Formulations of anhydrous sodium thiosulfate

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 5 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. 20 25 20 47 21 23 J un 2 02 5 A B S T R A C T D e s c r i b e d h e r e i n i s a n h y d r o u s s o d i u m t h i o s u l f a t e , m e t h o d s f o r s y n t h e s i z i n g a n h y d r o u s 2 0 2 5 2 0 4 7 2 1 2 3 J u n 2 0 2 5 s o d i u m t h i o s u l f a t e , p h a r m a c e u t i c a l c o m p o s i t i o n s t h e r e o f , a n d m e t h o d s o f t r e a t i n g o t o t o x i c i t y . A n h y d r o u s s o d i u m t h i o s u l f a t e i s s y n t h e s i z e d f r o m s o d i u m s u l f i t e , s u l f u r , a n d c e t y l p y r i d i n i u m 5 c h l o r i d e . T h e a n h y d r o u s s o d i u m t h i o s u l f a t e i s f o r m u l a t e d i n t o a p h a r m a c e u t i c a l c o m p o s i t i o n c o m p r i s i n g a b u f f e r a n d s o l v e n t . T h e s e c o m p o s i t i o n s a r e u s e f u l f o r e l i m i n a t i n g o r r e d u c i n g o t o t o x i c i t y i n p e d i a t r i c p a t i e n t s r e c e i v i n g p l a t i n u m b a s e d c h e m o t h e r a p e u t i c s . 2 0 2 5 2 0 4 7 2 1 2 3 J u n 2 0 2 5

