Methods of normalizing amino acid metabolism

Abstract

Methods of normalizing amino acid metabolism in subjects on restricted protein diets and supplemental amino acids, using specially formulated amino acids that mimic the absorption and metabolism of naturally occurring proteins, are described.

What is claimed is: 
     
         1 . A method of treating or preventing elevated phenylalanine concentrations or fluctuations in a subject on a restricted protein diet supplemented by oral amino acids comprising orally administering to the subject a therapeutically effective amount of a modified release amino acid formulation, thereby prolonging the release of the oral amino acids and mimicking the metabolism of natural proteins by the amino acids. 
     
     
         2 . The method of  claim 1 , wherein the subject has classic phenylketonuria (PKU), defined as a phenylalanine concentration of greater than 1200 micromole/L (20 mg/dL), and the modified release amino acid formulation lacks phenylalanine. 
     
     
         3 . The method of  claim 1 , wherein the subject has mild PKU, defined as a phenylalanine concentration of from 600 to 1200 micromole/L (from 10 to 20 mg/dL), and the modified release amino acid formulation lacks phenylalanine. 
     
     
         4 . The method of  claim 1 , wherein the subject has mild hyperphenylalaninemia, defined as a phenylalanine concentration of from 300 to 600 micromole/L (from 5 to 10 mg/dL), and the modified release amino acid formulation lacks phenylalanine. 
     
     
         5 . The method of  claim 1 , wherein the elevated phenylalanine concentrations manifest as an intellectual disability, anxiety, depression, an executive functioning deficit, a cognitive deficit, a reduced intelligence quotient, seizures, delayed development, behavioral problems, a psychiatric disorder, unstable moods, inability to focus, tremors, information processing delays, memory deficits, body protein deficits, height deficits, bone loss, muscle weakness, gait disorders, decreased energy, or lethargy. 
     
     
         6 . The method of  claim 1 , wherein:
 a) the modified release amino acid formulation is in the form ofparticles comprising a binder selected from polyvinyl pyrrollidone, starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution, guar gum, xanthan gum, acacia, tragacanth, locust bean gum, and an alginic acid salt;   b) the modified release amino acid formulation is in the form of particles comprising a modified release coating comprising ethylcellulose, glyceryl dibehenate, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, stearyl alcohol, acrylic acid copolymers, sodium alginate, carrageenan, alginic acid, pectin, sodium carboxymethyl cellulose, or a combination thereof;   c) the modified release amino acid formulation further comprises one or more additional ingredients selected from the group consisting of:
 i) vitamins, minerals, carbohydrates; 
 ii) choline, inositol, vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, biotin, pantothenic acid, potassium, calcium, magnesium, iron, zinc, copper, manganese, selenium, chromium, molybdenum, iodine, sodium, sulfur, phosphorus, docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, lutein, salts thereof, chelates thereof, esters thereof, and other derivatives thereof; 
   d) the modified release amino acid formulation further comprises:
 i) a bulking agent selected from lactose, sucrose, dextrose, sorbitol, fructose, and cellulose powder; 
 ii) a disintegrating agent selected from microcrystalline cellulose, starches, crospovidone, sodium starch glycolate, and crosscarmellose sodium; 
 iii) a glidant or lubricant selected from talc, corn starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, hydrogenated cotton seed oil, talc, waxes, cetyl alcohol, glyceryl stearate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol; 
 iv) a taste-masking agent selected from cellulose hydroxypropyl ethers (HPC), low-substituted hydroxypropyl ethers (L-HPC), cellulose hydroxypropyl methyl ethers (HPMC), methylcellulose polymers, ethylcelluloses (EC),polyvinyl alcohol (PVA), hydroxyethylcelluloses, carboxymethylcelluloses; salts of carboxymethylcelluloses (CMC), polyvinyl alcohol and polyethylene glycol co-polymers, monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers, mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms, cyclodextrins, and mixtures thereof; or 
 v) a flavoring agent selected from acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and combinations thereof; 
   e) the modified release amino acid formulation is in the form of a tablet, a pill, a soft or hard gelatin capsules, a powder, a granulate, a microsphere, a lozenge, a sachet of packaged powders, a sachet of packaged granulates, a sachet of packaged microspheres, an elixir, a suspension, an emulsion, a chewable tablet, or a syrup; or   f) the modified release amino acid formulation comprises granulated particles of tyrosine and alginic acid or a pharmaceutically acceptable salt thereof, uncoated by a modified release coating.   
     
     
         7 . A method of normalizing one or more metabolic markers selected from plasma insulin, plasma glucose, blood urea nitrogen, urine urea nitrogen, and plasma phenylalanine in a subject on a restricted protein diet supplemented by oral amino acids comprising orally administering to the subject a therapeutically effective amount of a modified release amino acid formulation, thereby prolonging the release of the oral amino acids and mimicking the metabolism of natural proteins by the amino acids. 
     
