阅读说明：本技术 无水硫代硫酸钠和其调配物 (Anhydrous sodium thiosulfate and formulations thereof ) 是由 T·C·洛维拉茨 J·A·莫莱三世 C·M·李 D·L·基什内尔 于 2019-07-01 设计创作，主要内容包括：本文描述了无水硫代硫酸钠、用于合成无水硫代硫酸钠的方法、其药物组合物和治疗耳毒性的方法。无水硫代硫酸钠由亚硫酸钠、硫和氯化十六烷基吡啶合成。所述无水硫代硫酸钠被调配成包括缓冲剂和溶剂的药物组合物。这些组合物可用于消除或降低接受基于铂的化学治疗药物的小儿患者的耳毒性。(Anhydrous sodium thiosulfate, methods for synthesizing anhydrous sodium thiosulfate, pharmaceutical compositions thereof, and methods of treating ototoxicity are described herein. Anhydrous sodium thiosulfate is synthesized from sodium sulfite, sulfur and cetylpyridinium chloride. The anhydrous sodium thiosulfate is formulated into a pharmaceutical composition comprising a buffer and a solvent. These compositions are useful for eliminating or reducing ototoxicity in pediatric patients receiving platinum-based chemotherapeutic drugs.)

1. An anhydrous sodium thiosulfate comprising an XRPD pattern comprising 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 2 Θ ± 0.2 when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 Θ using copper ka radiation.

2. The anhydrous sodium thiosulfate of claim 1, wherein the anhydrous sodium thiosulfate is characterized in that an XRPD pattern 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, and 38.16 degrees 2 Θ ± 0.2 when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 Θ using copper ka radiation.

3. The anhydrous sodium thiosulfate of claim 1 or 2, wherein the anhydrous sodium thiosulfate is characterized by a differential scanning calorimetry melting onset at about 331 ℃; and thermogravimetric analysis showed that the weight loss from ambient temperature to 162 ℃ was negligible, the weight loss from 162 ℃ to 309 ℃ was 14.8% and decomposition started at 436 ℃.

4. An anhydrous sodium thiosulfate comprising:

cadmium of not more than 0.1 mug/g;

not more than 0.25 mug/g lead;

not more than 0.75 μ g/g arsenic;

not more than 0.15 μ g/g mercury;

not more than 0.25 mug/g cobalt;

not more than 0.5 mug/g vanadium;

not more than 1.0 [ mu ] g/g nickel;

no more than 12.5 μ g/g lithium;

not more than 4.5 mug/g antimony;

not more than 15.0 [ mu ] g/g copper;

not more than 1500ppm methanol;

no greater than 3% (w/w) water; and

not more than 1.65% (w/w) total impurities or related substances.

5. A process for the synthesis of sodium thiosulfate, comprising reacting sodium sulfite with sulfur in the presence of a surfactant.

6. The method of claim 5, wherein the surfactant comprises cetylpyridinium chloride.

7. The method of claim 5 or 6, wherein the reaction is aqueous.

8. The process of any one of claims 5 to 7, wherein the reaction is carried out at about 80 ℃ to about 100 ℃.

9. The method of any one of claims 5 to 8, wherein the sodium thiosulfate is crystallized and washed with acetone.

10. A process for the synthesis of anhydrous sodium thiosulfate comprising reacting sodium sulfite with sulfur in the presence of cetylpyridinium chloride and dehydrating the sodium thiosulfate product.

11. The process of claim 10, wherein the reaction comprises 1.0 molar equivalent of sodium sulfite; 1.1 molar equivalents of sulfur; and 0.00013 molar equivalents of cetylpyridinium chloride.

12. The method of claim 10 or 11, wherein the reaction is aqueous.

13. The process of any one of claims 10 to 12, wherein the reaction is carried out at about 80 ℃ to about 100 ℃.

14. The method of any one of claims 10-13, wherein the sodium thiosulfate is crystallized and washed with acetone.

15. The method of any one of claims 10-14, wherein the sodium thiosulfate is dehydrated and washed with methanol.

16. The method of any one of claims 10 to 15, wherein the sodium thiosulfate is dried.

17. A method for synthesizing anhydrous sodium thiosulfate, comprising:

(a) reacting an aqueous sodium sulfite solution with sulfur and cetylpyridinium chloride;

(b) crystallizing sodium thiosulfate and washing with acetone;

(c) dehydrating the washed sodium thiosulfate with methanol; and

(d) the dehydrated sodium thiosulfate was dried.

18. The process of claim 17, wherein the reaction comprises 1.0 molar equivalent of sodium sulfite; 1.1 molar equivalents of sulfur; and 0.00013 molar equivalents of cetylpyridinium chloride.

19. A method for synthesizing anhydrous sodium thiosulfate, comprising:

(a) reacting 1.0 molar equivalent of an aqueous sodium sulfite solution with 1.1 molar equivalent of sulfur in the presence of 0.00013 molar equivalent of cetylpyridinium chloride at about 90 ℃ to about 100 ℃;

(b) crystallizing sodium thiosulfate at < 2 ℃ and washing with acetone;

(c) dehydrating the washed sodium thiosulfate with methanol; and

(d) the dehydrated sodium thiosulfate is dried at about 25 ℃ to about 60 ℃.

20. Anhydrous sodium thiosulfate synthesized by the method of claim 19.

21. A means for synthesizing 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.

22. Anhydrous sodium thiosulfate synthesized by the means of claim 21.

23. Anhydrous sodium thiosulfate that substantially excludes sodium thiosulfate pentahydrate.

24. A method for measuring the binding ability of sodium thiosulfate to cisplatin, comprising:

(a) mixing one or more molar ratios of sodium thiosulfate with a predetermined amount of cisplatin;

(b) incubating the mixture for a period of time; and

(c) analysis of apparent concentration of cisplatin

25. The method of claim 24, wherein the molar ratio of sodium thiosulfate to cisplatin comprises from 10: 1 to 1: 1.

26. The method of claim 24 or 25, wherein the molar ratio of sodium thiosulfate to cisplatin comprises 10: 1, 6: 1, and 5: 1.

27. The method of any one of claims 24 to 26, wherein the incubation period comprises 1 minute to 180 minutes.

28. The method of any one of claims 24 to 27, wherein the incubation period comprises about 5 minutes; about 35 minutes, about 65 minutes; and about 95 minutes.

29. The method of any one of claims 24 to 28, wherein the analysis comprises HPLC and UV detection.

Technical Field

Anhydrous sodium thiosulfate, methods for synthesizing anhydrous sodium thiosulfate, and pharmaceutical compositions thereof are described herein. These compositions are useful for eliminating or reducing ototoxicity in patients receiving platinum-based chemotherapeutic drugs.

Background

Platinum-based therapeutics are a very important component of therapeutic regimens used in a variety of pediatric malignancies, including neuroblastoma, hepatoblastoma, medulloblastoma, osteosarcoma, malignant germ cell tumors, and nasopharyngeal carcinoma. Platinum-based therapeutic drugs such as cisplatin (cissplatin) and carboplatin (carboplatin) frequently cause hearing loss that is progressive, bilateral, irreversible and often accompanied by tinnitus at commonly used doses and schedules. Hearing loss based on platinum chemotherapy drugs may affect all hearing frequencies due to the death of extracochlear hair cells.

These toxicities can be dose-limiting and are often clinically significant, particularly in young children who rely heavily on normal hearing for cognitive, psychological and speech development. Approximately 40% of children develop cisplatin-induced hearing loss, with the incidence of some debilitating populations approaching 100%. Even mild hearing loss can have a significant impact on the child, especially reducing language acquisition, learning, academic performance, social and emotional development, and quality of life. Thus, there is a need for safe and effective pharmaceutical compositions and methods for treating pediatric patients to reduce ototoxicity and hearing loss in these patients without compromising the efficacy of platinum-based therapeutic agents.

Disclosure of Invention

One embodiment described herein is an anhydrous sodium thiosulfate characterized in that when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 theta using copper ka radiation, the XRPD pattern 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 2 theta ± 0.2. In one aspect, the anhydrous sodium thiosulfate is characterized by an 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, and 38.16 degrees 2 Θ, plus or minus 0.2 when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 Θ using copper ka radiation. In another aspect, the anhydrous sodium thiosulfate is characterized by a differential scanning calorimetry melting onset at about 331 ℃; and thermogravimetric analysis showed that the weight loss from ambient temperature to 162 ℃ was negligible, the weight loss from 162 ℃ to 309 ℃ was 14.8% and decomposition started at 436 ℃.

Another embodiment described herein is an anhydrous sodium thiosulfate comprising: cadmium of not more than 0.1 mug/g; not more than 0.25 mug/g lead; not more than 0.75 μ g/g arsenic; not more than 0.15 μ g/g mercury; not more than 0.25 mug/g cobalt; not more than 0.5 mug/g vanadium; not more than 1.0 [ mu ] g/g nickel; no more than 12.5 μ g/g lithium; not more than 4.5 mug/g antimony; not more than 15.0 [ mu ] g/g copper; not more than 1500ppm methanol; no greater than 3% (w/w) water; and not more than 1.65% (w/w) total impurities or related substances.

