSR modulator and a GPRC6A modulator.

[0035] In a further aspect, the herein composition is for use in treating a metabolic disease, condition or disorder.

[0036] In a further aspect, the herein composition is for use in suppressing appetite in a subject.

[0037] In yet a further aspect, the herein composition is for use in weight loss in a subject.

[0038] In one or more embodiments, the metabolic disease is diabetes or obesity.

[0039] In one or more embodiments, the herein composition is useful in affecting at least one of weight loss, reduced appetite, increase in satiety and treating obesity.

[0040] In one or more embodiments, the T1R1 / T1R3 modulator is at least one umami agent selected from glutamate, 5 - guanosine mono phosphate (5-GMP) and inosine monophosphate (IMP).

[0041] In one or more embodiments, the T1R2 / T1R3 modulator is a sweetener.

[0042] In one or more embodiments, the first composition is a first component formulated in an immediate release form and the second composition is a second component formulated in a delayed release form in a combined composition.

[0043] In one or more embodiments, the method further comprising administering a probiotic concomitantly or after the administration of the first and second compositions.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The various features of the invention will best be appreciated by simultaneous reference to the description which follows and the accompanying drawings, which are not drawn to scale and in which:

[0045] FIG. 1 illustrates a first embodiment of the invention which provides component A and component B, each present in a separate tablet, wherein component A is prescribed for administration prior to or during a meal and component B is prescribed for administration after a meal.

[0046] FIG. 2 illustrates a second embodiment of the invention which provides component A and component B in one tablet, wherein component A is rapidly released, and component B is slowly released.DETAILED DESCRIPTION

[0047] The present invention pertains to a composition comprising two components, i.e., component A and component B, wherein component A is being formulated in an immediate release form and component B is being formulated in a slow-release form. Component A is provided to allow a rapid satiety sensation prior to, or in conjunction with consuming a meal to reduce the amounts of food consumed by a subject and component B is provided to induce or optimizeinsulin secretion to accelerate and optimize glucose intake in the cells, and to prolong the satiating feeling after the meal.

[0048] The herein composition is to be provided along with meals, optionally, already provided within food products (e.g., smoothies, snacks, beverages, chewing gums, etc.). The administration of the herein composition in conjunction with food consumption enhances the effect of the composition and affords its benefits, i.e., increasing satiety sensation, or suppressing appetite, and optimizing sugar metabolism.

[0049] Component A

[0050] According to an embodiment of the invention, component A comprises as a major ingredient, at least one compound that promotes satiety sensation. Satiety sensation may be promoted inter aha by reduction of ghrelin hormone and / or by increasing the serotonin secretion.

[0051] By providing agents that promote satiety in a rapid release form that can be released in the stomach and / or small intestine, reduction of ghrelin hormone secretion may be effectively achieved. Ghrelin also promotes fat accumulation in the body. Accordingly, less ghrelin effects less fat accumulation.

[0052] It is known that serotonin suppresses appetite. Serotonin also enhances insulin secretion from pancreatic islets. Tryptophan (Trp) is a precursor Serotonin. One of Tryptophan receptor in the gut is GPR142 which is located in the stomach and small intestine. Thus, in one or more embodiments, component A further includes Tryptophan.

[0053] As used herein the term “Ghrelin” refers to a hormone (a.k.a, the "hunger hormone") that is produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and that increases food intake. Reduction of the ghrelin secretion is mediated for example by leptin. In the stomach, induction of the taste 1 receptor (T1R1), the taste 3 receptor (T1R3), calcium- sensing receptor (CaSR), and G protein-coupled receptor family C group 6 member A (GPRC6A) mediate reduction of ghrelin. For example, amino acids induce GLP-1 secretion through T1R1+T1R3 which in turn induces Leptin secretion and Gherlin reduction.

[0054] Thus, in one or more embodiments, component A being formulated in an immediate release form that aims at affecting the reduction of ghrelin secretion in the stomach, includes as a major ingredient one or more compound that modulates one or more of: the taste 1 receptor (T1R1), the taste 3 receptor (T1R3), calcium-sensing receptor (CaSR), G protein-coupled receptor family C group 6 member A (GPRC6A).

[0055] As used herein, compounds that modulates one or more of: T1R1, T1R3, CaSR, GPRC6A, include, for example, umami compounds (such as glutamic acid), L-Arg, L-Lyc, osteocalcin (Ocn), Cations (such as calcium), amino acids, except branched chained positively charged amino acids.

