Formulation of anhydrous sodium thiosulfate

Abstract

To provide sodium thiosulfate-containing formulations for alleviating or preventing ototoxicity in pediatric patients caused by platinum-based chemotherapeutics.SOLUTION: The present invention provides a pharmaceutical composition for alleviating or preventing ototoxicity in pediatric patients receiving platinum-based chemotherapeutics for the treatment of cancers sensitive to the platinum-based chemotherapy, wherein the pharmaceutical composition comprises about 0.5M concentration of sodium thiosulfate and a stabilizer, the pharmaceutical composition is adjusted to a pH of 6.5 to 8.9, as needed, and the pharmaceutical composition is free of borate ions.SELECTED DRAWING: Figure 6

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 62 / 693,502 and 62 / 693,503, both filed July 3, 2018, the entire contents of which are incorporated herein by reference. This application is related to U.S. Patent Application No. 16 / 458,261, entitled "ANHYDROUS SODIUM THIOSULFATE AND FORMULATIONS THEREOF," filed July 1, 2019, the entire contents of which are incorporated herein by reference.

[0002] Described herein are methods for synthesizing anhydrous sodium thiosulfate, the anhydrous sodium thiosulfate, and pharmaceutical compositions thereof that are useful in eliminating or reducing ototoxicity in patients undergoing platinum-based chemotherapy. [Background technology]

[0003] Platinum-based therapies are essential components of treatment regimens used in a variety of pediatric malignancies, including neuroblastoma, hepatoblastoma, medulloblastoma, osteosarcoma, malignant germ cell tumors, and nasopharyngeal carcinoma. At commonly used doses and schedules, platinum-based therapies such as cisplatin and carboplatin often cause progressive, bilateral, and irreversible disease, often accompanied by tinnitus. Platinum chemotherapy-induced hearing loss is due to the death of outer cochlear hair cells and can affect all hearing. Summary of the Invention [Problem to be solved by the invention]

[0004] These toxicities can be dose limiting and are often clinically significant, especially in young children who are critically dependent on normal hearing for cognitive, psychosocial, and language development. The incidence of cisplatin-induced hearing loss in young children reaches approximately 40%, with incidence approaching 100% in certain vulnerable groups. Even when hearing loss is mild in pediatrics, its impact is substantial, with impairments in language acquisition, learning, academic achievement, social and emotional development, and quality of life, among others. Therefore, there is a need for safe and effective pharmaceutical compositions and methods for treating pediatric patients and reducing ototoxicity and hearing loss in these patients without compromising the efficacy of platinum-based therapies. [Means for solving the problem]

[0005] One embodiment described herein is a pharmaceutical composition comprising sodium thiosulfate, one or more buffers, and a solvent. Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition consisting essentially of anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition consisting essentially of aqueous anhydrous sodium thiosulfate.

[0006] Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate and one or more buffers. Another embodiment described herein is a pharmaceutical composition consisting of anhydrous sodium thiosulfate and one or more buffers. In one aspect, the composition comprises about 20 mg to 32 g of anhydrous sodium thiosulfate. In another aspect, the composition comprises about 98% by weight of anhydrous sodium thiosulfate. In another aspect, the composition is a dry powder. In another aspect, the composition is a lyophilized solution.

[0007] Another embodiment described herein is a pharmaceutical composition comprising aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent.Another embodiment described herein is a pharmaceutical composition consisting essentially of anhydrous sodium thiosulfate, one or more buffers, and a solvent.

[0008] Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate, one or more buffers at 0.001M to about 0.5M, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate, 0.01M to about 0.5M sodium phosphate at pH 6.5, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate, 0.001M to about 0.5M boric acid or a salt thereof at pH 8.6-8.8, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate, 0.001M to about 0.5M glycine or a salt thereof at pH 8.5-8.9, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M tris(hydroxymethyl)aminomethane (tromethane) or a salt thereof, and water, and a pH of 8.5 to 8.9.

[0009] Another embodiment described herein is a pharmaceutical composition comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M sodium phosphate at pH 6.5, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.004M boric acid or a salt thereof at pH 8.6-8.8, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine at pH 8.5-8.9, and water. Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate, 0.001M to about 0.5M tris(hydroxymethyl)aminomethane (tromethane) or a salt thereof at pH 8.5-8.9, and water.

[0010] Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate, one or more buffers, and a solvent. In one aspect, the composition comprises about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. In another aspect, the composition comprises about 8% to about 32% by weight aqueous anhydrous sodium thiosulfate. In another aspect, the composition comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. In another aspect, the composition comprises about 0.001 M to about 0.5 M of one or more buffers. In another embodiment, the one or more buffers comprise phosphate, sulfate, carbonate, borate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. In another embodiment, the composition has a pH of about 5 to about 9.5. In another embodiment, the composition has a pH of about 6.5 or about 8.9. In another embodiment, the one or more buffers include borate or a salt thereof, glycine or a salt thereof, tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. In another embodiment, the one or more buffers include boric acid, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or sodium phosphate. In another embodiment, the solvent includes water. In another embodiment, the composition is sterile.

[0011] Another embodiment described herein is a pharmaceutical composition comprising about 0.1M to about 2M aqueous anhydrous sodium thiosulfate and 0.001M to about 0.5M sodium phosphate or boric acid. In one aspect, the composition comprises about 0.5M aqueous anhydrous sodium thiosulfate and about 0.01M sodium phosphate at a pH of 6.5. In another aspect, the composition comprises about 0.5M aqueous anhydrous sodium thiosulfate and about 0.004M borate or a salt thereof at a pH of 8.6-8.8. In another aspect, the composition comprises about 0.5M aqueous anhydrous sodium thiosulfate and about 0.01M to about 0.05M glycine or a salt thereof at a pH of 8.5-8.9. In another aspect, the composition comprises about 0.5M aqueous anhydrous sodium thiosulfate and about 0.01M to about 0.05M tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof at a pH of 8.5-8.9.

[0012] Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water.

[0013] Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M borate or a salt thereof and a pH of 8.6-8.8, and water.

[0014] Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine or a salt thereof and a pH of 8.5 to 8.9, and water.

[0015] Another embodiment described herein is a pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof and a pH of 8.5 to 8.9, and water.

[0016] Another embodiment described herein is a method for preparing an anhydrous sodium thiosulfate-containing pharmaceutical formulation comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. In one aspect, the method further comprises filtering and sterilizing the formulation. In another aspect, the formulation comprises about 20 mg / mL to 320 mg / mL aqueous anhydrous sodium thiosulfate. In another aspect, the formulation comprises about 8% to about 32% by weight aqueous anhydrous sodium thiosulfate. In another aspect, the formulation comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. In another aspect, the formulation comprises about 0.001 M to about 0.5 M of one or more buffers. In another embodiment, the one or more buffers comprise phosphate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. In another embodiment, the formulation has a pH of about 5 to about 9.5. In another embodiment, the formulation has a pH of about 6.5 or about 8.9. In another embodiment, 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. In another embodiment, the one or more buffers comprise sodium phosphate, glycine, or boric acid. In another embodiment, the solvent comprises water. In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at pH 8.6-8.8, and water. In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at pH 8.5-8.9, and water.In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate at about 0.5 M, tris(hydroxymethyl)aminomethane (tromethamine) at about 0.01 M to about 0.05 M and a pH of 8.5 to 8.9, and water.

[0017] Another embodiment described herein is a pharmaceutical formulation produced by the methods described herein, comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water.

[0018] Another embodiment described herein is a pharmaceutical formulation produced by the methods described herein, comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at a pH of 8.6-8.8, and water.

[0019] Another embodiment described herein is a pharmaceutical formulation produced by the methods described herein, comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine and a pH of 8.5 to 8.9, and water.

[0020] Another embodiment described herein is a pharmaceutical formulation made by the methods described herein, comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) and a pH of 8.5 to 8.9, and water.

[0021] Another embodiment described herein is a means for preparing anhydrous sodium thiosulfate-containing pharmaceutical formulations comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. Another embodiment is a pharmaceutical formulation prepared by the means described herein.

[0022] Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of about 0.2 M to about 2 M sodium thiosulfate, about 0.001 M to about 0.05 M of a pharma- ceutically acceptable buffer, and about 0.005 M to about 0.05 M of a pharma- ceutically acceptable salt, having a pH of about 5 to about 9.5.

[0023] Another embodiment described herein is a kit comprising an aqueous sodium thiosulfate formulation comprising one or more receptacles containing aqueous sodium thiosulfate and a document containing prescribing information or instructions for use. In one aspect, the kit further comprises one or more syringes, a hypodermic injection needle, and packaging.

[0024] Another embodiment described herein is a kit comprising one or more receptacles containing dried or lyophilized sodium thiosulfate, optionally one or more sterile solvents suitable for reconstitution, a needle and a syringe, and a document containing prescribing information or instructions for use.

[0025] Another embodiment described herein is a pharmaceutical formulation comprising an injectable aqueous anhydrous sodium thiosulfate that is stable and does not precipitate after sterilization and storage. In one aspect, the formulation comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or boric acid.

[0026] Another embodiment described herein is anhydrous sodium thiosulfate characterized by an X-ray powder diffraction (XRPD) pattern, when collected from about 2 to about 40 degrees 2θ using copper Kα radiation, that includes at least four peaks selected from 10.52, 15.13, 17.71, 19.70, 21.09, 21.49, 21.84, 27.40, 28.96, 30.46, 31.81, 32.52, 33.15, 37.40, or 38.16 degrees two theta (2θ) ±0.2. In one embodiment, the anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks selected from 10.52, 15.13, 19.70, 21.49, 21.84, 28.96, 30.46, 33.15, 37.40, and 38.16 degrees two theta (2θ) ±0.2, when the XRPD is collected using copper Kα radiation from about 2 to about 40 degrees two theta. In another embodiment, the anhydrous sodium thiosulfate is characterized by an onset of melting at about 331°C by differential scanning calorimetry, and by thermogravimetric analysis showing negligible weight loss from ambient to 162°C, 14.8% weight loss from 162°C to 309°C, and an onset of decomposition at 436°C.

[0027] Another embodiment described herein is anhydrous sodium thiosulfate having less than or equal to 0.1 μg / g cadmium, less than or equal to 0.25 μg / g lead, less than or equal to 0.75 μg / g arsenic, less than or equal to 0.15 μg / g mercury, less than or equal to 0.25 μg / g cobalt, less than or equal to 0.5 μg / g vanadium, less than or equal to 1.0 μg / g nickel, less than or equal to 12.5 μg / g lithium, less than or equal to 4.5 μg / g antimony, less than or equal to 15.0 μg / g copper, less than or equal to 1500 ppm methanol, less than or equal to 3% (w / w) water, and less than or equal to 1.65% (w / w) total impurities or related substances.

[0028] Another embodiment described herein is a method for synthesizing sodium thiosulfate comprising reacting sodium sulfite with sulfur in the presence of a surface acting agent. In one aspect, the surface acting agent comprises cetylpyridinium chloride. In another aspect, the reaction is aqueous. In another aspect, the reaction is carried out at about 80° C. to about 100° C. In another aspect, the sodium thiosulfate is crystallized and then washed with acetone.

[0029] Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate comprising reacting sodium sulfite with sulfur in the presence of cetylpyridinium chloride and dehydrating the sodium thiosulfate product. In one aspect, the reaction comprises 1.0 molar equivalent of sodium sulfite, 1.1 molar equivalent of sulfur, and 0.00013 molar equivalent of cetylpyridinium chloride. In another aspect, the reaction is aqueous. In another aspect, the reaction is carried out at about 80° C. to about 100° C. In another aspect, the sodium thiosulfate is crystallized and then washed with acetone. In another aspect, the sodium thiosulfate is dehydrated and washed with methanol. In another aspect, the sodium thiosulfate is dried.

[0030] Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate comprising: (a) reacting aqueous sodium sulfite with sulfur and cetylpyridinium chloride; (b) crystallizing and washing the sodium thiosulfate with acetone; (c) dehydrating the washed sodium thiosulfate with methanol; and (d) drying the dehydrated sodium thiosulfate. In one aspect, the reaction comprises 1.0 molar equivalent of sodium sulfite, 1.1 molar equivalent of sulfur, and 0.00013 molar equivalent of cetylpyridinium chloride.

[0031] Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate comprising: (a) reacting 1.0 molar equivalent of aqueous sodium sulfite with 1.1 molar equivalents of sulfur in the presence of 0.00013 molar equivalents of cetylpyridinium chloride at about 90° C. to about 100° C.; (b) crystallizing the sodium thiosulfate at less than 2° C. and washing with acetone; (c) dehydrating the washed sodium thiosulfate with methanol; and (d) drying the dehydrated sodium thiosulfate at about 25° C. to about 60° C.

[0032] Another embodiment described herein is anhydrous sodium thiosulfate synthesized by the methods described herein.

[0033] Another embodiment described herein is a means for the synthesis of anhydrous sodium thiosulfate comprising reacting sodium sulfite with sulfur in the presence of cetylpyridinium chloride, crystallizing the sodium thiosulfate product, and dehydrating the sodium thiosulfate product.

[0034] Another embodiment described herein is anhydrous sodium thiosulfate synthesized by the means described herein.

[0035] Another embodiment described herein is anhydrous sodium thiosulfate that is essentially free of sodium thiosulfate pentahydrate.

[0036] Another embodiment described herein is a method for measuring the binding ability of sodium thiosulfate to cisplatin, comprising: (a) mixing one or more ratios of sodium thiosulfate with a predetermined amount of cisplatin; (b) incubating the mixture for a period of time; and (c) analyzing the apparent concentration of cisplatin. In one aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1 to 1:1. In another aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1, 6:1, and 5:1. In another aspect, the incubation time includes 1 minute to 180 minutes. In another aspect, the incubation time includes about 5 minutes, about 35 minutes, about 65 minutes, and about 95 minutes. In another aspect, the analysis includes HPLC and UV detection.

[0037] Another embodiment described herein is a method for preventing or reducing the incidence of cisplatin (CIS) chemotherapy-induced ototoxicity in patients aged 1 month to less than 18 years with localized non-metastatic solid tumors, the method comprising administering sodium thiosulfate for injection as a 15 minute infusion 6 hours after completion of each CIS dose if the CIS is infused within 6 hours.

[0038] Also described herein are compositions and methods for reducing ototoxicity in patients undergoing platinum-based chemotherapy. In particular, compositions and intravenous formulations for reducing ototoxicity in pediatric patients are described. Also described are methods for administering the compositions and formulations. The method includes administering an effective amount of sodium thiosulfate to the patient following administration of a platinum-based chemotherapy agent. As described herein, administration of sodium thiosulfate has been found to reduce the incidence and severity of ototoxicity in pediatric patients without adversely affecting the efficacy of the platinum-based chemotherapy agent. In one embodiment, the method includes administering a sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition includes about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. In another embodiment, the formulation includes about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at pH 8.6-8.8, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine and a pH of 8.5-8.9, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) and a pH of 8.5-8.9, and water. Another embodiment is a method of reducing ototoxicity in a patient suffering from cancer and receiving platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate.

[0039] Another embodiment is a method of prophylactically treating a patient suffering from cancer and reducing the likelihood that the patient will suffer ototoxicity from platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate. In one aspect, the method comprises administering a sodium thiosulfate pharmaceutical composition as described herein. In one aspect, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at a pH of 6.5, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at a pH of 8.6-8.8, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at a pH of 8.5-8.9, and water. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate at about 0.5 M, tris(hydroxymethyl)aminomethane (tromethamine) at about 0.01 M to about 0.05 M and a pH of 8.5 to 8.9, and water.

[0040] Another embodiment is a method of reducing long-term ototoxicity in a patient suffering from cancer and undergoing platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate. In one aspect, the method comprises administering a sodium thiosulfate pharmaceutical composition as described herein. In another aspect, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at a pH of 6.5, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at a pH of 8.6-8.8, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at a pH of 8.5-8.9, and water. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate at about 0.5 M, tris(hydroxymethyl)aminomethane (tromethamine) at about 0.01 M to about 0.05 M and a pH of 8.5 to 8.9, and water.

[0041] Another embodiment is a method of reducing the concentration of cisplatin in the ear cavity of a patient suffering from cancer and receiving platinum-based chemotherapy, the method comprising administering to the patient an effective amount of sodium thiosulfate, the method reducing the effects of ototoxicity caused by platinum-based chemotherapy to the patient receiving sodium thiosulfate with substantially no detectable cisplatin in the ear cavity.

[0042] Another embodiment is a method of inhibiting ototoxic effects associated with administration of a platinum-based chemotherapy compound to a patient, the method comprising administering to the patient an effective amount of sodium thiosulfate.

[0043] In some embodiments described herein, a patient who is a carrier has a single nucleotide polymorphism in the gene ACYP2 at locus rs1872328. In some embodiments, a patient administered sodium thiosulfate is about 20% to about 75% less likely to experience ototoxicity than a patient not administered sodium thiosulfate. In some embodiments, a patient administered sodium thiosulfate is about 50% less likely to experience ototoxicity than a patient not administered sodium thiosulfate. In some embodiments, ototoxicity includes hearing loss, balance disorders, tinnitus, hyperacusis, or a combination thereof.