Description

Sodium thiosulfate anhydrous, the active ingredient, is an inorganic salt with reducing 25 agent properties. It is a white to off-white crystalline solid, that is soluble in water, but insoluble in alcohol. The aqueous solution is practically neutral with a pH ranging from 6.5 to 9.0. The 2025204721   23 Jun 2025 molecular formula is Na2S2O3. It has a molecular weight of 158.1 Ig / mol. The structural formula is: r          12 S II 2 Na+ o^\\ 0 _ o _ Sodium thiosulfate for injection as described herein is a sterile, preservative-free, clear 5 solution for intravenous use. Each vial contains 80 mg / mL sodium thiosulfate anhydrous (United States Pharmacopeia, USP), water for injection (USP), boric acid or sodium phosphate as a buffer component, and sodium hydroxide and / or hydrochloric acid for pH adjustment. Mechanism of Action 10           Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea. The cochlea is very sensitive to oxidative stress, which has been shown to be involved in CIS induced hearing loss. The mechanism of STS protection against ototoxicity is not fully understood, but may include increasing levels of endogenous antioxidants, scavenging reactive oxygen species, and direct interaction between CIS and the thiol group in STS. STS has the ability 15 to enter cells at least partly through the sodium sulfate cotransporter 2 and can cause intracellular effects such as the increase in antioxidant glutathione levels and inhibition of intracellular oxidative stress. Pharmacodynamics 20          STS prevented ototoxicity in at doses equivalent to 6.4 to 12.8 g / m2 sodium thiosulfate for injection. In preliminary clinical studies, lower STS dose levels (equivalent to 5.1 g / m2 sodium thiosulfate for injection) resulted in low maximum plasma levels (3.9 mM) and did not show hearing protection. The 6-hour delay of STS treatment after CIS chemotherapy is important to circumvent 25 potential interference with the anti-tumor activity of CIS, which is supported by data from non-clinical studies and preliminary clinical studies. During CIS infusion, bioactive unbound CIS distributes to cancer cells; it is cleared through renal excretion and rapid binding to proteins leading to inactivation of its tumoricidal activity. The initial decline of unbound platinum in plasma is rapid, with a half-life ranging from 0.6 to 1.35 hours. Together with the fact that STS distribution 2025204721   23 Jun 2025 is largely limited to extracellular spaces, administration of sodium thiosulfate for injection 6 hours after completion of each CIS infusion should prevent a tumor protective effect of STS. As shown in studies, treatment 6 hours after completion of each CIS infusion did not affect survival. Based on the half-life of STS in plasma, a negligible amount remains 6 hours after completion of an STS infusion. Therefore, subsequent CIS infusions should be administered no sooner than 6 hours after the completion of a sodium thiosulfate infusion to avoid a pharmacodynamic interaction. A 12.8 g / m2 dose of sodium thiosulfate for injection delivers a sodium load of 162 mmol / m2. Doses of STS equivalent to this resulted in a small, transient increase in serum sodium levels. When evaluated using non-compartmental pharmacokinetic analysis at the recommended sodium thiosulfate for injection dose levels, this transient increase in sodium was independent of age, body surface area, body weight, total daily STS dose, or CIS cycle. Pharmacokinetics 15 Absorption STS is poorly absorbed after oral administration and has to be administered intravenously. At the end of an STS intravenous infusion, plasma levels of STS are maximal and decline rapidly thereafter with a half-life of approximately 20 to 50 minutes. A return to pre-dose levels occurs within 3 to 6 hours after infusion. More than 95% of STS excretion in urine occurs within the first 20   4 hours after administration. There is no plasma accumulation when STS is administered on 2 consecutive days. In children and adults, the maximum STS plasma levels after a 15-minute infusion of a dose equivalent to 12.8 g / m2 sodium thiosulfate for injection was approximately 13.3 mM. STS plasma levels change in a dose proportional manner. Age did not appear to influence the maximum 25 plasma levels of STS or the decline afterwards. A population pharmacokinetic model incorporating growth and maturation variables for the pediatric population showed that the predicted STS plasma levels at the end of infusion were consistent across the recommended sodium thiosulfate for injection dose levels for the indicated age and body weight ranges. 30 Distribution 2025204721   23 Jun 2025 STS does not bind to human plasma proteins. STS is an inorganic salt and thiosulfate anions do not readily cross membranes. Hence, the volume of distribution appears largely confined to extracellular spaces and estimated at 0.23 L / kg in adults. In animals, STS has been found to distribute to the cochlea. Distribution across the blood brain barrier or placenta appears absent or limited. Thiosulfate is an endogenous compound ubiquitously present in all cells and organs. Endogenous serum thiosulfate levels were 5.5 ±1.8 pM in adult volunteers. Elimination Metabolism: Metabolites of STS have not been determined as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate metabolism does not involve CYP enzymes; it is metabolized through thiosulfate sulfur transferase and thiosulfate reductase activity to sulfite, which is rapidly oxidized to sulfate. Excretion: STS (thiosulfate) is excreted through glomerular filtration. After administration, STS (thiosulfate) levels in urine are high, and approximately half of the STS dose 15 is retrieved unchanged in urine, nearly all excreted within the first 4 hours after administration. STS renal clearance related well with inulin clearance as a measure for the GFR. Excretion of endogenously produced thiosulfate in bile was very low and did not increase after STS administration. No mass balance studies have been performed, but it is expected that non renal clearance will mainly result in renal excretion of sulfates. A small part of the sulfane 20 sulfur of STS may become part of endogenous cellular sulfur metabolism. Drug Product and Storage and Handling Sodium thiosulfate for injection is supplied as 100 mL of a clear, colorless, sterile solution in flint glass vials with 20-mm stoppers and capped with aluminum overseals. Each 100 mL of 25 sodium thiosulfate for injection contains sodium thiosulfate, anhydrous (80 mg per mL) for intravenous administration (8 g of STS per vial). Sodium thiosulfate for injection should be stored at controlled room temperature, between 15 °C and 30 °C. It will be apparent to one of ordinary skill in the relevant art that suitable modifications and 30 adaptations to the compositions, formulations, methods, processes, reactions, and applications described herein can be made without departing from the scope of any embodiments or aspects 2025204721   23 Jun 2025 thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any and all variations or iterations. The scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. The exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of any terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meanings of the terms or phrases in this disclosure are controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for 15 the specific teachings thereof. 