[0056] Component A may further comprise as a minor ingredient at least one compound that promotes insulin secretion. Such compounds may include a modulator of the taste 2 receptor (T1R2) and / or T1R3.

[0057] As used herein, the term “immediate release form” refers to compositions (e.g., a tablet) that disintegrates rapidly and gets dissolved to release the active pharmaceutical ingredient (API). Immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of API release and / or absorption. In an embodiment of the invention, component A of the herein invention is adapted to allow release of its APIs in the stomach and / or the small intestine. Without being bound by any theory or mechanism of action, CCK receptors are located in the duodenum. Inducing serotonin secretion by, for example, a precursor to Serotonin (e.g., L-Tryptophan) will effect Ghrelin inhibition.

[0058] Component B

[0059] According to an embodiment of the invention, component B comprises as a major ingredient, at least one compound that promotes insulin secretion to increase / optimize glucose intake by the cells.

[0060] Thus, in one or more embodiments, component B being formulated in a delayed release form that aims at increasing the secretion of insulin in the intestine, includes as a major ingredient one or more compound that modulates one or more of: T1R2 / T1R3.

[0061] Component B may further comprise as a minor ingredient at least one compound that promotes satiety sensation, to allow for an extended / longer satiety sensation. Such compounds may include a modulator of the T1R1, the T1R3, CaSR, and GPRC6A.

[0062] As used herein, the term “delayed release form” (a.k.a., “modified”, “controlled”, “sustained”, “prolonged”, “extended” or “delayed”, release of API) refers to compositions (e.g., a tablet) that disintegrates slowly. A delayed release form is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration. In an embodiment of the invention, component B of the herein invention is adapted to allow release of its API(s) in the duodenum, the jejunum, the ileum and / or the colon. In an embodiment of the invention, component B is adapted to allow release of its API(s) at an environmental pH having a value between 5.5 and 7.5, optionally at a pH value of below 7.5. For example, below 7, below, 6, or below 5.5.

[0063] In an embodiment of the invention, a compound that modulates the herein receptors is an agonist of said receptor.

[0064] In an embodiment of the invention, the T1R1 / T1R3, CaSR, and GPRC6A modulators of component A may be similar or different from the T1R1 / T1R3, CaSR, and GPRC6A modulators of component B.

[0065] As used herein, the term “a major ingredient” means that the API ingredient within a component (A or B) is present in a higher amount relative to other ingredients. Optionally, the higher amount means a higher weight and / or a higher molarity.

[0066] As used herein, the term “a minor ingredient” means that the API ingredient within a component (A or B) is present in a lower amount relative to other ingredients. Optionally, the lower amount means a lower weight and / or a lower molarity.

[0067] In an exemplary embodiment, the molar ratio between the at least one first T1R1 / T1R3, CaSR, and / or GPRC6A modulator and the at least one first T1R2 / T1R3 modulator of component A is bigger than 1. In one or more embodiments, the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator. For example, the molar ratio between the at least one first T1R1 / T1R3, CaSR, and / or GPRC6A modulator and the at least one first T1R2 / T1R3 modulator of component A is bigger than 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, or above.

[0068] In an exemplary embodiment, the molar ratio between the at least one second T1R1 / T1R3, CaSR, and / or GPRC6A modulator and the at least one second T1R1 / T1R3 modulator of component B is smaller than 1. In one or more embodiments, the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator. For example, the molar ratio between the at least one second T1R1 / T1R3, CaSR, and / or GPRC6A modulator and the at least one second T1R1 / T1R3 modulator of component B is smaller than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or below.

[0069] In an exemplary embodiment, the molar ratio of the at least one first T1R1 / T1R3, CaSR, and / orGPRC6A modulator is at least 0.6, 0.7, 0.8, or 0.9 of the total concentration of the component A.

[0070] In an exemplary embodiment, the molar ratio of the at least one second T1R1 / T1R3, CaSR, and / or GPRC6A modulator is less than 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 of the total concentration of component B.

[0071] In an embodiment of the invention, a modulator of the T1R1 / T1R3 includes an umami agent. Various umami agents are contemplated, including without limitation glutamate, glutamic acid and a salt thereof, 5-guanosine monophosphate (5-GMP), and 5- inosine monophosphate (5- IMP). Advantageously, umami compounds induce CCK, GIP, GLP-1, and PYY secretion which assists in inducing insulin secretion. Optionally, a combination of umami agents, in particular a combination of a nucleotide and an amino acid is provided (e.g., glutamate and at least one of 5-GMP and 5-IMP) .Is herein further contemplated such that the umami agents when combined effect a synergistic reaction on T1R1 / T1R3.