[0044] In some embodiments described herein, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the platinum-based chemotherapeutic agent is cisplatin.

[0045] In some embodiments, the cancer being treated is localized or disseminated. In some embodiments, the cancer being treated is localized. In some embodiments, the cancer being treated is selected from germ cell tumors, hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma. In some embodiments, the cancer being treated is hepatoblastoma. In some embodiments, the cancer being treated is a standard risk cancer, a medium risk cancer, or a high risk cancer. In some embodiments, the cancer being treated is a standard risk cancer or a medium risk cancer. In some embodiments, the cancer being treated is a standard risk or a medium risk hepatoblastoma.

[0046] In some embodiments, sodium thiosulfate is administered prior to, simultaneously with, or after administration of a platinum-based chemotherapy agent. In some embodiments, sodium thiosulfate is administered about 0.5 hours to about 10 hours after administration of a platinum-based chemotherapy agent. In some embodiments, sodium thiosulfate is administered intravenously. In some embodiments, an effective amount of sodium thiosulfate is about 5 g / m per cycle of a platinum-based chemotherapy agent. 2 ~about 25g / m 2 In some embodiments, patients receive between about 1 mg / kg to about 5 mg / kg or about 10 mg / m per cycle of platinum-based chemotherapy. 2 ~about 300mg / m 2In one embodiment, the sodium thiosulfate comprises a pharmaceutical composition as described herein. In another embodiment, the sodium thiosulfate pharmaceutical composition comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M sodium phosphate at pH 6.5, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.004M boric acid at pH 8.6-8.8, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine at pH 8.5-8.9, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M tris(hydroxymethyl)aminomethane (tromethamine) at pH 8.5-8.9, and water.

[0047] In some embodiments described herein, ototoxicity is determined by one or more criteria including Tinnitus Functional Index, Brock grading, American Speech-Language-Hearing Association criteria, or International Society of Pediatric Oncology Boston Ototoxicity Scale. In some embodiments, ototoxicity is measured by measuring hearing loss at one or more frequencies including 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz, or 8,000 Hz, or a combination of frequencies thereof. Changes in hearing are then assessed relative to baseline measurements before the patient received platinum-based chemotherapy or sodium thiosulfate, or both.

[0048] In some embodiments described herein, ototoxicity is assessed by one or more criteria, including the following: (a) a decrease in hearing as measured by a loss of 20 dB at a single frequency; (b) a decrease in hearing as measured by a loss of 10 dB at two consecutive frequencies; (c) a loss of response at three consecutive test frequencies where a response was previously obtained; (d) a reduction in bilateral high frequency hearing loss characterized by: (i) a hearing loss of less than 40 dB at all frequencies, indicating a Grade 0 or minimal hearing loss; (ii) a hearing loss of 40 dB or more only at 8,000 Hz, indicating a Grade 1 or mild hearing loss; (iii) a hearing loss of 40 dB or more at 4,000 Hz or above, indicating a Grade 2 or moderate hearing loss; (iv) a hearing loss of 40 dB or more at 2,000 Hz or above, indicating a Grade 3 or significant hearing loss. (v) a hearing loss of 40 dB or more at 1,000 Hz or above, indicating a Grade 4 or profound hearing loss; or (e) a decrease in hearing characterized by the following: (i) a hearing loss of 20 dB or less at all frequencies, indicating a Grade 0 hearing loss; (ii) a HL of more than 20 dB above 4,000 Hz, indicating a Grade 1 hearing loss; (iii) a HL of more than 20 dB above 4,000 Hz, indicating a Grade 2 hearing loss; (iv) a HL of more than 20 dB at 2,000 Hz or 3,000 Hz, indicating a Grade 3 hearing loss; (v) a HL of more than 40 dB above 2,000 Hz, indicating a Grade 1 hearing loss; or (f) an improvement in the Tinnitus Functional Index, where the change in hearing is calculated compared to a baseline measurement before the patient received platinum-based chemotherapy or sodium thiosulfate, or both. In some embodiments, pediatric patients administered sodium thiosulfate have reduced ototoxicity as assessed by criterion (d) above, compared to pediatric patients not administered sodium thiosulfate.

[0049] In some embodiments described herein, administration of sodium thiosulfate to a patient does not result in an increase in serum creatinine or a decrease in glomerular filtration rate compared to a patient not receiving sodium thiosulfate. In some embodiments, administration of sodium thiosulfate to a patient does not affect progression-free survival or overall survival compared to a patient not receiving sodium thiosulfate. In some embodiments, administration of sodium thiosulfate to a patient does not increase the incidence of one or more adverse events, including febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea.

[0050] In some embodiments described herein, ototoxicity is measured at least 4 weeks after administration of the platinum-based chemotherapy agent and sodium thiosulfate to the patient. In one aspect, the sodium thiosulfate comprises a pharmaceutical composition described herein. In another aspect, the sodium thiosulfate pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at pH 8.6-8.8, and water. In another aspect, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at pH 8.5-8.9, and water. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate at about 0.5 M, tris(hydroxymethyl)aminomethane (tromethamine) at about 0.01 M to about 0.05 M and a pH of 8.5 to 8.9, and water.

[0051] In some embodiments described herein, the patient is a pediatric patient. In some embodiments described herein, the pediatric patient is between 1 week and 18 years of age. In some embodiments, the pediatric patient is about 12 years of age or younger. In some embodiments, the pediatric patient is about 5 years of age or younger. In some embodiments, the pediatric patient is about 2 years of age or younger. In some embodiments, the pediatric patient is about 1 year of age or younger.

[0052] Another embodiment is a dosing regimen for treating hepatoblastoma in a pediatric patient, the dosing regimen comprising: (a) about 1 mg / kg to about 5 mg / kg or about 10 mg / m per cycle; 2 ~about 300mg / m 2 (b) administering cisplatin at a dose of about 5 g / m per cycle of cisplatin; 2 ~about 25g / m 2and (c) a loss of response at three consecutive test frequencies where a response was previously obtained; or (d) a reduction in hearing loss characterized by the following criteria: (i) a hearing loss of less than 40 dB at all frequencies, indicating a Grade 0 or minimal hearing loss; (ii) a hearing loss of 40 dB or more only at 8,000 Hz, indicating a Grade 1 or mild hearing loss; (iii) a hearing loss of 40 dB or more at 4,000 Hz or greater, indicating a Grade 2 or moderate hearing loss; or (iv) a hearing loss of 40 dB or more at 2,000 Hz or greater, indicating a Grade 3 or moderate hearing loss. (v) a hearing loss of 40 dB or more at 1,000 Hz or greater, indicating a Grade 4 or profound hearing loss; or (e) a hearing loss characterized by the following criteria: (i) a hearing loss of 20 dB or less at all frequencies, indicating a Grade 0 hearing loss; (ii) a HL of more than 20 dB above 4,000 Hz, indicating a Grade 1 hearing loss; (iii) a hearing loss of 20 dB or more above 4,000 Hz, indicating a Grade 2 hearing loss; The hearing loss is determined by one or more criteria selected from (iv) HL of more than 20 dB at 2,000 Hz or 3,000 Hz, indicating a grade 2 hearing loss, (v) HL of more than 40 dB at 2,000 Hz or higher, indicating a grade 3 hearing loss, and the change in hearing is calculated relative to a baseline measurement before the patient was administered platinum-based chemotherapy or sodium thiosulfate, or both. In one embodiment, the regimen comprises administering a sodium thiosulfate pharmaceutical composition described herein. In another embodiment, the pharmaceutical composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water.In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at a pH of 8.6-8.8, and water. In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at a pH of 8.5-8.9, and water. In another embodiment, the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) at a pH of 8.5-8.9, and water.

[0053] Another embodiment is for patients with standard or intermediate risk hepatoblastoma at about 12 years of age, receiving between about 1 mg / kg and about 5 mg / kg or about 10 mg / m 2 ~~About 300mg / m 2 and about 5 g / m per cycle of cisplatin, about 6 hours after administration of cisplatin. 2 ~about 25g / m 2In this method, one or more criteria for assessing ototoxicity include: (a) a hearing loss measured by a loss of 20 dB at a single frequency, (b) a hearing loss measured by a loss of 10 dB at two consecutive frequencies, (c) a loss of response at three consecutive test frequencies where a response was previously obtained, (d) a reduction in bilateral high frequency hearing loss characterized by the following criteria: (i) a hearing loss of less than 40 dB at all frequencies indicating a grade 0 or minimal hearing loss, (ii) a hearing loss of less than 40 dB at 8,000 Hz only, (iii) a hearing loss of less than 40 dB at 8,000 Hz only, (iv) a hearing loss of less than 40 dB at 8,000 Hz only, (v) a hearing loss of less than 40 dB at 8,000 Hz only, (vi) a hearing loss of less than 40 dB at 8,000 Hz only, (vii) a hearing loss of less than 40 dB at 8,000 Hz only, (viii ... (iii) a hearing loss of 40 dB or more at 4,000 Hz or greater indicating a grade 2 or moderate hearing loss; (iv) a hearing loss of 40 dB or more at 2,000 Hz or greater indicating a grade 3 or significant hearing loss; (v) a hearing loss of 40 dB or more at 1,000 Hz or greater indicating a grade 4 or profound hearing loss; or (e) a hearing loss characterized by the following criteria: (i) a hearing loss of 20 dB or more at all frequencies (ii) HL greater than 20 dB above 4,000 Hz, indicating a Grade 1 hearing loss; (iii) HL greater than 20 dB above 4,000 Hz, indicating a Grade 2 hearing loss; (iv) HL greater than 20 dB at 2,000 Hz or 3,000 Hz, indicating a Grade 3 hearing loss; (v) HL greater than 40 dB above 2,000 Hz, indicating a Grade 1 hearing loss, and the hearing change is not related to the patient's treatment with platinum-based chemotherapy or and wherein the administration of sodium thiosulfate does not substantially affect progression-free survival or overall survival compared to pediatric patients not receiving sodium thiosulfate, and wherein the administration of sodium thiosulfate does not substantially increase the incidence of one or more adverse events including febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea, in one embodiment. In one embodiment, the method comprises administering a sodium thiosulfate pharmaceutical composition described herein.In another embodiment, the pharmaceutical composition comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M sodium phosphate at pH 6.5, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.004M boric acid at pH 8.6-8.8, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine at pH 8.5-8.9, and water. In another embodiment, the formulation comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M tris(hydroxymethyl)aminomethane (tromethamine) at pH 8.5-8.9, and water.

[0054] One or more embodiments or aspects may be incorporated in a different embodiment or aspect, even if not specifically described above, i.e. all embodiments and aspects may be used together in any manner or combination. [Brief description of the drawings]

[0055] [Figure 1] FIG. 1 shows a scheme for synthesizing anhydrous sodium thiosulfate. [Diagram 2] Figure 2A shows the X-ray powder diffraction pattern of anhydrous sodium thiosulfate synthesized as described herein. The peaks are as shown in Table 5. Figure 2B shows the X-ray powder diffraction pattern of sodium thiosulfate pentahydrate. The peaks are as shown in Table 6. [Diagram 3] FIG. 3 shows overlaid X-ray powder diffraction patterns for sodium thiosulfate pentahydrate (top pattern) and anhydrous sodium thiosulfate (bottom pattern) synthesized as described herein. [Figure 4]FIG. 4A shows overlaid differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for anhydrous sodium thiosulfate synthesized as described herein. The DSC thermogram shows a single sharp endotherm with onset at 331.4° C. The thermogravimetric analysis shows minimal weight loss from 25° C. to 162° C., followed by a 14.81% weight loss from 162° C. to 309° C., followed by the onset of decomposition at 436° C. FIG. 4B shows a dynamic vapor sorption (DVS) isotherm for anhydrous sodium thiosulfate synthesized as described herein. Minimal weight change was observed in the DVS isotherm upon equilibration to 0% relative humidity. Upon sorption, a weight gain of 165% was observed. Upon desorption, hysteresis was observed and a weight loss of 51% was observed. [Diagram 5] Figure 5 illustrates plots of cisplatin concentration versus time for cisplatin (control) or sodium thiosulfate in combination with cisplatin at sodium thiosulfate:cisplatin ratios of 5:1, 6:1, or 10:1. Data are shown in Table 7. [Figure 6] FIG. 6 shows a scheme for preparing a pharmaceutical formulation containing anhydrous sodium thiosulfate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] As used herein, the terms "active ingredient," "pharmaceutical active ingredient," or "API" refer to a drug, pharmaceutical active ingredient, compound or substance, composition, or mixture thereof that provides a pharmacological, often beneficial, effect.

[0057] As used herein, the term "dose" refers to any form of formulation of active ingredient that contains a sufficient amount to produce a therapeutic effect in a single administration.

[0058] As used herein, the term "dosage" refers to the administration of a particular amount, number and frequency over a particular period of time, usually daily.

[0059] As used herein, the term "active pharmaceutical ingredient load" or "drug load" refers to the amount (by mass) of an active pharmaceutical ingredient contained in a single soft capsule fill.

[0060] As used herein, the term "formulation" or "pharmaceutical composition" refers to a drug in combination with a pharma-ceutical acceptable excipient.

[0061] As used herein, the term "particle size distribution" (PSD) refers to the average particle size according to a statistical distribution of the particle size ranges described herein. The distribution may be Gaussian, normal, or non-normal.

[0062] Terms such as "d90", "d50", and "d10" refer to the percentage of particle sizes smaller than a specified size, range, or distribution (e.g., 90%, 50%, or 10%, respectively). For example, "d90≦100 μm" means that 90% of the particles whose sizes fall within the distribution range are 100 μm or smaller.

[0063] As used herein, the term "patient" refers to any subject, including mammals and humans. A patient is suffering from a disease or is suspected of having a disease and is therefore being treated with a drug. In some instances, a patient is a mammal, such as a human, or a premature, neonatal, infant, juvenile, adolescent or adult thereof, a non-human primate, a dog, a cat, a horse, a cow, a goat, a pig, a rabbit, a rat, or a mouse. In some instances, the term "patient" as used herein refers to a human (e.g., a man, a woman, or an infant). In some instances, the term "patient" as used herein refers to an experimental animal in an animal model study. A patient or subject may be of any age, sex, or combination thereof. In some embodiments described herein, a patient is treated with a platinum-based chemotherapeutic agent, such as cisplatin, followed by administration of sodium thiosulfate or a formulation thereof.

[0064] The term "pediatric patient" refers to a pediatric mammal or human. In some instances, the patient is a human or a mammal, such as a premature infant, newborn, baby, toddler, infant, adolescent, young adult or teenager, non-human primate, dog, cat, horse, cow, goat, pig, rabbit, rat, mouse, etc. Pediatric patients can be of any ethnicity or gender. Pediatric patients can be of any age that would be understood by those skilled in the art to be pediatric patients in medicine and veterinary medicine. For example, a human pediatric patient can be a newborn up to 18 years of age. A newborn is understood to be 1 month old, an infant is understood to be 1 month to 2 years old, a toddler is understood to be 2 to 12 years old, and an adolescent is understood to be 12 to 18 years old. In some countries, pediatric patients include patients up to 21 years old. Pediatric patients are being treated with a drug because they are believed to be suffering from or suspected of suffering from a disease. In some embodiments described further herein, the pediatric patient is treated with a platinum-based chemotherapy agent, such as cisplatin.

[0065] The term "ototoxicity" refers to any type of toxicity affecting the ear. Toxicity may be to the cochlea (e.g., cochleotoxicity), cochlear hair cells, auditory nerve or vestibular system, or any of these systems found in the ear, or a combination of any of these systems. Toxicity may manifest as hearing loss, sensorineural hearing loss, balance disorders, tinnitus or hyperacusis, or a combination thereof. When referring to hearing loss, the amount of toxicity that causes hearing loss is a total that results in mild, moderate, severe, profound, or complete hearing loss. Alternatively, hearing loss may be present at specific frequencies, including both high and low frequencies, and all repetitions of frequencies normal to mammalian hearing. Toxicity may be unilateral, bilateral, bilateral symmetric, or bilateral asymmetric, with one ear being affected more than the other.

[0066] As used herein, the term "biological sample" or "sample" refers to a sample taken from or derived from a patient. By way of example, biological samples include materials selected from the group consisting of bodily fluids, blood, whole blood, plasma, serum, mucous secretions, saliva, cerebrospinal fluid (CSF), bronchoalveolar lavage fluid (BALF), urine, ocular fluids (vitreous humor, aqueous humor, etc.), lymphatic fluid, lymph node tissue, splenic tissue, bone marrow, and auditory cavity.

[0067] The term "treating" refers to administering a treatment in an amount, manner, or mode effective to ameliorate a condition, symptom, disorder, or parameter associated with a disorder, or the probability thereof (e.g., a therapeutic effect).

[0068] The term "prevention" refers to preventing or reducing the progression of a disorder to a statistically significant degree or to a degree detectable by one of skill in the art.

