Compositions and methods for the treatment of liver diseases and disorders associated with one or both of hyperammonemia or muscle wasting

1. A composition comprising:

a) a Branched Chain Amino Acid (BCAA) entity chosen from a leucine amino acid entity, an isoleucine amino acid entity, a valine amino acid entity, or a combination of two or three BCAA entities;

b) a Urea Cycle Amino Acid (UCAA) entity chosen from an ornithine amino acid entity chosen from L-ornithine or a salt thereof, citrulline, or a combination of either thereof; an aspartate amino acid entity; or a combination of two UCAA entities; and

c) an essential amino acid (EAA) entity chosen from a histidine amino acid entity, a lysine amino acid entity, or a threonine amino acid entity or a combination of two or three EAA entities;

wherein:

i) at least one amino acid entity of (a)-(c) is not provided as a peptide of more than 20 amino acid residues in length;

ii) the total weight (wt.) % of (a)-(c) is greater than the total wt. % of non-protein components or other protein components in the composition on a dry weight basis;

iii) one or two of tyrosine or glutamine, if present, is present at less than 1 wt. % of the total wt. of the composition on a dry weight basis; and

iv) two or three of phenylalanine, methionine, or tryptophan are absent from the composition.

2. The composition of claim 1 , wherein two, three, four, five, six, seven, or eight amino acid entities of (a)-(c) is not provided as a peptide of more than 20 amino acid residues in length.

3. The composition of claim 1 , wherein the composition does not comprise a peptide of more than 20 amino acid residues in length, or if a peptide of more than 20 amino acid residues in length is present, the peptide is present at less than 10 wt. % of the total wt. of amino acid entities in the composition in dry form.

4. The composition of claim 1 , wherein three, four, five, six, seven, or eight amino acid entities in (a)-(c) are in one or both of free amino acid form or salt amino acid form in the composition in dry form.

5. The composition of claim 4 , wherein at least 35 wt. % of the total wt. of the composition in dry form is three, four, five, six, seven, or eight amino acid entities in (a)-(c) in one or both of free amino acid form or salt amino acid form.

6. The composition of claim 1 , wherein:

i) the wt. % of the BCAA entities is at least 37 wt. % of the total wt. of amino acid entities in the composition in dry form;

ii) the wt. % of the UCAA entities is at least 25 wt. % of the total wt. of amino acid entities in the composition in dry form; or

iii) the wt. % of the EAA entities is at least 16 wt. % of the total wt. of amino acid entities in the composition in dry form.

7. The composition of claim 1 , wherein a wt. ratio of the BCAA entity or BCAA entities:the UCAA entity or UCAA entities:the EAA entity or EAA entities is 20+/−15%: 15+/−15%: 9+/−15%, where the ratios are determined based on an equivalent amount of each amino acid in free form.

8. The composition of claim 1 , wherein three, four, five, six, or seven amino acid entities in (a)-(c) are selected as follows:

i) the leucine amino acid entity is selected from: L-Leucine, Oxo-leucine (Alphaketoisocaproate (KIC)), HMB (betahydroxy-betamethylbutyrate), Isovaleryl-CoA, or N-Acetyl-Leucine;

ii) the isoleucine amino acid entity is selected from: L-Isoleucine, 2-Oxo-3-methyl-valerate (Alpha-ketobetamethylvaleric acid (KMV)), Threonine, Methylbutyrl-CoA, or N-Acetyl-Isoleucine;

iii) the valine amino acid entity is selected from: L-Valine, 2-Oxo-valerate (alphaketoisovalerate (KIV)), Isobutryl-CoA, or N-Acetyl-Valine;

iv) the ornithine amino acid entity is selected from: L-ornithine or salt thereof, or citrulline;

v) the aspartate amino acid entity is selected from: L-Aspartate, Fumarate, or Adenylosuccinate;

vi) the histidine amino acid entity is selected from: L-Histidine, Histidinol, Histidinal, Ribose-5-phosphate, Carnosine, Histamine, Urocanate, or N-Acetyl-Histidine;

vii) the lysine amino acid entity is selected from: L-Lysine, Diaminopimelate, Aspartate Trimethylhistidine, Carnitine, Saccharopine, N-Acetyl-Lysine, or L-Lysine Acetate; or

viii) the threonine amino acid entity is selected from: L-Threonine, Homoserine, O-PhosphoHomoserine, Oxobutyrate, or N-Acetyl-Threonine.

9. The composition of claim 1 , wherein the composition comprises:

a) the leucine amino acid entity is chosen from:

i) L-leucine or a salt thereof,

ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or

iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof;

b) one or both of:

i) the ornithine amino acid entity is L-ornithine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-ornithine; or

ii) the aspartate amino acid entity is L-aspartate or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-aspartate; and

c) the EAA entity is chosen from:

i) L-histidine or a salt thereof,

ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine,

iii) L-lysine or a salt thereof,

iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine,

v) L-threonine or a salt thereof, or

vi) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-threonine.

10. The composition of claim 9 , wherein the composition further comprises one or both of an isoleucine amino acid entity or a valine amino acid entity.

