Anhydrous sodium thiosulfate and formulations thereof

Abstract

Described herein is anhydrous sodium thiosulfate, methods for synthesizing anhydrous sodium thiosulfate, pharmaceutical compositions thereof, and methods of treating ototoxicity. Anhydrous sodium thiosulfate is synthesized from sodium sulfite, sulfur, and cetylpyridinium chloride. The anhydrous sodium thiosulfate is formulated into a pharmaceutical composition comprising a buffer and solvent. These compositions are useful for eliminating or reducing ototoxicity in pediatric patients receiving platinum-based chemotherapeutics.

We claim: 
     
         1 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an antacid, wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the antacid is Mg(OH) 2 . 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the antacid is ZnCO 3 . 
     
     
         4 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an isotonicity modifier wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         5 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and a preservative, wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the preservative is selected from m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the preservative is m-cresol. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein the preservative is phenol. 
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein the preservative is methylparaben. 
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein the preservative is ethylparaben. 
     
     
         11 . The pharmaceutical composition of  claim 5 , wherein the preservative is propylparaben. 
     
     
         12 . The pharmaceutical composition of  claim 5 , wherein the preservative is butylparaben. 
     
     
         13 . The pharmaceutical composition of  claim 5 , wherein the preservative is chlorobutanol. 
     
     
         14 . The pharmaceutical composition of  claim 5 , wherein the preservative is benzyl alcohol. 
     
     
         15 . The pharmaceutical composition of  claim 5 , wherein the preservative is phenylmercuric nitrate. 
     
     
         16 . The pharmaceutical composition of  claim 5 , wherein the preservative is thimerosol. 
     
     
         17 . The pharmaceutical composition of  claim 5 , wherein the preservative is sorbic acid. 
     
     
         18 . The pharmaceutical composition of  claim 5 , wherein the preservative is potassium sorbate. 
     
     
         19 . The pharmaceutical composition of  claim 5 , wherein the preservative is benzoic acid. 
     
     
         20 . The pharmaceutical composition of  claim 5 , wherein the preservative is chlorocresol. 
     
     
         21 . The pharmaceutical composition of  claim 5 , wherein the preservative is benzalkonium chloride. 
     
     
         22 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and a stabilizer; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is selected from alanine, arginine, aspartic acid, histidine, lysine, proline, glucose, sucrose, trehalose, glycerol, mannitol, sorbitol, sodium sulphate, EDTA, hexaphosphate, zinc, calcium, cyclodextrin, dextran, a dendrimer, polyethylene glycol, polyvinylpyrrolidone, protamine, and albumin. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is alanine. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is arginine. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is aspartic acid. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is histidine. 
     
     
         28 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is lysine. 
     
     
         29 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is proline. 
     
     
         30 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is glucose. 
     
     
         31 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is sucrose. 
     
     
         32 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is trehalose. 
     
     
         33 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is glycerol. 
     
     
         34 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is mannitol. 
     
     
         35 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is sorbitol. 
     
     
         36 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is sodium sulphate. 
     
     
         37 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is EDTA. 
     
     
         38 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is hexaphosphate. 
     
     
         39 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is zinc. 
     
     
         40 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is calcium. 
     
     
         41 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is cyclodextrin. 
     
     
         42 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is dextran. 
     
     
         43 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is a dendrimer. 
     
     
         44 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is polyethylene glycol. 
     
     
         45 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is polyvinylpyrrolidone. 
     
     
         46 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is protamine. 
     
     
         47 . The pharmaceutical composition of  claim 22 , wherein the stabilizer is albumin. 
     
     
         48 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an anti-adsorption agent; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is an ionic surfactant. 
     
     
         50 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is a non-ionic surfactant. 
     
     
         51 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is a poloxamer. 
     
     
         52 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is a PEG. 
     
     
         53 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is dodecyl ether. 
     
     
         54 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is polysorbate 20. 
     
     
         55 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is polysorbate 80. 
     
     
         56 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is dextran. 
     
     
         57 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is polyethylene glycol. 
     
     
         58 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is PEG-polyhistidine. 
     
     
         59 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is BSA. 
     
     
         60 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is HAS. 
     
     
         61 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is a gelatine. 
     
     
         62 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is Pluronic F-68. 
     
     
         63 . The pharmaceutical composition of  claim 48 , wherein the anti-adsorption agent is Brij 35. 
     
     
         64 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and a lyophilization or cryoprotectant agent; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         65 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a sugar. 
     
     
         66 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a polyol. 
     
     
         67 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a surfactant. 
     
     
         68 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is an amino acid. 
     
     
         69 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a non-aqueous solvent. 
     
     
         70 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a peptide. 
     
     
         71 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a trehalose. 
     
     
         72 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is mannitol. 
     
     
         73 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is sucrose. 
     
     
         74 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is sorbitol. 
     
     
         75 . The pharmaceutical composition of  claim 64 , wherein the lyophilization or cryoprotectant agent is a starch. 
     