[0069] As used herein, the terms "essentially" or "substantially" mean to a large extent or to a significant degree, but not completely. As used herein, the term "about" refers to any value, including both integer and fractional components, that falls within a range of variation of up to ±10% of the value modified by the term "about."

[0070] As described herein, sodium thiosulfate (STS) has been found to reduce ototoxicity in pediatric patients undergoing treatment with platinum-based chemotherapy agents. A surprising discovery has been made: children under the age of 12 have a higher rate of ototoxicity, and children under the age of 5 are even more at risk. A further discovery is that administration of STS after platinum-based chemotherapy agents (such as cisplatin) significantly reduced ototoxicity in these pediatric patients. A specific discovery is that STS may reduce the severity of ototoxicity, such as block grade 2 and 3 ototoxicity. It has also been identified that the total or cumulative dose of cisplatin exposure did not prevent STS-mediated otoprotection. In addition, it has also been discovered that STS is highly suitable as an otoprotectant when used in conjunction with localized (non-disseminated) cancer. See International Patent Application Publication No. WO2019 / 108592, a continuation of U.S. Patent Application No. 15 / 826,243, filed November 29, 2017. The entire contents of both documents are incorporated herein by reference.

[0071] Sodium thiosulfate (also known as sodium hyposulfite) has the formula Na 2 S 2 O 3 STS is a water-soluble thiol compound of the formula 1. The compound is available in anhydrous and crystalline forms. Among the hydrate forms, the most common is the pentahydrate crystalline form. STS is commercially available as an established antidote for acute cyanide poisoning. STS is a reducing agent and has been used as an antidote for the extravasation of various chemotherapeutic agents in oncology to prevent cisplatin nephrotoxicity and carboplatin ototoxicity. The mechanism by which sodium thiosulfate reduces cisplatin-induced nephrotoxicity and carboplatin-induced ototoxicity is not understood. Proposed mechanisms of action include its thiol group, which allows it to act as a free radical scavenger and / or by covalent binding and inactivation of platinum compounds. Sodium thiosulfate reacts irreversibly with cisplatin to form Pt(S 2 O 3 )4 The formation of cisplatin is observed when the drugs are administered simultaneously, sequentially, or nearly simultaneously. Sodium thiosulfate is also thought to protect against nephrotoxicity by reducing the delivery of cisplatin to the kidney and neutralizing cisplatin in the kidney, where sodium thiosulfate is highly concentrated. After intravenous administration, sodium thiosulfate is distributed throughout the extracellular fluid. Some sodium thiosulfate is converted to sulfate in the liver, and up to 95% is excreted unprocessed in the urine. The biological half-life is 0.65 hours (range: 16.5-182 minutes depending on dose). When administered intravenously, STS is rapidly excreted by the kidney.

[0072] Without being bound by any theory, the biological effects of STS in preventing cisplatin-induced ototoxicity are believed to involve binding to electrophilic platinum molecules, scavenging reactive oxygen species, and increasing their concentration in the endolymph of the cochlea. Therefore, an effective single dose scavenges residual platinum chemotherapy agents, preventing their accumulation and damage to cochlear hairs. As demonstrated by the results of two phase III clinical trials, the efficacy of cisplatin-based chemotherapy in pediatric patients was not affected when STS was administered.

[0073] In addition, STS does not adversely affect the efficacy of several other non-platinum-based chemotherapy drugs, such as doxorubicin and etoposide. In vitro studies of small cell lung cancer cell cultures showed no reduction in the cytotoxicity of etoposide after 72 hours of incubation following immediate or delayed addition of STS. Similar studies showed no reduction in the antitumor activity of doxorubicin, carmustine (BCNU), paclitaxel, or methotrexate by STS. Due to its ability to scavenge free platinum-containing compounds, STS has been extensively tested in the clinic, as described further herein, and has been found to be a highly effective otoprotectant compound for pediatric patients.

[0074] One embodiment described herein is sodium thiosulfate. Another embodiment described herein is anhydrous sodium thiosulfate. In another embodiment, the sodium thiosulfate does not include a hydrate. In another embodiment, the sodium thiosulfate does not include sodium thiosulfate pentahydrate. In one embodiment, the sodium thiosulfate includes crystalline anhydrous sodium thiosulfate. In one embodiment, the sodium thiosulfate includes amorphous anhydrous sodium thiosulfate. In another embodiment, the sodium thiosulfate includes aqueous anhydrous sodium thiosulfate.

[0075] One embodiment is anhydrous sodium thiosulfate, synthesized as described herein.

[0076] Another embodiment described herein is a method of synthesizing anhydrous sodium thiosulfate. In one aspect, sodium thiosulfate is synthesized by reacting aqueous sodium sulfite with sulfur in the presence of a surfactant such as cetylpyridinium chloride (CPC). In one embodiment, about 1.0 molar equivalent of sodium sulfite is reacted with 1.1 molar equivalent of sulfur and 0.00013 molar equivalent of cetylpyridinium chloride. In one aspect, the reaction is carried out at an elevated temperature. In another aspect, the reaction is carried out at about 75° C. to about 100° C. for about 5 minutes to 5 hours. In another aspect, the reaction is carried out at about 90° C. for about 5 minutes to 3 hours. In one aspect, the reaction is heated to about 90° C. Upon reaching about 90° C., the reaction is complete. In another aspect, after the reaction, the reaction is allowed to cool. In one aspect, the reaction is cooled to room temperature. In another aspect, the reaction is cooled to less than 2° C. In another aspect, the sodium thiosulfate is washed using a wash solvent. In another aspect, the sodium thiosulfate is washed using acetone. In another embodiment, the sodium thiosulfate is washed multiple times. In another embodiment, the sodium thiosulfate is washed once. In another embodiment, the sodium thiosulfate is dehydrated by heating and / or filtration. In another embodiment, the sodium thiosulfate is dehydrated using a dehydrating solvent. In one embodiment, the dehydrating solvent is alcohol. In another embodiment, the dehydrating solvent is methanol. In another embodiment, the dehydrating solvent is methanol heated to 30°C to 80°C. In another embodiment, the sodium thiosulfate is dehydrated multiple times. In another embodiment, the sodium thiosulfate is dehydrated once.

[0077] In one embodiment, the anhydrous sodium thiosulfate is milled or micronized to a defined particle size. In one embodiment, the anhydrous sodium thiosulfate comprises a particle size range of about 1 μm to about 500 μm, including all integers and fractions within the specified range. In one aspect, the particle size of the micronized anhydrous sodium thiosulfate particles is about 1 μm to about 100 μm. In one aspect, the particle size of the micronized anhydrous sodium thiosulfate particles is about 5 μm to about 50 μm. In another aspect, the anhydrous sodium thiosulfate solid particles comprise a distribution of particle sizes, including particles of any of the aforementioned particle sizes.

[0078] In another embodiment, the mean particle size distribution (PSD) of the anhydrous sodium thiosulfate particles ranges from about 5 μm to about 300 μm, including all integers and fractions within the specified range. In one aspect, the mean particle size distribution of the anhydrous sodium thiosulfate solid particles includes about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about 190 μm, about 200 μm, about 220 μm, about 240 μm, about 260 μm, about 280 μm, or about 300 μm.

[0079] In one embodiment, the mean particle size distribution d50 of the anhydrous sodium thiosulfate solid particles is from about 5 μm to about 100 μm. In one embodiment, the mean particle size distribution d50 of the anhydrous sodium thiosulfate solid particles is from about 5 μm to about 50 μm. In one aspect, the mean particle size distribution d50 of the anhydrous sodium thiosulfate solid particles is from about 10 μm to about 25 μm.

[0080] In another embodiment, the particle size distribution d90 of the anhydrous sodium thiosulfate particles is about 100 μm or less. In one aspect, the particle size distribution d90 of the anhydrous sodium thiosulfate solid particles is about 50 μm or less to about 50 μm. In one aspect, the particle size distribution d90 of the anhydrous sodium thiosulfate solid particles is about 25 μm or less (d90≦25 μm).

[0081] In another embodiment, the anhydrous sodium thiosulfate solid particles include a plurality of particle size distributions. In one aspect, the anhydrous sodium thiosulfate solid particles can include a plurality of independently combined average particle size distributions, each independent average particle size distribution ranging from about 5 μm to about 100 μm, inclusive of all integers and fractions within the specified range. In another aspect, the anhydrous sodium thiosulfate solid particles can include a plurality of independently combined average particle size distributions, each independent average particle size distribution ranging from about 5 μm to about 50 μm, inclusive of all integers and fractions within the specified range. In another aspect, the anhydrous sodium thiosulfate solid particles include a combination of independently combined average particle size distributions. The average particle size distributions ranging from about 10 μm to about 30 μm, inclusive of all integers and fractions within the specified range. Any of the aforementioned particle size distributions can be combined to provide a desired size distribution range.

[0082] The aforementioned size of anhydrous sodium thiosulfate particles can be calculated using standard techniques known to those skilled in the art. Exemplary techniques that can be used to measure the particle size of anhydrous sodium thiosulfate include laser diffraction analysis, light scattering (e.g., dynamic light scattering), microscopic particle image analysis, elutriation, or aerosol mass spectrometry. Samples of anhydrous sodium thiosulfate particles can be measured as dry or wet samples. Any commercially available instrument for measuring particle size, such as Cilas, Brookhaven Instruments Corporation, Malvern Instruments, Horiba Scientific, or Wyatt, can be used according to the manufacturer's instructions and recommended operating procedures.

[0083] Particle sizes measured using the techniques described herein can be expressed as derived diameters having a normal distribution, or as non-normal distributions having a mean, median (e.g., mass median diameter), and mode of particle diameter size. Particle size distributions can be expressed as diameter number distributions, surface area distributions, or particle volume distributions. The mean of a particle size distribution is the volume mean diameter (D[4,3] or d 43 ), mean surface area diameter (D[3,2] i.e. d 32 ) or the average grain size (D[1,0] i.e. d 10 ), and can be calculated and expressed in a variety of ways. Because particle size distribution values ​​vary depending on the measurement method and the way the distribution is expressed, comparisons of different average particle size distributions should be calculated in the same way to make accurate comparisons. For example, a sample whose volume average diameter has been measured and calculated should be compared to a second sample whose volume average diameter has been measured and calculated, ideally measured under the same conditions using the same measuring instrument. Thus, the specific particle size distributions described herein are not intended to be limited to any one type of method for measuring or calculating particle size distributions (e.g., diameter number distribution, surface area distribution, or particle volume distribution), but rather to indicate the particle size values ​​and their distributions for each method of measuring particle size described herein.

[0084] Another embodiment described herein is anhydrous sodium thiosulfate produced by the methods described herein. Another embodiment is a means for preparing anhydrous sodium thiosulfate.

[0085] Another embodiment described herein is anhydrous sodium thiosulfate characterized by an X-ray powder diffraction (XRPD) pattern that includes at least four peaks at 10.52, 15.13, 17.71, 19.70, 21.09, 21.49, 21.84, 27.40, 28.96, 30.46, 31.81, 32.52, 33.15, 37.40, or 38.16 degrees two theta (2θ) ±0.2 when collected using copper Kα radiation from about 2 to about 40 degrees two-theta. In one embodiment, the anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern that includes at least four peaks selected from 10.52, 15.13, 19.70, 21.49, 21.84, 28.96, 30.46, 33.15, 37.40, or 38.16 degrees two theta (2θ) ±0.2, when the XRPD is collected using copper Kα radiation from about 2 to about 40 degrees two theta. In one embodiment, the anhydrous sodium thiosulfate is characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG. 2A. In another embodiment, the anhydrous sodium thiosulfate is characterized by an X-ray powder diffraction (XRPD) pattern that includes at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 of the peaks shown in Table 5.

[0086] Another embodiment described herein is anhydrous sodium thiosulfate having less than or equal to 0.1 μg / g cadmium, less than or equal to 0.25 μg / g lead, less than or equal to 0.75 μg / g arsenic, less than or equal to 0.15 μg / g mercury, less than or equal to 0.25 μg / g cobalt, less than or equal to 0.5 μg / g vanadium, less than or equal to 1.0 μg / g nickel, less than or equal to 12.5 μg / g lithium, less than or equal to 4.5 μg / g antimony, less than or equal to 15.0 μg / g copper, less than or equal to 1500 ppm methanol, less than or equal to 3% (w / w) water, and less than or equal to 1.5% (w / w) total impurities.

[0087] Another embodiment described herein is anhydrous sodium thiosulfate that is essentially free of sodium thiosulfate pentahydrate. In one aspect, the anhydrous sodium thiosulfate contains less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.001% sodium thiosulfate pentahydrate.

[0088] Another embodiment described herein is an assay for measuring the concentration of cisplatin. In one aspect, the assay comprises measuring the concentration of cisplatin using HPLC and UV detection, and comparing the retention time and peak area with a standard curve of cisplatin concentrations assayed under similar conditions. Another embodiment described herein is a means for calculating the concentration of cisplatin described herein.

[0089] Another embodiment described herein is an assay for determining the cisplatin binding ability of sodium thiosulfate compositions. The sodium thiosulfate composition can be sodium thiosulfate pentahydrate, anhydrous sodium thiosulfate, aqueous anhydrous sodium thiosulfate, or a pharmaceutical composition of sodium thiosulfate. The assay involves combining various concentrations of sodium thiosulfate with a concentration of cisplatin and then measuring the apparent decrease in cisplatin concentration over time using HPLC and UV detection. In one aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1, 7:1, 6:1, 5:1, 3:1, 2:1, or 1:1. In one aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1, 6:1, or 5:1. In one aspect, the apparent decrease in cisplatin concentration due to sodium thiosulfate binding is linear over time. In another embodiment, the cisplatin concentration is measured about 5 minutes after mixing with sodium thiosulfate and every 10, 20, 30, or 60 minutes for 0.5, 1, 2, 3, 4, 5, or 6 hours. In one embodiment, the cisplatin concentration is measured about 5 minutes after mixing with sodium thiosulfate and every 30 minutes for 2 hours. In one embodiment, the mixed-mode C-18 chromatography column used in the assay has both hydrophobic interaction and ion exchange functionality. In another embodiment, the HPLC run time of the assay is about 2 minutes, about 5 minutes, about 7.5 minutes, about 10 minutes, or about 15 minutes. In one embodiment, the HPLC run time is about 5 minutes or about 10 minutes. In another embodiment, the cisplatin elutes from the HPLC under assay conditions after about 1.5 minutes to about 2.5 minutes. In one embodiment, the cisplatin elutes from the HPLC under assay conditions after about 2 minutes. In another embodiment, sodium thiosulfate elutes from the HPLC under assay conditions after about 5 minutes to about 7.0 minutes, hi one embodiment, cisplatin elutes from the HPLC under assay conditions after about 6 minutes.

[0090] Another embodiment described herein is a means for determining sodium thiosulfate binding capacity for cisplatin as described herein.

[0091] Without being bound by any theory, factors that affect cisplatin binding by sodium thiosulfate in the assay described herein include temperature, the relative concentration of sodium thiosulfate, and the time elapsed between mixing cisplatin with sodium thiosulfate and HPLC measurement. The HPLC autosampler allows for strict temperature control, facilitating sample preparation and analysis. In addition, the change in cisplatin concentration produced in this method is over time, rather than at a single time point. The method can be used to calculate reaction rates under given conditions or half-lives and to compare between different samples of sodium thiosulfate.

[0092] Another embodiment described herein is an assay for measuring the binding ability of sodium thiosulfate to cisplatin based on the apparent decrease in cisplatin concentration after combining various molar ratios of cisplatin and sodium thiosulfate, the method comprising mixing various molar ratios of sodium thiosulfate with a predetermined amount of cisplatin, incubating the mixture for a period of time, and analyzing the concentration of cisplatin. In one aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1 to 1:1. In one aspect, the molar ratio of sodium thiosulfate to cisplatin includes 10:1, 7:1, 6:1, 5:1, 3:1, 2:1, or 1:1. In one aspect, the mixture is incubated at about 25° C. for about 5 minutes, about 35 minutes, about 65 minutes, about 95 minutes, and about 125 minutes and analyzed. In another aspect, the concentration is analyzed using HPLC using a mixed mode C-18 chromatography column with a column temperature of 35° C., a flow rate of 400 μL / min, and UV detection at 220 nm. In one embodiment, the HPLC method comprises a gradient of 100% Buffer A (0.5 mM ammonium formate in acetonitrile at pH 4; water:acetonitrile 9:1) in 3 minute steps, followed by a gradient of 90% Buffer A and 10% Buffer B (200 mM ammonium formate in acetonitrile at pH 4; water:acetonitrile 7:3) in 3.5 minute steps, followed by a gradient of 100% Buffer A in 4.5 minute steps.

[0093] Another embodiment described herein is a pharmaceutical composition or formulation comprising sodium thiosulfate. In one aspect, the sodium thiosulfate comprises anhydrous sodium thiosulfate. The formulation is suitable for administration via any conventional route, including intravenous, subcutaneous, intramuscular, intraperitoneal, intrathecal, oral, rectal, vaginal, or combinations thereof. In one aspect, the formulation is administered intravenously.