Another embodiment described herein is a method for synthesizing sodium thiosulfate that includes reacting sodium sulfite with sulfur in the presence of a surfactant. In one aspect, the surfactant comprises cetylpyridinium chloride. In another aspect, the reaction is aqueous. In another aspect, the reaction is carried out at about 80 ℃ to about 100 ℃. In another aspect, the sodium thiosulfate is crystallized and washed with acetone.

Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate that includes 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 equivalents of sulfur; and 0.00013 molar equivalents of cetylpyridinium chloride. In another aspect, the reaction is aqueous. In another aspect, the reaction is carried out at about 80 ℃ to about 100 ℃. In another aspect, the sodium thiosulfate is crystallized and washed with acetone. On the other hand, the sodium thiosulfate was dehydrated and washed with methanol. In another aspect, the sodium thiosulfate is dried.

Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate, comprising: (a) reacting an aqueous sodium sulfite solution with sulfur and cetylpyridinium chloride; (b) crystallizing sodium thiosulfate and washing 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 equivalents of sulfur; and 0.00013 molar equivalents of cetylpyridinium chloride.

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

Another embodiment described herein is an anhydrous sodium thiosulfate synthesized by the method described herein.

Another embodiment described herein is a means for synthesizing 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.

Another embodiment described herein is an anhydrous sodium thiosulfate synthesized by the means described herein.

Another embodiment described herein is an anhydrous sodium thiosulfate that does not substantially include sodium thiosulfate pentahydrate.

Another embodiment described herein is a method for measuring the binding capacity of sodium thiosulfate for cisplatin, the method 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 ratio of sodium thiosulfate to cisplatin comprises from 10: 1 to 1: 1. In another aspect, the ratio of sodium thiosulfate to cisplatin includes 10: 1, 6: 1, and 5: 1. In another aspect, the incubation period comprises 1 minute to 180 minutes. In another aspect, the incubation period comprises about 5 minutes; about 35 minutes, about 65 minutes; and about 95 minutes. In another aspect, the analysis includes HPLC and UV detection.

Another 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 an anhydrous aqueous solution of sodium thiosulfate.

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

Another embodiment described herein is a pharmaceutical composition comprising an aqueous anhydrous sodium thiosulfate solution, 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.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in an amount of about 0.1M to about 2M, one or more buffers in an amount of 0.001M to about 0.5M, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.1M to about 2M, sodium phosphate in about 0.01M to about 0.5M, pH 6.5, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.1M to about 2M, boric acid or a salt thereof in about 0.001M to about 0.5M, pH 8.6-8.8, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.1M to about 2M, glycine or a salt thereof in about 0.001M to about 0.5M, pH8.5-8.9, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.1M to about 2M, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof in about 0.001M to about 0.5M, ph8.5-8.9, and water.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, boric acid or a salt thereof of about 0.004M, pH 8.6-8.8, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of about 0.5M anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine, pH8.5-8.9, and water. Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.1M to about 2M, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof in 0.001M to about 0.5M, pH8.5-8.9, and water.

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

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

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water.

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

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.5M, glycine or a salt thereof in about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) or a salt thereof in about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment described herein is a method for preparing a pharmaceutical formulation comprising anhydrous sodium thiosulfate, 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 includes an aqueous solution of anhydrous sodium thiosulfate from about 20mg/mL to 320 mg/mL. In another aspect, the formulation includes from about 8% to about 32% by mass of an anhydrous aqueous solution of sodium thiosulfate. In another aspect, the formulation includes an anhydrous aqueous solution of sodium thiosulfate in an amount of about 0.1M to about 2M. In another aspect, the formulation comprises from about 0.001M to about 0.5M of the one or more buffering agents. In another aspect, the one or more buffering agents include phosphate, sulfate, carbonate, formate, acetate, propionate, butyrate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, alpha-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine), combinations thereof, or salts thereof. In another aspect, the formulation has a pH of about 5 to about 9.5. In another aspect, the pH of the formulation is about 6.5 or about 8.9. In another aspect, the one or more buffering agents include a borate or salt thereof, glycine or salt thereof, tris (hydroxymethyl) aminomethane (tromethamine) or salt thereof, or a phosphate or salt thereof. In another aspect, the one or more buffering agents include sodium phosphate, glycine, or boric acid. In another aspect, the solvent comprises water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, sodium phosphate at about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment described herein is a pharmaceutical formulation comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water prepared by the method described herein.

Another embodiment described herein is a pharmaceutical formulation comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, boric acid of about 0.004M, pH 8.6-8.8, and water prepared by the method described herein.

Another embodiment described herein is a pharmaceutical formulation comprising an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water prepared by the method described herein.

Another embodiment described herein is a pharmaceutical formulation comprising an aqueous solution of anhydrous sodium thiosulfate in about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) in about 0.01M to about 0.05M, pH8.5-8.9, and water prepared by the method described herein.

Another embodiment described herein is a means for preparing a pharmaceutical formulation comprising anhydrous sodium thiosulfate, the method comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. Another embodiment is a pharmaceutical formulation prepared by the means described herein.

Another embodiment described herein is a pharmaceutical composition comprising about 0.2M to about 2M sodium thiosulfate, about 0.001M to about 0.05M pharmaceutically acceptable buffer and about 0.005M to about 0.05M pharmaceutically acceptable salt in water and having a pH of about 5 to about 9.5.

Another embodiment described herein is a kit comprising an aqueous sodium thiosulfate formulation, the kit comprising: one or more reservoirs comprising an aqueous solution of sodium thiosulfate; and files containing prescription information or instructions for use. In one aspect, the kit further comprises one or more of a syringe, a hypodermic needle, and packaging.

Another embodiment described herein is a kit comprising: one or more reservoirs comprising dried or lyophilized sodium thiosulfate; and optionally: one or more sterile solvents suitable for reconstitution; a needle and syringe; and files containing prescription information or instructions for use.

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

Another embodiment described herein is a method for preventing or reducing the incidence of Cisplatin (CIS) chemotherapy-induced ototoxicity in a patient having a localized non-metastatic solid tumor in a period of 1 month to < 18 years of age, the method comprising administering sodium thiosulfate for injection as a 15 minute infusion 6 hours after completion of each CIS administration when the time of CIS infusion does not exceed 6 hours.

Also described herein are compositions and methods for reducing ototoxicity in a patient who has received a platinum-based chemotherapeutic drug. In particular, compositions and intravenous formulations for reducing ototoxicity in pediatric patients are described. Methods for administering the compositions and formulations are also described. The method comprises administering to the patient an effective amount of sodium thiosulfate following administration of the platinum-based chemotherapeutic drug. As described herein, it was found that the administration of sodium thiosulfate did not adversely affect the efficacy of platinum-based chemotherapeutic drugs and reduced the incidence and severity of ototoxicity in pediatric patients. In one aspect, the method comprises administering a sodium thiosulfate pharmaceutical composition as described herein. In another aspect, the pharmaceutical composition comprises an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water. Another embodiment is a method of reducing ototoxicity in a patient having cancer and receiving a platinum-based chemotherapeutic drug, the method comprising administering to the patient an effective amount of sodium thiosulfate.

Another embodiment is a method of prophylactically treating a patient having cancer and receiving a platinum-based chemotherapeutic drug to reduce the likelihood that the patient will incur ototoxicity, 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 an aqueous solution of about 0.5M anhydrous sodium thiosulfate, about 0.01M sodium phosphate, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment is a method of chronically reducing ototoxicity in a patient having cancer and receiving a platinum-based chemotherapeutic drug, 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 an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment is a method of reducing the concentration of cisplatin in the ear cavity of a patient having cancer and receiving a platinum-based chemotherapeutic drug, the method comprising administering an effective amount of sodium thiosulfate to the patient, wherein cisplatin is not substantially detectable in the ear cavity, and wherein the patient administered the sodium thiosulfate is less susceptible to incurring ototoxicity from the platinum-based chemotherapeutic drug.

Another embodiment is a method of inhibiting an ototoxic effect associated with administration of a platinum-based chemotherapeutic compound in a patient, comprising administering to the patient an effective amount of sodium thiosulfate.

In some embodiments described herein, the patient carries a single nucleotide polymorphism in the gene ACYP2 at locus rs 1872328. In some embodiments, the patient administered sodium thiosulfate has a lower likelihood of experiencing ototoxicity than a patient not administered sodium thiosulfate by about 20% to about 75%. In some embodiments, the patient administered sodium thiosulfate has about 50% less likelihood of experiencing ototoxicity than a patient not administered sodium thiosulfate. In some embodiments, the ototoxicity comprises hearing loss, balance disorders, tinnitus, hearing sensitivity, or a combination thereof.

In some embodiments described herein, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin (oxaliplatin), nedaplatin (nedaplatin), triplatin tetranitrate (triplatin tetranitrate), phenanthroline (phenonthriplatin), picoplatin (picoplatin), and satraplatin (satraplatin). In some embodiments, the platinum-based chemotherapeutic agent is cisplatin.

In some embodiments, the cancer treated is localized or disseminated. In some embodiments, the cancer treated is local. In some embodiments, the cancer treated is selected from the group consisting of germ cell tumors, hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma. In some embodiments, the cancer treated is hepatoblastoma. In some embodiments, the cancer treated is a standard risk cancer, an intermediate risk cancer, or a high risk cancer. In some embodiments, the cancer treated is a standard risk cancer or an intermediate risk cancer. In some embodiments, the cancer treated is standard risk hepatoblastoma or intermediate risk hepatoblastoma.