2025204721   23 Jun 2025 EXAMPLES Example 1 Synthesis Process 5          An overview of the synthesis process is shown in Fig. 1. The synthesis of sodium thiosulfate (wet) was accomplished by reacting 1.0 mole equivalent of aqueous sodium sulfite with 1.1 mole equivalents of elemental sulfur in the presence of 0.00013 mole equivalents of cetylpyridinium chloride (CPC) at 90 °C for up to 3 hr as shown in Scheme I. Scheme I O             CPC       $ S + s -----► +Na O-S-O’ Na+ +Na’O' 'O’Na+            A           s In some instances, the reaction was heated to about 90 °C and was completed upon reaching 90 °C. Without being bound by any theory, the reaction rate appears to depend on the size, surface area, and solubility of the sulfur (e.g., fine powder reacts more rapidly than flakes). Once the 15 reaction was complete, the mixture was cooled to 25 °C, filtered through a 10 pm filter, and transferred to a crystallization vessel. The sodium thiosulfate solution was then cooled to less than 2 °C, and acetone was slowly added over at least 1 h while maintaining a temperature of <2 °C (except during the initial nucleation where a 5-7 °C exotherm was observed). The slurry was then held at <2 °C for at least 0.5 h and stepwise transferred to a filter dryer in portions. The slurry was 20 filtered to the point where the filtrate drops just below the level of the cake after each portion of slurry was added; this process minimized cracking of the resulting cake. The cake was then washed twice with acetone and filtered until no liquid exited. The resulting cake of “wet sodium thiosulfate” was then dried at 45 °C overnight while mixing under vacuum. The term “wet sodium thiosulfate” as used herein refers to sodium thiosulfate that has not been dehydrated. 25 Dehydration Filtered methanol was used to charge a crystallization vessel and heated to 60 °C. This warm methanol was then transferred into a filter dryer containing the overnight-dried “wet sodium thiosulfate” cake. The cake was slurried with the hot methanol and the filtrate was removed by 30 pressure. A second charge of hot methanol was added, mixed, and the filtrate removed. This was 2025204721   23 Jun 2025 followed by two additional washes with ambient temperature methanol and vacuum drying at 55 °C overnight. This process produced anhydrous sodium thiosulfate. Example 2 Milling Some batches of the anhydrous sodium thiosulfate were milled using a jet mill to a particle size distribution of 50% of the population, dso, of 10-20 pm. The unmilled anhydrous sodium thiosulfate synthesized as described herein has a particle size distribution of 50-75 pm. Without being bound by any theory, milling increased the surface area of the sodium thiosulfate particles and was believed to permit enhanced evaporation of any residual solvent(s). Example 3 Analysis The dried and / or milled anhydrous sodium thiosulfate was collected at stored at ambient 15 temperature. Samples were analyzed for sodium sulfite, sulfur, acetone, and methanol levels among other trace elements using HPLC, inductively coupled plasma mass spectrometry (ICP-MS), FTIR spectroscopy, and X-ray powder diffraction. Specifications and representative data for anhydrous sodium thiosulfate synthesized as described using the foregoing methods are shown in Table 4. 20 2025204721   23 Jun 2025 Table 4. Specifications and Representative STS Parameters Parameter Specification Result Appearance White to off-white solid, White to off-white solid, free of particulate free of particulate Cadmium <0.10 pg / g < 0.05 pg / g Lead < 0.25 pg / g <0.125 pg / g Arsenic < 0.75 pg / g < 0.375 pg / g Mercury <0.15 pg / g < 0.075 pg / g Cobalt < 0.25 pg / g <0.125 pg / g Vanadium <0.50 pg / g < 0.25 pg / g Nickel <1.00 pg / g <0.50 pg / g Lithium < 12.5 pg / g < 6.25 pg / g Antimony <4.50 pg / g <2.25 pg / g Copper < 15.0 pg / g < 7.5 pg / g Methanol < 1500 ppm 841 ppm Water < 3% (w / w) 0.07% (w / w) FTIR Indentification Conforms to known Conforms reference spectrum XRPD Results Report result See Figs. 2 and 3. Differential Scanning Calorimetry Onset Temp Report result 330.6 °C Peak Temp Report result 334.0 °C Heat Flow Report result -122.73 J / g Total Aerobic Microbial Count <100 CFU <1 CFU Total Combined Yeast / Mold <100 CFU <1 CFU Count Retention time conforms to HPLC Conforms reference standard Assay, as is 98-102% (w / w) 98.50% Total Impurities <1.5% (w / w) <1.5% (w / w) Example 4 X-ray Powder Diffraction Characterization Samples of anhydrous sodium thiosulfate as described herein or sodium thiosulfate 5 pentahydrate were analyzed by X-Ray Powder Diffraction (XRPD). Between 2 and 50 mg of sample were placed in a zero background holder coated with a thin layer of petroleum jelly and leveled with a glass plate. XRPD data was acquired using a Bruker D8 X-ray Diffractometer from 2° to 40° 29 with a 0.05° step size (1 sec / step) with copper Ka radiation (40 kV). The sample was rotated at 15 RPM during acquisition. Peak picking was performed in Materials Data Jade 9.7.0 10 software. 2025204721   23 Jun 2025 The XRPD patterns for anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate are shown in FIG. 2A and 2B, respectively; XRPD peaks are listed in Tables 5 and 6, respectively. Significant peaks are shown in bold. An overlay of the anhydrous sodium thiosulfate pattern in 2A (bottom pattern) and sodium thiosulfate pentahydrate pattern in 2B (top pattern) is shown in 5 FIG. 3. Table 5. Anhydrous Sodium Thiosulfate X-ray Powder Diffraction Peaks 2-theta (deg.) d(A) Height Height Percent (%) 10.523 8.4000 7.6 4.8 15.138 5.8481 36.6 23.2 17.712 5.0036 5.9 3.7 19.021 4.6620 1.8 1.1 19.702 4.5023 29.8 18.9 20.199 4.3927 0.5 0.3 21.086 4.2099 157.9 100 21.490 4.1315 14.3 9.1 21.848 4.0647 5.2 3.3 23.767 3.7407 3.7 2.3 24.288 3.6617 5.7 3.6 25.986 3.4261 3.8 2.4 26.260 3.3909 2.8 1.7 27.402 3.2522 11.8 7.4 28.012 3.1828 4.6 2.9 28.962 3.0805 67.5 42.8 30.465 2.9318 145.4 92.1 31.814 2.8105 6.8 4.3 32.516 2.7514 6.0 3.8 33.147 2.7005 84.0 53.2 34.740 2.5802 2.8 1.7 34.916 2.5676 4.0 2.5 35.786 2.5071 4.5 2.9 36.365 2.4686 1.7 1.1 37.029 2.4258 3.1 2.0 37.396 2.4028 11.2 7.1 37.499 2.3964 9.2 5.8 38.157 2.3566 11.0 7.0 38.260 2.3505 5.9 3.8 Significant peaks are bolded. Peaks unique to or prominent in the anhydrous sodium thiosulfate form are: 10.52, 15.13, 19.70, 21.49, 21.84, 28.96, 30.46, 33.15, 37.40, and 38.16. 