[0094] In one embodiment, the pharmaceutical compositions described herein provide compositions of sodium thiosulfate for administration to a subject. For example, sodium thiosulfate can be administered to a subject or a subject in need thereof.

[0095] Another embodiment described herein is a pharmaceutical composition comprising sodium thiosulfate. In one aspect, the composition comprises sodium thiosulfate and one or more pharma- ceutically acceptable excipients. In another aspect, the composition comprises sodium thiosulfate and a buffer. In another aspect, the composition comprises anhydrous sodium thiosulfate and a buffer. In one aspect, the composition comprises a liquid formulation of anhydrous sodium thiosulfate and a buffer. In another aspect, the composition is a dry or lyophilized composition comprising sodium thiosulfate and one or more buffers that are reconstituted with sterile water for injection prior to administration. In another aspect, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. As used herein, "aqueous anhydrous sodium thiosulfate" refers to anhydrous sodium thiosulfate solubilized in an aqueous solvent. In another aspect, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, one or more pH adjusters, and a solvent. In another aspect, the composition comprises aqueous anhydrous sodium thiosulfate, one or more buffers, one or more pH adjusters, a solvent, and one or more preservatives, saline, carriers, or pharma-ceutically acceptable excipients. In one embodiment, the contents of the pharmaceutical formulation are as shown in Table 1. [Table 1]

[0096] In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate and water. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate, water, a buffer, and one or more pH adjusters. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate, water, a phosphate buffer, and one or more pH adjusters to a pH of about 6.5. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate, water, a borate buffer, and one or more pH adjusters to a pH of about 8.5 to 8.8. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate, water, glycine, and one or more pH adjusters to a pH of about 8.5 to 8.9. In another embodiment, the formulation comprises aqueous anhydrous sodium thiosulfate, water, tris(hydroxymethyl)aminomethane (tromethamine) buffer, and one or more pH adjusters to a pH of about 8.5 to 8.9. In one embodiment, the pharmaceutical formulation comprises one of the formulations shown in Table 2. The following formulations are exemplary, and the identity and concentration of the buffer can be adjusted over a range of about 0.001M to about 0.5M, and the mg / mL and weight percentages may be adjusted accordingly. [Table 2]

[0097] In one embodiment, the formulation comprises about 0.1M, about 0.2M, about 0.3M, about 0.4M, about 0.5M, about 0.6M, about 0.7M, about 0.8M, about 0.9M, about 1.0M, about 1.1M, about 1.2M, about 1.3M, about 1.4M, about 1.5M, about 1.6M, about 1.7M, about 1.8M, about 1.9M, or about 2.0M aqueous anhydrous sodium thiosulfate.

[0098] In another embodiment, the formulation contains about 0.1M to about 2.0M, about 0.1M to about 0.5M, about 0.1M to about 0.6M, about 0.1M to about 0.7M, about 0.1M to about 0.8M, about 0.1M to about 1.0M, about 0.2M to about 0.5M, about 0.2M to about 0.6M, about 0.2M to about 0.7M, about 0.2M to about 0.8M, about 0.2M to about 1.0M, about 0.3M to about 0.5M, about 0.3M to about 0.6M, about 0.3M to about 0.7M, about 0. 0.3M to about 0.8M, about 0.3M to about 1.0M, about 0.4M to about 0.5M, about 0.4M to about 0.6M, about 0.4M to about 0.7M, about 0.4M to about 0.8M, about 0.4M to about 1.0M, about 0.5M to about 0.6M, about 0.5M to about 0.7M, about 0.5M to about 0.8M, about 0.5M to about 1.0M, about 0.6M to about 0.7M, about 0.6M to about 0.8M, or about 0.6M to about 1.0M aqueous anhydrous sodium thiosulfate.

[0099] In another embodiment, the formulation comprises about 20 mg / mL, about 40 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, about 240 mg / mL, about 260 mg / mL, about 280 mg / mL, about 300 mg / mL, or about 320 mg / mL aqueous anhydrous sodium thiosulfate.

[0100] In another embodiment, the formulation comprises about 10 mg / mL, about 320 mg / mL, about 10 mg / mL, about 80 mg / mL, about 10 mg / mL, about 100 mg / mL, about 10 mg / mL, about 110 mg / mL, about 10 mg / mL, about 120 mg / mL, about 10 mg / mL, about 160 mg / mL, about 20 mg / mL, about 80 mg / mL, about 20 mg / mL, about 100 mg / mL , about 20 mg / mL, about 110 mg / mL, about 20 mg / mL, about 120 mg / mL, about 20 mg / mL, about 160 mg / mL, about 30 mg / mL, about 80 mg / mL, about 30 mg / mL mL, approx. 100 mg / mL, approx. 30 mg / mL, approx. 110 mg / mL, approx. 30 mg / mL, approx. 120 mg / mL, approx. 30 mg / mL, approx. 160 mg / mL, approx. 40 mg / mL, approx. 80 m g / mL, about 40 mg / mL, about 100 mg / mL, about 40 mg / mL, about 110 mg / mL, about 40 mg / mL, about 120 mg / mL, about 40 mg / mL, about 160 mg / mL, about 60mg / mL, approximately 80mg / mL, approximately 60mg / mL, approximately 100mg / mL, approximately 60mg / mL, approximately 110mg / mL, approximately 60mg / mL, approximately 120mg / mL, approximately 60mg / mL, About 160 mg / mL, about 80 mg / mL, about 100 mg / mL, about 80 mg / mL, about 110 mg / mL, about 80 mg / mL, about 120 mg / mL, about 80 mg / mL, about 160 mg / mL, about 100 mg / mL, about 110 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 100 mg / mL, about 160 mg / mL aqueous anhydrous sodium thiosulfate.

[0101] In another embodiment, the formulation comprises about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, or about 32% by weight aqueous anhydrous sodium thiosulfate.

[0102] In another embodiment, the formulation comprises about 1% to about 32%, about 1% to about 8%, about 1% to about 10%, about 1% to about 11%, about 1% to about 12%, about 1% to about 16%, about 2% to about 8%, about 2% to about 10%, about 2% to about 11%, about 2% to about 12%, about 2% to about 16%, about 3% to about 8%, about 3% to about 10%, about 3% to about 11%, about 3% to about 12%, about 3% to about 16%, about 4% to about 8%, about The aqueous anhydrous sodium thiosulfate solution may comprise 4% to about 10%, about 4% to about 11%, about 4% to about 12%, about 4% to about 16%, about 6% to about 8%, about 6% to about 10%, about 6% to about 11%, about 6% to about 12%, about 6% to about 16%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 16%, about 10% to about 11%, about 10% to about 12%, or about 10% to about 16% by weight of aqueous anhydrous sodium thiosulfate.

[0103] In one embodiment described herein, the formulation comprises one or more buffers. Exemplary buffers are pharma- ceutically acceptable buffers. In one embodiment, the one or more buffers are selected from the group consisting of acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bisulfuric acid, boric acid, butanoic acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfuric acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, glycglycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfuric acid, heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthyl acid, nicotinic acid, nitrous acid, sulphuric ... acid, pelargonic, phosphoric acid, propionic acid, pyruvic acid, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, tosylic acid, undecylenic acid, MES, bis-trismethane, ADA, ACES, bis-trispropane, PIPES, MOPSO, coramine chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, acetamidoglycine, TAPSO, TEA, POPSO, HEPPSO, EPS, HEPPS, tricine, tris(hydroxymethyl)aminomethane (tromethamine), glycineamide, glycine lysine, HEPBS, bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS, CABS, combinations thereof, or salts thereof. In one embodiment, the buffer comprises one or more of phosphate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitrate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof.In one embodiment, the buffer is phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or borate. In one embodiment, the buffer is borate. In one embodiment, the buffer is phosphate. In one embodiment, the buffer is glycine. In one embodiment, the buffer is tris(hydroxymethyl)aminomethane (tromethamine).

[0104] In another embodiment, the concentration of the one or more buffers is about 0.001M to about 0.5M. In one embodiment, the concentration of the one or more buffers is about 0.005M to about 0.2M, about 0.01M to about 0.1M, about 0.005M to about 0.05M, about 0.01M to about 0.05M, or about 0.005M to about 0.01M. In one embodiment, the concentration of the one or more buffers is about 0.005M, about 0.075M, about 0.01M, about 0.02M, about 0.05M, about 0.1M, about 0.2M, or about 0.5M. In one embodiment, the concentration of the one or more buffers is about 0.01M. In another embodiment, the concentration of the one or more buffers is about 0.05M.

[0105] In another embodiment, the formulation comprises one or more buffers titrated with one or more pharma- ceutically acceptable acids or bases for pH adjustment. In one aspect, the formulation has a pH of about 2 to about 10, about 3 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 6.0 to about 6.5, about 6 to about 7, about 6.5 to about 7, or about 6 to about 8. In one aspect, the formulation has a pH of about 5.0, about 5.5, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, or about 7.5. In one aspect, the formulation has a pH of about 6.5.

[0106] In another embodiment, the formulation includes one or more buffers that are titrated with one or more pharma- ceutically acceptable acids or bases to adjust the pH to about 6.5. The acids and bases are typically selected to match the buffer and the ions present in the solution. In one embodiment, the pH is increased by adding a Group IA hydroxide. In one embodiment, the hydroxide may be sodium hydroxide or potassium hydroxide. In another embodiment, the pH is decreased by adding an acid (i.e., a proton donor). Any pharma-ceutically acceptable acid can be used. In one embodiment, the acid is phosphoric acid. In another embodiment, the acid is hydrochloric acid. In one embodiment, both sodium hydroxide and hydrochloric acid (or phosphoric acid) are added to the formulation to titrate the pH to about 6.5.

[0107] One embodiment described herein is a pharmaceutical formulation as shown in Table 3. [Table 3]

[0108] Another embodiment described herein is a pharmaceutical formulation comprising about 0.25M to about 1.0M aqueous anhydrous sodium thiosulfate, about 1.0mM to about 500mM and a buffer having a pH of 5-9, and water. In one aspect, the pharmaceutical formulation comprises about 40mg / mL to about 160mg / mL aqueous anhydrous sodium thiosulfate, about 1.4mg / mL phosphate buffer having a pH of 5-8, and water. In another aspect, the pharmaceutical formulation comprises about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.14% sodium phosphate buffer having a pH of 5-8, and water. In another aspect, the pharmaceutical formulation comprises about 40mg / mL to about 160mg / mL aqueous anhydrous sodium thiosulfate, about 0.25mg / mL borate buffer having a pH of 6-9, and water. In another embodiment, the pharmaceutical formulation comprises about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.023% borate buffer at pH 6-9, and water. In another embodiment, the pharmaceutical formulation comprises about 40 mg / mL to about 160 mg / mL aqueous anhydrous sodium thiosulfate, about 0.75 mg / mL glycine buffer at pH 6-9, and water. In another embodiment, the pharmaceutical formulation comprises about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.069% glycine buffer at pH 6-9, and water. In another embodiment, the pharmaceutical formulation comprises about 40 mg / mL to about 160 mg / mL aqueous anhydrous sodium thiosulfate, about 1.21 mg / mL tris(hydroxymethyl)aminomethane (tromethamine) buffer at pH 6-9, and water. In another embodiment, the pharmaceutical formulation comprises about 4% to about 16% aqueous anhydrous sodium thiosulfate, about 0.11% tris(hydroxymethyl)aminomethane (tromethamine) buffer of pH 6-9, and water.

[0109] Another embodiment described herein is a pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. In one aspect, the pharmaceutical formulation comprises about 80 mg / mL aqueous anhydrous sodium thiosulfate, about 1.4 mg / mL sodium phosphate at pH 6.5, and water. In another aspect, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.14% sodium phosphate at pH 6.5.

[0110] Another embodiment described herein is a pharmaceutical formulation comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.004M boric acid at a pH of 8.6-8.8, and water. In one aspect, the pharmaceutical formulation comprises about 80mg / mL aqueous anhydrous sodium thiosulfate, about 0.25mg / mL boric acid at a pH of 8.6-8.8, and water. In another aspect, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.023% boric acid at a pH of 8.6-8.8.

[0111] Another embodiment described herein is a pharmaceutical formulation comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine and a pH of 8.5-8.9, and water. In one aspect, the pharmaceutical formulation comprises about 80mg / mL aqueous anhydrous sodium thiosulfate, about 0.75mg / mL, about 3.8mg / mL glycine and a pH of 8.5-8.9, and water. In another aspect, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate and about 0.069% to about 0.35% glycine and a pH of 8.5-8.9.

[0112] Another embodiment described herein is a pharmaceutical formulation comprising about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M to about 0.05M tris(hydroxymethyl)aminomethane (tromethamine) at a pH of 8.5-8.9, and water. In one aspect, the pharmaceutical formulation comprises about 80mg / mL aqueous anhydrous sodium thiosulfate, about 1.2mg / mL, about 3.6mg / mL tris(hydroxymethyl)aminomethane (tromethamine) at a pH of 8.5-8.9, and water. In another aspect, the pharmaceutical formulation comprises about 8% aqueous anhydrous sodium thiosulfate, about 0.1% to about 0.33% tris(hydroxymethyl)aminomethane (tromethamine) at a pH of 8.5-8.9, and water.

[0113] Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of sodium thiosulfate and one or more pharma- ceutically acceptable excipients.

[0114] Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of sodium thiosulfate and one or more pharma- ceutically acceptable buffers. In one aspect, the pharmaceutical composition has a pH of 4-8. In another aspect, the pharmaceutical composition has a pH of 5-7. In another aspect, the pharmaceutical composition has a pH of 6-7. In another aspect, the pharmaceutical composition has a pH of 6-8. In another aspect, the pharmaceutical composition has a pH of about 6. In another aspect, the pharmaceutical composition has a pH of about 6.5. In another aspect, the pharmaceutical composition has a pH of about 7. In another aspect, the pharmaceutical composition has a pH of about 7.5.

[0115] Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of sodium thiosulfate, one or more pharma- ceutically acceptable buffers, and one or more salts. In one aspect, the one or more salts include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, ammonium chloride, ammonium carbonate, ammonium phosphate, ammonium sulfate, potassium citrate, potassium phosphate, among others, potassium lactate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate. In one aspect, the concentration of the one or more salts is about 0.001M to about 0.5M. In another aspect, the concentration of the one or more salts is about 0.001M, about 0.005M, about 0.01M, about 0.05M, about 0.1M, about 0.2M, or about 0.5M. In one aspect, the concentration of the one or more salts is about 0.05M to about 0.2M.

[0116] Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of about 0.2M to about 2M sodium thiosulfate, a pharma- ceutically acceptable buffer of about 0.001M to about 0.05M, and a pharma- ceutically acceptable salt of about 0.005M to about 0.05M. In one aspect, the pharmaceutical composition has a pH of about 6 to 8. In one aspect, the pharmaceutical composition is a pharmaceutical composition comprising about 1M sodium thiosulfate, about 0.05M pharma- ceutically acceptable buffer, and about 0.05M and a pharma- ceutically acceptable salt of about 6 to about 8.

[0117] Another embodiment described herein is a sodium thiosulfate pharmaceutical composition that is essentially free of borate ions. In one aspect, the sodium thiosulfate composition contains less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.001% borate ions. In one aspect, the sodium thiosulfate composition contains phosphate ions instead of borate ions.

[0118] Another embodiment is a method of producing a pharmaceutical sodium thiosulfate formulation. In one embodiment, such a composition is produced by: (i) combining sodium thiosulfate with a solvent and, optionally, one or more pharma- ceutically acceptable excipients; (ii) transferring a single or multiple doses of the liquid or suspension into a suitable container; and (iii) sealing the container. In one aspect, the liquid or suspension is filtered and / or sterilized before or after transferring into the suitable container. In one aspect, the container is an injectable vial or syringe.

[0119] One embodiment is a method for preparing an anhydrous sodium thiosulfate-containing formulation, comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. The method further comprises adjusting the pH with a pharma- ceutically acceptable acid or base. In one aspect, the buffer is sodium phosphate, and the acid and base are hydrochloric acid and sodium hydroxide. The method further comprises filtering the solution, transferring the solution to a suitable receptacle, and sealing the receptacle to sterilize the formulation. In one aspect, the formulation is sterilized by filtering and autoclaving.