In some embodiments, the sodium thiosulfate is administered prior to, concurrently with, or after the administration of the platinum-based chemotherapeutic drug. In some embodiments, the sodium thiosulfate is administered about 0.5 hours to about 10 hours after the platinum-based chemotherapeutic drug is administered. In some embodiments, the sodium thiosulfate is administered intravenously. In some embodimentsWherein said effective amount of sodium thiosulfate in each cycle of said platinum-based chemotherapeutic drug is about 5g/m²To about 25g/m². In some embodiments, the platinum-based chemotherapeutic agent is used at about 1mg/kg to about 5mg/kg or about 10mg/m with each cycle²To about 300mg/m²To treat said patient. In one aspect, sodium thiosulfate includes a pharmaceutical composition as described herein. In another aspect, the sodium thiosulfate pharmaceutical composition includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

In some embodiments described herein, ototoxicity is determined by one or more criteria including: tinnitus function index, Brock grading, American Speech-Language Hearing Association Standard (American Speech-Language-Hearing Association Critical) or International Society of Pediatric Oncology Boston Ototoxicity Scale (International Society of Pediatric Oncology Boston oxygen Scale). In some embodiments, ototoxicity is determined by measuring hearing loss at one or more frequencies comprising 500Hz, 1,000Hz, 2,000Hz, 4,000Hz, or 8,000Hz, or a frequency combination thereof, wherein the change in hearing is calculated relative to a baseline measurement prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both.

In some embodiments described herein, ototoxicity is determined by one or more criteria including: (a) hearing loss measured by a 20dB loss at a single frequency; (b) hearing loss measured by 10dB loss at two consecutive frequencies; (c) (ii) loss of response at three consecutive test frequencies at which a response was previously obtained; (d) bilateral high-frequency hearing loss, characterized by: (i) hearing loss < 40dB at all frequencies, indicating a 0 th order or minimum hearing loss; (ii) hearing loss ≧ 40dB at only 8,000Hz, which indicates a grade 1 or mild hearing loss; (iii) hearing loss ≧ 40dB at 4,000Hz and higher, indicating a 2-level or moderate hearing loss; (iv) hearing loss ≧ 40dB at 2,000Hz and higher, which indicates a 3-level or significant hearing loss; (v) hearing loss ≧ 40dB at 1,000Hz and higher, which indicates a 4-level or severe hearing loss; or (e) hearing loss, characterized by: (i) hearing loss ≦ 20dB at all frequencies, indicating a 0-level hearing loss; (ii) HL > 20dB above 4,000Hz, which indicates a grade 1 hearing loss; (iii) HL > 20dB at 4,000Hz and higher, which indicates a level 2 hearing loss; (iv) HL > 20dB at 2,000Hz or 3,000Hz, which indicates a 3-grade hearing loss; (v) HL > 40dB at 2,000Hz and higher, which indicates a grade 1 hearing loss; or (f) an increase in tinnitus function index; and wherein hearing changes are calculated relative to a baseline measurement prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both. In some embodiments, the ototoxicity of a pediatric patient administered sodium thiosulfate is reduced as assessed by the criteria (d) described above as compared to a pediatric patient not administered sodium thiosulfate.

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 as compared to a patient not administered sodium thiosulfate. In some embodiments, administration of sodium thiosulfate to a patient does not affect relapse-free survival or overall survival as compared to a patient not administered sodium thiosulfate. In some embodiments, administration of sodium thiosulfate to a patient does not result in an increased incidence of one or more adverse events including febrile neutropenia, infection, hypomagnesias, hypernatremia, vomiting, or nausea.

In some embodiments described herein, ototoxicity is measured at least 4 weeks after administration of the platinum-based chemotherapeutic agent and the sodium thiosulfate to a patient. In one aspect, the sodium thiosulfate comprises a pharmaceutical composition as described herein. In another aspect, the sodium thiosulfate pharmaceutical composition includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

In some embodiments described herein, the patient is a pediatric patient. In some embodiments described herein, the pediatric patient is from 1 week to 18 years old. In some embodiments, the pediatric patient is about 12 years of age or less. In some embodiments, the pediatric patient is about 5 years of age or less. In some embodiments, the pediatric patient is about 2 years of age or less. In some embodiments, the pediatric patient is about 1 year of age or less.

Another embodiment is a dosing regimen for treating hepatoblastoma in a pediatric patient, the dosing regimen comprising: (a) about 1mg/kg to about 5mg/kg or about 10mg/m of cisplatin is administered per cycle²To about 300mg/m²The dosage of (a); (b) (ii) about 5g/m per cycle of said cisplatin²To about 25g/m²Wherein said sodium thiosulfate of (a) is administered from about 2 hours to about 6 hours after administering said cisplatin; and wherein the dosing regimen, when administered to a pediatric patient, reduces ototoxicity as compared to a dosing regimen administered to a pediatric patient that does not comprise the sodium thiosulfate, wherein ototoxicity is determined by one or more criteria selected from the group consisting of: (a) hearing loss measured by a 20dB loss at a single frequency; (b) hearing loss measured by 10dB loss at two consecutive frequencies; (c) (ii) loss of response at three consecutive test frequencies at which a response was previously obtained; (d) bilateral high frequency hearing loss characterized by the following criteria: (i) hearing loss < 40dB at all frequencies, indicating a 0 th order or minimum hearing loss; (ii) hearing loss ≧ 40dB at only 8,000Hz, which indicates a grade 1 or mild hearing loss(ii) a (iii) Hearing loss ≧ 40dB at 4,000Hz and higher, indicating a 2-level or moderate hearing loss; (iv) hearing loss ≧ 40dB at 2,000Hz and higher, which indicates a 3-level or significant hearing loss; (v) hearing loss ≧ 40dB at 1,000Hz and higher, which indicates a 4-level or severe hearing loss; or (e) hearing loss, characterized by the following criteria: (i) hearing loss ≦ 20dB at all frequencies, indicating a 0-level hearing loss; (ii) HL > 20dB above 4,000Hz, which indicates a grade 1 hearing loss; (iii) HL > 20dB at 4,000Hz and higher, which indicates a level 2 hearing loss; (iv) HL > 20dB at 2,000Hz or 3,000Hz, which indicates a 3-grade hearing loss; (v) HL > 40dB at 2,000Hz and higher, which indicates a grade 1 hearing loss; wherein hearing change is calculated relative to a baseline measurement prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both. In one aspect, the regimen comprises administering a sodium thiosulfate pharmaceutical composition as described herein. In another aspect, the pharmaceutical composition comprises an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (tromethamine) of about 0.01M to about 0.05M, pH8.5-8.9, and water.

Another embodiment is a method of reducing standard or intermediate risk hepatoblastoma and receiving about 1mg/kg to about 5mg/kg or about 10mg/m of each cycle²To about 300mg/m²A method of ototoxicity in a pediatric patient having a dose of cisplatin of about 12 years of age, the method comprising administering about 5g/m per cycle of said cisplatin about six hours after administration of said cisplatin²To about 25g/m²Wherein ototoxicity is determined by one or more criteria selected from the group consisting of: (a) hearing loss measured by a 20dB loss at a single frequency; (b) hearing measured by 10dB loss at two consecutive frequenciesDescending; (c) (ii) loss of response at three consecutive test frequencies at which a response was previously obtained; (d) bilateral high frequency hearing loss characterized by the following criteria: (i) hearing loss < 40dB at all frequencies, indicating a 0 th order or minimum hearing loss; (ii) hearing loss ≧ 40dB at only 8,000Hz, which indicates a grade 1 or mild hearing loss; (iii) hearing loss ≧ 40dB at 4,000Hz and higher, indicating a 2-level or moderate hearing loss; (iv) hearing loss ≧ 40dB at 2,000Hz and higher, which indicates a 3-level or significant hearing loss; (v) hearing loss ≧ 40dB at 1,000Hz and higher, which indicates a 4-level or severe hearing loss; or (e) hearing loss, characterized by the following criteria: (i) hearing loss ≦ 20dB at all frequencies, indicating a 0-level hearing loss; (ii) HL > 20dB above 4,000Hz, which indicates a grade 1 hearing loss; (iii) HL > 20dB at 4,000Hz and higher, which indicates a level 2 hearing loss; (iv) HL > 20dB at 2,000Hz or 3,000Hz, which indicates a 3-grade hearing loss; (v) HL > 40dB at 2,000Hz and higher, which indicates a grade 1 hearing loss; wherein hearing changes are calculated relative to a baseline measurement prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both; and wherein the administration of sodium thiosulfate does not substantially affect relapse-free survival or overall survival as compared to a pediatric patient not administered sodium thiosulfate; and wherein administration of the sodium thiosulfate does not result in a substantial increase in the incidence of one or more adverse events including febrile neutropenia, infection, hypomagnesemia, hypernatremia, vomiting, or nausea. In one aspect, the method comprises administering a sodium thiosulfate pharmaceutical composition as described herein. In another aspect, the pharmaceutical composition comprises an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, sodium phosphate of about 0.01M, pH 6.5, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate at about 0.5M, boric acid at about 0.004M, pH 8.6-8.8, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, glycine of about 0.01M to about 0.05M, pH8.5-8.9, and water. In another aspect, the formulation includes an aqueous solution of anhydrous sodium thiosulfate of about 0.5M, tris (hydroxymethyl) aminomethane (aminobutanes) of about 0.01M to about 0.05MTriol), pH8.5-8.9 and water.