2025204721   23 Jun 2025 Table 6. Sodium Thiosulfate Pentahydrate X-ray Powder Diffraction Peaks 2-theta (deg.) d(A) Height Height Percent (%) 8.344 10.5876 2.4 1.3 9.189 9.6164 2.6 1.5 12.129 7.2914 1.8 1.0 14.747 6.0022 2.1 1.2 14.946 5.9225 2.4 1.3 15.438 5.7351 41.6 23.3 15.906 5.5674 6.2 3.5 16.534 5.3573 178.8 100 17.388 5.0961 1.6 0.9 18.408 4.8159 16 8.9 18.961 4.6767 0.5 0.3 19.790 4.4825 1.2 0.7 20.014 4.433 11.1 6.2 20.251 4.3816 1.7 1.0 21.249 4.1780 42.4 23.7 23.448 3.7909 3.6 2.0 24.123 3.6863 16.2 9.1 24.35 3.6524 5.6 3.1 24.847 3.5805 18.7 10.4 25.435 3.4991 7.0 3.9 25.933 3.4329 5.5 3.1 26.189 3.4000 1.0 0.5 27.049 3.2938 3.6 2.0 27.462 3.2453 9.1 5.1 27.974 3.1870 19.4 10.9 30.438 2.9343 5.9 3.3 31.045 2.8783 11.2 6.2 31.691 2.8212 4.4 2.4 32.654 2.7401 4.7 2.6 33.198 2.6964 1.8 1.0 33.805 2.6494 6.9 3.9 34.151 2.6233 1.2 0.7 34.400 2.6049 4.0 2.2 35.016 2.5605 0.1 0.0 35.243 2.5445 0.1 0.1 36.097 2.4862 0.5 0.3 36.656 2.4496 3.7 2.1 37.167 2.4171 2.2 1.2 38.281 2.3493 3.0 1.7 38.573 2.3322 0.9 0.5 38.966 2.3095 6.5 3.6 39.488 2.2802 1.1 0.6 2025204721   23 Jun 2025 39.622 Significant peaks are bolded. 2.2728 1.5 0.8 Example 4 Sodium Thiosulfate Binding Capacity Assay 5          A high performance liquid chromatography ultra-violet spectroscopy (HPLC-UV) assay was developed to quantitate the binding capacity of thiosulfate for cisplatin. This method permits comparison of the binding capacity of different lots of sodium thiosulfate or pharmaceutical compositions containing sodium thiosulfate. The HPLC-UV method directly measures the diminution of cisplatin over time in the presence of varying concentrations of sodium thiosulfate. 10         The method uses a Waters Acquity H-Class HPLC system with an Imtakt Scherzo SW- C18 mixed mode column. The HPLC method conditions are outlined in Table 7. The method has a linear response covering cisplatin concentrations from 3.3 pM (0.001 mg / mL) to 666 pM (0.2 mg / mL). This range covers greater than two orders of magnitude at dose-relevant concentrations. Table 7. Sodium Thiosulfate HPLC-UV Method________________ HPLC System: Waters Acquity H-Class__________________________ Column: Imtakt Scherzo SW C18 Mixed-Mode, 150 mm x 3 mm, 3 pm MPA: 0.5 mM Ammonium formate in 9:1 H2O: Acetonitrile, pH 4 MPB: 200 mM Ammonium formate in 7:3 H2O: Acetonitrile, pH 4 Detection: UV 220 nm Column Temperature: 35 °C Diluent: 0.9% NaCl in H2O Flow Rate: 0.4 mL / min Gradient Conditions Time (min) MPA (%) MPB (%) 0 100 0 3 100 0 4.5 90 10 6.5 90 10 6.6 100 0 10.0 100 0 15 2025204721   23 Jun 2025 The assay was performed by mixing equal volumes containing 333 pM, 400 pM, or 666 pM of sodium thiosulfate with 666 pM cisplatin (ratios of 5:1, 6:1, or 10:1 thiosulfate:cisplatin, respectively). Each sample was transferred to an HPLC vial and placed in an autosampler chamber held at 24 °C. Samples were injected onto the HPLC system approximately every 30 minutes to obtain 4 time-points for each sample. A gradient was run and the retention time and peak area were obtained. The decrease in concentration of cisplatin was monitored over time to obtain a reaction rate (e.g., the slope of the line, [cisplatin] / min) and calculated half-life (the time to reach 333 / 2 pM cisplatin based on the slope of the line). Control samples contained 333 pM cisplatin. Exemplary results are summarized in Table 8 and Figure 4. Table 8. Sodium Thiosulfate-Cisplatin Binding Assay Results Cisplatin Concentration (pM) Time ,   * Cntrl Cntrl Cntrl 5:1      5:1 6:1      6:1 10:1     10:1 (mm) 4     328.7 333.1    328.1 323.7   323.7 319.5 5 325.4    324.5 320.3 37     317.9 322.3    316.3 294.2   294.0 269.4 38 286.4   293.2 278.5 70     295.4 308.6   303.6 266.8   268.0 235.2 71 259.8   266.2 239.6 103    286.9 296.6   292.5 243.7   245.3 205.6 104 235.6   240.5 209.3 Linear Regression of Cisplatin Cone. vs. Time Control (n = 3) 5:1 (n = 2) 6:1 (n = 2) 10:1 (n = 2) Slope (Cisplatin -0.40 -0.80 -0.87 -1.13 Area / min) R2 0.99 1.00 0.99 0.99 y-int 332 325 326 321 Half-life (min) 423 198 184 136 2025204721   23 Jun 2025 Example 5 Formulation Preparation The process for preparing the sodium thiosulfate formulation is shown in Fig. 5. Anhydrous sodium thiosulfate was dissolved in sodium phosphate buffer (~10 mM sodium phosphate). An exemplary sodium thiosulfate pharmaceutical formulation is shown in Table 9. The pH was adjusted to ca. 6.5 with NaOH and HC1 or phosphoric acid. The solution was filtered twice through 0.22 pm filters. The filtered solution was filled into glass vials. The vials were sealed with septa and crimped. The sealed filled vials were autoclaved at 121 °C, 15 psi for at least 0.5 h to sterilize the contents. The vials were inspected, labled, and stored at ambient temperature. Table 9. Exemplary Sodium Thiosulfate Formulation Component MassAohime Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Sodium phosphate, monobasic, monohydrate 1.23 mg / mL 0.0087 M Sodium phosphate, dibasic, anhydrous 0.16 mg / mL 0.0012 M Total phosphate buffer 1.39 mg / mL 0.01 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 7,0-8,0 2025204721   23 Jun 2025 Example 6 The manufacturing process for anhydrous sodium thiosulfate as described herein comprises the following steps: Step 1: Chemical synthesis of sodium thiosulfate, aqueous; 5           Step 2: Crystallization of sodium thiosulfate (wet) and washing with acetone; Step 3: Dehydration and isolation of anhydrous sodium thiosulfate; and Step 4: Packaging. The synthesis route is presented in Scheme II and each step is described futher below. Scheme II 10 O ii +Na O"5'©’ Na+ H2O, 95 °C Acetone ---► Step 1A O +Na O-S-CT Na+ S 5 H2O MeOH       O ----► +Na O-S-O" Na+ SteplB       q Synthesis of Sodium Thiosulfate The synthesis of aqueous sodium thiosulfate was accomplished by reacting 1.0 mole equivalents of aqueous sodium sulfite with 1.1 mole equivalents of solid elemental sulfur (trace 15 metals) under aqueous conditions at 95 ± 5 °C in the presence of catalytic amounts of cetylpyridinium chloride (0.00013 mole equivalents) to form sodium thiosulfate. See Scheme II. The reaction completeness was verified after 6 hours by measuring the amount of residual sodium sulfite present (e.g., <0.15% w / w sulfite by HPLC-CAD). The finished reaction was then cooled to 20 ± 5 °C for at least 3 hours and held at 20 ± 5 °C for at least 1 hour. The product solution was 20 passed through a 1 pm bag filter followed by a 0.45 pm cartridge polishing filter to remove any residual sulfur while transferring the product to a crystallization vessel. Crystallization of Sodium Thiosulfate (wet) The product solution was cooled in a crystallization vessel to 0 ± 5 °C with vigorous 25 agitation, and about 35% of the total acetone was added and mixed for at least 20 min while maintaining a temperature of no more than 10 °C. After incubation at 0 ± 5 °C for about 5 to about 20 min, a sodium thiosulfate seed crystal was added and the crystallization was performed at 0 ± 5 °C for about 5 to about 20 min. The remaining quantity of acetone was added while the temperature was maintained at 0 ± 5 °C. The slurry was then held at 0 ± 5 °C for at least 0.5 hour 2025204721   23 Jun 2025 and then transferred to a filter dryer. The filtrate was removed by pressure filtration. The slurry was filtered to the point where the filtrate drops just below the level of the cake after each portion of slurry was added; this process minimized cracking of the resulting cake. The cake was then washed twice with acetone and blown with N2 gas until no liquid exited. The resulting cake of “wet sodium thiosulfate” was then dried at ambient temperature and atmospheric pressure with N2 blowing through the cake for at least 1 hour. The term “wet sodium thiosulfate” or “sodium thiosulfate (wet)” as used herein refers to sodium thiosulfate that has not been dehydrated. Dehydration and Isolation of Anhydrous Sodium Thiosulfate Filtered methanol, heated to 60 ± 5 °C was charged into the filter dryer containing the dried “wet” sodium thiosulfate material and agitated continuously at 45 ± 5 °C for at least 3 hours. The material was blown with nitrogen for at least 2 hours. The temperature was then raised to 55 ± 5 °C and the solid is dried under vacuum for at least 24 hours. Afterwards, the residual solvents were tested using gas chromatography for volatile impurities. The anhydrous sodium thiosulfate 15 material was cooled to 20 ± 5 °C under slight nitrogen pressure. Packaging Immediately after cooling, the anhydrous sodium thiosulfate drug substance was transferred into HDPE drums that were double lined with LDPE bags and contained a desiccant 20 between the LDPE liners. The drums were purged with nitrogen gas prior to sealing. 