Parenteral administration of pyrophosphate for prevention or treatment of phosphate or pyrophosphate depletion

Abstract

Phosphate depletion, a physiological condition commonly seen in certain patient populations, including alcoholics, malnourished, acutely ill patients, patients receiving parenteral nutrition, patients being re-fed after prolong fasting, and dialysis patients, requires intravenous supplementation when oral repletion is not feasible. This invention provides a method and pharmaceutical composition for therapeutic administration of pyrophosphate, instead of phosphate, for phosphate or pyrophosphate repletion. During hemodialysis or peritoneal dialysis significant removal of phosphate and pyrophosphate occurs. Pyrophosphate depletion predisposes patients to vascular calcification. This invention further provides a method and pharmaceutical composition for therapeutic administration of pyrophosphate for phosphate or pyrophosphate repletion by addition of pyrophosphate to hemodialysis or peritoneal dialysis solutions.

1 . A method for the replenishment of plasma phosphate and/or pyrophosphate in a subject in need thereof, said method comprising parenterally administering into the subject's circulation a liquid composition comprising a compound selected from the group consisting of: pyrophosphoric acid, an inorganic salt of pyrophosphoric acid, and organic salt of organic pyrophosphate, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate in an effective amount. 
     
     
         2 . The method of  claim 1  wherein the liquid composition is administered intravenously. 
     
     
         3 . The method of  claim 2  wherein the liquid composition is administered intravenously by a slow, continuous infusion into the subject. 
     
     
         4 . The method of  claim 2  wherein the liquid composition is administered intravenously into a hemodialysis patient during hemodialysis using an extracorporeal circuit. 
     
     
         5 . The method of  claim 2  wherein the liquid composition is administered intravenously into a peritoneal dialysis patient during peritoneal dialysis. 
     
     
         6 . The method of  claim 1  wherein the liquid composition is administered to a hemodialysis patient during hemodialysis using an extracorporeal circuit by addition of a pyrophosphate to a hemodialysis solution. 
     
     
         7 . The method of  claim 6  wherein the liquid composition is added to a hemodialysis solution by addition of the pyrophosphate to a bicarbonate concentrate used to make the hemodialysis solution. 
     
     
         8 . The method of  claim 1  wherein the liquid composition is administered to a peritoneal dialysis patient during dialysis by addition of the pyrophosphate to a peritoneal dialysis solution. 
     
     
         9 . The method of  claim 1  wherein the amount of the compound is from about 2 μmol to about 12 mmol per liter or from about 0.05 μmol to about 100 mmol per day. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . A method of preparing a composition for the replenishment of plasma phosphate and/or pyrophosphate in a subject comprising adding an effective amount of a compound selected from the group consisting of pyrophosphoric acid, an inorganic salt of pyrophosphoric acid, and organic salt of organic pyrophosphate, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate to a dialysis solution that is to be used to dialyze said subject. 
     
     
         13 . The method of  claim 12  wherein the dialysis solution is a hemodialysis solution or a concentrate used to prepare the dialysis solution. 
     
     
         14 . The method of  claim 12  wherein the dialysis solution is a peritoneal dialysis solution. 
     
     
         15 . A liquid or solid composition for replenishing phosphate and/or pyrophosphate in a subject's plasma comprising a a compound selected from the group consisting of pyrophosphoric acid, an inorganic salt of pyrophosphoric acid, and organic salt of organic pyrophosphate, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate in an effective amount and the composition is suitable for addition to a peritoneal dialysis or hemodialysis solution. 
     
     
         16 . A liquid composition according to  claim 15  comprising a water for injection and up to 700 gm per deciliter of a pyrophosphate, wherein the compound is pyrophosphoric acid or an inorganic or organic salt thereof. 
     
     
         17 . A solid or liquid hemodialysis concentrate composition that is suitable for generating a hemodialysis solution used to replenish plasma phosphate and/or pyrophosphate comprising a compound selected from the group consisting of pyrophosphoric acid, an inorganic salt of pyrophosphoric acid, and organic salt of organic pyrophosphate, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate in an effective. 
     
     
         18 . A solid or liquid hemodialysis concentrate composition of  claim 17  wherein the composition is useful to replenish phosphate and/or pyrophosphate in a subject's plasma, and wherein the composition comprises pyrophosphoric acid or an inorganic or organic salt thereof in a concentration sufficient to provide an inorganic phosphorus concentration of 0.5-4.5 mg per deciliter and bicarbonate. 
     
     
         19 . A solid or liquid hemodialysis concentrate composition of  claim 17  wherein the composition is useful for the generation of a hemodialysis solution, and wherein the composition comprises pyrophosphoric acid or an inorganic or organic salt thereof, wherein the hemodialysis solution used to dialyze a subject contains a pyrophosphate in a concentration of from about 2 to about 4 micromoles per liter. 
     
     
         20 . A solid or liquid hemodialysis concentrate composition of  claim 17  wherein the composition is useful for the generation of a hemodialysis solution and wherein the composition comprises pyrophosphoric acid or an inorganic or organic salt thereof, wherein the hemodialysis solution used to dialyze a subject contains a pyrophosphate in a concentration that exceeds the subject's plasma pyrophosphate concentration. 
     
     
         21 . A solid or liquid hemodialysis concentrate composition of  claim 17  wherein the composition is useful for the preparation of a hemodialysate to replenish phosphate and/or pyrophosphate in a subject's plasma and wherein the composition comprised pyrophosphoric acid or an inorganic or organic salt thereof in a concentration of pyrophosphate that is 30- to 50-fold higher than the desired concentration of pyrophosphate in the hemodialysate. 
     
     
         22 . A liquid peritoneal dialysate composition that is suitable for replenishing plasma phosphate and/or pyrophosphate in a subject undergoing peritoneal dialysis comprising a compound selected from the group consisting of pyrophosphoric acid, an inorganic salt of pyrophosphoric acid, and organic salt of organic pyrophosphate, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate in an effective amount. 
     
     
         23 . A method of preventing or treating vascular calcification in a hemodialysis or peritoneal dialysis patient, said method comprising parenterally administering into the patient's circulation a liquid composition comprising a compound selected from the group consisting of pyrophosphoric acid, an organic pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate, sodium pyrophosphate and potassium pyrophosphate in an effective amount wherein said compound is added to the dialysis solution. 
     
     
         24 . The method of  claim 23  wherein the patient is suffering from hypo-phosphatemia, hypo-pyrophosphatemia, calciphylaxis, vascular calcification or soft tissue calcification.