[0072] CaSR when activated stimulates GLP-1 secretion which act as incretin hormones, amplifying insulin secretion following oral glucose administration. In an embodiment of the invention, a modulator of the CaSR includes a natural ligand (such as a metabolite) or a synthetic ligand. In one embodiment, the CaSR modulator is selected from an L amino acid, a non-branched neutral or negatively charged amino acid. Optionally, the amino acid is L-histidine, L- phenyalanine, L- L-tryptophan, L-phenylalanine, L- Alanine, L-serine, L-proline, L-glutamic acid, L-aspartic acid, and L-isoleucine, or a combination thereof. Further examples of possible CaSR modulators include Ca2+, an oligopeptide, a polyamine. Exemplary synthetic modulators include the agonists cinacalcet and R-568.

[0073] In an embodiment of the invention, GPRC6A modulator is a sweetener which may be artificial or natural sweetener. Exemplary possible sweeteners include, for example, saccharin, sucralose, sucrose. Further suitable sweeteners are herein contemplated.

[0074] In an embodiment of the invention, the T1R2 / T1R3 modulator is a sweetener. In one embodiment, T1R2 / T1R3 modulator is an oligofructose enriched inulin. Exemplary sweeteners include, without limitation, a natural sweetener, an artificial sweetener, a high intensity sweetener, a low caloric sweetener, and a combination thereof. In one embodiment, the sweetener is selected from at least one of a sugar, a sugar alcohol and a modified sugar. Further exemplary examples for a suitable sweetener include at least one of fructose, sucrose, glucose, stevia, erythritol, xylitol, sucralose, aspartame, olgifructose, Advantame, Steviol glycosides, Acesulfame potassium (Ace-K), Neotame, Luo Han Guo fruit extracts Siraitia grosvenorii Swingle fruit extract (SGFE) and saccharine.

[0075] In an embodiment of the invention, component A comprises Ca2+, or a Ca2+source.

[0076] In an embodiment of the invention, component A comprises 5’-GMP.

[0077] An exemplary composition of component A includes: glutamine, glutamic acid 5’-GMP, calcium salt,at least one of L-histidine and / or L-phenylalanine, saccharine and / or sucralose.

[0078] For example, component A may include: about 400 mg glutamic acid, about 400 mg 5’-GMP (a T1R1 / T1R3 modulator) about 100 mg calcium salt, (a CaSR modulator) about at least one of L-histidine and / or L-phenylalanine (a CaSR modulator) about 10 mg saccharine and / or sucralose (a T1R2 / T1R3 modulator)

[0079] An exemplary composition of component B includes:L-glutamic acid or salt thereof,5-GMP,L-arginine and / or L- lysine.In example, component B includes: about 60 mg saccharine and / or sucralose, about 450 mg glutamic acid, about 450 mg 5-GMP.In example, component B includes: about 60 mg saccharine and / or sucralose, about 450 mg 5-GMP.

[0080] Another exemplary composition of component B includes:50 mg sucralose;175 gr glutamic acid;175 mg 5’-GMP;400 mg GLN;300 mg Lys

[0081] In one or more embodiments, the herein composition may further comprise probiotics, or other ingredients relevant as a nutrition product.

[0082] In one or more embodiments, the composition is suitable for use in treating type 2 diabetes. In one or more embodiments, the composition is suitable for use in treating obesity. In one or more embodiments, the composition is suitable as an appetite suppressant and can be used in suppressing appetite.

[0083] As used herein, the term "administering" refers to administration of the composition of the present invention to a subject. In one embodiment of the invention, administration is an oral administration.

[0084] The term "about" as used herein refers to + / -10% of the indicated amount.

[0085] As used herein, the term "appetite" refers to the instinctive desires necessary to keep up organic life; especially, the desire to eat or an inherent craving to eat.

[0086] As used herein, the term "appetite suppressant" refers to a substance, such as a pharmaceutical ingredient, that has activity in suppressing appetite.

[0087] As used herein, the term “appetite-suppressing amount” refers to an amount of a substance, such as a pharmaceutical ingredient that substantially suppresses appetite in a subject.

[0088] As used herein, the term “obesity” refers to the condition in which the fatty tissue reserve of a mammal, such as a human, is increased to a point at which it is associated with adverse health conditions and / or increased mortality. Obesity may be measured in objective terms, for example, according to a body mass index (BMI) equal to or greater than 30.0, or between 27- 30, or according to a waist circumference greater than a 102 cm in men and greater than 88 cm in women. Optionally, the composition is useful for conditions of pre-obesity, or prediabetes.

