Compositions and methods for modulating metabolic pathways

• US 9,682,053 B2
• Filed: 05/25/2016
• Issued: 06/20/2017
• Est. Priority Date: 07/15/2011
• Status: Active Grant

• Current Assignee: Nusirt Sciences, Inc.
• Original Assignee: Nusirt Sciences, Inc.
• Inventors: Grindstaff, II, E. Douglas, Bruckbauer, Antje, Zemel, Michael
• Primary Examiner(s): LOVE, TREVOR M
• Application Number:
  US15/164,647
• Publication Number:
  US 20160338983A1
• Time in Patent Office: 391 Days
• CPC Class Codes: A23L 2/52 Adding ingredients adding preservatives A23L2/44
• CPC Class Codes: A23L 33/175 Amino acids
• CPC Class Codes: A23L 33/30 Dietetic or nutritional methods, e.g. for losing weight A23L33/10 takes precedence
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 36/87 : Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
• CPC Class Codes: A61K 38/22 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications

Abstract

Compositions and methods useful for inducing an increase in fatty acid oxidation or mitochondrial biogenesis, reducing weight gain, inducing weight loss, or increasing Sirt1, Sirt3, or AMPK activity are provided herein. Such compositions can contain synergizing amounts of a sirtuin-pathway activators, including but not limited to resveratrol, in combination with beta-hydroxymethylbutyrate (HMB), keto isocaproic acid (KIC), leucine, or combinations of HMB, KIC and leucine.

Claims

1. A composition comprising:

(a) at least 500 mg of leucine and/or at least 200 mg of one or more metabolites thereof, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

(b) at least 1 mg of a sirtuin pathway activator that is an anti-diabetic agent selected from the group consisting of a dipeptidyl peptidase (DPP) inhibitor, incretin and/or incretin mimetic;

wherein the composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline;

wherein the composition is formulated as a tablet, capsule, gel capsule, beverage, snack bar or a food composition;

wherein when (a) is a metabolite of leuine the molar ratio of (a) to (b) is greater than 10; and

wherein when (a) is leucine, the molar ratio of (a) to (b) is greater than 500.

2. The composition of claim 1, wherein the composition comprises a subtherapeutic amount of the anti-diabetic agent.

3. The composition of claim 1, wherein when (a) is leucine, the molar ratio of (a) to (b) is greater than 1000.

4. The composition of claim 1, wherein when (a) is HMB.

5. The composition of claim 1, wherein the anti-diabetic agent is a DPP inhibitor.

6. The composition of claim 1, wherein the DPP inhibitor is selected from a group consisting of sitagliptin, vildagliptin, saxagliptin, lingliptin, dutogliptin, gemigliptin, alogliptin, and berberine.

7. The composition of claim 1, wherein the anti-diabetic agent is an incretin.

8. The composition of claim 1, wherein the anti-diabetic agent is an incretin mimetic.

9. The composition of claim 1, wherein the incretin mimetic is selected from the group consisting of exenatide and liraglutide.

10. The composition of claim 1, further comprising a biguanide.

11. The composition of claim 10, wherein the biguanide is metformin.

12. The composition of claim 11, wherein the metformin is at an amount about 25 mg to about 2000 mg.

13. The composition of claim 1, further comprising thiazolidinedione.

14. The composition of claim 1, further comprising rosiglitazone.

15. The composition of claim 1, further comprising an additional sirtuin pathway activator that activates one or more of SIRT1, SIRT3, AMPK, and PGC1α

.

16. The composition of claim 1, further comprising at least one of a hydroxycinnamic acid, a stilbene, a polyphenol or a polyphenol precursor.

17. The composition of claim 16, wherein the polyphenol or polyphenol precursor is selected from a group consisting of chlorogenic acid, resveratrol, caffeic acid, cinnamic acid, ferulic acid, piceatannol, ellagic acid, epigallocatechin gallate, grape seed extract, and any analog thereof.

18. The composition of claim 1, further comprising resveratrol.

19. The composition of claim 1, further comprising a phosphodiesterase inhibitor.

20. The composition of claim 1, wherein the composition is substantially free of an individual non-branched amino acid.

21. The composition of claim 1, wherein the composition is formulated as a unit dose.

22. A method for treating diabetes in a subject in need thereof comprising:

administering to the subject the composition of claim 1, wherein the insulin sensitivity in the subject is increased.

23. The method of claim 22, wherein the fat oxidation in the subject is increased or the inflammatory response in the subject is decreased.

24. A method for increasing mitochondrial biogenesis in a subject in need thereof comprising:

administering to the subject the composition of claim 1, wherein the mitochondrial biogenesis levels in the subject is increased.

25. The method of claim 24, wherein the mitochondrial biogenesis output is increased by at least 1 fold.

26. A method for treating a metabolic disorder in a subject in need thereof comprising:

administering to the subject the composition of claim 1, wherein the condition of the subject'"'"'s metabolic disease is improved.