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

1. A method of treating a liver disease or disorder with one or both of hyperammonemia or muscle wasting, wherein the method comprises administering to a subject in need thereof an effective amount of 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) 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) one, two, or three of phenylalanine, methionine, and tryptophan is absent from the composition.

2. The method of claim 1 , wherein the subject has cirrhosis.

3. The method of claim 1 , wherein the subject has sarcopenia.

4. The method of claim 1 , wherein the subject has hepatic encephalopathy.

5. The method of claim 1 , wherein the subject has hepatic insufficiency.

6. The method of claim 1 , wherein the subject has End Stage Liver Disease.

7. The method of claim 1 , wherein the composition is administered within one hour of a meal.

8. The method of claim 1 , wherein the composition is administered at least once in the late evening or once before bedtime.

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

10. The method of claim 1 , wherein tyrosine is absent from the composition.

11. The method of claim 1 , wherein tyrosine is present at less than 1 wt. % of the total wt. of the composition on a dry weight basis.

12. The method 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 on a dry weight basis.

13. The method of claim 1 , wherein at least 35 wt. % of the total wt. of the composition on a dry weight basis is three, four, five, six, or seven amino acid entities in (a)-(e) in one or both of free amino acid form or salt amino acid form.

14. The method of claim 1 , 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.

15. The method of claim 1 , 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.

16. The method of claim 1 , 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.

17. The method of claim 16 , 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.

18. The method of claim 1 , wherein the composition is formulated with one or more pharmaceutically acceptable carriers.

19. The method 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.

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

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

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

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

24. A method of treating a liver disease or disorder with one or both of hyperammonemia or muscle wasting, wherein the method comprises administering to a subject in need thereof an effective amount of 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;

(e) a histidine amino acid entity chosen from:

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

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

(f) a lysine amino acid entity chosen from:

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

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

(g) a threonine amino acid entity chosen from:

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

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

(h) 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 of (i)-(iii), wherein:

(i) 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

(j) 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.

25. A method of treating a liver disease or disorder having one or both of hyperammonemia or muscle wasting, wherein the method comprises administering to a subject in need thereof an effective amount of 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) one, two, or three of phenylalanine, methionine, and tryptophan is absent from the composition.

26. The method of claim 25 , wherein the L-ornithine or a salt thereof is chosen from L-ornithine, L-ornithine L-aspartate (LOLA), ornithine α-ketoglutarate, or ornithine HCl.

27. The method of claim 25 , wherein the L-ornithine or a salt thereof in (d) and the L-aspartate or salt thereof in (h) are provided in L-ornithine L-aspartate (LOLA).

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