[0089] Pharmaceutical ingredients

[0090] The herein composition may comprise in addition to the API indicated above at least one excipient, such as a sweetening agent, a flavoring agent, a protecting agent, a plasticizer, awax, an elastomeric solvent, a filler material, a preservative, a lubricating agent, a wetting agent, an emulsifying agent, solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof. It is to be understood that some excipients may fall within more than one class of the aforementioned excipients.

[0091] In one embodiment, component A of the herein composition is provided in an immediate release form. In one embodiment, component B of the herein composition is provided in a sustained release dosage form. Exemplary sustained release dosage forms include, without limitation, polymers, various coating substances, semipermeable membranes, liposomes, hydrogels, and the like.

[0092] The herein composition may be provided in various forms, including, a tablet, a paste, droplets, lozenges.

[0093] The herein composition may be a food supplement, provided within foods, beverages, or provided as a tablet (a pill) taken prior to, or concomitantly to a meal.

[0094] Methods for appetite suppression or method for treating a metabolic disorder.

[0095] The invention further provides a method for suppressing the appetite of a mammal in need thereof, wherein the method comprises administrating the herein composition.

[0096] The composition is preferably formulated as an orally administrable dosage form, such as a tablet. Advantageously, immediate release of appetite suppressing agents offers a rapid response to hunger cravings and appetite urges which are apparently part of the cycle of overeating in obese and morbidly obese subjects. Furthermore, the provision of an appetite suppressant in an immediate release form addresses the need for oral gratification which is prevalent in many obese subjects.

[0097] Accordingly, the composition and method of the invention, can be used in programs of weight loss and weight control in overweight subjects, including those who are classified as obese and morbidly obese or diabetic subjects.

[0098] According to one embodiment, the mammal is a human. According to one embodiment, the mammal is obese. According to another embodiment, the mammal is morbidly obese. According to another embodiment, the mammal is having diabetes. According to another embodiment, the mammal is having a type II diabetes.

[0099] In an embodiment of the invention, a method for treating diabetes comprising administering to a subject in need a first composition before or with a meal and a second composition after the meal, wherein the first composition comprising as a major ingredient a first T1R1 / T1R3, CaSR, GPRC6A modulator, and as a minor ingredient a first T1R2 / T1R3 modulator. The second composition comprising as a major ingredient a second T1R2 / T1R3 modulator and as a minor ingredient a second T1R1 / T1R3 , CaSR, GPRC6A modulator.

[0100] In one or more embodiments, the composition is effective in at least one of weight loss, reduced appetite, increase in satiety and treating obesity. In one or more embodiments, treatment further comprises administering a probiotic concomitantly or after the administration of the first and second compositions

[0101] One skilled in the art can appreciate from the foregoing description that the broad systems, devices, and techniques of the aspects of the present invention can be implemented in a variety of forms. Therefore, while the aspects of this invention have been described in connection with particular examples thereof, the true scope of the aspects of the invention should not be so limited since other modifications will become apparent to the skilled practitioner upon a study of the specification, and following claims.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising: component A and component B, wherein component A being formulated in an immediate release form and comprising at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator as a major active ingredient and at least one first T1R2 / T1R3 modulator as a minor active ingredient; component B being formulated in a delayed release form and comprising at least one second T1R2 / T1R3 modulator as a major ingredient and at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator as a minor ingredient; wherein the at least one first and second T1R1 / T1R3 - CaSR - GPRC6A modulators, each comprise, at least one modulator independently selected from the group consisting of a T1R1 / T1R3 modulator, a CaSR modulator and a GPRC6A modulator.

2. The composition according to claim 1, wherein the composition is for treating at least one of type 2 diabetes and obesity.

3. The composition according to claim 1, wherein the at least one first and second T1R1 / T1R3 - CaSR - GPRC6A modulators can be same or different and the at least one first and second T1R2 / T1R3 modulators can be same or different.

4. The composition according to claim 1, wherein the molar ratio between the at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator and the at least one first T1R2 / T1R3 modulator of component A is bigger than 1, and wherein the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator.

5. The composition according to claim 1 , wherein the molar ratio between the at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator and the at least one second T1R1 / T1R3 modulator of component B is smaller than 1, and wherein the T1R2 / T1R3 modulator molarity is normalized by multiplying by the sweetness index of the T1R2 / T1R3 modulator.

6. The composition according to claim 1, wherein the at least one T1R1 / T1R3 modulator is independently selected from at least one umami agent.