Although not specifically described, one or more embodiments or aspects may be incorporated in different embodiments or aspects. That is, all embodiments and aspects may be combined in any manner or combination.

Drawings

Figure 1 shows a scheme for the synthesis of anhydrous sodium thiosulfate.

Figure 2A shows an X-ray powder diffraction pattern of anhydrous sodium thiosulfate synthesized as described herein. The peaks are shown in table 5.

Figure 2B shows the X-ray powder diffraction pattern of sodium thiosulfate pentahydrate. The peaks are shown in table 6.

Figure 3 shows overlapping X-ray powder diffraction patterns of sodium thiosulfate pentahydrate (top panel) and anhydrous sodium thiosulfate synthesized as described herein (bottom panel).

Figure 4A shows overlapping Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) of anhydrous sodium thiosulfate synthesized as described herein. The DSC thermogram shows a single sharp endotherm with an onset temperature of 331.4 ℃. In thermogravimetric analysis, weight loss from 25 ℃ to 162 ℃ was negligible; the weight loss was 14.81% from 162 ℃ to 309 ℃ and the decomposition was then started at 436 ℃.

Figure 4B shows a Dynamic Vapor Sorption (DVS) isotherm for anhydrous sodium thiosulfate synthesized as described herein. DVS isotherms showed minimal weight change after equilibration to 0% relative humidity. After adsorption, a weight gain of 165% was exhibited. Hysteresis was observed after desorption, with a weight loss of 51%.

FIG. 5 shows a plot of cisplatin concentration versus time for cisplatin (control) or cisplatin combined with sodium thiosulfate in a 5: 1, 6: 1, or 10: 1 sodium thiosulfate to cisplatin ratio. The data are shown in table 7.

Figure 6 shows a protocol for preparing a pharmaceutical formulation comprising anhydrous sodium thiosulfate.

Detailed Description

As used herein, the term "active ingredient", "active pharmaceutical ingredient" or "API" refers to an agent, active ingredient, compound or substance, composition or mixture thereof that provides a (generally beneficial) pharmacological effect.

As used herein, the term "administering" means any form of the active ingredient formulation that contains an amount of active ingredient sufficient to produce a therapeutic effect by a single administration.

As used herein, the term "dose" refers to a dose that is administered in a specified amount, quantity, and frequency over a specified period of time (typically 1 day).

As used herein, the term "active pharmaceutical ingredient loading" or "drug loading" refers to the amount (mass) of active pharmaceutical ingredient included in a single soft capsule fill.

As used herein, the term "formulation" or "pharmaceutical composition" refers to a drug in combination with a pharmaceutically acceptable excipient.

As used herein, the term average "particle size distribution" (PSD) refers to the average particle size of a statistical distribution of a range of particle sizes as described herein. The distribution may be a Gaussian (Gaussian) distribution, a normal distribution, or a non-normal distribution.

Terms such as "d 90", "d 50", and "d 10" refer to a percentage (e.g., 90%, 50%, or 10%, respectively) of particle sizes that are less than the specified size, range, or distribution. For example, "d 90 ≦ 100 μm" means that 90% of the particles in the particle distribution are less than or equal to 100 μm in size.

As used herein, the term "patient" refers to any subject including mammals and humans. The patient may have a disease or be suspected of having a disease and is therefore being treated with a drug. In some cases, the patient is a mammal, such as a human, a non-human primate, a dog, a cat, a horse, a cow, a goat, a pig, a rabbit, a rat, a mouse, or a premature infant, a newborn, an infant, a juvenile, an adolescent, or an adult thereof. In some cases, as used herein, the term "patient" refers to a human (e.g., a man, a woman, or a child). In some cases, as used herein, the term "patient" refers to an experimental animal for animal model studies. The patient or subject may be of any age, gender, or combination thereof. In some embodiments described herein, a patient is treated with a platinum-based chemotherapeutic drug, such as cisplatin, followed by administration of sodium thiosulfate or a formulation thereof.

The term "pediatric patient" refers to a pediatric mammal or a human. In some cases, the patient is a mammal, such as a human, a non-human primate, a dog, a cat, a horse, a cow, a goat, a pig, a rabbit, a rat, a mouse, or a preterm, neonatal, infant, toddler, child, adolescent (adolescent), juvenile, or adolescent (teenager) thereof. The pediatric patient may be of any race or gender. The pediatric patient may be of any age, which would be understood by a person skilled in the art as a medical and veterinary pediatric patient. For example, a human pediatric patient may be a neonate up to 18 years of age. Newborn infants are understood to be as large as 1 month old; infants are 1 month old to 2 years old; children are between 2 and 12 years of age; and adolescents are 12 to 18 years old. In some countries, pediatric patients include patients up to 21 years of age. Pediatric patients may have a disease or be suspected of having a disease and are therefore being treated with a drug. In some embodiments as further described herein, the pediatric patient is treated with a platinum-based chemotherapeutic drug, such as cisplatin.

The term "ototoxicity" refers to any type of toxicity that affects the ear. Toxicity may be to the cochlea (e.g., cochlear toxicity), 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 be manifested as hearing loss, sensorineural hearing loss, balance disorders, tinnitus, or hearing sensitivity, or a combination thereof. When referring to hearing loss, the amount of toxicity causing hearing loss may be mild, moderate, severe, maximal, or complete toxicity resulting in complete deafness. Alternatively, hearing loss may occur at a specific frequency that encompasses both high and low frequencies, as well as all iterations of frequencies where mammalian hearing is normal. Toxicity may be unilateral, bilateral, bilaterally symmetric or bilaterally asymmetric (one ear is more affected than the other).

As used herein, the term "biological sample" or "sample" refers to a sample obtained or derived from a patient. For example, the biological sample comprises a material selected from the group consisting of: body fluids, blood, whole blood, plasma, serum, mucous secretions, saliva, cerebrospinal fluid (CSF), bronchoalveolar lavage (BALF), urine, ocular fluids (e.g., vitreous humor, aqueous humor), lymph fluid, lymph node tissue, spleen tissue, bone marrow, and fluids from the auditory cavity.

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

The term "preventing" refers to preventing or reducing the progression of a disease to a statistically significant degree or to a degree detectable by one of skill in the art.

As used herein, the term "substantially" or "substantially" means to a substantial or significant extent but not completely.

As used herein, the term "about" refers to any value, including both whole and fractional parts, within at most ± 10% variation of the value modified by the term "about".

As described herein, Sodium Thiosulfate (STS) was found to reduce ototoxicity in pediatric patients treated with platinum-based chemotherapeutic drugs. It was surprisingly found that the rate of ototoxicity was higher in children under 12 years of age, and that the risk faced by children under 5 years of age was even higher. It was further found that STS administration after platinum-based chemotherapeutic drugs (e.g., cisplatin) significantly reduced ototoxicity in these pediatric patients. Specifically, STS was found to reduce the severity of ototoxicity, such as burrock grade 2 and 3 ototoxicity. Further, it has been identified that the total or cumulative amount of cisplatin exposure does not interfere with STS-mediated otoprotectant effects. In addition, STS was found to be well suited as an otoprotective drug when used with localized (non-disseminated) cancer. Reference is made to international patent application publication No. WO 2019/108592, which is a continuation of U.S. patent application No. 15/826,243 filed on 29.11.2017, both of which are incorporated herein by reference in their entirety.

Sodium thiosulfate (also known as sodium dithionite) is a water-soluble thiol compound of the formula Na₂S₂O₃. The compounds may be obtained in anhydrous and crystalline forms; the pentahydrate crystalline form is the most common hydrate form. STS is commercially available as an existing antidote to acute cyanide poisoning. STS is a reducing agent and has been used in oncology to prevent cisplatin nephrotoxicity, carboplatin ototoxicity and as an antidote to extravasation of various chemotherapeutic agents. The mechanism by which sodium thiosulfate reduces nephrotoxicity caused by cisplatin and ototoxicity caused by carboplatin is not clear. The proposed mechanism of action involves its thiol group, which makes it act as a radical scavenger and/or through covalent binding and inactivation of the platinum compound. Sodium thiosulfate reacts irreversibly with cisplatin to form Pt (S) when drugs are administered simultaneously, sequentially, or nearly simultaneously₂O₃)₄. It is also believed that sodium thiosulfate prevents nephrotoxicity by reducing the delivery of cisplatin to the kidney and by neutralizing the cisplatin in the kidney where sodium thiosulfate is highly concentrated. After IV administration, sodium thiosulfate is distributed throughout the extracellular fluid. Some sodium thiosulfate is converted to sulfate in the liver. Up to 95% is excreted unmodified in urine. The biological half-life is 0.65 hours (range: 16.5-182 minutes, depending on the dose). When administered intravenously, STS is rapidly excreted by the kidney.

While not being bound by any theory, it is believed that the biological effects of STS in preventing cisplatin-induced ototoxicity include binding to electrophilic platinum molecules, scavenging reactive oxygen species, and increased intracochlear lymph concentration. Thus, a single effective dose clears any residual platinum chemotherapeutic drug so that it does not accumulate and damage the cochlear hairs. The results of two phase III clinical trials demonstrate that the efficacy of cisplatin-based chemotherapeutic drugs in pediatric patients is not affected when STS is administered.

