Mineral amino-acid complexes of active agents

1. A compound of Formula I which is a mono or bis salt of a polyunsaturated fatty acid having an amino acid component, which consists of two amino acid moieties coordinated around a divalent metal cation, a metal component, which consists of a divalent metal cation, and a counter-ion component, which consists of one or two additional molecules, A and B, ionically bound to the amino acid component,

wherein

R 1 and R 2 each refer to a branched or unbranched carbon chain of from 1 to 20 carbons having at least one basic function;

R 1 and R 2 are the same or different and the at least one basic function is independently selected from a primary amine, a secondary amine, a tertiary amine, and a guanidine;

X 1 and X 2 are independently selected from H and —CO—Z, where Z is a peptide moiety incorporating from 1 to 5 amino acids, or a pharmaceutically acceptable salt thereof;

X 1 and X 2 are the same or different;

M is a divalent metal cation selected from magnesium (Mg 2+ ), calcium (Ca 2+ ), and zinc (Zn 2+ );

A and B are each independently selected from a polyunsaturated fatty acid having 16 to 24 carbon atoms

either A or B, but not both, may be absent, and

when both A and B are present, A and B may be the same or different.

2. The compound of claim 1 , wherein X 1 and X 2 are each H.

3. The compound of claim 2 , wherein R 1 and R 2 are each (CH 2 ) 3 —Y 1 and Y 1 is NHC(NH 2 +)NH 2 .

4. The compound of claim 2 , wherein R 1 and R 2 are each (CH 2 ) 4 —Y 2 and Y 2 is NH 3 +.

5. The compound of claim 4 , wherein each polyunsaturated fatty acid is independently selected from an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, and an omega-9 fatty acid.

6. The compound of claim 5 , wherein A and B are independently selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA), hexadecatrienoic acid (HTA), α-Linolenic acid (ALA), stearidonic acid (SDA), eicosenoic acid, eicosatrienoic acid (ETE), all-cis-5,8,11-eicosatrienoic acid, eicosatetraenoic acid (ETA), heneicosapentaenoic acid (HPA), tetracosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, gamma-linolenic acid (GLA), calendic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid, adrenic acid, docosadienoic acid, docosapentaenoic acid (Osbond acid), tetracosapentaenoic acid, 24:5 (n-6), tetracosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, mead acid, erucic acid, and nervonic acid.

7. The compound of claim 6 , wherein the polyunsaturated fatty acid is an omega-3 fatty acid selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), hexadecatrienoic acid (HTA), α-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), heneicosapentaenoic acid (HPA), tetracosapentaenoic acid, and tetracosahexaenoic acid.

8. The compound of claim 7 , wherein the omega-3 fatty acid is selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

9. The compound of claim 6 , wherein the polyunsaturated fatty acid is an omega-6 fatty acid selected from the group consisting of linoleic acid, gamma-linolenic acid (GLA), eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid (Osbond acid), tetracosatetraenoic acid, and tetracosapentaenoic acid, 24:5 (n-6).

10. The compound of claim 6 , wherein the polyunsaturated fatty acid is an omega-9 fatty acid selected from the group consisting of mead acid, 20:3 (n-9), all-cis-5,8,11-eicosatrienoic acid, oleic acid, eicosenoic acid, erucic acid, and nervonic acid.

11. A dosage form comprising the compound of claim 1 and an optional carrier, the dosage form selected from a gel, a cream, a powder, a tablet, a capsule, a caplet, or an aqueous solution.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , wherein the composition further comprises one or more additional active pharmaceutical agents (APIs).

14. The pharmaceutical composition of claim 13 , wherein the one or more additional APIs is selected from the group consisting of antihyperlipidemic agent, an anti-diabetic agent, an anti-epileptic agent, and an anti-inflammatory agent, and combinations thereof.

15. The pharmaceutical composition of claim 14 , wherein the one or more additional APIs is an antihyperlipidemic agent is selected from an HMG CoA enzyme inhibitor, a cholesterol absorption inhibitor, and a cholesterol esterase transfer protein (CETP) inhibitor, and combinations thereof.

16. The pharmaceutical composition of claim 15 , wherein the antihyperlipidemic agent is a statin.

17. The pharmaceutical composition of claim 16 , wherein the statin is selected from the group consisting of atorvastatin, risuvostatin, simvastatin, pravastatin, and pharmaceutically acceptable salts or prodrugs thereof.

18. A solid unit dosage form comprising the compound claim 1 .

19. The solid unit dosage form of claim 18 , wherein the unit dosage form comprises from about 0.05 g to 12 g of total fatty acids.

20. A method for delivering free fatty acids, or a mixture of two or more different free fatty acids, in ionic form to a subject, the method comprising administering to the subject the compound of claim 1 .

21. A method for delivering free fatty acids, or a mixture of free fatty acids, in ionic form and at least one divalent metal cation selected from magnesium (Mg 2+ ), calcium (Ca 2+ ), and zinc (Zn 2+ ) to a subject, the method comprising administering to the subject the compound of claim 1 .

22. A method for treating a disease or disorder responsive to treatment with a polyunsaturated fatty acid, the method comprising administering to the subject the compound of claim 1 .

23. The method of claim 22 , wherein at least 50 wt % of the fatty acid component of the compound or composition consists of one or more omega-3 fatty acids independently selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

24. The method of claim 22 , wherein the disease or disorder is selected from a metabolic disease or disorder, a cardiovascular disease or disorder, a hematological disorder, cancer, an inflammatory disease or disorder, and a neurological disease or disorder.

25. The method of claim 24 , wherein the metabolic disease or disorder is type 2 diabetes, pre-diabetes, insulin resistance, hypertriglyceridemia due to elevated triglycerides, mixed dyslipidemia, hypercholesterolemia, fatty liver or obesity due to the combination of abnormal glucose and lipid metabolism.