     
         8 . The method of  claim 7 , wherein the subject is suffering from a metabolic disorder selected from the group consisting of phenylketonuria, tyrosinemia, leucinosis, methylmalonic acidemia, homocystinuria, hyperglycinemia, isovaleric acidemia, propionic acidemia, and glutamic acidemia. 
     
     
         9 . The method of  claim 7 , wherein the subject has chronic kidney disease, liver disease, diabetes, cardiovascular disease, sarcopenia, cachexia, low plasma albumin (>3.5 g/L-1), is recovering from neurosurgery, is in need of increased muscle mass for sporting activities, or is engaged in another activity in which amino supplementation is required. 
     
     
         10 . The method of  claim 7 , wherein the modified release amino acid formulation comprising 2 g of the modified release amino acids releases no more than 70% of the modified release amino acids in 30 minutes of dissolution testing performed in a <711> USP 39 NF 34, paddle apparatus, at 37° C., in 450 or 500 mL, 0.1 N hydrochloric acid (pH 1.2), paddle speed 50 rpm. 
     
     
         11 . The method of  claim 7 , wherein the modified release amino acid formulation is modified to produce a maximum plasma concentration in humans for total amino acids, essential amino acids, large neutral amino acids, or branched chain amino acids, of less than 80%, 75%, or 70% of the maximum plasma concentration produced by an equipotent immediate release amino acid formulation. 
     
     
         12 . The method of  claim 7 , wherein the modified release amino acid formulation is modified to produce an area under the curve (AUC) of amino acids in humans for total amino acids, essential amino acids, large neutral amino acids, or branched chain amino acids, of greater than 80%, 85%, or 90% the AUC produced by an equipotent immediate release amino acid formulation. 
     
     
         13 . The method of  claim 7 , wherein the modified release amino acid formulation comprises as amino acids: 0.47 to 0.97 weight parts of L-alanine, 0.66 to 1.26 weight parts of L-arginine, 1.04 to 1.84 weight parts of L-aspartic acid, 0.0.28 to 0.68 weight parts of L-cystine, 4.1 to 5.6 weight parts of L-glutamine, 0.9 to 1.5 weight parts of L-glycine, 0.5 to 0.85 weight parts of L-histidine, 1.0 to 1.65 weight parts of L-isoleucine, 2.25 to 3.25 weight parts of L-leucine, 1.45 to 2.0 weight parts of L-lysine, 0.23 to 0.43 weight parts of L-methionine, 0.0000 weight parts of L-phenylalanine, 1.2 to 1.8 weight parts of L-proline, 0.6 to 1.1 weight parts of L-serine, 0.9 to 1.6 weight parts of L-threonine, 0.35 to 0.65 weight parts of L-tryptophan, 2.0 to 3.0 weight parts of L-tyrosine, and 0.9 to 1.6 weight parts of L-valine. 
     
     
         14 . The method of  claim 7 , wherein the modified release amino acid formulation comprises as amino acids: 0.7200 g of L-alanine, 0.9600 g of L-arginine, 1.4400 g of L-aspartic acid, 0.4800 g of L-cystine, 4.8000 g of L-glutamine, 1.2000 g of L-glycine, 0.6710 g of L-histidine, 1.3200 g of L-isoleucine, 2.7600 g of L-leucine, 1.6800 g of L-lysine, 0.3334 g of L-methionine, 0.0000 g of L-phenylalanine, 1.4400 g of L-proline, 0.8134 g of L-serine, 1.2000 g of L-threonine, 0.4800 g of L-tryptophan, 2.400 g of L-tyrosine, and 1.2000 g of L-valine, and produces, upon oral administration:
 a) an amino acid pharmacokinetic profile substantially as depicted in  FIG.  6   ; or   b) an amino acid C max  of less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, or 3600 µM; or   c) both a) and b).   
     
     
         15 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 0.66 to 1.26 weight parts of L-arginine, 0.5 to 0.85 weight parts of L-histidine, 1.0 to 1.65 weight parts of L-isoleucine, 2.25 to 3.25 weight parts of L-leucine, 1.45 to 2.0 weight parts of L-lysine, 0.23 to 0.43 weight parts of L-methionine, 0.9 to 1.6 weight parts of L-threonine, 0.35 to 0.65 weight parts of L-tryptophan, 2.0 to 3.0 weight parts of L-tyrosine, and 0.9 to 1.6 weight parts of L-valine. 
     