2025204721   23 Jun 2025 Manufacturing specifications are shown in Table 10. Table 10. Anhydrous Sodium Thiosulfate Manufacturing Specifications Section I: General Information Name Sodium Thiosulfate Anhydrous Specification Classification Drug Substance Molecular Weight 158.11 g / mol Structure Storage Condition Bulk Primary Storage Container Test Sample Amount Room Temperature (25 °C) HDPE Keg with Heat-sealed foil pouch containing double-lined poly bag with desiccant Release: 5 grams MET: 15 grams Retest Date Sample Container(s) Retention Sample Amount 12 months from manufacture Heat-sealed foil pouch containing double-lined poly bag with desiccant N / A Section II: Testing Attributes and Methods Test Method Attribute Specification (Limit / Range / Description) Appearance Identification by FTIR Identification Identification by IC Impurities by HPLC Internal cUSP (197A) cUSP Sodium (191) Internal Internal Appearance Identification conforms to reference spectrum Identification meets the requirements Identification Residual Sulfite White to off-white solid, free of particulates Retention time of Thiosulfate in sample corresponds to that of reference standard NMT 0.5% Assay by IC Internal Residual Sulfate Assay, solvent free and anhydrous basis NMT 1.5% 97.5-102.5% NMT: not more than. The following pages show manufacturing specifications of anhydrous sodium thiosulfate 5 produced by the method described above in 10 kg and 30 kg batches (Tables 11 and 12). Table 11: Specifications for Anhydrous Sodium Thiosulfate Manufactured at 10 kg Scale Test Method Specification 1-A 1-B 1-C 1-D 1-E 1-F 2-A 2-B White to White to White to White to White to White to White to White to White to off- off-white off-white off-white off-white off-white off-white off-white off-white Appearance Visual solid, free solid, free solid, free solid, free solid, free solid, free solid, free solid, free white solid, free of of of of of of of of of particulates particulate particulate particulate particulate particulate particulate particulate particulate s s s s s s s s Identification cUSP Conforms to reference Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms by FTIR (197 A) spectrum cUSP Meets the Identification Sodium (191) Ion chromatog raphy Present Present Present Present Present Present Present Present requirements Retention time of Thiosulfate Identification by IC in sample corresponds to that of reference standard 97.5-102.5% (as is) Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms Ion Assay by IC chromatog raphy 99.1% 101.1% 101.3% 100.4% 99.3% 99.5% 99.9% 101.2% Ion chromatog raphy Residual Sulfite: NMT Sulfite: Sulfite: Sulfite: Sulfite: Sulfite: Sulfite: Sulfite: Sulfite: Impurities by 0.15% ND ND ND ND ND ND ND ND IC Residual Sulfate: Sulfate: Sulfate: Sulfate: Sulfate: Sulfate: Sulfate: Sulfate: Sulfate: NMT 1.5% 0.56% 0.56% 0.54% 0.6% 0.6% 0.55% 0.55% 0.52% Karl Water Fischer NMT 3.0% 0.1% 0.1% 0.1% 0.1% 0.1% 0.0% 0.1% 0.04% Content USP (921) (w / w) 1c Acetone: <2500 Acetone: Acetone: Acetone: Acetone: Acetone: Acetone: Acetone: Acetone: OVIby GC ND <100 ppm MeOH: < ND ND ND ND ND ND GC ppm Methanol: <1500 ppm MeOH: MeOH: MeOH: MeOH: MeOH: MeOH: MeOH: ND 100 ppm <100 ppm ND ND ND ND ND Polymorphic Form XRPD Sample pattern conforms with reference Conforms Conforms spectrum Cd: <0.1 ppm Pb: <0.25 ppm As: <0.7 5ppm Hg: <0.15 ppm Co: <0.25 ppm V: <0.5 ppm Cd: <0.05 Pb: <0.125 Cd: <0.05 Pb: <0.125 Elemental Impurities or Elemental ICP-MS As: <0.375 Hg: <0.075 Co: <0.125 As: <0.375 Hg: <0.075 Co: <0.125 Limit V: <0.25 V: <0.25 Analysis Ni. <1 ppm Li: <12.5 ppm Sb: <4.5 ppm Cu: <15.0 ppm Ni: <0.5 Li: <2.25 Ni: <0.5 Li: <2.25 Sb: <6.25 Cu: <7.5 Sb: <6.25 Cu: <7.5 Total Aerobic Microbial Microbial Enumeration Tests Count: <100 USP (61) cfu / g Total Yeasts and Molds 2 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g Count: <100 cfu / g Endotoxin USP (85) NMT 5.0 EU / g <0.5 EU / g <0.5 EU / g Conforms Conforms Conforms Conforms Conforms Conforms Cd: <0.05 Cd: <0.05 Cd: <0.05 Cd: <0.05 Cd: <0.05 Cd: <0.05 Pb: <0.125 Pb: <0.125 Pb: <0.125 Pb: <0.125 Pb: <0.125 Pb: <0.125 As: <0.375 As: <0.375 As: <0.375 As: <0.375 As: <0.375 As: <0.375 Hg: Hg: Hg: Hg: Hg: Hg: <0.075 <0.075 <0.075 <0.075 <0.075 <0.075 Co: <0.125 Co: <0.125 Co: <0.125 Co: <0.125 Co: <0.125 Co: <0.125 V: <0.25 V: <0.25 V: <0.25 V: <0.25 V: <0.25 V: <0.25 Ni: <0.5 Ni: <0.5 Ni: <0.5 Ni: <0.5 Ni: <0.5 Ni: <0.5 Li: <2.25 Li: <2.25 Li: <2.25 Li: <2.25 Li: <2.25 Li: <2.25 Sb: <6.25 Sb: <6.25 Sb: <6.25 Sb: <6.25 Sb: <6.25 Sb: <6.25 Cu: <7.5 Cu: <7.5 Cu: <7.5 Cu: <7.5 Cu: <7.5 Cu: <7.5 3 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <0.5 EU / g <0.5 EU / g <0.5 EU / g <0.5 EU / g <0.5 EU / g <0.5 EU / g NMT: not more than. Table 12: Specifications for Anhydrous Sodium Thiosulfate Manufactured at 30 kg Scale Test Method Specification 1 2 3 Appearance Visual White to off-white White solid free of White solid free of White to off-white solid, free of particulates particulates particulates solid, free of particulates Identification by FTIR Identification cUSP (197A) cUSP Sodium Conforms to reference spectrum Meets the Conforms Conforms Conforms Present Present Present (191) requirements Retention time of Identification by IC Ion Thiosulfate in sample Conforms Conforms Conforms chromatography corresponds to that of reference standard Assay by IC Ion chromatography 97.5-102.5% (as is) 98.9% 98.3% 98.1% Residual Sulfite: Impurities by IC Ion NMT 0.15% Sulfite: ND Sulfite: <0.10% Sulfite: ND chromatography Residual Sulfate: NMT 1.5% Sulfate: 0.9% Sulfate: 1.0% Sulfate: 0.9% Karl Fischer USP NMT 3.0% (w / w) Water Content (921)1c 0.0% 0.1% 0.0% OVI by GC nr Acetone: <2500 ppm Methanol: <1500 Acetone: ND Acetone: ND Acetone: ND VrU MeOH: <100 ppm MeOH: 133 ppm MeOH: 238 ppm ppm Sample pattern Polymorphic Form XRPD conforms with reference spectrum Conforms Conforms Conforms Elemental Cd: <0.1ppm Impurities or Elemental Limit ICP-MS Pb: <0.25ppm As: <0.75ppm Analysis Hg: <0.15ppm Co: <0.25ppm V: <0.5ppm Ni: <lppm Li: <12.5ppm Sb: <4.5ppm Cu: <15.0ppm Total Aerobic Microbial Count: Microbial Enumeration Tests USP (61) <100 cfu / g Total Yeasts and Molds