     
         76 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an antioxidant; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is ascorbic acid. 
     
     
         78 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is ectoine. 
     
     
         79 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is methionine. 
     
     
         80 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is glutathione. 
     
     
         81 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is monothioglycerol. 
     
     
         82 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is morin. 
     
     
         83 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is polyethylenimine. 
     
     
         84 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is propyl gallate. 
     
     
         85 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is vitamin E. 
     
     
         86 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is a chelating agent. 
     
     
         87 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is citric acid. 
     
     
         88 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is EDTA. 
     
     
         89 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is hexaphosphate. 
     
     
         90 . The pharmaceutical composition of  claim 76 , wherein the antioxidant is thioglycolic acid. 
     
     
         91 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and a viscosity enhancer; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a carbomer. 
     
     
         93 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is Carbopol 940. 
     
     
         94 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is Carbopol Ultrez 10. 
     
     
         95 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a cellulose derivative. 
     
     
         96 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is hydroxypropylmethylcellulose. 
     
     
         97 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is diethylaminoethyl cellulose. 
     
     
         98 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is colloidal magnesium silicate. 
     
     
         99 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is sodium silicate. 
     
     
         100 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is hydroxyapatite gel. 
     
     
         101 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is tricalcium phosphate gel. 
     
     
         102 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is xanthan. 
     
     
         103 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a carrageenan. 
     
     
         104 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is Satiagum UTC 30. 
     
     
         105 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is an aliphatic poly(hydroxy acids). 
     
     
         106 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is poly(D,L- or L-lactic acid). 
     
     
         107 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is poly(glycolic acid). 
     
     
         108 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is PLGA. 
     
     
         109 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a terpolymers of D,L-lactide, glycolide and caprolactone. 
     
     
         110 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a poloxamers. 
     
     
         111 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a triblock of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene). 
     
     
         112 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a polyetherester copolymer. 
     
     
         113 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a polyethylene glycol terephthalate/polybutylene terephthalate copolymer. 
     
     
         114 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is sucrose acetate isobutyrate. 
     
     
         115 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is dextran or a derivative thereof. 
     
     
         116 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a polydimethylsiloxane. 
     
     
         117 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a collagen. 
     
     
         118 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is chitosan. 
     
     
         119 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a polyvinyl alcohol. 
     
     
         120 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a polyalkylimides. 
     
     
         121 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is a poly (acrylamide-co-diallyldimethyl ammonium), polyvinylpyrrolidone, or a glycosaminoglycan. 
     
     
         122 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, or hyaluronan. 
     
     
         123 . The pharmaceutical composition of  claim 91 , wherein the viscosity enhancer is an ABA triblock or AB block copolymers composed of hydrophobic A-blocks selected from polylactide (PLA) and poly(lactide-co-glycolide) (PLGA), and hydrophilic B-blocks selected from polyethylene glycol (PEG) and polyvinyl pyrrolidone. 
     
     
         124 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and one or more auxiliary agents selected from a wetting agent, viscosity modifier, antibiotic, polyol, hyaluronic acid, and hyaluronidase; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         125 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is a wetting agent. 
     
     
         126 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is a viscosity modifier. 
     
     
         127 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is an antibiotic. 
     
     
         128 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is a hyaluronidase. 
     
     
         129 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is a hyaluronic acid. 
     
     
         130 . The pharmaceutical composition of  claim 124 , wherein the auxiliary agent is a polyol. 
     
     
         131 . The pharmaceutical composition of  claim 130 , wherein the polyol is glycerol. 
     
     
         132 . The pharmaceutical composition of  claim 130 , wherein the polyol is propylene glycol. 
     
     
         133 . The pharmaceutical composition of  claim 130 , wherein the polyol is polyethylene glycol. 
     
     
         134 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an antibacterial or antifungal agent; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         135 . The pharmaceutical composition of  claim 134 , wherein the antibacterial or antifungal agent is a paraben. 
     
     
         136 . The pharmaceutical composition of  claim 134 , wherein the antibacterial or antifungal agent is chlorobutanol. 
     
     
         137 . The pharmaceutical composition of  claim 134 , wherein the antibacterial or antifungal agent is phenol. 
     
     
         138 . The pharmaceutical composition of  claim 134 , wherein the antibacterial or antifungal agent is ascorbic acid. 
     
     
         139 . The pharmaceutical composition of  claim 134 , wherein the antibacterial or antifungal agent is a thimerosal. 
     
     
         140 . A pharmaceutical composition consisting essentially of sodium thiosulfate at a concentration of about 0.5M and an isotonic agent; wherein the pharmaceutical composition is adjusted as necessary to achieve a pH of about 6.5 to about 8.9. 
     
     
         141 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is a sugar. 
     
     
         142 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is a polyalcohol. 
     
     
         143 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is mannitol. 
     
     
         144 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is an amino acid. 
     
     
         145 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is sorbitol. 
     
     
         146 . The pharmaceutical composition of  claim 140 , wherein the isotonic agent is sodium chloride.