In addition, STS does not adversely affect the efficacy of several other non-platinum based chemotherapeutic agents such as doxorubicin (doxorubicin) and etoposide (etoposide). In vitro studies of small cell lung carcinoma cell cultures showed that the immediate or delayed addition of STS followed by 72 hours of incubation did not reduce etoposide cytotoxicity. Similar studies have shown that the antitumor activity of doxorubicin, carmustine (BCNU), paclitaxel (paclitaxel) or methotrexate (methotrexate) is not reduced by STS. STS is widely tested clinically as further described herein, since it is able to scavenge free platinum-containing compounds, and is found to be a very effective otoprotective compound for pediatric patients.

One example described herein is a sodium thiosulfate. Another embodiment described herein is an 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 comprises crystalline anhydrous sodium thiosulfate. In one embodiment, the sodium thiosulfate comprises amorphous anhydrous sodium thiosulfate. In another embodiment, the sodium thiosulfate comprises an anhydrous aqueous sodium thiosulfate solution.

One example is anhydrous sodium thiosulfate, synthesized as described herein.

Another embodiment described herein is a method for synthesizing anhydrous sodium thiosulfate. In one aspect, sodium thiosulfate is synthesized by reacting an aqueous solution of sodium sulfite with sulfur in the presence of a detergent such as cetylpyridinium chloride (CPC). In one example, about 1.0 molar equivalent of sodium sulfite is reacted with 1.1 molar equivalents of sulfur and 0.00013 molar equivalents of cetylpyridinium chloride. In one aspect, the reaction is carried out at elevated temperature. In another aspect, the reaction is conducted at about 75 ℃ to about 100 ℃ for a period of about 5 minutes to 5 hours. In another aspect, the reaction is carried out at about 90 ℃ for about 5 minutes to 3 hours. In one aspect, the reaction is heated to about 90 ℃ and completed when about 90 ℃ is reached. On the other hand, the reaction was cooled after the reaction. In one aspect, the reaction is cooled to room temperature. On the other hand, the reaction was cooled to < 2 ℃. On the other hand, sodium thiosulfate was washed with a washing solvent. On the other hand, sodium thiosulfate was washed with acetone. On the other hand, sodium thiosulfate was washed multiple times. On the other hand, sodium thiosulfate was washed once. In another aspect, the sodium thiosulfate is dehydrated by heating and/or filtration. On the other hand, sodium thiosulfate is dehydrated using a dehydrating solvent. In one aspect, the dehydrating solvent is an alcohol. In another aspect, the dehydrating solvent is methanol. On the other hand, the dehydrating solvent is methanol that has been heated to between 30 ℃ and 80 ℃. On the other hand, sodium thiosulfate was dehydrated multiple times. On the other hand, sodium thiosulfate was dehydrated once.

In one embodiment, the anhydrous sodium thiosulfate is ground or micronized to a defined particle size. In one embodiment, the particle size range of the anhydrous sodium thiosulfate includes from about 1 μm to about 500 μm, including all integers and fractions within the specified ranges. In one aspect, the micronized anhydrous sodium thiosulfate particles have a particle size of about 1 μm to about 100 μm. In one aspect, the micronized anhydrous sodium thiosulfate particles have a particle size of about 5 μm to about 50 μm. In another aspect, the solid particles of anhydrous sodium thiosulfate comprise a particle size distribution that includes particles of any of the foregoing particle sizes.

In another embodiment, the anhydrous sodium thiosulfate particles have a mean Particle Size Distribution (PSD) in the range of 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 comprises 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.

In one embodiment, the anhydrous sodium thiosulfate solid particles have a mean particle size distribution d50 of about 5 μm to about 100 μm. In one embodiment, the anhydrous sodium thiosulfate solid particles have a mean particle size distribution d50 of about 5 μm to about 50 μm. In one aspect, the anhydrous sodium thiosulfate solid particles have a mean particle size distribution d50 of about 10 μm to about 25 μm.

In another embodiment, the anhydrous sodium thiosulfate particles have a particle size distribution d90 that is less than or equal to about 100 μm. In one aspect, the anhydrous sodium thiosulfate solid particles have a particle size distribution d90 of less than or equal to about 50 μm. In one aspect, the anhydrous sodium thiosulfate solid particles have a particle size distribution d90 of less than or equal to about 25 μm (d90 less than or equal to 25 μm).

In another embodiment, the anhydrous sodium thiosulfate solid particles comprise 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, wherein each of the independent average particle size distributions ranges from about 5 μm to about 100 μm, inclusive of all integers and fractions within the specified ranges. In another aspect, the anhydrous sodium thiosulfate solid particles can include a plurality of independently combined average particle size distributions, wherein each of the independently combined average particle size distributions ranges from about 5 μm to about 50 μm, inclusive of all integers and fractions within the specified ranges. In another aspect, the anhydrous sodium thiosulfate solid particles include a combination of average particle size distributions of separate combinations of about 10 μm to about 30 μm (including all integers and fractions within the specified ranges). Any of the foregoing particle size distributions can be combined to provide a desired size distribution range.

The foregoing size of the anhydrous sodium thiosulfate particles can be determined using standard techniques known to those of ordinary skill in the art. Exemplary techniques that may be used to measure the size of anhydrous sodium thiosulfate particles may include laser diffraction analysis, light scattering (e.g., dynamic light scattering), microscopic particle image analysis, elutriation, or aerosol mass spectrometry. The sample of anhydrous sodium thiosulfate particles can be measured as a dry sample or a wet sample. Any commercially available instrument for measuring particle size may be used following the recommended operating procedures according to the manufacturer's instructions, including instruments from the following companies: cilas; brookhaven Instruments Corporation (Brookhaven Instruments Corporation); malvern Instruments (maltem Instruments); horiba Scientific instruments division (Horiba Scientific); or white-top corporation (Wyatt).

Particle size measured using the techniques described herein can be expressed as a diameter with a normal or non-normal distribution derived from the mean, median (e.g., mass median diameter), and particle size mode. The particle size distribution can be expressed as a distribution of the number of diameters,Surface area distribution or particle volume distribution. The average value of the particle size distribution can be calculated and expressed in various ways, such as the volume mean diameter (D [4, 3 ]]Or d₄₃) Average surface area diameter (D3, 2)]Or d₃₂) Or average number particle diameter (D1, 0)]Or d₁₀). Since the particle size distribution values differ depending on the measurement method and the expression of the distribution, the comparison of different average particle size distributions must be calculated by the same method in order to make an accurate comparison. For example, a sample having a measured and calculated volume average diameter must be compared to a second sample having a measured and calculated volume average diameter, ideally measured under the same conditions using the same measuring instrument. Thus, the particular particle size distribution described herein is not intended to be limited to any of the methods for measuring or calculating particle size distribution (e.g., diameter number distribution, surface area distribution, or particle volume distribution), but rather indicates a particle size value and its distribution for each of the methods of measuring particle size described herein.

Another embodiment described herein is anhydrous sodium thiosulfate made by the method described herein. Another embodiment is a means for preparing anhydrous sodium thiosulfate.

Another embodiment described herein is an anhydrous sodium thiosulfate 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 2 θ ± 0.2 when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 θ using copper ka radiation. In one embodiment, the anhydrous sodium thiosulfate is characterized by an 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 2 Θ ± 0.2 when X-ray powder diffraction (XRPD) is collected from about 2 to about 40 degrees 2 Θ using copper ka radiation. In one embodiment, the anhydrous sodium thiosulfate is characterized by an XRPD pattern substantially similar to that 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.

Another embodiment described herein is an anhydrous sodium thiosulfate comprising: cadmium of not more than 0.1 mug/g; not more than 0.25 mug/g lead; not more than 0.75 μ g/g arsenic; not more than 0.15 μ g/g mercury; not more than 0.25 mug/g cobalt; not more than 0.5 mug/g vanadium; not more than 1.0 [ mu ] g/g nickel; no more than 12.5 μ g/g lithium; not more than 4.5 mug/g antimony; not more than 15.0 [ mu ] g/g copper; not more than 1500ppm methanol; no greater than 3% (w/w) water; and not more than 1.5% (w/w) total impurities.

Another embodiment described herein is an anhydrous sodium thiosulfate that does not substantially include sodium thiosulfate pentahydrate. In one aspect, anhydrous sodium thiosulfate includes 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.

Another embodiment described herein is an assay for measuring cisplatin concentration. In one aspect, the assay comprises measuring cisplatin concentration using HPLC and UV detection, and comparing retention times and peak areas to a standard curve of cisplatin concentrations determined under similar conditions. Another embodiment described herein is a means for determining the concentration of cisplatin as described herein.

