Formulations of l-ornithine phenylacetate

Abstract

Some embodiments of the present application are directed to oral formulations of L-ornithine phenylacetate and methods of using the same. These oral formulations offer alternative administration route than the standard intravenous administration of L-ornithine phenylacetate for treating hyperammonemia in patients having various acute and chronic liver diseases and disorders, for example, acute liver failure, liver cirrhosis, liver decompensation, portal hypertension, hepatic encephalopathy, or patients with urea cycle disorders.

1 .- 51 . (canceled) 
     
     
         52 . A method for treating or ameliorating hyperammonemia in a subject in need thereof, comprising orally administering a pharmaceutical formulation comprising L-ornithine phenylacetate in a daily oral dosage of about 8 g to about 15 g to the subject. 
     
     
         53 . The method of  claim 52 , wherein the pharmaceutical formulation comprising L-ornithine phenylacetate is an immediate release formulation. 
     
     
         54 . The method of  claim 52 , wherein the subject has acute liver failure, a chronic liver disease, liver cirrhosis, liver decompensation or portal hypertension. 
     
     
         55 . The method of  claim 52 , wherein the subject has hepatic encephalopathy or a urea cycle disorder. 
     
     
         56 . The method of  claim 52 , wherein the pharmaceutical formulation is administered once a day. 
     
     
         57 . The method of  claim 56 , wherein the pharmaceutical formulation is in a single unit dosage form or two or more unit dosage forms. 
     
     
         58 . The method of  claim 52 , wherein the pharmaceutical formulation is administered two or more times a day. 
     
     
         59 . The method of  claim 58 , comprising orally administering 2 to 5 unit dosage forms each comprising from about 0.5 g to about 2 g L-ornithine phenylacetate two or three times a day. 
     
     
         60 . The method of  claim 58 , wherein the pharmaceutical formulation is administered two times a day, each time administering about 4 g to about 6 g L-ornithine phenylacetate. 
     
     
         61 . The method of  claim 52 , wherein the administration provides conversion of phenylacetate to phenylacetylglutamine over 24 hours of greater than about 80%. 
     
     
         62 . A method for treating or ameliorating hyperammonemia in a subject in need thereof, comprising orally administering a pharmaceutical formulation comprising L-ornithine phenylacetate in a daily dosage of about 8 g to about 15 g to the subject, wherein said administration provides a plasma Cmax of phenylacetic acid ranging from about 10 μg/mL to about 150 μg/mL. 
     
     
         63 . The method of  claim 62 , wherein the pharmaceutical formulation comprising L-ornithine phenylacetate is an immediate release formulation. 
     
     
         64 . The method of  claim 62 , wherein the subject has acute liver failure, a chronic liver disease, liver cirrhosis, liver decompensation, portal hypertension, hepatic encephalopathy or a urea cycle disorder. 
     
     
         65 . The method of  claim 62 , wherein the pharmaceutical formulation is administered once a day. 
     
     
         66 . The method of  claim 62 , wherein the pharmaceutical formulation is administered two or more times a day. 
     
     
         67 . The method of  claim 66 , comprising orally administering 2 to 5 unit dosage forms each comprising from about 0.5 g to about 2 g L-ornithine phenylacetate two or three times a day. 
     
     
         68 . The method of  claim 66 , wherein the pharmaceutical formulation is administered two times a day, each time administering about 4 g to about 6 g L-ornithine phenylacetate. 
     
     
         69 . The method of  claim 62 , wherein the plasma Cmax level of phenylacetic acid is from about 40 μg/mL to about 120 μg/mL. 
     
     
         70 . The method of  claim 62 , wherein the administration provides a plasma Cmax of phenylacetylglutamine ranging from about 5 μg/mL to about 100 μg/mL. 
     
     
         71 . The method of  claim 70 , wherein the plasma Cmax of phenylacetylglutamine is from about 25 μg/mL to about 50 μg/mL.