26. The method of claim 24 , wherein the metabolic disease or disorder is hypertriglyceridemia, severe hypertriglyceridemia, hypercholesterolemia, pre-diabetes, fatty liver disease, or obesity.

27. The method of claim 24 , wherein the cardiovascular disease or disorder is atrial fibrillation, myocardial infarction, or congestive heart failure.

28. The method of claim 24 , wherein the cancer is familial adenomatous polyposis.

29. The method of claim 24 , wherein the inflammatory disease or disorder is arthritis, inflammatory bowel disease, or psoriasis.

30. The method of claim 24 , wherein the inflammatory disease or disorder is an ophthalmic inflammation disorder or dry eye syndrome.

31. The method of claim 24 , wherein the neurological disease or disorder is a psychiatric disorder selected from Alzheimer's disease, attention deficit hyperactivity disorder (ADHD) or depression.

32. The method of claim 24 , wherein the neurological disease or disorder is a neuro trauma injury selected from traumatic brain injury, spinal cord injury, ischemic stroke, or concussion.

33. The compound of claim 1 , wherein R 1 and R 2 are each (CH 2 ) 4 —NH 3 + , X 1 and X 2 are each H, and A and B are both present and the same and are selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and arachidonic acid (AA).

34. The compound of claim 33 , wherein the divalent metal cation is Mg 2+ .

35. The compound of claim 33 , wherein the divalent metal cation is Ca 2+ or Zn 2+ .

36. The compound of claim 34 , wherein A and B are AA.

37. The compound of claim 35 , wherein A and B are EPA.

38. The compound of claim 35 , wherein A and B are DHA.

39. The compound of claim 35 , wherein A and B are DPA.

40. The compound of claim 35 , wherein A and B are AA.

41. A compound of Formula I which is a bis salt of a polyunsaturated fatty acid having an amino acid component, which consists of two amino acid moieties coordinated around a divalent metal cation, a metal component, which consists of a divalent metal cation, and a counter-ion component, which consists of one or two additional molecules, A and B, ionically bound to the amino acid component,

wherein

R 1 and R 2 are each (CH 2 ) 4 —NH 3 + ;

X 1 and X 2 are each H;

M is magnesium (Mg 2 + ); and

A and B are each eicosapentaenoic acid (EPA).

42. A dosage form comprising the compound of claim 41 and an optional carrier, the dosage form selected from a gel, a cream, a powder, a tablet, a capsule, a caplet, or an aqueous solution.

43. A pharmaceutical composition comprising the compound of claim 41 and a pharmaceutically acceptable carrier.

44. The pharmaceutical composition of claim 43 , wherein the composition further comprises one or more additional active pharmaceutical agents (APIs).

45. The pharmaceutical composition of claim 44 , wherein the one or more additional APIs is selected from the group consisting of antihyperlipidemic agent, an anti-diabetic agent, an anti-epileptic agent, and an anti-inflammatory agent, and combinations thereof.

46. The pharmaceutical composition of claim 45 , wherein the one or more additional APIs is an antihyperlipidemic agent selected from an HMG CoA enzyme inhibitor, a cholesterol absorption inhibitor, and a cholesterol esterase transfer protein (CETP) inhibitor, and combinations thereof.

47. The pharmaceutical composition of claim 46 , wherein the antihyperlipidemic agent is a statin.

48. The pharmaceutical composition of claim 47 , wherein the statin is selected from the group consisting of atorvastatin, risuvostatin, simvastatin, pravastatin, and pharmaceutically acceptable salts or prodrugs thereof.

49. A solid unit dosage form comprising the compound of claim 41 .

50. The solid unit dosage form of claim 49 , wherein the unit dosage form comprises from about 0.05 g to 12 g of total fatty acids.

51. A method for treating a metabolic disease or disorder in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 41 , wherein the metabolic disease or disorder is selected from, type 2 diabetes, pre-diabetes, insulin resistance hypertriglyceridemia due to elevated triglycerides, mixed dyslipidemia, hypercholesterolemia, fatty liver or obesity due to the combination of abnormal glucose and lipid metabolism.

52. The method of claim 51 , wherein the metabolic disease or disorder is selected from hypertriglyceridemia, severe hypertriglyceridemia, hypercholesterolemia, pre-diabetes, fatty liver disease, and obesity.

53. A method for treating an inflammatory disease or disorder in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 41 , wherein the inflammatory disease or disorder is arthritis or psoriasis.

54. A method for treating inflammatory bowel disease in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 41 .

55. A method for treating familial adenomatous polyposis in a human subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of claim 41 .

56. A compound of Formula I which is a bis salt of a polyunsaturated fatty acid having an amino acid component, which consists of two amino acid moieties coordinated around a divalent metal cation, a metal component, which consists of a divalent metal cation, and a counter-ion component, which consists of one or two additional molecules, A and B, ionically bound to the amino acid component,

wherein

R 1 and R 2 are each (CH 2 ) 4 —NH 3 + ;

X 1 and X 2 are each H;

M is magnesium (Mg 2+ ); and

A and B are each docosahexaenoic acid (DHA).

57. A compound of Formula I which is a bis salt of a polyunsaturated fatty acid having an amino acid component, which consists of two amino acid moieties coordinated around a divalent metal cation, a metal component, which consists of a divalent metal cation, and a counter-ion component, which consists of one or two additional molecules, A and B, ionically bound to the amino acid component,

wherein

R 1 and R 2 are each (CH 2 ) 4 —NH 3 + ;

X 1 and X 2 are each H;

M is magnesium (Mg 2+ ); and

A and B are each docosapentaenoic acid (DPA).