Another embodiment described herein is an assay for determining the cisplatin-binding capacity of a sodium thiosulfate composition. The sodium thiosulfate composition can be sodium thiosulfate pentahydrate, anhydrous sodium thiosulfate, an anhydrous aqueous solution of sodium thiosulfate or a pharmaceutical composition of sodium thiosulfate. The assay involves combining different concentrations of sodium thiosulfate with a concentration of cisplatin, and then measuring a significant decrease in cisplatin concentration over a period of time using HPLC and UV detection. In one aspect, the molar ratio of sodium thiosulfate to cisplatin is 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 is 10: 1, 6: 1, or 5: 1. On the one hand, the significant decrease in cisplatin concentration due to sodium thiosulfate binding was linear over time. In another aspect, the cisplatin concentration is measured about 5 minutes after mixing with sodium thiosulfate and every 10 minutes, 20 minutes, 30 minutes, or 60 minutes for a period of 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In one aspect, the cisplatin concentration is determined about 5 minutes after mixing with sodium thiosulfate and measured every 30 minutes over a 2 hour period. In one aspect, a mixed mode C-18 column having hydrophobic interaction and ion exchange capabilities is used in the assay. In another aspect, the HPLC run time is determined to be about 2 minutes, about 5 minutes, about 7.5 minutes, about 10 minutes, or about 15 minutes. In one aspect, the HPLC run time is about 5 minutes or about 10 minutes. Cisplatin, on the other hand, elutes from the HPLC under assay conditions after about 1.5 minutes to about 2.5 minutes. In one aspect, cisplatin elutes from the HPLC under assay conditions after about 2 minutes. Sodium thiosulfate, on the other hand, elutes from the HPLC under the assay conditions after about 5 minutes to about 7.0 minutes. In one aspect, cisplatin elutes from the HPLC under assay conditions after about 6 minutes.

Another embodiment described herein is a means for determining the binding capacity of sodium thiosulfate for cisplatin as described herein.

Without being bound by any theory, the factors that influence sodium thiosulfate in combination with cisplatin in the assays described herein include temperature, relative concentration of sodium thiosulfate, and the time elapsed between mixing cisplatin with sodium thiosulfate and HPLC measurements. HPLC autosamplers allow for tight temperature control and facilitate sample preparation and analysis. In addition, this approach provides for changes in cisplatin concentration over time, rather than at a single time point. This method can be used to determine the reaction rate or half-life under given conditions for comparison between different sodium thiosulfate samples.

Another embodiment described herein is an assay for measuring the binding capacity of sodium thiosulfate to cisplatin based on the significant decrease in cisplatin concentration after combining cisplatin and sodium thiosulfate in different molar ratios, comprising: mixing various molar ratios of sodium thiosulfate with predetermined amounts 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 is from 10: 1 to 1: 1. In one aspect, the molar ratio of sodium thiosulfate to cisplatin is 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 ℃ for about 5 minutes, about 35 minutes, about 65 minutes, about 95 minutes, and about 125 minutes and analyzed. On the other hand, the concentration was analyzed by HPLC with a mixed-mode C-18 column at a column temperature of 35 ℃ and a flow rate of 400. mu.l/min and UV detection at 220 nm. In one aspect, the HPLC method comprises the following step gradient: 100% buffer A (9: 1 water: acetonitrile containing 0.5mM ammonium formate, pH 4) for 3 minutes; then 90% buffer A and 10% buffer B (7: 3 water containing 200mM ammonium formate: acetonitrile, pH 4) for 3.5 minutes; then 100% buffer a for 4.5 minutes.

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

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

Another embodiment described herein is a pharmaceutical composition comprising sodium thiosulfate. In one aspect, the composition comprises sodium thiosulfate and one or more pharmaceutically acceptable excipients. In another aspect, the composition includes sodium thiosulfate and a buffer. In another aspect, the composition includes 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 dried or lyophilized composition comprising sodium thiosulfate and one or more buffers, which is reconstituted with sterile water for injection prior to administration. In another aspect, the composition includes an aqueous anhydrous sodium thiosulfate solution, one or more buffers, and a solvent. As used herein, "anhydrous aqueous sodium thiosulfate solution" refers to anhydrous sodium thiosulfate that has been dissolved in an aqueous solvent. In another aspect, the composition includes an aqueous anhydrous sodium thiosulfate solution, one or more buffers, one or more agents to adjust the pH, and a solvent. In another aspect, the composition comprises an aqueous anhydrous sodium thiosulfate solution, one or more buffers, one or more agents to adjust pH, a solvent, and one or more preservatives, physiological salts, carriers, or pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical formulation comprises the pharmaceutical formulation shown in table 1.

In another embodiment, the formulation comprises an anhydrous aqueous sodium thiosulfate solution and water. In another aspect, the formulation includes an aqueous anhydrous sodium thiosulfate solution, water, a buffer, and one or more pH adjusting agents. In another aspect, the formulation includes an aqueous anhydrous sodium thiosulfate solution, water, a phosphate buffer, and one or more pH adjusting agents to adjust the pH to about 6.5. In another aspect, the formulation includes an aqueous anhydrous sodium thiosulfate solution, water, a borate buffer, and one or more pH adjusting agents to adjust the pH to about 8.5-8.8. In another aspect, the formulation includes an aqueous anhydrous sodium thiosulfate solution, water, glycine, and one or more pH adjusting agents to adjust the pH to about 8.5-8.9. In another aspect, the formulation includes an aqueous anhydrous sodium thiosulfate solution, water, a tris (hydroxymethyl) aminomethane (tromethamine) buffer, and one or more pH adjusting agents to adjust the pH to about 8.5-8.9. In one embodiment, the pharmaceutical formulation comprises one of the formulations shown in table 2. The following formulations are exemplary, and the nature and concentration of the buffer may be adjusted within the range of about 0.001M to about 0.5M, and mg/mL and weight percent adjusted accordingly.

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 anhydrous aqueous sodium thiosulfate.

In another embodiment, the formulation comprises from 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 0.3M 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 from about 0.6M to about 1.0M of an aqueous anhydrous sodium thiosulfate solution.

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 320mg/mL of anhydrous aqueous sodium thiosulfate.

In another embodiment, the formulation comprises from about 10mg/mL to about 320 mg/mL; about 10mg/mL to about 80 mg/mL; about 10mg/mL to about 100 mg/mL; about 10mg/mL to about 110 mg/mL; about 10mg/mL to about 120 mg/mL; about 10mg/mL to about 160 mg/mL; about 20mg/mL to about 80 mg/mL; about 20mg/mL to about 100 mg/mL; about 20mg/mL to about 110 mg/mL; about 20mg/mL to about 120 mg/mL; about 20mg/mL to about 160 mg/mL; about 30mg/mL to about 80 mg/mL; about 30mg/mL to about 100 mg/mL; about 30mg/mL to about 110 mg/mL; about 30mg/mL to about 120 mg/mL; about 30mg/mL to about 160 mg/mL; about 40mg/mL to about 80 mg/mL; about 40mg/mL to about 100 mg/mL; about 40mg/mL to about 110 mg/mL; about 40mg/mL to about 120 mg/mL; about 40mg/mL to about 160 mg/mL; about 60mg/mL to about 80 mg/mL; about 60mg/mL to about 100 mg/mL; about 60mg/mL to about 110 mg/mL; about 60mg/mL to about 120 mg/mL; about 60mg/mL to about 160 mg/mL; about 80mg/mL to about 100 mg/mL; about 80mg/mL to about 110 mg/mL; about 80mg/mL to about 120 mg/mL; about 80mg/mL to about 160 mg/mL; about 100mg/mL to about 110 mg/mL; about 100mg/mL to about 120 mg/mL; or from about 100mg/mL to 160mg/mL of an aqueous anhydrous sodium thiosulfate solution.

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

In another embodiment, the formulation comprises from about 1% to about 32% by mass; about 1 mass% to about 8 mass%; about 1 mass% to about 10 mass%; about 1 mass% to about 11 mass%; about 1 mass% to about 12 mass%; about 1 mass% to about 16 mass%; about 2 mass% to about 8 mass%; about 2 mass% to about 10 mass%; about 2 mass% to about 11 mass%; about 2 mass% to about 12 mass%; about 2 mass% to about 16 mass%; about 3 mass% to about 8 mass%; about 3 mass% to about 10 mass%; about 3 mass% to about 11 mass%; about 3 mass% to about 12 mass%; about 3 mass% to about 16 mass%; about 4 mass% to about 8 mass%; about 4 mass% to about 10 mass%; about 4 mass% to about 11 mass%; about 4 mass% to about 12 mass%; about 4 mass% to about 16 mass%; about 6 mass% to about 8 mass%; about 6 mass% to about 10 mass%; about 6 mass% to about 11 mass%; about 6 mass% to about 12 mass%; about 6 mass% to about 16 mass%; about 8 mass% to about 10 mass%; about 8 mass% to about 11 mass%; about 8 mass% to about 12 mass%; about 8 mass% to about 16 mass%; about 10 mass% to about 11 mass%; about 10 mass% to about 12 mass%; or from about 10 to about 16 mass% of an aqueous anhydrous sodium thiosulfate solution.