7. The composition according to claim 6, wherein the umami agent is selected from the group consisting of glutamate, glutamic acid and a salt thereof, 5 -guanosine monophosphate (5- GMP), 5- inosine monophosphate (5-IMP), aspartic acid, theanine, Ac-Glu, lactoyl-Glu, succinoyl-glu, a-glu-ala, y-glu-ala, fruvtosyl-pryroglutamic acid, (S)-morelid, (R)-strombine, L-AP4, NMD A, ibotemc acid, tricholomic acid, AMP, XMP, NHCH3, OCH3, SCH3, NH-CH2- CH2SCH3.NH-CH2CH2SCH3, NH-CO-CH2CH2S-CH3,Spilanthol, Ferna 4113, Ferna 4087, Ferna 4267, Rubemanine Ferna 4310 and Rebescenamine Ferna 4773.

8. The composition according to claim 1, wherein the molar ratio of the at least one first T1R1 / T1R3 - CaSR - GPRC6A modulator is at least 0.6, 0.7, 0.8, or 0.9 of the total concentration of component A.

9. The composition according to claim 1, wherein the molar ratio of the at least one second T1R1 / T1R3 - CaSR - GPRC6A modulator is less than 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 of the total concentration of component B.

10. The composition according to claim 1, wherein the delayed release formulation is adapted to release the second component in at least one of the duodenum, jejunum, ileum, and / or colon or at a pH environment of between 5.5 and 7.5, or below.

11. The composition according to claim 1, wherein the CaSR modulator is selected from at least one non-branched neutral or negatively charged amino acid.

12. The composition according to claim 1, wherein the CaSR modulator is selected from at least one of L-histidine and L-phenyalanine.

13. The composition according to claim 1, wherein component A comprises Ca2+, or Ca2+source, or an amino acid other than a branched chained positively charged amino acid.

14. The composition according to claim 1, wherein the GPRC6A modulator is saccharin.

15. The composition according to claim 1, wherein the T1R2 / T1R3 modulator is a sweetener or an oligofructose enriched inulin.

16. The composition according to claim 1, further comprising probiotics.

17. The composition according to claim 15, wherein the sweetener is characterized as at least one of a natural sweetener, artificial sweetener, high intensity sweetener, a low caloric sweetener, a non-nutritive sweetener or combination thereof.

18. The composition according to claim 15, wherein the sweetener is selected from at least one of a sugar, a sugar alcohol and a modified sugar.

19. The composition according to claim 15, wherein the sweetener is at least one of fructose, glucose, stevia, erythritol, xylitol, sucralose, and saccharine.

20. The composition according to claim 1, wherein component A comprises Glutamic acid, IMP and 5’-GMP.

21. The composition according to claim 1, wherein component A comprises: glutamine, 5’-GMP, calcium salt, at least one of L-histidine or L-phenylalanine, saccharine and sucralose; and component B comprises: sucralose, L-glutamic acid or salt thereof, glutamine, L-arginine and L-lysine.

22. A method for treating diabetes comprising administering to a subject in need a first composition before or with a meal and a second composition after the meal, wherein the first composition comprising a major ingredient and a minor ingredient, the major ingredient being a first T1R1 / T1R3 - CaSR - GPRC6A modulator mixture and the minor ingredient being a first T1R2 / T1R3 modulator; the second composition comprising a major ingredient and a minor ingredient, the major ingredient being a second T1R2 / T1R3 modulator and the minor ingredient being a second T1R1 / T1R3 - CaSR - GPRC6A modulator mixture wherein the first and second T1R1 / T1R3 - CaSR - GPRC6A modulator mixtures comprise at least one modulator independently selected from the group consisting of a T1R1 / T1R3 modulator, a CaSR modulator and a GPRC6A modulator.

23. The method according to claim 22, further affecting at least one of weight loss, reduced appetite, increase in satiety and treating obesity.

24. The method according to claim 22, wherein the T1R1 / T1R3 modulator is at least one umami agent selected from glutamate, guanosine mono phosphate (GMP) and inosine monophosphate (IMP).

25. The method according to claim 22 wherein the T1R2 / T1R3 modulator is a sweetener.

26. The method according to claim 22 wherein the first composition is a first component formulated in an immediate release form and the second composition is a second component formulated in a delayed release form in a combined composition.

27. The method according to claim 26, wherein the composition is as defined in claim 1.

28. The method according to claim 22 further comprising administering a probiotic concomitantly or after the administration of the first and second compositions.

Images