11. The composition of claim 10 , wherein the isoleucine amino acid-entity is L-isoleucine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-isoleucine.

12. The composition of claim 10 , wherein the valine amino acid entity is L-valine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine.

13. The composition of claim 10 , wherein a wt. ratio of the leucine amino acid entity:the isoleucine amino acid entity:the valine amino acid entity:the ornithine amino acid entity:the aspartate amino acid entity:the histidine amino acid entity:the threonine amino acid entity:the lysine amino acid entity is 8+/−20%:4+/−20%:8+/−20%:7.5+/−20%: 7.5+/−20%:3+/−20%:3+/−20%:3+/−20%, where the ratios are determined based on an equivalent amount of each amino acid in free form.

14. The composition of claim 1 , wherein the composition comprises: L-leucine or a salt thereof, L-isoleucine or a salt thereof, L-valine or a salt thereof, L-ornithine or a salt thereof, L-aspartate or a salt thereof, L-histidine or a salt thereof, L-threonine or a salt thereof, and L-lysine or a salt thereof.

15. The composition of claim 1 , wherein the composition is formulated with a pharmaceutically acceptable carrier.

16. The composition of claim 1 , wherein the composition is formulated as a dietary composition.

17. The composition of claim 1 , wherein the composition comprises:

(a) a leucine amino acid entity chosen from:

(i) L-leucine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or

(iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof;

(b) an isoleucine amino acid entity chosen from:

(i) L-isoleucine or a salt thereof, or

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-isoleucine;

(c) a valine amino acid entity chosen from:

(i) L-valine or a salt thereof, or

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine;

(d) an ornithine amino acid entity chosen from:

(i) L-ornithine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-ornithine,

(iii) L-citrulline or a salt thereof, or

(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-citrulline; and

(e) an essential amino acid (EAA) entity chosen from:

(i) L-histidine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine,

(iii) L-lysine or a salt thereof,

(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine,

(v) L-threonine or a salt thereof,

(vi) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-threonine, or

(vii) or a combination of one, two, or three EAA entities, wherein:

(f) the total weight (wt.) % of (a)-(e) is greater than the total wt. % of non-protein components or other protein components in the composition on a dry weight basis;

(g) glutamine, if present, is present at less than 1 wt. % of the total wt. of the composition on a dry weight basis; and

(h) two or three of phenylalanine, methionine, or tryptophan are absent from the composition.

18. The composition of claim 17 , wherein the wt. % of the leucine amino acid entity, isoleucine amino acid entity, and valine amino acid entity is greater than the wt. % of the ornithine amino acid entity.

19. The composition of claim 17 , wherein the wt. % of the leucine amino acid entity, isoleucine amino acid entity, valine amino acid entity, and ornithine amino acid entity is greater than the wt. % of the EAA or the combination or two or three EAAs.

20. The composition of claim 17 , further comprising an aspartate amino acid entity chosen from L-aspartate or a salt thereof, or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-aspartate; fumarate; adenylosuccinate; or a combination thereof.

21. The composition of claim 20 , wherein a wt. ratio of the leucine amino acid entity:the isoleucine amino acid entity:the valine amino acid entity:the ornithine amino acid entity:the aspartate amino acid entity:the L-histidine or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine:the L-threonine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-threonine:the L-lysine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine is 8+/−20%:4+/−20%:8+/−20%:7.5+/−20%:7.5+/−20%:3+/−20%:3+/−20%:3+/−20%, where the ratios are determined based on an equivalent amount of each amino acid in free form.

22. The composition of claim 1 , wherein methionine is absent from the composition.

23. The composition of claim 1 , wherein tryptophan is absent from the composition.

24. The composition of claim 1 , wherein methionine and tryptophan are absent from the composition.

25. The composition of claim 1 , wherein methionine, phenylalanine, and tryptophan are absent from the composition.

26. A composition comprising:

a) a Branched Chain Amino Acid (BCAA) entity chosen from a leucine amino acid entity, an isoleucine amino acid entity, a valine amino acid entity, or a combination of two or three BCAA entities;

b) a Urea Cycle Amino Acid (UCAA) entity chosen from an ornithine amino acid entity chosen from L-ornithine or salt thereof, citrulline, or a combination of either thereof; an aspartate amino acid entity; or a combination of two UCAA entities; and

c) an essential amino acid (EAA) entity chosen from a histidine amino acid entity, a lysine amino acid entity, or a threonine amino acid entity or a combination of two or three EAA entities;

wherein:

i) at least one amino acid entity of (a)-(c) is not provided as a peptide of more than 20 amino acid residues in length;

ii) the total weight (wt.) % of (a)-(c) is greater than the total wt. % of non-protein components or other protein components in the composition on a dry weight basis;

iii) two or more of phenylalanine, tyrosine, or glutamine is absent from the composition, or if present, is present at less than 1 wt. % of the total wt. of the composition on a dry weight basis; and

iv) wherein a wt. ratio of the BCAA entity or BCAA entities:the UCAA entity or UCAA entities:the EAA entity or EAA entities is 20+/−15%: 15+/−15%: 9+/−15%, where the ratios are determined based on an equivalent amount of each amino acid in free form.