Count: <100 cfu / g Endotoxin USP (85) NMT 5.0 EU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <1 CFU / g <0.5 EU / g <0.5 EU / g <0.5 EU / g ND: Not determined; NMT: not more than. 2025204721   23 Jun 2025 Example 7 The anhydrous sodium thiosulfate synthesized as described herein is a crystalline material that exhibits sharp XRPD peaks (FIG. 2A) and birefringent particles with blade- and plate-like crystal morphology. Thermal analysis by differential scanning calorimetry (DSC) showed a single, sharp endotherm with an onset of 331.4 °C that is the apparent melting temperature (FIG 4A). In the thermogravimetric analysis (TGA), there was negligible weight loss from ambient temperature to 162 °C. From 162 °C to 309 °C, there was a weight loss of 14.81% followed by an onset of decomposition at 436 °C (FIG. 4A). The dynamic vapor sorption (DVS) isotherm showed a minimal weight change upon equilibration to 0% relative humidity (FIG. 4B). Upon sorption, the exhibits a weight gain of 165%. Hysteresis was observed upon desorption, with a weight loss of 51%. By comparision, the DSC thermogram of sodium thiosulfate pentahydrate showed multiple endothermic events with maxima at 56, 111, 131, and 141 °C, with a melt onset at 331 °C. A 45.33% weight loss was observed in TGA from 25 °C until -300 °C, followed by decomposition 15 at 456 °C. The DVS isotherm showed a 27% weight loss upon drying. The material had a weight gain of 81% upon sorption. Hysteresis was observed upon desorption, with a weight loss of 51%. Example 8 A process for preparing the sodium thiosulfate formulation for injection is shown in Fig. 20   5. Anhydrous sodium thiosulfate was dissolved in borate buffer (-4 mM boric acid). An exemplary sodium thiosulfate pharmaceutical formulation is shown in Table 13. The pH was adjusted to ca. 8.6-8.8 with NaOH and HC1. The solution was filtered twice through 0.22 pm filters. The filtered solution was filled into glass vials. The vials were sealed with septa, aluminum rings, and crimped. The sealed filled vials were autoclaved at 121 °C, 15 psi for at least 0.5 h to 25 sterilize the contents. The vials were inspected, labled, and stored at ambient temperature. Table 13. Exemplary Sodium Thiosulfate Formulation Component                             Mass / Vohime Molarity Sodium thiosulfate, anhydrous                    80.0 mg / mL Boric acid                                     0.25 mg / mL Hydrochloric acid                                       q.s. Sodium hydroxide                                   q.s. Final pH: 8.6-8.8 0.5 M 0.004 M q.s. q.s. 2025204721   23 Jun 2025 Table 14 shows the manufacturing specifications for the sodium thiosulfate formulation for injection. Table 14. Sodium Thiosulfate For Injection Drug Product Specifications Parameters Method / Laboratory Acceptance Criteria Clear, colorless solution Appearance Visual essentially free of particulate matter Retention time of thiosulfate in Identification: Thiosulfate HPLC sample agrees with retention time of reference material Clarity and Degree of Opalescence of Liquids Ph. Eur. 2.2.1 NMT Reference suspension 1 Degree of Coloration of a Liquid Ph. Eur. 2.2.2 Identification STS by FTIR USP (197) Conforms to reference spectrum Identification for Sodium USP (191) Meets requirements pH USP (791) Ph. Eur. 2.2.3 7.0-9.0 US Release: 90.0-110.0% label claim Stability: 90.0-110.0% label Assay IC claim EU Release: 95.0-105.0% label claim Stability: 90-100.0% lable claim Sulfite IC NMT 0.15% Sulfate IC NMT 1.5% Sulfur HPLC-UV NMT 0.15% Extractable Volume USP (1) Ph. Eur 2.9.17 NLT 100 mL Particulate Matter USP (788) Ph. Eur. 2.9.19 10 pm: <3000 25 pm: <3000 Sterility USP (71) Ph. Eur. 2.6.1 No growth observed Bacterial Endotoxin USP (85) <0.10EU / mL NMT: not more than 2025204721   23 Jun 2025 Example 9 Exemplary sodium thiosulfate pharmaceutical formulations are shown in Tables 15-23. These formulations are prepared as described herein. Table 15. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Sodium phosphate, monobasic, monohydrate 1.23 mg / mL 0.0012 M Sodium phosphate, dibasic, anhydrous 0.16 mg / mL 0.0087 M Total phosphate buffer 1.39 mg / mL 0.01 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 7,5-8,0 Table 16. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Sodium phosphate, monobasic, monohydrate 2.46 mg / mL 0.017 M Sodium phosphate, dibasic, anhydrous 0.31 mg / mL 0.0023 M Total phosphate buffer 2.77 mg / mL 0.02 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 7,5-8,0 Table 17. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Boric acid 0.25 mg / mL 0.004 M Hydrochloric acid q.s. q.s. Sodium hydroxide Final pH: 8.6-8.8 q.s. q.s. Table 18. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Glycine 1.5 mg / mL 0.02 M Hydrochloric acid q.s. q.s. Sodium hydroxide Final pH: 8.5-8.9 q.s. q.s. 2025204721   23 Jun 2025 Table 19. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Glycine 2.3 mg / mL 0.03 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 8.5-8.9 Table 20. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Glycine 3.8 mg / mL 0.05 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 8.5-8.9 Table 21. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Tris(hydroxymethyl)aminomethane (Tromethane) 1.21 mg / mL 0.01 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 8.5-8.9 Table 22. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Tris(hydroxymethyl)aminomethane (Tromethane) 2.42 mg / mL 0.02 M Hydrochloric acid q.s. q.s. Sodium hydroxide q.s. q.s. Final pH: 8.5-8.9 Table 23. Exemplary Sodium Thiosulfate Formulation Component MassAolume Molarity Sodium thiosulfate, anhydrous 80.0 mg / mL 0.5 M Tris(hydroxymethyl)aminomethane (Tromethane) 3.63 mg / mL 0.03 M Hydrochloric acid q.s. q.s. Sodium hydroxide Final pH: 8.5-8.9 q.s. q.s. 2025204721   23 Jun 2025 Other aspects of the invention as described herein are defined in the following paragraphs: 1. A pharmaceutical composition comprising aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. 2. The composition of paragraph 1, wherein the composition comprises about 20 mg / mL to 320 mg / mL of aqueous anhydrous sodium thiosulfate. 3. The composition of paragraph 1 or 2, wherein the composition comprises about 8% by mass to about 32% by mass of aqueous anhydrous sodium thiosulfate. 4. The composition of any one of paragraphs 1-3, wherein the composition comprises about 0.1 M to about 2 M of aqueous anhydrous sodium thiosulfate. 5. The composition of any one of paragraphs 1-4, wherein the composition comprises about 0.001 M to about 0.5 M of the one or more buffers. 6.     The composition of any one of paragraphs 1-5, wherein the one or more buffers comprise phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, a-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. 7. The composition of any one of paragraphs 1-6, wherein the composition has a pH of about 5 to about 9.5. 8. The composition of any one of paragraphs 1-7, wherein the composition has a pH of about 6.5 or about 8.9. 2025204721   23 Jun 2025 9. The composition of any one of paragraphs 1-8, wherein the one or more buffers comprise borate or a salt thereof, glycine or a salt thereof, tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. 