In one embodiment described herein, the formulation includes one or more buffering agents. Typical buffers are pharmaceutically acceptable buffers. In one aspect, the one or more buffering agents include acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, disulfuric acid (bisfic acid), boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, diglucosic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, gly-glycine, glucoheptonic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfuric acid (hemisulffic acid), heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric, hydroiodic, hydroxyethanesulfonic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalenedicarboxylic, nicotinic, nitrous, oxalic, nonanoic, phosphoric, propionic, pyruvic, saccharin, salicylic acid, benzoic acid, fumaric acid, glyceric acid, glutamic acid, glycolic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid, toluenesulfonic acid, undecylenic acid, MES, bis-trimethane, ADA, ACES, bis-trimethylolpropane, PIPES, MOPSO, cholamine chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, acetamidoglycine, TAPSO, TEA, POPSO, HEPSO, EPS, HEPPS, Tricine, tris (hydroxymethyl) aminomethane (tromethamine), glycinamide, glycylglycine, HEPBS, dihydroxyethylglycine (Bicine), TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS, CABS, combinations thereof, or salts thereof. In one aspect, the buffer comprises one or more of: phosphate, sulfate, carbonate, formate, acetate, propionate, butyrate, lactate, glycine, maleate, pyruvate, citrate, aconitate, isocitrate, alpha-ketoglutarate, succinate, fumarate, malate, oxaloacetate, aspartate, glutamate, tris (hydroxymethyl) aminomethane (tromethamine), combinations thereof, or salts thereof. In one aspect, the buffering agent is phosphate, glycine, tris (hydroxymethyl) aminomethane (tromethamine), or borate. In one aspect, the buffering agent is a borate. In one aspect, the buffer is phosphate. In one aspect, the buffering agent is glycine. In one aspect, the buffering agent is tris (hydroxymethyl) aminomethane (tromethamine).

In another embodiment, the concentration of the one or more buffers is from about 0.001M to about 0.5M. In one aspect, the concentration of the one or more buffering agents is from 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 from about 0.005M to about 0.01M. In one aspect, the concentration of the one or more buffering agents 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 aspect, the concentration of the one or more buffers is about 0.01M. In another aspect, the concentration of the one or more buffers is about 0.05M.

In another embodiment, the formulation includes one or more buffers titrated with one or more pharmaceutically acceptable acids or bases to adjust the pH. In one aspect, the pH of the formulation is from about 2 to about 10; about 3 to about 9; from 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; from about 5 to about 8; about 6.0 to about 6.5; about 6 to about 7; about 6.5 to about 7; or from about 6 to about 8. In one aspect, the pH of the formulation is about 5.0; about 5.5; about 6.0; about 6.1; or 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 pH of the formulation is about 6.5.

In another embodiment, the formulation includes one or more buffers titrated with one or more pharmaceutically acceptable acids or bases to adjust the pH to about 6.5. Typically, the acid and base are chosen to match the buffer and the ions present in the solution. In one aspect, the pH is increased by the addition of a group IA hydroxide. In one aspect, the hydroxide may be sodium hydroxide or potassium hydroxide. On the other hand, the pH is lowered by adding an acid (i.e., proton donor). Any pharmaceutically acceptable acid may be used. In one aspect, the acid is phosphoric acid. In another aspect, the acid is hydrochloric acid. In one aspect, sodium hydroxide and hydrochloric (or phosphoric) acid are added to the formulation to titrate the pH to about 6.5.

One embodiment described herein is a pharmaceutical formulation as shown in table 3.

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

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

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

Another embodiment described herein is a pharmaceutical formulation comprising an aqueous solution of about 0.5M anhydrous sodium thiosulfate, about 0.01M to about 0.05M glycine, pH8.5-8.9, and water. In one aspect, the pharmaceutical formulation comprises about 80mg/mL of an aqueous anhydrous sodium thiosulfate solution, about 0.75mg/mL to about 3.8mg/mL of glycine, pH8.5-8.9, and water. In another aspect, the pharmaceutical formulation comprises an aqueous solution of about 8% anhydrous sodium thiosulfate; about 0.069% to about 0.35% glycine, pH 8.5-8.9.

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), pH8.5-8.9, and water. In one aspect, the pharmaceutical formulation comprises an aqueous solution of anhydrous sodium thiosulfate in about 80mg/mL, tris (hydroxymethyl) aminomethane (tromethamine) in about 1.2mg/mL to about 3.6mg/mL, pH8.5-8.9, and water. In another aspect, the pharmaceutical formulation comprises an aqueous solution of about 8% anhydrous sodium thiosulfate; from about 0.1% to about 0.33% tris (hydroxymethyl) aminomethane (tromethamine) at a pH of 8.5-8.9.

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of sodium thiosulfate and one or more pharmaceutically acceptable excipients.

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

Another embodiment described herein is a pharmaceutical composition comprising an aqueous solution of sodium thiosulfate, one or more pharmaceutically 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, potassium lactate, sodium acetate, sodium citrate, sodium lactate, sodium phosphate, and the like. In one aspect, the concentration of the one or more salts is from 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 from about 0.05M to about 0.2M.

Another embodiment described herein is a pharmaceutical composition comprising about 0.2M to about 2M sodium thiosulfate, about 0.001M to about 0.05M pharmaceutically acceptable buffer, and about 0.005M to about 0.05M pharmaceutically acceptable salt in water. In one aspect, the pH of the pharmaceutical composition is about 6 to 8. In one aspect, the pharmaceutical composition comprises about 1M sodium thiosulfate, about 0.05M pharmaceutically acceptable buffer and about 0.05M pharmaceutically acceptable salt, and has a pH of about 6 to 8.

Another embodiment described herein is a sodium thiosulfate pharmaceutical composition that includes substantially no borate ions. In one aspect, the sodium thiosulfate composition includes 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 includes phosphate ions instead of borate ions.

Another embodiment is a method of preparing a pharmaceutical sodium thiosulfate formulation. In one embodiment, such compositions are prepared by: (i) combining sodium thiosulfate with a solvent and optionally one or more pharmaceutically acceptable excipients; (ii) transferring 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 transfer to a suitable container. In one aspect, the container is an injectable vial or syringe.

One embodiment is a method for preparing a formulation comprising anhydrous sodium thiosulfate, the method comprising combining anhydrous sodium sulfate with one or more buffers and a solvent. The method further comprises adjusting the pH with a pharmaceutically acceptable acid or base. In one aspect, the buffering agent is sodium phosphate and the acid and base are hydrochloric acid and sodium hydroxide. The method further includes filtering the solution and transferring the solution into a suitable receptacle, sealing the receptacle, and sterilizing the formulation. In one aspect, the formulation is sterilized by filtration and autoclaving.

Another embodiment is a formulation comprising anhydrous sodium thiosulfate made by the method described herein. Another embodiment is a means for preparing a formulation comprising anhydrous sodium thiosulfate.

Another embodiment described herein is a pharmaceutical composition of an STS formulation as described herein. The pharmaceutical composition may include one or more excipients, such as:

(i) buffering agent: physiologically tolerable buffers that maintain the pH within the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate. Also useful are compositions such as Mg (OH)₂Or ZnCO₃And the like. The buffering capacity can be adjusted to match the conditions most sensitive to pH stability.

(ii) Isotonicity modifier: for minimizing pain due to cell damage resulting from osmotic pressure differentials from the injection reservoir. Glycerol and sodium chloride are examples. The effective concentration can be determined by osmometry assuming an osmolality of 285-315mOsmol/kg of serum.

(iii) Preservatives and/or antibacterial agents: multiple dose parenteral formulations may require the addition of preservatives at sufficient concentrations to minimize the risk of infection in the subject at the time of injection, and corresponding regulatory requirements have been established. Typical preservatives include m-cresol, phenol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride.

(iv) A stabilizer: stabilization is achieved by enhancing the protein stabilizing power, by destabilizing the denatured state, or by direct binding of excipients to the protein. The stabilizer may be: amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars, such as glucose, sucrose, trehalose; polyols, such as glycerol, mannitol, sorbitol; salts, such as potassium phosphate, sodium sulfate; chelating agents, such as EDTA, hexaphosphate; ligands, such as divalent metal ions (zinc, calcium, etc.); other salts or organic molecules, such as phenolic derivatives. In addition, oligomers or polymers such as cyclodextrins, dextrans, dendrimers, polyethylene glycols, polyvinylpyrrolidone, protamine or human serum albumin may be used.

(v) Anti-adsorption agent: ionic or nonionic surfactants or other proteins or soluble polymers are primarily used to competitively coat or adsorb to the interior surface of the composition container, for example, poloxamer (pluronic F-68), PEG didodecyl ethyl ether (Brij 35), polysorbates 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA and gelatin. The selected concentration and type of excipient depends on the effect to be avoided, but typically a monolayer of surfactant is formed at the interface just above the CMC value.

(vi) Lyophilization or cryoprotectant: during freeze-drying or spray-drying, excipients can counteract the destabilization effects caused by hydrogen bond cleavage and water removal. For this purpose, sugars and polyols can be used, but corresponding positive effects are also observed for 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 result from exposure of the hydrophobic groups of proteins to water. Mannitol and sucrose may also be used as separate lyoprotectants or in combination with each other where higher ratios of mannitol or sucrose are known to enhance the physical stability of the lyophilized cake. Mannitol may also be combined with trehalose. Trehalose may also be combined with sorbitol, or sorbitol may be used as a separate protectant. Starch or starch derivatives may also be used.

(vii) Oxidation protective agent: antioxidants, such as ascorbic acid, tetrahydropyrimidine, methionine, glutathione, monothioglycerol, morin, Polyethyleneimine (PEI), propyl gallate, vitamin E; chelating agents, such as citric acid, EDTA, hexaphosphoric acid, thioglycolic acid.

