Methods and formulations for treating sialic acid deficiencies

Abstract

The present invention relates to compositions and methods for treating sialic acid deficiencies comprising extended release formulations.

1 .- 23 . (canceled) 
     
     
         24 . A method for treating a sialic acid deficiency in a human patient in need thereof comprising orally administering a solid dosage form two, three, or four times per day, wherein the solid dosage form is an extended release formulation comprising a blend of:
 a) N-acetylneuraminic acid (NeuAc), or a pharmaceutically acceptable salt, or solvate thereof;   b) one or more hydrophilic polymers or hydrogel;   c) one or more anionic, pH-dependent, gel-forming polymers; and   d) one or more hydrocolloid polymers or one or more cationic polymers;   
       wherein the method provides a therapeutically effective amount of NeuAc over a period of greater than about four hours and a steady plasma level of free NeuAc. 
     
     
         25 . The method of  claim 24 , wherein the solid dosage form comprises about 20% to about 80% w/w NeuAc. 
     
     
         26 . The method of  claim 24 , wherein the solid dosage form comprises about 30% to about 60% w/w NeuAc. 
     
     
         27 . The method of  claim 24 , wherein the solid dosage form comprises about 40% to about 45% w/w NeuAc. 
     
     
         28 . The method of  claim 24 , wherein the one or more hydrophilic polymers comprise one or more water-swellable, pH independent polymers selected from the group consisting of hypromellose; hydroxypropyl ethyl cellulose; hydroxypropyl cellulose; hydroxyethyl cellulose; and methyl cellulose. 
     
     
         29 . The method of  claim 28 , wherein the one or more water-swellable, pH independent polymers comprise hypromellose. 
     
     
         30 . The method of  claim 24 , wherein the hydrogel is selected from polyhydroxyethyle methylacrylate (PHEMA), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), or polyacrylamide (PA). 
     
     
         31 . The method of  claim 24 , wherein one or more anionic, pH-dependent, gel-forming polymers comprise an alginate salt. 
     
     
         32 . The method of  claim 24 , wherein the alginate salt comprises sodium alginate. 
     
     
         33 . The method of  claim 24 , wherein the one or more hydrocolloid polymers comprise one or more carrageenans. 
     
     
         34 . The method of  claim 33 , wherein the one or more carrageenans comprise lamda carrageenan. 
     
     
         35 . The method of  claim 24 , wherein the solid dosage form further comprises about 1% to about 10% of a mixture of microcrystalline cellulose and colloidal silicon dioxide. 
     
     
         36 . The method of  claim 24 , wherein the solid dosage form further comprises about 0.1% to about 1% of one or more lubricants. 
     
     
         37 . The method of  claim 36 , wherein the one or more lubricants comprise magnesium stearate. 
     
     
         38 . The method of  claim 24 , which provides a therapeutically effective amount of sialic acid over a period of greater than about eight hours or twelve hours. 
     
     
         39 . The method of  claim 24 , wherein the solid dosage form further comprises an immediate release formulation containing N-acetylneuraminic acid (NeuAc), or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 24 , wherein the method provides a mean plasma concentration of free NeuAc at steady state during dosing intervals that is at least about 50% higher than the mean plasma concentration of free NeuAc in the human patient before the administration of the NeuAc, or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 24 , wherein the method provides a mean plasma concentration of free NeuAc at steady state during the dosing intervals that is at least about 0.16 mcg/ml. 
     
     
         42 . The method of  claim 24 , wherein the method provides a plasma concentration profile of free NeuAc at steady state such that the minimum plasma concentration of free NeuAc during the dosing interval is at least about 35% of the maximum plasma concentration during the dosing interval. 
     
     
         43 . The method of  claim 24 , wherein the method provides an improved absorption profile when the extended release formulation is administered under fed conditions than being administered under fasting conditions. 
     
     
         44 . The method of  claim 43 , wherein the mean C max  determined at a fasted state is higher than the mean C max  determined at a fed state. 
     
     
         45 . The method of  claim 43 , wherein the mean T max  determined at a fed state is higher than the mean T max  determined at a fasted state. 
     
     
         46 . The method of  claim 24 , wherein a total amount of about 3000 mg to about 12000 mg NeuAc, or a pharmaceutically acceptable salt thereof, is administered per day. 
     
     
         47 . The method of  claim 24 , wherein the sialic acid deficiency is a myopathy associated with sialic acid deficiency. 
     
     
         48 . The method of  claim 47 , the myopathy associated with sialic acid deficiency is Hereditary Inclusion Body Myopathy (HIBM), Nonaka myopathy, and/or Distal Myopathy with Rimmed Vacuoles (DMRV). 
     
     
         49 . The method of  claim 24 , wherein the method provides a mean plasma concentration of free NeuAc of at least about 0.20 mcg/ml at steady state during the dosing intervals.