[0120] Another embodiment is a formulation comprising anhydrous sodium thiosulfate produced by the methods described herein. Another embodiment is a means for preparing a formulation comprising anhydrous sodium thiosulfate. Another embodiment described herein is a pharmaceutical composition of the STS formulation described herein. The pharmaceutical composition may include one or more excipients, as described below: (i) Buffering agents: Physiologically acceptable buffers to maintain pH within the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate, etc. Also, Mg(OH) 2 or ZnCO 3 Antacids such as may be used. The buffering capacity can be adjusted to meet the conditions most sensitive to pH stability. (ii) Isotonicity adjusters: to minimize pains possibly due to cell damage caused by osmotic pressure differences in the infusion depot. Examples are glycerin and sodium chloride. Effective concentrations can be calculated by osmolarity measurements assuming serum osmolarity of 285-315 mOsmol / kg. (iii) Preservatives and / or antimicrobial agents: In multi-dose parenteral formulations, preservatives may need to be added in sufficient concentrations to minimize the risk of subject infection upon injection, for which corresponding regulatory requirements have been established. Typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosol, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride. (iv) Stabilizers: Stabilization is achieved by enhancing protein stabilizing power, destabilizing denatured states, or directly binding excipients to proteins. Stabilizers can be amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, and proline, sugars such as glucose, sucrose, and trehalose, polyols such as glycerol, mannitol, and sorbitol, salts such as potassium phosphate and sodium sulfate, chelating agents such as EDTA and hexaphosphate, ligands such as divalent metal ions (zinc, calcium, etc.), other salts, or organic molecules such as phenol derivatives. In addition, oligomers or polymers such as cyclodextrin, dextran, dendrimers, polyethylene glycol, polyvinylpyrrolidone, protamine, or human serum albumin may be used. (v) Anti-adsorption agents: Primarily ionic or ion-ionic surfactants or other proteins or soluble polymers are used to competitively coat or adsorb to the interior surface of the composition's container (e.g., poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin). The concentration and type of excipient chosen will vary depending on the effects to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value. (vi) Lyophilization or cryoprotectants: During lyophilization or spray drying, the destabilizing effects due to hydrogen bond breaking and water removal can be counteracted by excipients. Sugars and polyols are sometimes used for this purpose, but corresponding positive effects have also been observed with surfactants, amino acids, non-aqueous solvents, and other peptides. Trehalose is particularly effective in reducing moisture-induced aggregation and also improves thermal stability that may be caused by exposing hydrophobic groups of proteins to water. Mannitol and sucrose can also be used as the sole lyophilization agents or in combination with each other, and it is known that increasing the proportion of mannitol or sucrose enhances the physical stability of the lyophilized cake. Mannitol can also be combined with trehalose. Trehalose can also be combined with sorbitol, which can be used as the only protective agent. Starch or starch derivatives can also be used. (vii) Antioxidants: Antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, vitamin E, etc.; chelating agents such as citric acid, EDTA, hexaphosphate, thioglycolic acid, etc. (viii) Thickeners or Viscosity Enhancers: These are used to retard settling of particles in vials and syringes, facilitate mixing and resuspension of particles, and facilitate injection of the suspension (i.e., reduce the force applied to the syringe plunger). Suitable thickeners or viscosity enhancers are, for example, carbomer thickeners such as Carbopol 940, Carbopol Ultrez 10, hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAE-C), cellulose derivatives such as colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan, Satiagum UTC 30, aliphatic poly(hydroxy acids), such as poly(d,l- or l-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), terpolymers of d,l-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks, thereby forming poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblocks (e.g., Pluronic™), polyethylene glycol terephthalate / polybutylene terephthalate copolymers, sucrose isobutyrate (SAIB), polyether esters, such as dextran or derivatives thereof. copolymers, combinations of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and derivatives, polyalkylimides, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs) such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronic acid, ABA triblocks or AB block copolymers composed of a hydrophobic A block, such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA), and a hydrophilic B block, such as polyethylene glycol (PEG) or polyvinylpyrrolidone.Such block copolymers and the poloxamers described above may exhibit inverse thermogelation behavior (a fluid state at room temperature to facilitate administration, and a gel state above the sol-gel transition temperature at body temperature after injection). (ix) Diffusion Agents: Alter the permeability of connective tissue through hydrolysis of components of the extracellular matrix in the interstitial space, such as, but not limited to, hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue. Diffusion agents, such as, but not limited to, hyaluronidase, temporarily reduce the viscosity of the extracellular matrix, facilitating the diffusion of injected drugs. (x) Other auxiliary agents: wetting agents, viscosity adjusters, antibiotics, hyaluronidase, etc. Acids or bases such as hydrochloric acid or sodium hydroxide are auxiliary agents required for pH adjustment during production.

[0121] The foregoing list is not meant to be exhaustive, but instead is merely representative of classes of excipients and particular excipients that may be used in pharmaceutical preparations as described herein.

[0122] The STS formulation may be provided as a liquid, a suspension, or a dry composition.

[0123] In one embodiment, the STS formulation is a sterile liquid composition. The formulation may be administered intravenously using direct venipuncture or an intravenous line.

[0124] In one embodiment, the pharmaceutical composition is a sterile solution.

[0125] In another embodiment, the STS formulation is a dry composition.Suitable drying methods include, for example, spray drying and freeze-drying (lyophilization).In one embodiment, the STS formulation is prepared as a solution and dried by freeze-drying.In another embodiment, the STS formulation is prepared as a dry composition that is reconstituted immediately before use with sterile water for injection, and then administered intravenously either directly through venipuncture or intravenous line.

[0126] In another embodiment, the composition is a dried or lyophilized composition that can be reconstituted with sterile water for injection, PBS, saline, or other sterile, parenterally compatible solution to produce a solution suitable for injection. In one embodiment, the composition comprises about 20 mg to 32 g of anhydrous sodium thiosulfate. In one embodiment, the composition comprises about 98% by weight of anhydrous sodium thiosulfate. In one embodiment, the composition comprises about 1% to 2% by weight of one or more buffers. When a specified amount of sterile water for injection is added, the reconstituted dried or lyophilized composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water.

[0127] Pharmaceutical compositions suitable for administration by injection include sterile aqueous solutions, suspensions or dispersions and sterile powders or lyophilisates for the extemporaneous preparation of sterile injectable solutions or dispersions.

[0128] Suitable solvents for intravenous administration include sterile water for injection, phosphate buffered saline (PBS), physiological saline, or Ringer's solution. In all cases, the composition should be sterile and fluid to the extent that easy syringability exists. Preferred pharmaceutical preparations are those that are stable under the conditions of manufacture and storage and require protection against the contaminating action of microorganisms, such as bacteria and fungi. In general, the relevant solvent or carrier can be, for example, a solvent or dispersion medium containing water, a buffer, ethanol, a polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, amino acids, sorbitol, sodium chloride, or combinations thereof, in the composition.

[0129] Certain injectable compositions are isotonic aqueous solutions or suspensions. Suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. Each of the compositions may be prepared according to conventional mixing, granulating, or coating methods and may contain about 0.1-75%, or about 1-50% of the active ingredient. In one embodiment described herein, the composition comprises about 7.5% of the active ingredient, aqueous anhydrous sodium thiosulfate. The composition may contain up to 98% sodium thiosulfate when in a dry composition suitable for reconstitution.

[0130] Sterile injectable solution or suspension may be prepared by incorporating sodium thiosulfate in the required amount of suitable solvent containing one or a combination of raw materials as necessary, followed by filtration and / or sterilization.Solution or suspension is generally prepared by incorporating active compound into a sterile vehicle such as sterile water or PBS and any excipient.In one embodiment, sterilization is carried out by autoclaving the final preparation in injection vial.In the case of preparing sterile injectable solution with sterile powder, the preferred preparation method is vacuum drying and freeze drying.These drying methods obtain the powder of active raw material and additional excipient from the solution that has been previously sterile filtered.

[0131] Also possible is a transmucosal or transdermal administration means. Suitable compositions for transdermal application include an effective amount of biologically active agent with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents that aid in passing through the host's skin. For example, a transdermal device is in the form of a bandage that includes a backing member, a reservoir that optionally contains a compound with a carrier, and optionally a rate-controlling barrier that delivers the compound to the host's skin at a controlled, predetermined rate over an extended period of time, which means that the device is fixed to the skin.

[0132] For example, compositions suitable for topical application to skin, eye or joint include, for example, aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations or the like for delivery via aerosol.Such topical delivery systems are particularly suitable for application to skin.Therefore, they are particularly suitable for use in topical formulations, including cosmetics, well known in the art.Such may contain solubilizers, stabilizers, tonicity enhancers, buffers or preservatives.

[0133] As used herein, topical application may also refer to inhalation or intranasal application.Conveniently, dry powder inhaler or aerosol spray presentation can be delivered in the form of dry powder (alone, for example, mixed with lactose, or mixed component particles, for example, mixed with phospholipids) from pressurized container, pump, spray, atomizer or nebulizer with or without using suitable propellant.

[0134] Also described herein are pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which the compositions described herein as active ingredients decompose. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, salts, sugars, and the like.

[0135] Another embodiment described herein is a pharmaceutical composition comprising anhydrous sodium thiosulfate. In one aspect, the composition comprises any of the formulations shown in the tables or examples described herein. Any of the ingredients in the formulations described herein are shown in the tables or examples. By enhancing, reducing, combining, substituting, or omitting those ingredients, it is possible to provide a formulation that contains about 100% by weight. Such compositions are disclosed herein as if they were expressly disclosed herein.

[0136] The effective amount of the pharmaceutical active ingredient to be administered therapeutically depends, for example, on the condition and purpose of treatment.As recognized by those skilled in the art, the dosage level suitable for treatment varies in part depending on the concentration of the STS formulation, the administration regimen in which the STS formulation is used, the route of administration, and the size (weight or body surface area) of the subject and the condition (age and general health) of the patient.Therefore, clinicians can titrate the dosage and modify the route of administration to obtain optimal therapeutic effect.

[0137] The frequency of dosing depends on the pharmacokinetic parameters of the therapeutic agent incorporated in the STS formulation being used. The composition may be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule), or as a continuous infusion via an implanted device or catheter. Further fine-tuning of the appropriate dosage is routine and within the scope of tasks routinely performed by those skilled in the art. Appropriate doses can be confirmed using appropriate dose-response data.

[0138] Sodium thiosulfate can be administered, for example, once, twice, three times, four times, five times, six times, or more times a day. One or more doses can be administered, for example, for one, two, three, four, five, six, seven, or even more days. One or more doses can be administered, for example, for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months, one, two, three, four, five, more than five years, ten years, decades, or even more. One or more doses can be administered periodically until the subject or the subject in need thereof no longer requires treatment, prevention, or remission of ototoxicity.

[0139] In one embodiment, the pharmaceutical compositions described herein are administered simultaneously in a single or multiple doses. For example, two or more identical doses are administered at the same time. In another embodiment, two or more different doses are administered at the same time. Such dual or separate simultaneous administration may be used to provide an effective amount of the pharmaceutical composition to a subject in need thereof.

[0140] In another embodiment, the pharmaceutical compositions described herein can be used to treat, prevent, delay progression, delay onset, ameliorate, reduce symptoms, or prevent ototoxicity.

[0141] In one embodiment, the STS formulation is a composition sufficient to provide a therapeutically effective amount of sodium thiosulfate in a single application, hi one aspect, a single application of the STS formulation is sufficient for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, or even longer.

[0142] The phrases and terms "administrable by injection," "injectable," or "injectability" refer to a combination of factors such as a certain force applied to the plunger of a syringe containing an STS formulation described herein dissolved in a liquid at a certain concentration (w / v) and at a certain temperature, a needle of a given inner diameter connected to the outlet of such a syringe, and the time required to expel a certain amount of the STS formulation from the syringe through the needle.

[0143] In one embodiment, the STS formulation is provided as a single dose, i.e., the container in which the STS formulation is supplied contains a single pharmaceutical dose.

[0144] In another embodiment, the composition is provided as a multi-dose composition.That is, it contains multiple therapeutic doses.Preferably, the multi-dose composition contains at least two doses.Such a multi-dose STS formulation may be used for different subjects who need it, or is intended for use in one subject, and the remaining doses are stored after application of the first dose until needed.

[0145] In another embodiment, the STS formulation is configured in one or more containers.When intended for liquid or suspension compositions, the container is preferably a single-chamber syringe.When intended for dry compositions, the container is preferably a dual-chamber syringe.The first chamber of the dual-chamber syringe is provided with the dry composition, and the second chamber of the dual-chamber syringe is provided with the reconstitution solution.

[0146] Before administering the dry STS formulation to a subject in need thereof, the dry composition is reconstituted. The container that can perform reconstitution is the container in which the dry STS formulation is provided, such as a vial, a syringe, a dual-chamber syringe, an ampoule, or a cartridge. Reconstitution is performed by adding a predefined amount of reconstitution solution to the dry composition. The reconstitution solution is a sterile liquid, such as water for injection, phosphate buffered saline, isotonic saline, or other buffer, and may contain additional excipients, such as preservatives and / or antibacterial agents, for example, benzyl alcohol and cresol. The reconstitution solution is preferably sterile water for injection. Alternatively, the reconstitution solution is sterile phosphate buffered saline (PBS) or saline.

[0147] Another embodiment is a method of preparing a reconstituted composition comprising a therapeutically effective amount of an STS formulation, and optionally one or more pharma- ceutically acceptable excipients, comprising contacting the composition with a volume of a reconstitution vehicle. The reconstituted STS formulation may then be administered via injection or other route.

[0148] Another embodiment is a reconstituted composition comprising a therapeutically effective amount of an STS formulation, a reconstitution vehicle, and optionally one or more pharma- ceutically acceptable excipients.

[0149] Another embodiment is a pre-filled syringe containing a solution or suspension comprising a therapeutically effective amount of an STS formulation, and optionally one or more pharma- ceutically acceptable excipients. In one aspect, the syringe is filled with about 0.01 mL to about 5 mL of an STS formulation as described herein. In one aspect, the syringe is filled with about 0.05 mL to about 5 mL, about 1 mL to about 2 mL, about 0.1 mL to about 0.15 mL, about 0.1 mL, about 0.5 mL, about 0.15 mL to about 0.175 mL, or about 0.5 to about 5 mL. In one embodiment, the syringe is filled with 0.165 mL of an STS formulation as described herein. In some embodiments, the syringe is filled with about 0.01 mL, about 0.02 mL, about 0.03 mL, about 0.04 mL, about 0.05 mL, about 0.06 mL, about 0.07 mL, about 0.08 mL, about 0.09 mL, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.2 mL, about 1.5 mL, about 1.75 mL, about 2 mL, about 2.5 mL, about 3 mL, about 4 mL, or about 5 mL of the STS formulation described herein. Syringes are often filled with an amount in excess of the desired dose suitable for administration to a patient, taking into account waste due to "dead space" in the syringe and needle. Additionally, when a physician primes a syringe, a predetermined amount of waste may be present so that the syringe is ready to be injected into a patient.

[0150] In one embodiment, the syringe is filled with a dosage (e.g., the amount of drug intended to effect patentability) of about 0.01 mL to about 5 mL (e.g., about 0.01 mL to about 0.1 mL, about 0.1 mL to about 0.5 mL, about 0.2 mL to about 2 mL, about 0.5 mL to about 5 mL, or about 1 mL to about 5 mL) of an STS formulation described herein, depending on the route of injection.

[0151] In one embodiment, when the composition is intended for injection, a syringe is filled with a dosage of about 0.01 mL to about 5.0 mL of an STS formulation solution or suspension with a drug concentration of 0.1 mg / mL to 40 mg / mL, as described herein. In some embodiments, the syringe is filled with about 0.01 mL, about 0.02 mL, about 0.03 mL, about 0.04 mL, about 0.05 mL, about 0.06 mL, about 0.07 mL, about 0.08 mL, about 0.09 mL, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.2 mL, about 1.5 mL, about 1.75 mL, about 2 mL, about 2.5 mL, about 3 mL, about 4 mL, or about 5 mL of an STS formulation described herein and is capable of being delivered to a patient in need thereof.

[0152] The outlet of the syringe containing the drug is reversibly sealed to maintain sterility of the drug This sealing can be accomplished by sealing devices known in the art, such as a Luer lock or a tamper-evident seal.

[0153] Another embodiment is a kit comprising one or more vials or pre-filled syringes containing a solution or suspension of one or more STS formulations described herein. In one embodiment, such a kit comprises a vial or pre-filled syringe containing an STS formulation as described herein in a blister pack or sealed sleeve. The blister pack or sleeve may be sterile on the inside. In one aspect, the vial or pre-filled syringe described herein may be subjected to sterilization, e.g., terminal sterilization, after being placed inside such a blister pack or sleeve. The kit may also comprise a document containing prescribing information or instructions for use.

[0154] Such kits may further comprise one or more needles for administration of the STS formulations as described herein. Such kits may further comprise instructions for use, drug labels, contraindications, warnings, or other relevant information. One embodiment described herein is a carton or package containing one or more vials or pre-filled syringes containing one or more STS formulations as described herein contained within a blister pack, syringe, needle, and optionally documentation or instructions for administration, drug labels, contraindications, warnings, or other relevant information.