10. The composition of any one of paragraphs 1-9, wherein the one or more buffers comprise boric acid, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or sodium phosphate. 11.    The composition of any one of paragraphs 1-10, wherein the solvent comprises water. 12.    The composition of any one of paragraphs 1-11, wherein the composition is sterile. 13. A pharmaceutical composition comprising about 0.1 M to about 2 M of aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M of sodium phosphate, boric acid, glycine, or tris(hydroxymethyl)aminomethane (tromethamine). 14. The composition of paragraph 13, wherein the composition comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, and about 0.01 M of sodium phosphate, pH 6.5. 15. The composition of paragraph 13 or 14 wherein the composition comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, and about 0.004 M of borate or a salt thereof, pH 8.6-8.8. 16. The composition of any one of paragraphs 13-15, wherein the composition comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, and about 0.01 M to about 0.05 M of glycine or a salt thereof, pH 8.5-8.9. 17. The composition of any one of paragraphs 13-16, wherein the composition comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, and about 0.01 M to about 0.05 M of tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, pH 8.5-8.9. 2025204721   23 Jun 2025 18. A pharmaceutical composition comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M of sodium phosphate, pH 6.5, and water. 19. A pharmaceutical composition comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.004 M of borate or a salt thereof, pH 8.6-8.8, and water. 20. A pharmaceutical composition comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of glycine or a salt thereof, pH 8.5-8.9, and water. 21. A pharmaceutical composition comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, pH 8.5-8.9, and water. 22. A method for preparing a pharmaceutical formulation comprising anhydrous sodium thiosulfate, the method comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. 23.    The method of paragraph 22, further comprising filtering and sterilizing the formulation. 24. The method of paragraph 22 or 23, wherein the formulation comprises about 20 mg / mL to 320 mg / mL of aqueous anhydrous sodium thiosulfate. 25. The method of any one of paragraphs 22-24, wherein the formulation comprises about 8% by mass to about 32% by mass of aqueous anhydrous sodium thiosulfate. 26. The method of any one of paragraphs 22-25, wherein the formulation comprises about 0.1 M to about 2 M of aqueous anhydrous sodium thiosulfate. 27. The method of any one of paragraphs 22-26, wherein the formulation comprises about 0.001 M to about 0.5 M of the one or more buffers. 2025204721   23 Jun 2025 28. The method of any one of paragraphs 22-27, wherein the one or more buffers comprise phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, a-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. 29. The method of any one of paragraphs 22-28, wherein the formulation has a pH of about 5 to about 9.5. 30. The method of any one of paragraphs 22-29, wherein the formulation has a pH of about 6.5 or about 8.9. 31. The method of any one of paragraphs 22-30, wherein the one or more buffers comprise glycine or a salt thereof, borate or a salt thereof, tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. 32. The method of any one of paragraphs 22-31, wherein the one or more buffers comprise sodium phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or boric acid. 33.    The method of any one of paragraphs 22-32, wherein the solvent comprises water. 34.    The method of any one of paragraphs 22-33, wherein the formulation comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M of sodium phosphate, pH 6.5, and water. 35. The method of any one of paragraphs 22-33, wherein the formulation comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.004 M of boric acid, pH 8.6-8.9, and water. 2025204721   23 Jun 2025 36.    The method of any one of paragraphs 22-33, wherein the formulation comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of glycine, pH 8.5-8.9, and water. 37.    The method of any one of paragraphs 22-33, wherein the formulation comprises about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of tris(hydroxymethyl)aminomethane (tromethamine), pH 8.5-8.9, and water. 38. A pharmaceutical formulation comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M of sodium phosphate, pH 6.5, and water made by the method of paragraph 22. 39. A pharmaceutical formulation comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.004 M of boric acid, pH 8.6-8.8, and water made by the method of paragraph 22. 40. A pharmaceutical formulation comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of glycine, pH 8.5-8.9, and water made by the method of paragraph 22. 41. A pharmaceutical formulation comprising about 0.5 M of aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M of tris(hydroxymethyl)aminomethane (tromethamine), pH 8.5-8.9, and water made by the method of paragraph 22. 42. Means for preparing a pharmaceutical formulation comprising anhydrous sodium thiosulfate, the method comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. 43. The formulation prepared by the means of paragraph 42. 2025204721   23 Jun 2025 44. A pharmaceutical composition comprising a sterile aqueous solution of about 0.2 M to about 2 M of sodium thiosulfate, about 0.001 M to about 0.05 M of a pharmaceutically acceptable buffer, and about 0.005 M to about 0.05 M of a pharmaceutically acceptable salt, and a pH of about 5 to about 9.5. 45. A kit comprising a sterile aqueous sodium thiosulfate formulation comprising one or more receptacles comprising aqueous sodium thiosulfate; and documents comprising prescribing information or instructions for use. 46. The kit of paragraph 45, further comprising one or more syringes, hypodermic needles, and packaging. 47. A kit comprising one or more receptacles comprising dry or lyophilized sodium thiosulfate; and optionally: one or more sterile solvents appropriate for reconstitution; a needle and syringe; and documents comprising prescribing information or instructions for use. 48. A pharmaceutical formulation comprising aqueous anhydrous sodium thiosulfate for injection that is stable and does not precipitate after sterilization and storage. 49. The pharmaceutical formulation of paragraph 48, wherein the formulation comprises about 0.1 M to about 2 M of aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M of sodium phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or boric acid. 50. A method for preventing or reducing the incidence of by cisplatin (CIS) chemotherapy induced ototoxicity in patients 1 month to <18 years of age with localized, non-metastatic, solid tumors comprising administering sodium thiosulfate for injection as a 15-minute infusion, about 6 hours after the completion of each CIS administration, when CIS is infused for no longer than 6 hours. Still further aspects are in the scope of the following claims.