     
         16 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 0.6710 g of L-histidine, 1.3200 g of L-isoleucine, 2.7600 g of L-leucine, 1.6800 g of L-lysine, 0.3334 g of L-methionine, 1.2000 g of L-threonine, 0.4800 g of L-tryptophan, 1.2000 g of L-valine, 0.9600 g of L-arginine, and 2.400 g of L-tyrosine and upon oral administration produces:
 a) an essential amino acid pharmacokinetic profile substantially as depicted in  FIG.  2   ; or   b) an essential amino acid C max  of less than 2300, 2200, 2100, 2000, 1900, or 1800 µM; or   c) both a) and b).   
     
     
         17 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 0.5 to 0.85 weight parts of L-histidine, 1.0 to 1.65 weight parts of L-isoleucine, 2.25 to 3.25 weight parts of L-leucine, 0.23 to 0.43 weight parts of L-methionine, 0.9 to 1.6 weight parts of L-threonine, 0.35 to 0.65 weight parts of L-tryptophan, 2.0 to 3.0 weight parts of L-tyrosine, and 0.9 to 1.6 weight parts of L-valine. 
     
     
         18 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 0.6710 g of L-histidine, 1.3200 g of L-isoleucine, 2.7600 g of L-leucine, 0.3334 g of L-methionine, 1.200 g of L-threonine, 0.4800 g of L-tryptophan, 1.200 g of L-valine, and 2.400 g of L-tyrosine and upon oral administration produces:
 a) a large neutral amino acid pharmacokinetic profile substantially as depicted in  FIG.  4   ;   b) a large neutral amino acid C max  of less than 1700, 1600, 1500, 1400, or 1300 µM; or   c) both a) and b).   
     
     
         19 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 1.0 to 1.65 weight parts of L-isoleucine, 2.25 to 3.25 weight parts of L-leucine, and 0.9 to 1.6 weight parts of L-valine. 
     
     
         20 . The method of  claim 7 , wherein the modified release amino acid formulation comprises 1.200 g of L-valine, 2.7600 g of L-leucine, and 1.3200 g of L-isoleucine and upon oral administration produces:
 a) a branched chain amino acid pharmacokinetic profile substantially as depicted in  FIG.  5   ; or   b) a branched chain amino acid C max  of less than 1100, 1000, 900, 800, or 700 µM; or   c) both a) and b).   
     
     
         21 . The method of  claim 7 , wherein:
 a) the modified release amino acid formulation is in the form of particles comprising a binder selected from polyvinyl pyrrollidone, starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution, guar gum, xanthan gum, acacia, tragacanth, locust bean gum, and an alginic acid salt;   b) the modified release amino acid formulation is in the form of particles comprising a modified release coating comprising ethylcellulose, glyceryl dibehenate, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, stearyl alcohol, acrylic acid copolymers, sodium alginate, carrageenan, alginic acid, pectin, sodium carboxymethyl cellulose, or a combination thereof;   c) the modified release amino acid formulation further comprises one or more additional ingredients selected from the group consisting of:
 i) vitamins, minerals, carbohydrates; 
 ii) choline, inositol, vitamin A, vitamin D, vitamin E, vitamin K, vitamin C, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, biotin, pantothenic acid, potassium, calcium, magnesium, iron, zinc, copper, manganese, selenium, chromium, molybdenum, iodine, sodium, sulfur, phosphorus, docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, lutein, salts thereof, chelates thereof, esters thereof, and other derivatives thereof; 
   d) the modified release amino acid formulation further comprises:
 i) a bulking agent selected from lactose, sucrose, dextrose, sorbitol, fructose, and cellulose powder; 
 ii) a disintegrating agent selected from microcrystalline cellulose, starches, crospovidone, sodium starch glycolate, and crosscarmellose sodium; 
 iii) a glidant or lubricant selected from talc, corn starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, hydrogenated cotton seed oil, talc, waxes, cetyl alcohol, glyceryl stearate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol; 
 iv) a taste-masking agent selected from cellulose hydroxypropyl ethers (HPC), low-substituted hydroxypropyl ethers (L-HPC), cellulose hydroxypropyl methyl ethers (HPMC), methylcellulose polymers, ethylcelluloses (EC),polyvinyl alcohol (PVA), hydroxyethylcelluloses, carboxymethylcelluloses; salts of carboxymethylcelluloses (CMC), polyvinyl alcohol and polyethylene glycol copolymers, monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers, mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms, cyclodextrins, and mixtures thereof; or 
 v) a flavoring agent selected from acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and combinations thereof; 
   e) the modified release amino acid formulation is in the form of a tablet, a pill, a soft or hard gelatin capsules, a powder, a granulate, a microsphere, a lozenge, a sachet of packaged powders, a sachet of packaged granulates, a sachet of packaged microspheres, an elixir, a suspension, an emulsion, a chewable tablet, or a syrup; or   f) the modified release amino acid formulation comprises granulated particles of tyrosine and alginic acid or a pharmaceutically acceptable salt thereof, uncoated by a modified release coating.