[0155] A terminal sterilization process may be used to sterilize the vial or syringe. Such processes include autoclaving, ethylene oxide, or hydrogen peroxide (H 2 O 2 ) sterilization process. Needles used in the syringes can be sterilized in the same manner as the kits described herein. In one aspect, the packaging is autoclaved or exposed to sterilizing gas until the exterior of the package is sterilized. Following such a process, it is believed that the exterior surface of the syringe can remain sterile (while in the blister pack) for up to 6, 9, 12, 15, 18, 24, or more months. Thus, in one embodiment, the shelf life of the prefilled syringes described herein (in a blister pack) can be up to 6, 9, 12, 15, 18, 24, or more months. In one embodiment, after 18 months of storage, less than 1 in 1 million syringes have microorganisms detected on the exterior of the syringe. In one aspect, the prefilled syringes have a shelf life of at least 10 -6 In another embodiment, the prefilled syringe is sterilized using ethylene oxide at a sterility assurance level of at least 10 -6The pre-filled syringe is sterilized using a sterilization assurance level of hydrogen peroxide of 100 ppm or less. It is necessary to prevent any significant amount of sterilization gas from entering the variable volume chamber of the syringe. As used herein, the term "significant amount" refers to an amount of gas that may cause unacceptable alteration of the STS formulation solution or suspension in the variable volume chamber. In one embodiment, the sterilization process results in 10% or less alkylation of the STS formulation (preferably 5% or less, 2% or less, 1% or less, 0.5% or less, 0.1% or less). In one embodiment, the pre-filled syringe is sterilized using ethylene oxide, but has 1 ppm or less, preferably 0.2 ppm or less of ethylene oxide residual on the exterior surface of the syringe. In one embodiment, the pre-filled syringe is sterilized using hydrogen peroxide, but has 1 ppm or less, preferably 0.2 ppm or less of hydrogen peroxide residual on the exterior surface of the syringe. In another embodiment, the pre-filled syringe is sterilized using ethylene oxide, and has a total of 0.1 mg or less of ethylene oxide residual found on the exterior of the syringe and inside the blister pack. In another embodiment, the prefilled syringes are sterilized using hydrogen peroxide, with the total amount of hydrogen peroxide residue found on the outside of the syringe and inside the blister pack being 0.1 mg or less.

[0156] Another embodiment described herein is a kit comprising sodium thiosulfate for administration to a subject. For liquid and suspension compositions, and when the administration device is simply a hypodermic syringe, the kit may also comprise a syringe, needle, and a container containing an STS formulation for use with the syringe. For dry compositions, the container may contain one chamber containing a dry STS composition and a second chamber containing a reconstituted solution. In one embodiment, the injection device is a hypodermic syringe adapted to engage with the container containing the STS formulation so that the liquid, suspension, or reconstituted dry composition in the container can be fluidly connected to the outlet of the injection device. Examples of administration devices include, but are not limited to, hypodermic syringes and pen syringes.

[0157] Another embodiment includes a kit comprising a needle and a container containing an STS formulation composition, optionally further comprising a reconstitution solution, the container adapted to be used with the needle. In one aspect, the container is a pre-filled syringe. In another aspect, the container is a dual-chamber syringe. In another aspect, the STS formulation is provided as a lyophilizate in a sealed vial, and the reconstitution solution is provided in a separate receptacle, such as a sealed vial or a pre-filled syringe. An appropriate amount of the reconstitution solution is used to resuspend the lyophilizate. In another aspect, the kit includes instructions, labels, or other printed materials.

[0158] Another embodiment is a cartridge containing a composition described herein for use with a pen injector device. The cartridge may contain a single or multi-dose STS formulation.

[0159] In another embodiment, one or more STS formulations are administered simultaneously, each STS formulation having distinct or related biological activity.

[0160] In an alternative embodiment, the STS formulation is combined with a second biologically active compound in such a manner that it is first administered to a subject in need thereof, followed by administration of the second compound. Alternatively, the STS formulation composition is administered to a subject in need thereof after another compound has been administered to the same subject.

[0161] Another embodiment described herein is a method for reducing ototoxicity in a patient (e.g., a pediatric patient) suffering from cancer and undergoing platinum-based chemotherapy for the purpose of cancer treatment. The method comprises administering an effective amount of STS to the patient. In one aspect, the STS comprises one or more of the STS formulations described herein. STS has been found to significantly reduce the risk of ototoxicity, particularly in a pediatric patient population. Thus, one embodiment described herein is a method for reducing ototoxicity in a pediatric patient suffering from cancer and undergoing platinum-based chemotherapy, the method comprises administering an effective amount of STS to the pediatric patient. In some aspects, the pediatric patient has already suffered from ototoxicity, and administering the STS reduces the amount of future ototoxicity the pediatric patient will suffer.

[0162] The risk of a pediatric patient having detectable ototoxicity, e.g., hearing loss measured on one or more block scales, is significantly reduced by treatment with STS after administration of a cisplatin-based chemotherapy agent. The risk of ototoxicity is relative to a pediatric patient not receiving STS. Thus, in some embodiments, the probability that a pediatric patient will suffer ototoxicity is reduced by about 10% to about 100%, about 30% to about 90%, or about 40% to about 70%, inclusive of each integer within the specified range, with STS administration. In some embodiments, the risk of a pediatric patient suffering ototoxicity is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or even about 100% with STS administration. In some embodiments, the risk of a pediatric patient suffering ototoxicity is about 50% according to the ASHA-defined hearing loss criteria.

[0163] Similarly, treatment of pediatric patients with STS can further reduce long-term ototoxicity in pediatric patients suffering from cancer and undergoing platinum-based chemotherapy. It is known that pediatric patients after treatment with STS can develop ototoxicity weeks, months, or even years after successive treatments with platinum-based chemotherapy agents. Therefore, another embodiment described herein is a method for reducing long-term ototoxicity in pediatric patients suffering from cancer and undergoing platinum-based chemotherapy, the method comprising administering an effective amount of sodium thiosulfate to the pediatric patient.

[0164] As discussed above, platinum-based chemotherapeutic agents, such as cisplatin, are believed to exert their ototoxic effects by concentrating in the ear cavity of a patient (e.g., a pediatric patient). As further contemplated herein, STS allows for a reduction in the amount of platinum-based chemotherapeutic agents in the ear cavity by binding to the agent and reducing its accumulation in the ear cavity. Another embodiment described herein is a method of reducing the concentration of cisplatin in the ear cavity of a pediatric patient suffering from cancer and receiving platinum-based chemotherapy, the method comprising administering an effective amount of sodium thiosulfate to the pediatric patient. In some embodiments, the concentration of cisplatin in the ear cavity is about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% lower compared to a pediatric patient receiving platinum-based chemotherapy but not receiving STS. In some embodiments, the concentration of cisplatin in the ear cavity is undetectable. In some embodiments, patients receiving STS are less susceptible to ototoxicity due to a reduction in the amount of platinum-based chemotherapeutic agents in the ear cavity. Methods for detecting cisplatin in the ear cavity include extracting a sample from the ear cavity and measuring the amount of cisplatin present in the sample, for example, by high performance liquid chromatography (HPLC) or other methods known in the art.

[0165] The methods described herein are also useful for preventing or inhibiting ototoxicity in pediatric patients who have cancer and are receiving platinum-based chemotherapy for the treatment of the cancer. Pediatric patients are particularly susceptible to ototoxicity, and it has been discovered that prophylactically treating the pediatric patient can reduce the ototoxicity in the pediatric patient. Thus, another embodiment described herein is a method of prophylactically treating a pediatric patient who has cancer and is receiving platinum-based chemotherapy, including an effective amount of STS, where the treatment reduces the likelihood that the pediatric patient will experience ototoxicity.

[0166] Certain genetic variants have been identified that may increase the probability of ototoxicity in pediatric patients and cause severe ototoxicity in patients. Genes TPMT, COMT, and ABCC3 have been identified as being at high risk of causing ototoxicity in pediatric patients. Source: Ross et al., “Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy,” Nat. Genet. 41:1345-1349 (2009); Pussegoda et al., “Replication of TPMT and ABCC3 genetic variants is highly associated with cisplatin-induced hearing loss in children,” Clin. Pharmacol. Ther. 94:243-251 (2013). In addition, a single nucleotide polymorphism in the ACYP2 gene at locus rs1872328 has more recently been identified as being associated with cisplatin-based ototoxicity. Source: Xu, K. et al., "Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss," Nat. Genet. 47(3):263-266 (2015). Thus, in some embodiments, pediatric patients undergoing cisplatin-based chemotherapy who have been identified as being at high risk for genetic variants in one or more of the following genes: TPMT, COMT, ABCC3, and ACYP2 are treated with STS to reduce the probability of, prevent, inhibit, or treat ototoxicity.

[0167] In some embodiments described herein, the pediatric patient has cancer and is receiving platinum-based chemotherapy. In other embodiments, the pediatric patient has not yet been diagnosed with cancer, but is receiving treatment with platinum-based chemotherapy agents. The platinum-based agents are expected to be removed by STS, reducing ototoxicity. Thus, in some embodiments, the platinum-based chemotherapy agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, the platinum-based chemotherapy agent is cisplatin.

[0168] The amount of platinum-based chemotherapy that a pediatric patient receives is determined by the treating physician, the type of disease or cancer being treated, and the age or weight of the pediatric patient. In some embodiments, the amount of platinum-based chemotherapy (e.g., cisplatin) per administration cycle is about 1 mg / kg to about 5 mg / kg, inclusive of each integer within the range specified. In some embodiments, the amount of platinum-based chemotherapy (e.g., cisplatin) per administration cycle is about 10 mg / m, inclusive of each integer within the range specified. 2 ~about 300mg / m 2 , 10 mg / m 2 ~about 100mg / m 2 , or about 40 mg / m 2 ~about 80mg / m 2 It is.

[0169] Many cancers are treated with platinum-based chemotherapy in pediatric patients to which STS may be administered. In some aspects of the embodiments described herein, the pediatric patient's cancer is treated with platinum-based chemotherapy followed by STS, and the cancer is localized or disseminated. In some aspects, the cancer is low-risk, medium-risk, or high-risk (e.g., metastatic) cancer. In some aspects, the cancer is low-risk or medium-risk. In some aspects, the cancer being treated with platinum-based chemotherapy is localized and not disseminated or metastatic. Non-limiting exemplary cancers that can be treated with platinum-based chemotherapy followed by STS include germ cell tumors (e.g., testicular or ovarian cancer), hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma. In some aspects, the pediatric patient has hepatoblastoma cancer and is treated with platinum-based chemotherapy and STS. In some aspects, the pediatric patient has low-risk or medium-risk hepatoblastoma cancer and is treated with platinum-based chemotherapy and STS.

[0170] In some embodiments, the STS is administered to a pediatric patient undergoing treatment with a platinum-based chemotherapeutic agent prior to, concurrently with, or following administration of the platinum-based chemotherapeutic agent. In some embodiments, the STS is administered 0 minutes or about 5 minutes to about 96 hours, inclusive of each integer number of hours within the range specified, after administration of the platinum-based chemotherapeutic agent. In some embodiments, the STS is administered about 30 minutes to about 24 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 1 hour to about 8 hours, or about 4 hours to about 7 hours, inclusive of each integer number of hours within the range specified, after administration of the platinum-based chemotherapeutic agent. In one embodiment, the STS is administered about 6 hours after administration of the platinum-based chemotherapeutic agent.

[0171] Administration of the STS can be accomplished by any method known for administering an STS. For example, the STS may be administered parenterally or enterally. For parenteral administration, the STS may be administered intravenously (IV), subcutaneously (SC), or intramuscularly (IM). Enteral administration includes oral, sublingual, or rectal. In one embodiment, the STS is administered intravenously.

[0172] An effective amount of STS is an amount of STS that prevents, reduces, or inhibits ototoxicity in pediatric patients receiving platinum-based chemotherapy. In some embodiments, the amount of STS administered is about 0.5 g / m, inclusive of each integer within the specified range. 2 ~about 50g / m 2 , about 1g / m 2 ~about 25g / m 2 or 15 g / m 2 ~about 25g / m 2 In some embodiments, the amount of STS administered is about 1 g / m 2 , about 2g / m 2 , about 4g / m 2 , about 6g / m 2 , about 8g / m 2 , about 10g / m 2 , about 15g / m 2 , about 20g / m 2 , about 25g / m 2 , about 30g / m 2 , about 40g / m 2 , or about 50 g / m 2 An effective amount of STS is administered before, after, or concurrently with each cycle of platinum-based chemotherapy.

[0173] Some additional embodiments described herein are dosing regimens for treating cancer in pediatric patients, including administration of a platinum-based chemotherapeutic agent and an STS. One embodiment is a dosing regimen for treating hepatoblastoma in a pediatric patient, the dosing regimen comprising about 1 mg / kg to about 5 mg / kg or about 10 mg / m2 of platinum-based chemotherapeutic agent (including each integer within the ranges described) per cycle. 2 ~about 300mg / m 2and administering a dose of about 5 g / m per cycle of a platinum-based chemotherapy agent (including each integer within the specified range). 2 ~about 25g / m 2 In one embodiment, the STS is administered about 2 hours to about 6 hours after administration of the platinum-based chemotherapy agent, including each integer within the recited range.

[0174] Measurement of ototoxicity after administration of platinum-based chemotherapy and STS should be performed after a certain period of time after the last treatment with platinum-based chemotherapy and STS. In some embodiments, measurement of ototoxicity is performed after a period of at least 3 days to about 3 months, 1 week to about 3 months, 1 week to about 2 months, or 1 week to about 4 weeks after the last treatment with platinum-based chemotherapy and STS. This period includes each integer within the specified time range. In one embodiment, ototoxicity is measured at least 4 weeks after the last treatment with platinum-based chemotherapy and STS.

[0175] Measurement of ototoxicity after administration of platinum-based chemotherapy and STS can be performed several times and up to several years after the last administration of STS and platinum-based chemotherapy.Hearing loss measurement methods are well known to those skilled in the art and are used with various scales to evaluate ototoxicity.Evaluation of ototoxicity can, for example, evaluate potential ototoxicity or prevent long-term ototoxicity caused by STS.Evaluation of ototoxicity can be calculated by one or more criteria known in the art. For example, ototoxicity can include assessment using the Tinnitus Functional Index, Block Grading, the Children's Cancer Group 1996 Study Scale, the Children's Hospital Boston Scale, the Chang and Chinosornvatana Scale, the American Speech-Language-Hearing Association criteria, the Common Terminology Criteria for Adverse Events Criteria Scale (CTCAE Pediatric Grading), or the International Society of Pediatric Oncology Boston Ototoxicity Scale, or a combination of these scales. See Gurney, et al., "Oncology," J. Clin. Onc. 30(19):2303-2306 (2012). In most cases, after completing the hearing function measurements, treatment with an ototoxic drug such as cisplatin or another platinum-based chemotherapy agent is required. This treatment establishes a baseline measurement of hearing function against which potential ototoxic effects can be compared. Therefore, any change in hearing, or enhancement or reduction in ototoxicity, is calculated relative to the baseline measurement before the patient received the platinum-based chemotherapy drug or sodium thiosulfate, or both.

[0176] The block scale is defined as follows: A hearing loss of less than 40 dB at all frequencies, indicating a grade 0 or minimal hearing loss; a hearing loss of 40 dB or more at 8,000 Hz only, indicating a grade 1 or mild hearing loss; a hearing loss of 40 dB or more at 4,000 Hz or above, indicating a grade 2 or moderate hearing loss; a hearing loss of 40 dB or more at 2,000 Hz or above, indicating a grade 3 or significant hearing loss; or a hearing loss of 40 dB or more at 1,000 Hz or above, indicating a grade 4 or profound hearing loss.

[0177] The CTCAE scale is based on hearing at 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, and 8 kHz. Grade 1 is a threshold shift of more than 20 dB at 8 kHz in at least one ear. Grade 2 is a threshold shift of more than 20 dB at 4 kHz or greater in at least one ear. Grade 3 is sufficient hearing loss to indicate therapeutic intervention including hearing aids and threshold shifts of more than 20 dB at 3 kHz or greater in at least one ear. Instructed speech and language svcs; Grade 4 is auditory indication for cochlear implants and speech and language svcs.

[0178] The Children's Cancer Group 1996 scale is defined as follows: A HL loss of 40 dB or more at 6,000 Hz and / or 8,000 Hz indicates Grade 1. A HL loss of more than 25 dB at 3,000 and / or 4,000 Hz indicates Grade 2. A HL loss of more than 25 dB at 2,000 Hz indicates Grade 3. A HL loss of 40 dB or more at 2,000 Hz indicates Grade 4. The Children's Hospital Boston scale is defined as follows: Grade 1 hearing loss indicates slight hearing loss that may result in a decline in music appreciation; Grade 2 hearing loss indicates educationally significant hearing loss; and Grade 3 hearing loss indicates severe hearing loss requiring a hearing aid.

[0179] The Chang and Chinosornvatana scale is defined as 20 dB or less at 1 kHz, 2 kHz, and 4 kHz, indicating normal hearing; (1a) 40 dB or more at any frequency between 6 and 12 kHz, (1b) more than 20 dB and less than 40 dB at 4 kHz, indicating grades 1a and 1b, respectively; (2a) 40 dB or more at 4 kHz or more, (2b) more than 20 dB and less than 40 dB at frequencies less than 4 kHz, indicating grades 2a and 2b, respectively; 40 dB or more at 2 kHz or 3 kHz or more indicates grade 3; and 40 dB or more at 1 kHz or more indicates grade 4.