Claims

1. A method of reducing ototoxicity in a pediatric patient receiving a platinum based chemotherapeutic for the treatment of cancer sensitive to the platinum based chemotherapeutic comprising administering an effective amount of a pharmaceutical composition comprising sodium thiosulfate at a concentration of about 0.5 M and a stabilizer or mixture of stabilizers selected from alanine, arginine, aspartic acid, histidine, lysine, proline, glucose, sucrose, trehalose, glycerol, glycine, mannitol, sorbitol, sodium sulphate, ethylenediaminetetraacetic acid (EDTA), cyclodextrin, dextran, polyethylene glycol, polyvinylpyrrolidone, and tromethamine, wherein the pharmaceutical composition is adjusted if necessary to achieve a pH between 6.5 and 8.9, and wherein the pharmaceutical composition comprises no borate ions.

2. The method of claim 1, wherein the composition comprises a pH adjusting agent.

3. The method of claim 2, wherein the pH adjusting agent comprises hydrochloric acid.

4. The method of claim 2, wherein the pH adjusting agent comprises sodium hydroxide.

5. The method of any one of claims 1-4, wherein the pediatric patient is five or fewer years of age.

6. The method of any one of claims 1-5, wherein the platinum based chemotherapeutic is cisplatin.

7. The method of any one of claims 1-6, wherein the pharmaceutical composition is administered to the pediatric patient about 6 hours after the completion of the administration of platinum based chemotherapeutic.

8. The method of any one of claims 1-7, wherein the stabilizer is glycine.

9. The method of any one of claims 1-7, wherein the stabilizer is tromethamine.2025204721   23 Jun 202510. The method of any one of claims 1-7, wherein the stabilizer is alanine.

11. The method of any one of claims 1-7, wherein the stabilizer is arginine.

12. The method of any one of claims 1-7, wherein the stabilizer is aspartic acid.

13. The method of any one of claims 1-7, wherein the stabilizer is histidine.

14. The method of any one of claims 1-7, wherein the stabilizer is lysine.

15. The method of any one of claims 1-7, wherein the stabilizer is proline.

16. The method of any one of claims 1-7, wherein the stabilizer is glucose.

17. The method of any one of claims 1-7, wherein the stabilizer is sucrose.

18. The method of any one of claims 1-7, wherein the stabilizer is trehalose.

19. The method of any one of claims 1-7, wherein the stabilizer is glycerol.

20. The method of any one of claims 1-7, wherein the stabilizer is mannitol.

21. The method of any one of claims 1-7, wherein the stabilizer is sorbitol.

22. The method of any one of claims 1-7, wherein the stabilizer is sodium sulphate.

23. The method of any one of claims 1-7, wherein the stabilizer is EDTA.

24. The method of any one of claims 1-7, wherein the stabilizer is cyclodextrin or dextran.

25. The method of any one of claims 1-7, wherein the stabilizer is polyethylene glycol or polyvinylpyrrolidone.

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