Compositions and Methods for the Treatment of Metabolic Conditions

Abstract

The present invention relates to stable therapeutic compositions of pharmaceutical grade acids and pH buffering agents. The present invention also is directed to methods of treatment for mitochondrial disorders, metabolic conditions, diabetic conditions, and cardiovascular conditions, by administration of compositions of the present disclosure.

What is claimed is: 
     
         1 . A stable therapeutic composition formulated for intravenous administration to a subject, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         2 . The composition of  claim 1 , wherein the pharmaceutical grade acid is hydrochloric acid, ascorbic acid, acetic acid, (other physiologically acceptable acids), or a combination thereof. 
     
     
         3 . The composition of  claim 1 , wherein the at least one pH buffering agent is sodium bicarbonate, a phosphate buffer, sodium hydroxide, organic acid, organic amine, ammonia, citrate buffer, a synthetic buffer creating specific alkaline conditions (e.g., tris-hydroxymethyl amino methane), (other physiologically acceptable buffers), or a combination thereof. 
     
     
         4 . The composition of  claim 1 , further comprising one or more ingredients selected from the group consisting of vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidative species. 
     
     
         5 . The composition of  claim 4 , further comprising ascorbic acid. 
     
     
         6 . The composition of  claim 4 , further comprising dehydroascorbic acid 
     
     
         7 . The composition of  claim 4 , further comprising other recognized antioxidant defense compounds including nonenzymatic compounds such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH) and enzymatic components including manganese superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX), glutathione reductase (GR); peroxiredoxins (PRX3/5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). 
     
     
         8 . The composition of  claim 4 , further comprising one or more of a sodium salt, a magnesium salt, a potassium salt, and a calcium salt. 
     
     
         9 . The composition of  claim 4 , further comprising one or more of a B vitamin, vitamin C, and vitamin K. 
     
     
         10 . The composition of  claim 1 , wherein the composition is formulated for intravenous, bolus, dermal, oral, otic, suppository, buccal, ocular, or inhalation delivery. 
     
     
         11 . The composition of  claim 1 , wherein the composition is formulated as a topical liquid, gel, or paste. 
     
     
         12 . The composition of  claim 1 , wherein the composition is formulated for ocular administration in the form of eye drops. 
     
     
         13 . The composition of  claim 4 , formulated in hypotonic, isotonic, or hypertonic form. 
     
     
         14 . The composition of  claim 1 , wherein the intravenous administration is a bolus delivery. 
     
     
         15 . The composition of  claim 1 , wherein the composition is lyophilized or frozen. 
     
     
         16 . The composition of  claim 1 , wherein the composition is stored in a spectral-blocking vial. 
     
     
         17 . The composition of  claim 1 , wherein composition is formed by combining components from two or more vials. 
     
     
         18 . A stable therapeutic composition formulated for intravenous administration to a subject comprising pharmaceutical grade:
 900±90 mg of L-Ascorbic Acid;   63.33±6.33 mg Thiamine HCl;   808±80.8 mg of Magnesium Sulfate;   1.93±0.193 mg of Cyanocobalamin;   119±11.9 mg of Niacinamide;   119±11.9 mg of Pyridoxine HCl;   2.53±0.253 mg of Riboflavin 5′Phosphate;   2.93±0.293 mg of Calcium D-Pantothenate;   840±84 mg of Sodium Bicarbonate;   4.5±0.45 mM of HCl; and   water in an amount to obtain a final composition volume of 20 mL.   
     
     
         19 . The composition according to  claim 18 , further comprising 100±10 mg of dehydroascorbic acid. 
     
     
         20 . A method of treating or ameliorating acidosis in a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         21 . A method of treating or ameliorating base excess in a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         22 .- 35 . (canceled) 
     
     
         36 . A method of modifying the metabolism of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         37 . A method of treating a central nervous system disorder in a subject in need thereof, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         38 . (canceled) 
     
     
         39 . A method of enhancing mental or physical performance of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         40 . A method of reducing lactate burden in a subject in need thereof, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         41 . The method of  claim 40 , wherein the lactate burden is acidosis, sepsis, or multiple system atrophy (MSA) 
     
     
         42 . The method of  claim 40 , wherein the lactate burden is the result of physical exertion. 
     
     
         43 . A method of resolving or improving hypoxic stress in a subject in need thereof, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and   wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.   
     
     
         44 . (canceled) 
     
     
         45 . The method according to  claim 20 , wherein the subject is a human or veterinary subject. 
     
     
         46 . The method according to  claim 20 , wherein the buffer solution is administered in an effective amount that is sufficient to reduce the physiological bloodstream pH of a subject by 0.01 to 1.1. 
     
     
         47 . The method according to  claim 46 , wherein the buffer solution has a buffer capacity sufficient to sustain the reduction of the physiological bloodstream pH of the subject for between 1 minute and 1 week. 
     
     
         48 . The method according to  claim 46 , wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.15 to 0.75. 
     
     
         49 . The method according to  claim 46 , wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.15 to 0.5. 
     
     
         50 . The method according to  claim 46 , wherein the buffer solution has a buffer capacity sufficient to sustain the reduction of the physiological bloodstream pH of the subject for between 1 minute and 1 hour. 
     
     
         51 . The method according to  claim 46 , wherein the buffer solution has a buffer capacity sufficient to sustain the reduction of the physiological bloodstream pH of the subject for between 1 hour and 1 day. 
     
     
         52 . The method according to  claim 46 , wherein the buffer solution has a buffer capacity sufficient to sustain the reduction of the physiological bloodstream pH of the subject for between 1 day and 1 week. 
     
     
         53 . A kit comprising:
 a. a first vial containing a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution,
 wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and 
 wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7; and 
   b. instructions for use.   
     
     
         54 . A kit comprising:
 a. a first vial containing an intravenous buffer solution comprising at least one pharmaceutical grade acid in a sterile aqueous solution, and   b. a second vial containing at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution;
 wherein, when combined, the contents of the two vials form an intravenous buffer solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and 
 wherein the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7; and 
   c. instructions for use.