[0180] The American Speech-Language-Hearing Association defines the criteria as follows: (1) A decrease of 20 dB or more at any one frequency, (2) A decrease of 10 dB or more at two or more adjacent frequencies, or (3) A loss of response at three adjacent frequencies where a response was previously obtained. ASHA further specifies that a significant change in hyperacusis must be confirmed by repeated testing to be considered valid.

[0181] As defined by the International Society of Pediatric Oncology Boston Ototoxicity Scale, HL of 20 dB or less at all frequencies indicates normal hearing, i.e., HL >20 dB (e.g., HL >25 dB). SNHL >4,000 Hz (defined as 6 or 8 kHz) indicates Grade 1. HL SNHL of >20 dB at ≥4,000 Hz indicates Grade 2. HL SNHL of >20 dB at ≥2,000 Hz or ≥3,000 Hz indicates Grade 3. HL >40 dB at ≥2,000 Hz (e.g., HL >45 dB) indicates SNHL of Grade 4.

[0182] The Tinnitus Functional Index is a questionnaire-based index that quantifies the severity of tinnitus symptoms. See Henry JA et al., Audiology Today 26(6):40-48(2014). The index is defined as follows: A mean score of 14 (range 0-17) suggests no tinnitus, a mean score of 21 a low level of tinnitus. A mean score of 42 is moderate tinnitus. A mean score of 65 is high level of tinnitus, and a mean score of 78 is loud level of tinnitus. The range classification is considered as follows: less than 25 is relatively mild or no tinnitus; 25-50 indicates a significant problem with tinnitus; and greater than 50 indicates a level of tinnitus that requires active intervention.

[0183] In some embodiments, ototoxicity is measured by measuring hearing loss at one or more frequencies, including 500Hz, 1,000Hz, 2,000Hz, 4,000Hz, or 8,000Hz, or a combination of these frequencies.The change in hearing is then calculated relative to the baseline measurement before the patient receives platinum-based chemotherapy or sodium thiosulfate, or both.In some embodiments, an increase in ototoxicity may be determined as a decrease in hearing measured by a loss of 20dB at a single frequency, a decrease in hearing measured by a loss of 10dB at two consecutive frequencies, or a loss of response at three consecutive test frequencies where a response was previously obtained. In some further embodiments, the increased ototoxicity is measured as a decrease in bilateral high frequency hearing, characterized as: hearing loss of less than 40 dB at all frequencies, indicating a grade 0 or minimal hearing loss; hearing loss of 40 dB or more at only 8,000 Hz, indicating a grade 1 or mild hearing loss; hearing loss of 40 dB or more at 4,000 Hz or higher, indicating a grade 2 or moderate hearing loss; hearing loss of 40 dB or more at 2,000 Hz or higher, indicating a grade 3 or significant hearing loss; or hearing loss of 40 dB or more at 1,000 Hz or higher, indicating a grade 4 or profound hearing loss. In still some further embodiments, the increased ototoxicity is measured as a decrease in hearing, characterized as follows: hearing loss of 20 dB or less at all frequencies, indicating a grade 0 hearing loss; and hearing loss of more than 20 dB HL above 4,000 Hz, indicating a grade 1 hearing loss. More than 20 dB HL above 4,000 Hz indicates a grade 2 hearing loss. More than 20 dB HL at 2,000 Hz or 3,000 Hz indicates a grade 3 hearing loss. Or, more than 40 dB HL above 2,000 Hz indicates a grade 4 hearing loss. In some other embodiments, enhanced ototoxicity may be measured by a reduction in the tinnitus function index.

[0184] It has been found that administering STS to pediatric patients undergoing treatment with platinum-based chemotherapy does not lead to worsening renal or other toxicity. Thus, in some embodiments, patients administered STS do not experience more severe or increased incidence of adverse events compared to patients not administered STS. These adverse events include grade 3 or grade 4 neutropenia, decreased glomerular filtration rate, increased serum creatinine, infection, hypomagnesemia, hypernatremia, vomiting, or nausea. In some other embodiments, pediatric patients administered STS do not experience reduced progression-free survival or overall survival compared to patients not administered STS.

[0185] The methods described herein are well suited to reduce or prevent ototoxicity or reduce the likelihood of experiencing ototoxicity in any pediatric patient of any age. Thus, in some embodiments, the pediatric patient being treated according to the methods described herein is a newborn or is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about It has been described that the age of the pediatric patient may be about 6.5 years old, about 7 years old, about 7.5 years old, about 8 years old, about 8.5 years old, about 9 years old, about 9.5 years old, about 10 years old, about 10.5 years old, about 11 years old, about 11.5 years old, about 12 years old, about 12.5 years old, about 13 years old, about 13.5 years old, about 14 years old, about 14.5 years old, about 15 years old, about 15.5 years old, about 16 years old, about 16.5 years old, about 17 years old, about 17.5 years old, about 18 years old, about 18.5 years old, about 19 years old, about 19.5 years old, about 20 years old, about 20.5 years old, or about 21 years old. In some embodiments, the pediatric patient is about 12 years old or less, about 5 years old or less, about 2 years old or less, or about 1 year old or less.

[0186] Indications and Usage In one embodiment, sodium thiosulfate for injection as described herein is indicated for the prevention of ototoxicity induced by cisplatin (CIS) chemotherapy in patients aged 1 month to less than 18 years with localized non-metastatic solid tumors.

[0187] In one embodiment, sodium thiosulfate for injection as described herein is administered as a 15 minute infusion 6 hours after completion of each CIS administration if the CIS was infused within 6 hours. In one aspect, the recommended doses of sodium thiosulfate for injection as described herein for the prevention of CIS-induced ototoxicity are based on body weight and normalized for body surface area as shown below. [Table 4]

[0188] Dosage Form and Strength Sodium thiosulfate for injection, as described herein, is a sterile solution containing 80 mg / mL (8 g / 100 mL) sodium thiosulfate for intravenous (IV) administration in a single-use vial.

[0189] Sodium thiosulfate for injection as described herein is administered as a 15-minute infusion 6 hours after completion of each CIS dose if the CIS is infused within 6 hours. Pretreatment with an antiemetic is recommended to reduce the incidence of nausea and vomiting.

[0190] The timing of sodium thiosulfate for injection administration compared with CIS chemotherapy is important because earlier treatment may reduce the efficacy of CIS, and later treatment may be less effective in preventing ototoxicity.

[0191] Injectable sodium thiosulfate should only be administered after 1 to 6 hours of CIS infusion. Do not use injectable sodium thiosulfate if the CIS infusion lasts longer than 6 hours or if a subsequent CIS infusion is planned within 6 hours. [Table 5]

[0192] contraindication Sodium Thiosulfate Injection as described herein is contraindicated in patients with known hypersensitivity to Sodium Thiosulfate (STS) or any of the inactive raw materials of Sodium Thiosulfate Injection, as well as in neonates under one month of age due to the risk of hypernatremia.

[0193] explanation The active ingredient, anhydrous sodium thiosulfate, is an inorganic salt with reducing agent properties. It is a white to off-white crystalline solid that is soluble in water but insoluble in alcohol. Aqueous solutions are essentially neutral with a pH in the range of 6.5 to 9.0. The molecular formula is Na 2 S 2 O 3 The molecular weight is 158.11 g / mol. The structural formula is: [ka]

[0194] Sodium thiosulfate for injection, as described herein, is a sterile, preservative-free, clear solution for intravenous injection. Each vial contains 80 mg / mL anhydrous sodium thiosulfate (United States Pharmacopeia, USP), water for injection (USP), boric acid or sodium phosphate as buffer components, and sodium hydroxide and / or hydrochloric acid for pH adjustment.

[0195] Mechanism of action Cisplatin-induced ototoxicity is due to irreversible damage to cochlear hair cells. The cochlea is extremely 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 enhancement of endogenous antioxidant levels, scavenging of reactive oxygen species, and direct interaction between the thiol groups of CIS and STS. STS has the ability to enter cells at least in part via sodium sulfate cotransporter 2 and may also cause intracellular effects such as enhancement of antioxidant glutathione levels and inhibition of intracellular oxidative stress.

[0196] Pharmacodynamics STS is sodium thiosulfate for injection, 6.4 to 12.8 g / m 2 In preliminary clinical studies, the STS dose level (5.1 g / m for injection) 2 Lowering the concentration of nicotinamide adenine diphosphate (equivalent to sodium thiosulfate) resulted in lower maximum plasma levels (3.9 mM) but no hearing protection was observed.

[0197] Delaying STS treatment for 6 hours after CIS chemotherapy is important to avoid potential interference with the antitumor activity of CIS. This is supported by data from nonclinical and preliminary clinical studies. During CIS infusion, biologically active unbound CIS is distributed to cancer cells and removed by renal excretion and rapid binding to proteins, inactivating the tumoricidal activity. The initial decrease in unbound platinum in plasma is rapid, with a half-life ranging from 0.6 to 1.35 hours. Given the fact that the distribution of STS is largely restricted to the extracellular space, administration of injectable sodium thiosulfate 6 hours after completion of each CIS infusion should prevent the tumor-protective effect of STS. As demonstrated in these studies, treatment 6 hours after completion of each CIS infusion did not affect survival.

[0198] Based on the half-life of STS in plasma, negligible amounts remain 6 hours after completion of an STS infusion, therefore, to avoid a pharmacodynamic interaction, subsequent CIS infusions should be administered within 6 hours of completion of the sodium thiosulfate infusion.

[0199] 12.8g / m for injection 2 The dose of sodium thiosulfate was 162 mmol / m 2 sodium load of 100 mg / kg / day. Equivalent STS doses produced a small, transient increase in serum sodium levels. This transient sodium increase was independent of age, body surface area, weight, total daily STS dose, or CIS cycle when assessed using noncompartmental pharmacokinetic analysis at the recommended sodium thiosulfate for injection dose levels.

[0200] Pharmacokinetics absorption STS is poorly absorbed after oral administration and must be administered intravenously. At the end of an intravenous infusion of STS, plasma levels of STS reach a maximum and then decline rapidly, with a half-life of approximately 20-50 minutes. Return to pre-dosing levels occurs within 3-6 hours after infusion. More than 95% of urinary STS excretion occurs within the first 4 hours after administration. There is no accumulation in plasma when STS is administered on 2 consecutive days.

[0201] In children and adults, 12.8 g / m 2 Maximum STS plasma levels after a 15-minute infusion of the equivalent dose of sodium thiosulfate were approximately 13.3 mM. STS plasma levels vary proportionally with dose. Age did not appear to affect the maximum plasma levels or subsequent decline of STS. Predicted STS plasma levels at the end of infusion were consistent across recommended sodium thiosulfate for injection dose levels for the indicated age and weight ranges, as revealed by a population pharmacokinetic model incorporating growth and maturation variables for the pediatric population.

[0202] distribution STS does not bind to human plasma proteins. STS is an inorganic salt, and the thiosulfate anion does not cross membranes easily. Therefore, the volume of distribution appears to be mainly restricted to the extracellular space and has been estimated to be 0.23 L / kg in adults. In animals, STS has been found to distribute to the cochlea. Distribution across the blood-brain barrier or the placenta appears to be absent or limited. Thiosulfate is an endogenous compound that is ubiquitous in all cells and organs. In adult volunteers, endogenous serum thiosulfate levels were 5.5 ± 1.8 μM.

[0203] exclusion metabolism: The metabolites of STS have not been determined as part of clinical studies. Thiosulfate is an endogenous intermediate in the metabolism of sulfur-containing amino acids. Thiosulfate metabolism does not involve CYP enzymes and is metabolized to sulfite via thiosulfate sulfur transferase and thiosulfate reductase activity, which is rapidly oxidized to sulfate.

[0204] excretion: STS (thiosulfate) is excreted by glomerular filtration. After administration, urinary STS (thiosulfate) levels are high, with approximately half of the STS dose being recovered unchanged in the urine, and nearly all being excreted within the first 4 hours after administration. STS renal clearance correlated well with inulin clearance as a measure of GFR.

[0205] Excretion of endogenously produced thiosulfate in the bile was very low and did not increase after STS administration. Although mass balance studies have not been performed, nonrenal clearance is expected to result primarily from renal excretion of sulfate. It is possible that a small portion of the sulfane sulfur in STS becomes part of the endogenous cellular sulfur metabolism.

[0206] Pharmaceuticals, storage and handling Sodium Thiosulfate for Injection is supplied as 100 mL of clear, colorless, sterile solution contained in a 20 mm stoppered flint glass vial covered with an aluminum overseal. Each 100 mL serving of Sodium Thiosulfate for Injection contains anhydrous sodium thiosulfate (80 mg / mL) for intravenous administration (8 g STS per vial).

[0207] Sodium thiosulfate for injection should be stored at controlled room temperature between 15°C and 30°C.

[0208] As would be apparent to one skilled in the relevant art, suitable modifications can be made to adapt the compositions, formulations, methods, processes, reactions, and applications described herein without departing from the scope of any embodiment or aspect 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 may be combined in any and all variations or iterations. The scope of the compositions, formulations, methods, and processes described herein encompasses all actual or potential combinations of the embodiments, aspects, options, examples, and preferences described herein. The exemplary components and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratio of the mass of any component of any of the compositions or formulations disclosed herein to the mass of the other components in the formulation or the total mass of the other components in the formulation is disclosed herein as if the mass was expressly disclosed. In the event that the meaning of any term in a patent or publication incorporated by reference conflicts with the meaning of the term as used in this disclosure, the meaning of the term or phrase in this disclosure shall control. Furthermore, the foregoing discussion discloses and describes only exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for their specific teachings. Some embodiments are given below. Item 1 A pharmaceutical composition comprising aqueous anhydrous sodium thiosulfate, one or more buffers, and a solvent. Section 2 Item 2. The composition according to item 1, wherein the composition comprises about 20 mg / mL to 320 mg / mL of aqueous anhydrous sodium thiosulfate. Section 3 Item 3. The composition according to item 1 or 2, wherein the composition comprises about 8% by weight to about 32% by weight of aqueous anhydrous sodium thiosulfate. Section 4 Item 4. The composition according to any one of items 1 to 3, wherein the composition comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. Section 5 The composition according to any one of items 1 to 4, wherein the composition comprises about 0.001 M to about 0.5 M of the one or more buffers. Section 6 6. The composition of any one of claims 1 to 5, wherein the one or more buffers comprise phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. Section 7 Item 7. The composition according to any one of items 1 to 6, wherein the composition has a pH of about 5 to about 9.5. Section 8 The composition according to any one of items 1 to 7, wherein the composition has a pH of about 6.5 or about 8.9. Section 9 The composition according to any one of items 1 to 8, wherein the one or more buffers include borate or a salt thereof, glycine or a salt thereof, tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, or phosphate or a salt thereof. Section 10 Item 10. The composition of any one of items 1 to 9, wherein the one or more buffers comprise boric acid, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or sodium phosphate. Section 11 11. The composition according to any one of items 1 to 10, wherein the solvent comprises water. Item 12 Item 12. The composition according to any one of items 1 to 11, wherein the composition is sterile. Section 13 A pharmaceutical composition comprising about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, boric acid, glycine, or tris(hydroxymethyl)aminomethane (tromethamine). Section 14 Item 14. The composition of item 13, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M sodium phosphate at pH 6.5. Section 15 Item 15. The composition according to item 13 or 14, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.004 M borate or a salt thereof at a pH of 8.6 to 8.8. Section 16 Item 16. The composition according to any one of items 13 to 15, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M glycine or a salt thereof at a pH of 8.5 to 8.9. Item 17 Item 17. The composition according to any one of items 13 to 16, wherein the composition comprises about 0.5 M aqueous anhydrous sodium thiosulfate and about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof at a pH of 8.5 to 8.9. Section 18 A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. Section 19 A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M borate or a salt thereof at a pH of 8.6 to 8.8, and water. Section 20 A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine or a salt thereof having a pH of 8.5 to 8.9, and water. Section 21 A pharmaceutical composition comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) or a salt thereof, having a pH of 8.5 to 8.9, and water. Section 22 1. A method for preparing anhydrous sodium thiosulfate-containing pharmaceutical formulations comprising combining anhydrous sodium sulfate with one or more buffers and solvents. Section 23 23. The method of claim 22, further comprising filtering and sterilizing the formulation. Section 24 24. The method of claim 22 or 23, wherein the formulation comprises about 20 mg / mL to 320 mg / mL of aqueous anhydrous sodium thiosulfate. Section 25 25. The method of any one of items 22 to 24, wherein the formulation comprises about 8% to about 32% by weight of aqueous anhydrous sodium thiosulfate. Section 26 26. The method of any one of items 22 to 25, wherein the formulation comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate. Section 27 27. The method according to any one of items 22 to 26, wherein the formulation comprises about 0.001 M to about 0.5 M of the one or more buffers. Section 28 28. The method of any one of claims 22 to 27, wherein the one or more buffers comprise phosphate, borate, sulfate, carbonate, formate, acetate, propionate, butanoate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris(hydroxymethyl)aminomethane (tromethamine), combinations thereof, or salts thereof. Section 29 29. The method according to any one of items 22 to 28, wherein the formulation has a pH of about 5 to about 9.5. Item 30 30. The method according to any one of items 22 to 29, wherein the formulation has a pH of about 6.5 or about 8.9. Section 31 31. The method of any one of claims 22 to 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. Section 32 32. The method of any one of claims 22 to 31, wherein the one or more buffers comprise sodium phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or boric acid. Item 33 Item 33. The method according to any one of items 22 to 32, wherein the solvent comprises water. Section 34 Item 34. The method of any one of items 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. Item 35 Item 34. The method of any one of items 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid at a pH of 8.6 to 8.9, and water. Section 36 Item 34. The method of any one of items 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at a pH of 8.5 to 8.9, and water. Section 37 Item 34. The method of any one of items 22 to 33, wherein the formulation comprises about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) at a pH of 8.5 to 8.9, and water. Section 38 23. A pharmaceutical formulation produced by the method of claim 22, comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M sodium phosphate at pH 6.5, and water. Section 39 Item 23. A pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.004 M boric acid having a pH of 8.6 to 8.8, and water, produced by the method according to item 22. Section 40 Item 23. A pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M glycine at pH 8.5 to 8.9, and water, produced by the method according to item 22. Section 41 Item 23. A pharmaceutical formulation comprising about 0.5 M aqueous anhydrous sodium thiosulfate, about 0.01 M to about 0.05 M tris(hydroxymethyl)aminomethane (tromethamine) having a pH of 8.5 to 8.9, and water, produced by the method according to item 22. Section 42 1. A method for preparing anhydrous sodium thiosulfate-containing pharmaceutical formulations comprising combining anhydrous sodium sulfate with one or more buffers and solvents. Section 43 Item 43. A formulation prepared by the method described in item 42. Section 44 A pharmaceutical composition comprising a sterile aqueous solution of about 0.2M to about 2M sodium thiosulfate, about 0.001M to about 0.05M of a pharma- ceutical acceptable buffer, and about 0.005M to about 0.05M of a pharma- ceutical acceptable salt, at a pH of about 5 to about 9.5. Section 45 A kit comprising a sterile aqueous sodium thiosulfate formulation comprising one or more receptacles containing aqueous sodium thiosulfate and a document containing prescribing information or instructions for use. Section 46 46. ​​The kit of claim 45, further comprising one or more syringes, a hypodermic injection needle, and packaging. Section 47 A kit comprising one or more receptacles containing dried or lyophilized sodium thiosulfate, optionally one or more sterile solvents suitable for reconstitution, a needle and syringe, and a document containing prescribing information or instructions for use. Section 48 A pharmaceutical formulation comprising a stable injectable aqueous anhydrous sodium thiosulfate that does not precipitate after sterilization and storage. Section 49 Item 49. The pharmaceutical formulation of item 48, wherein the formulation comprises about 0.1 M to about 2 M aqueous anhydrous sodium thiosulfate, 0.001 M to about 0.5 M sodium phosphate, glycine, tris(hydroxymethyl)aminomethane (tromethamine), or boric acid. Section 50 1. A method for preventing or reducing the incidence of cisplatin (CIS) chemotherapy-induced ototoxicity in patients with localized non-metastatic solid tumors between 1 month and less than 18 years of age, comprising administering sodium thiosulfate for injection as a 15 minute infusion about 6 hours after completion of each dose of CIS when the CIS is infused for up to 6 hours. EXAMPLES