27. A composition comprising:

(a) a leucine amino acid entity chosen from:

(i) L-leucine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or

(iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof;

(b) an isoleucine amino acid entity chosen from:

(i) L-isoleucine or a salt thereof, or

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-isoleucine;

(c) a valine amino acid entity chosen from:

(i) L-valine or a salt thereof, or

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine;

(d) an ornithine amino acid entity chosen from:

(i) L-ornithine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-ornithine,

(iii) L-citrulline or a salt thereof, or

(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-citrulline; and

(e) an essential amino acid (EAA) entity chosen from:

(i) L-histidine or a salt thereof,

(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine,

(iii) L-lysine or a salt thereof,

(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine,

(v) L-threonine or a salt thereof,

(vi) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-threonine, or

(vii) or a combination of one, two, or three EAA entities, and

(f) an aspartate amino acid entity chosen from:

(i) L-aspartate or a salt thereof, or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-aspartate,

(ii) fumarate,

(iii) adenylosuccinate, or

(iv) a combination thereof,

wherein:

(g) the total weight (wt.) % of (a)-(f) is greater than the total wt. % of non-protein components or other protein components in the composition on a dry weight basis;

(h) glutamine, if present, is present at less than 1 wt. % of the total wt. of the composition on a dry weight basis; and

(i) a wt. ratio of the leucine amino acid entity:the isoleucine amino acid entity:the valine amino acid entity:the ornithine amino acid entity:the aspartate amino acid entity:the L-histidine or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-histidine:the L-threonine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-threonine:the L-lysine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-lysine is 8+/−20%:4+/−20%:8+/−20%:7.5+/−20%:7.5+/−20%:3+/−20%:3+/−20%:3+/−20%, where the ratios are determined based on an equivalent amount of each amino acid in free form.

28. A composition comprising:

(a) L-leucine or a salt thereof;

(b) L-isoleucine or a salt thereof;

(c) L-valine or a salt thereof;

(d) L-ornithine or a salt thereof;

(e) L-histidine or a salt thereof;

(f) L-lysine or a salt thereof;

(g) L-threonine or a salt thereof; and

(h) L-aspartate or a salt thereof,

wherein:

(h) the total weight (wt.) % of (a)-(h) is greater than the total wt. % of non-protein components or other protein components in the composition on a dry weight basis; and

(i) two or three of phenylalanine, methionine, and tryptophan is absent from the composition.

29. The composition of claim 28 , wherein the L-ornithine or a salt thereof is chosen from L-ornithine, L-ornithine L-aspartate (LOLA), ornithine α-ketoglutarate, or ornithine HCl.

30. The composition of claim 28 , wherein the L-ornithine or a salt thereof in (d) and the L-aspartate or salt thereof in (h) are provided as L-ornithine L-aspartate (LOLA).

31. The composition of claim 28 , wherein methionine, phenylalanine, and tryptophan are absent from the composition.

32. The composition of claim 1 , wherein the L-ornithine or salt thereof is chosen from L-ornithine, L-ornithine L-aspartate (LOLA), ornithine α-ketoglutarate, or ornithine HCl.

33. The composition of claim 1 , wherein the combination of two UCAA entities of b) comprises the ornithine amino acid entity and the aspartate amino acid entity.

34. The composition of claim 33 , wherein the ornithine amino acid entity is L-ornithine or a salt thereof, and the aspartate amino acid entity is L-aspartate or a salt thereof.

35. The composition of claim 34 , wherein the L-ornithine or a salt thereof and the L-aspartate or salt thereof are provided as L-ornithine L-aspartate (LOLA).

36. The composition of claim 26 , wherein the combination of two UCAA entities of b) comprises the ornithine amino acid entity and the aspartate amino acid entity.

37. The composition of claim 36 , wherein the ornithine amino acid entity is L-ornithine or a salt thereof, and the aspartate amino acid entity is L-aspartate or a salt thereof.

38. The composition of claim 37 , wherein the L-ornithine or a salt thereof and the L-aspartate or salt thereof are provided as L-ornithine L-aspartate (LOLA).

39. The composition of claim 26 , wherein the L-ornithine or salt thereof is chosen from L-ornithine, L-ornithine L-aspartate (LOLA), ornithine α-ketoglutarate, or ornithine HCl.

40. The composition of claim 27 , wherein the ornithine amino acid entity comprises L-ornithine or a salt thereof and the aspartate amino acid entity comprises L-aspartate or a salt thereof.

41. The composition of claim 40 , wherein the L-ornithine or a salt thereof and the L-aspartate or salt thereof are provided as L-ornithine L-aspartate (LOLA).

42. The composition of claim 27 , wherein the L-ornithine or salt thereof is chosen from L-ornithine, L-ornithine L-aspartate (LOLA), ornithine α-ketoglutarate, or ornithine HCl.