[0209] Example 1 Synthesis Process The synthesis process is outlined in Figure 1. As shown in Scheme I, the synthesis of sodium thiosulfate (wet) was achieved by reacting 1.0 molar equivalent of aqueous sodium sulfite with 1.1 molar equivalent of elemental sulfur in the presence of 0.00013 molar equivalent of cetylpyridinium chloride (CPC) at 90°C for up to 3 hours. [ka]

[0210] In some instances, the reaction was heated to approximately 90°C and was complete when it reached 90°C. Without being bound by theory, it is believed that the reaction rate depends on the size, surface area, and solubility of the sulfur (e.g., fine powders react faster than flakes). Once the reaction was complete, the mixture was cooled to 25°C, filtered through a 10 μm filter, and transferred to a crystallization vessel. The sodium thiosulfate solution was then cooled to below 2°C, and acetone was added slowly over at least 1 hour, maintaining a temperature below 2°C, except during the initial nucleation, where an exotherm of 5-7°C was observed. The slurry was then held below 2°C for at least 0.5 hours and transferred in small increments to the filter drier. After each portion of the slurry was added, the slurry was filtered to a point where the filtrate fell just below the level of the cake. This process minimized cracking in the resulting cake. The cake was then washed twice with acetone and filtered until no more liquid drained. The resulting "wet sodium thiosulfate" cake was then dried overnight at 45° C. with mixing under vacuum. As used herein, the term "sodium thiosulfate" refers to sodium thiosulfate that has not been dehydrated.

[0211] dehydration The filtered methanol was used to charge a crystallization vessel and heated to 60°C. The warm methanol was then transferred to a filter dryer containing a "wet sodium thiosulfate" cake that had been dried overnight. The cake was slurried with hot methanol and the filtrate was removed under pressure. A second charge of hot methanol was added, mixed, and the filtrate was removed. It was then washed two more times with ambient temperature methanol and dried under vacuum at 55°C overnight. This process produced anhydrous sodium thiosulfate.

[0212] Example 2 Crushing Using a jet mill, several batches of anhydrous sodium thiosulfate were milled. 50The particle size distribution of unmilled anhydrous sodium thiosulfate synthesized as described herein is 50-75 μm. Without being bound by any theory, it was believed that milling increases the surface area of ​​the sodium thiosulfate particles, facilitating evaporation of residual solvent.

[0213] Example 3 analysis Dried and / or ground anhydrous sodium thiosulfate was collected under storage conditions at ambient temperature. Samples were analyzed for levels of sodium sulfite, sulfur, acetone, and methanol, 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 methods described above are shown in Table 4. [Table 6]

[0214] Example 4 X-ray powder diffraction characterization Samples of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate described herein were analyzed by X-ray powder diffraction (XRPD). 2-50 mg of sample was placed in a zero background holder coated with a thin layer of petrolatum and flattened with a glass plate. XRPD data were obtained using a Bruker D8 X-ray diffractometer from 2° to 40° 2θ with a step size of 0.05° (1 sec / step) using copper Kα radiation (40 kV). Samples were rotated at 15 RPM during acquisition. Peak picking was performed with Materials Data Jade 9.7.0 software.

[0215] The XRPD patterns of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate are shown in Figures 2A and 2B, respectively. The XRPD peaks are shown in Tables 5 and 6, respectively. Significant peaks are in bold. An overlay of the anhydrous sodium thiosulfate pattern in 2A (lower pattern) and the sodium thiosulfate pentahydrate pattern in 2B (upper pattern) is shown in Figure 3. [Table 7] JPEG2024170538000011.jpg49166 [Table 8] JPEG2024170538000013.jpg139168

[0216] Example 4 Sodium thiosulfate binding assay A high performance liquid chromatography ultraviolet spectroscopy (HPLC-UV) assay was developed to quantify the binding capacity of thiosulfate for cisplatin. This method allows the comparison of the binding capacity of different lots of sodium thiosulfate or pharmaceutical compositions containing sodium thiosulfate. The HPLC-UV method directly measures the reduction of cisplatin over time in the presence of various concentrations of sodium thiosulfate.

[0217] The method uses a Waters Acquity H class HPLC system equipped with an Imtakt Scherzo SW-C18 mixed mode column. The HPLC method conditions are outlined in Table 7. The linear response of the method covers a range of cisplatin concentrations covered by 3.3 μM (0.001 mg / mL) to 666 μM (0.2 mg / mL). This range covers more than two orders of magnitude in dose-related concentrations. [Table 9]

[0218] The assay was performed by mixing equal volumes containing 333 μM, 400 μM, or 666 μM sodium thiosulfate with 666 μM cisplatin (5:1, 6:1, or 10:1 thiosulfate:cisplatin ratios, respectively). Each sample was transferred to an HPLC vial and housed in an autosampler chamber maintained at 24°C. Samples were injected into the HPLC system approximately every 30 minutes to obtain four time points for each sample. A gradient was run and retention times and peak areas were obtained. The decrease in concentration of cisplatin was monitored over time to obtain a half-life (time to reach 333 / 2 μM cisplatin based on the slope of the line) calculated as a reaction rate (e.g., slope of the line, [cisplatin] / min). The control sample contained 333 μM cisplatin.

[0219] Exemplary results are summarized in Table 8 and FIG. [Table 10]

[0220] Example 5 Preparation of formulations The process for preparing sodium thiosulfate formulations for injection is shown in Figure 5. Anhydrous sodium thiosulfate was dissolved in sodium phosphate buffer (about 10 mM sodium phosphate). An exemplary sodium thiosulfate pharmaceutical formulation is shown in Table 9. The pH was adjusted to about 6.5 with NaOH and HCl or phosphoric acid. The solution was filtered twice through a 0.22 μm filter. 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 and 15 psi for at least 0.5 hours to sterilize the contents. The vials were inspected, labeled, and stored at ambient temperature. [Table 11]

[0221] Example 6 The process for producing anhydrous sodium thiosulfate described herein includes the steps as follows: Step 1: Chemical synthesis of aqueous sodium thiosulfate, Step 2: Crystallization of sodium thiosulfate (wet) and washing with acetone; Step 3: Dehydration and isolation of anhydrous sodium thiosulfate, Step 4: Packaging.

[0222] The synthetic route is illustrated in Scheme II, with each step being detailed below. [ka]

[0223] Synthesis of sodium thiosulfate The synthesis of aqueous sodium thiosulfate was achieved by reacting 1.0 molar equivalent of aqueous sodium sulfite with 1.1 molar equivalent of solid elemental sulfur (trace metals) in the presence of a catalytic amount of cetylpyridinium chloride (0.00013 molar equivalents) under aqueous conditions at 95±5° C. to form sodium thiosulfate. See Formula II. After 6 hours, the completeness of the reaction was verified by measuring the amount of residual sodium sulfite present (e.g., by HPLC-CAD, less than 0.15% w / w sulfite). The completed 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 passed through a 1 μm bag filter, followed by a 0.45 μm cartridge polishing filter to remove any residual sulfur while transferring the product to a crystallization vessel.

[0224] Crystallization of sodium thiosulfate (wet) The product solution was cooled to 0±5°C under vigorous stirring in a crystallization vessel, and about 35% of the total acetone was added and mixed for at least 20 minutes while maintaining the temperature at or below 10°C. After incubation at 0±5°C for about 5 to about 20 minutes, sodium thiosulfate seed crystals were added and crystallization was carried out at 0±5°C for about 5 to about 20 minutes. The remaining amount of acetone was added while maintaining the temperature at 0±5°C. The slurry was then held at 0±5°C for at least 0.5 hours before being transferred to a filter dryer. The filtrate was removed by pressure filtration. After each portion of the slurry was added, the slurry was filtered to a point where the filtrate fell just below the level of the cake. This process minimized cracking in the resulting cake. The cake was then washed twice with acetone and N2O until no more liquid was draining. 2 The resulting cake of "wet sodium thiosulfate" was then dried at ambient temperature and atmospheric pressure and sprayed with N 2 The cake was blown with water for at least 1 hour. As used herein, the terms "wet sodium thiosulfate" or "sodium thiosulfate (wet)" refer to sodium thiosulfate that is not dehydrated.

[0225] Dehydration and separation of anhydrous sodium thiosulfate The filtered methanol, heated to 60±5°C, was placed into a filter drier containing the dried "wet" sodium thiosulfate material and stirred continuously at 45±5°C for at least 3 hours. The material was sparged with nitrogen for at least 2 hours. The temperature was then increased to 55±5°C and the solids were dried under vacuum for at least 24 hours. Gas chromatography was then used to test for residual solvent volatile impurities. The anhydrous sodium thiosulfate material was cooled to 20±5°C under slight nitrogen pressure.

[0226] Packaging Once cooled, the anhydrous sodium thiosulfate drug substance was transferred to an anhydrous HDPE drum that was double lined with an LDPE bag and the desiccant was enclosed in an LDPE liner. The drum was purged with nitrogen gas before sealing.

[0227] The manufacturing specifications are shown in Table 10. [Table 12] JPEG2024170538000019.jpg34167

[0228] The production specifications for anhydrous sodium thiosulfate produced in 10 kg and 30 kg batches by the above method are shown on the following pages (Tables 11 and 12). [Table 13] JPEG2024170538000021.jpg223155JPEG2024170538000022.jpg223155JPEG2024170538000023.jpg226148 [Table 14] JPEG2024170538000025.jpg214154JPEG2024170538000026.jpg226152

[0229] Example 7 Anhydrous sodium thiosulfate synthesized as described herein is a crystalline material exhibiting sharp XRPD peaks (Figure 2A) and birefringent particles with blade and plate crystalline morphology. Thermal analysis by differential scanning calorimetry (DSC) revealed a sharp single endotherm with onset at an apparent melting temperature of 331.4°C (Figure 4A). Thermogravimetric analysis (TGA) showed negligible weight loss from ambient to 162°C. From 162°C to 309°C, there was a 14.81% weight loss, followed by the onset of decomposition at 436°C (Figure 4A). Upon equilibration to 0% relative humidity, the dynamic vapor sorption (DVS) isotherm showed minimal weight change (Figure 4B). Upon sorption, a weight increase of 165% was observed. Upon desorption, hysteresis was observed and a weight loss of 51% was observed.

[0230] In comparison, the DSC thermogram of sodium thiosulfate pentahydrate revealed multiple endothermic events with maxima at 56, 111, 131, and 141 °C, with melting onset at 331 °C. TGA showed a weight loss of 45.33% from 25 to approximately 300 °C, followed by decomposition at 456 °C. DVS isotherm showed a weight loss of 27% upon drying. The material showed a weight gain of 81% upon sorption. Upon desorption, hysteresis was observed, with a weight loss of 51%.

[0231] Example 8 The preparation process of sodium thiosulfate formulation is as shown in Figure 5. Anhydrous sodium thiosulfate was dissolved in borate buffer (and 4 mM boric acid). An exemplary sodium thiosulfate pharmaceutical formulation is as shown in Table 13. The pH was adjusted to about 8.6-8.8 with NaOH and HCl. The solution was filtered twice through a 0.22 μm filter. 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 and 15 psi for at least 0.5 hours to sterilize the contents. The vials were inspected, labeled, and stored at ambient temperature. [Table 15]

[0232] The manufacturing specifications for the sodium thiosulfate injectable formulation are shown in Table 14. [Table 16] JPEG2024170538000029.jpg50166

[0233] Example 9 Exemplary sodium thiosulfate pharmaceutical formulations are set forth in Tables 15-23. These formulations are prepared as described herein. [Table 17]

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Claims

1. 1. A pharmaceutical composition for reducing or preventing ototoxicity in a pediatric patient receiving platinum-based chemotherapy for the treatment of a cancer sensitive to said platinum-based chemotherapy, said pharmaceutical composition comprising sodium thiosulfate at a concentration of about 0.5 M and a stabilizer, said pharmaceutical composition being adjusted to a pH of 6.5 to 8.9 as necessary, and said pharmaceutical composition being free of borate ions.

2. 2. The pharmaceutical composition of claim 1, wherein the stabilizer is selected from alanine, arginine, aspartic acid, histidine, lysine, proline, glucose, sucrose, trehalose, glycerol, glycine, mannitol, sorbitol, sodium sulfate, EDTA, cyclodextrin, dextran, polyethylene glycol, polyvinylpyrrolidone, and tromethamine.

3. The pharmaceutical composition of claim 1 , wherein the composition comprises a pH adjuster.

4. The pharmaceutical composition of claim 3 , wherein the pH adjuster comprises hydrochloric acid.

5. The pharmaceutical composition of claim 3 , wherein the pH adjuster comprises sodium hydroxide.

6. The pharmaceutical composition of claim 1 , wherein the pediatric patient is 5 years of age or younger.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition has a pH of 8.6 to 8.

8.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is glycine.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is tromethamine.

10. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is alanine.

11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is arginine.

12. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is aspartic acid.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is histidine.

14. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is lysine.

15. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is proline.

16. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is glucose.

17. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is sucrose.

18. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is trehalose.

19. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is glycerol.

20. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is mannitol.

21. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is sorbitol.

22. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is sodium sulfate.

23. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is EDTA.

24. The pharmaceutical composition of any one of claims 1 to 6, wherein the stabilizer is a cyclodextrin.

25. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is dextran.

26. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is polyethylene glycol.

27. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is polyvinylpyrrolidone.

28. The pharmaceutical composition of any one of claims 1 to 6, wherein the platinum-based chemotherapy is cisplatin.

29. 30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is administered to the pediatric patient about 6 hours after completion of administration of cisplatin.

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