(viii) Viscosifier or viscosity enhancer: retarding settling of the particles in the vial and syringe and serving to facilitate mixing and resuspension of the particles and making the suspension easier to inject (i.e., less force on the syringe plunger). Suitable tackifiers or viscosity enhancers are: for example, carbomer (carbomer) viscosifiers such as Carbopol 940, Carbopol Ultrez 10, cellulose derivatives such as hydroxypropylmethyl cellulose (hypromellose, HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan gum, carrageenans such as Satiaglum UTC 30, aliphatic poly (hydroxy acids) such as poly (D, L-or 1-lactic acid) (PLA) and poly (glycolic acid) (PGA) and copolymers thereof (PLGA), terpolymers of D, L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly (oxyethylene) blocks and hydrophobic poly (oxypropylene) blocks constituting poly (oxyethylene) -poly (oxypropylene) triblocks (for example, pluronic^TM) Polyether ester copolymers, such as polyethylene terephthalate/polybutylene terephthalate copolymers, Sucrose Acetate Isobutyrate (SAIB), dextran or derivatives thereof, combinations of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and derivatives thereof, polyimides, poly (acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAG) such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronic acid, copolymers of hydrophobic and/or hydrophobic polymers, and mixtures thereofABA triblock or AB block copolymers of a polar 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, as well as the poloxamers described above, can exhibit opposite thermogelling behavior (being in a fluid state at room temperature for ease of administration, and in a gel state at body temperature above the sol-gel transition temperature after injection).

(ix) Dispersing agent: the permeability of connective tissue is altered by hydrolyzing extracellular matrix components in the interstitial space, such as but not limited to hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue. Dispersants such as, but not limited to, hyaluronidase which temporarily reduces the viscosity of the extracellular matrix and facilitates diffusion of the injected drug.

(x) Other auxiliary agents: such as wetting agents, viscosity modifiers, antibiotics, hyaluronidase. Acids and bases such as hydrochloric acid and sodium hydroxide are necessary aids for adjusting the pH during preparation.

The foregoing list is not meant to be exclusive, but is merely representative of the types of excipients and the specific excipients that may be used in the medicaments as described herein.

STS formulations can be provided as liquids, suspensions, or dry compositions.

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

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

In another embodiment, the STS formulation is a dry composition. Suitable drying methods are, for example, spray drying and freeze drying (freeze drying). In one aspect, the STS formulation is prepared as a solution and then dried by lyophilization. On the other hand, STS formulations are prepared as dry compositions that are reconstituted with sterile water for injection immediately before use and then administered intravenously by direct venipuncture or using an intravenous tube.

In another embodiment, the composition is a dry or lyophilized composition that can be reconstituted with sterile water for injection, PBS, saline, or other sterile, parenterally compatible solutions to produce a solution suitable for injection. In one aspect, the composition comprises about 20mg to 32g of anhydrous sodium thiosulfate. In one aspect, the composition comprises about 98 mass% anhydrous sodium thiosulfate. In one aspect, the composition comprises about 1% to 2% by mass of one or more buffering agents. After addition of the indicated amount of sterile water for injection, the reconstituted dry or lyophilized composition comprises about 0.5M aqueous anhydrous sodium thiosulfate, about 0.01M sodium phosphate, pH 6.5, and water.

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

For intravenous administration, suitable solvents include sterile water for injection, Phosphate Buffered Saline (PBS), physiological saline, or Ringer's solution. In all cases, the composition should be sterile and should have fluidity to the extent that it is easily injectable. Preferred pharmaceutical formulations are stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Typically, the relevant solvent or carrier will be a solvent or dispersion medium containing: for example, water, buffers, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof. Prevention of the action of microorganisms can be achieved by various antibacterial agents as well as antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like). In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, amino acids, sorbitol, sodium chloride or combinations thereof in the composition.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the compositions may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and may contain from about 0.1% to 75% or from about 1% to 50% of the active ingredient. In one embodiment described herein, the composition comprises an aqueous solution of about 7.5% anhydrous sodium thiosulfate of the active ingredient. As a dry composition suitable for reconstitution, the composition may include up to 98% sodium thiosulfate.

Sterile injectable solutions or suspensions can be prepared as desired by incorporating the sodium thiosulfate in the desired amount in an appropriate solvent with one or a combination of ingredients, followed by filtration and/or sterilization. Typically, solutions or suspensions are prepared by incorporating the active compound into a sterile vehicle, such as sterile water or PBS and any excipients. In one aspect, sterilization is accomplished by autoclaving the final formulation in an injection vial. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional excipients from a previously sterile-filtered solution thereof.

Transmucosal or transdermal administration is also possible. Suitable compositions for transdermal application comprise an effective amount of the biologically active agent together with a suitable carrier. Carriers suitable for transdermal delivery may contain absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. For example, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with a carrier, a rate controlling barrier optionally for delivering the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and a means for securing the device to the skin.

Compositions suitable for topical application (e.g., to the skin, eye or joint) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems are particularly suitable for dermal applications. Thus, it is particularly useful in topical formulations (including cosmetic formulations) well known in the art. Such systems may contain solubilizers, stabilizers, tonicity enhancing agents, buffers or preservatives.

As used herein, topical application may also be suitable for inhalation or intranasal application. They can be conveniently delivered from a dry powder inhaler or aerosol spray presentation from a pressurised container, pump, spray, atomiser or aerosoliser, with or without the use of a suitable propellant, in dry powder form (alone or as a mixture, e.g. a dry blend with lactose, or mixed component particles, e.g. with a phospholipid).

Also described herein are pharmaceutical compositions and dosage forms comprising one or more pharmaceutical agents that reduce the rate of decomposition of a composition as an active ingredient as described herein. 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.

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 components in the formulations described herein, shown in the tables, or illustrated in the examples may be added, reduced, combined, substituted, or omitted to provide a formulation comprising about 100% by weight. Such compositions are hereby disclosed as if explicitly disclosed herein.

The effective amount of the active pharmaceutical ingredient to be therapeutically administered will depend on, for example, the environment of treatment and the goal of the treatment. One of ordinary skill in the art will appreciate that the appropriate dosage level for treatment will vary depending, in part, on the concentration of the STS formulation, the dosing regimen with the STS formulation, the route of administration, and the size (body weight or body surface area) of the subject and the condition (age and general health) of the patient. Thus, the clinician can titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect.

The frequency of administration will depend on the pharmacokinetic parameters of the therapeutic agent incorporated into the STS formulation used. The composition may be administered in a single dose, in two or more doses over time (which may or may not contain the same amount of the desired molecule), or as a continuous infusion through an implanted device or catheter. Further refinement of appropriate dosages is routinely made by those of ordinary skill in the art and is within the scope of their routinely performed tasks. Appropriate dosages may be determined by using appropriate dose-response data.

Sodium thiosulfate can be administered, for example, 1, 2, 3, 4, 5, 6, or even more times per day. One or more doses may be administered, for example, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or even longer. One or more doses may be administered, for example, for 1 week, 2 weeks, 3 weeks, 4 weeks, or even longer. One or more doses may be administered, for example, for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, more than 5 years, ten years, several decades, or even longer. One or more doses can be administered periodically until the subject, or a subject in need thereof, does not require treatment, prevention, or amelioration of ototoxicity.

In one embodiment, the pharmaceutical compositions described herein are administered simultaneously in one or more doses. For example, the same dose is administered two or more times at a time. In another embodiment, two or more different doses are administered at a time. Such dual or different simultaneous doses may be used to provide an effective amount of the pharmaceutical composition to a subject in need thereof.

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

In one embodiment, the dosage of STS formulation in the composition is sufficient to provide a therapeutically effective amount of sodium thiosulfate in one application. In one aspect, one application of the STS formulation is sufficient for a duration of 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, one month, 2 months, 3 months, 4 months, 6 months, 9 months, one year, 2 years, 3 years, 4 years, or even longer.

The phrase and the term "can be administered by injection", "injectable" or "syringeability" refers to a combination of factors such as a certain force applied to the plunger of a syringe containing an STS formulation as described herein dissolved in a liquid at a certain concentration (w/v) and at a certain temperature; a needle of a given internal diameter connected to the outlet of such a syringe; and the time required to extrude a volume of STS formulation from a syringe through a needle.

In one embodiment, the STS formulation is provided in a single dose, meaning that the container in which the formulation is provided contains one dose of the drug.

In another embodiment, the composition is provided as a multi-dose composition, meaning that the container contains more than one therapeutic dose. Preferably, the multi-dose composition contains at least 2 doses. Such multi-dose STS formulations may be used for different subjects in need thereof, or intended for one subject, wherein the remaining dose is stored after application of the first dose until needed.

In another embodiment, the STS formulation is included in one or more containers. For liquid or suspension compositions, the container is preferably a single-chamber syringe. For dry compositions, the container is preferably a dual chamber syringe. A dry composition is provided in a first chamber of a dual chamber syringe and a reconstitution solution is provided in a second chamber of the dual chamber syringe.

Reconstituting the dry composition prior to administering the dry STS formulation to a subject in need thereof. Reconstitution can be performed in a container providing the dry STS formulation, such as in a vial, syringe, double-chambered syringe, ampoule, or cartridge. Reconstitution is performed by adding a predetermined amount of the reconstitution solution to the dry composition. Reconstituting solutions are sterile liquids such as water for injection, phosphate buffered saline, isotonic saline, or other buffers, which may contain other excipients such as preservatives and/or antibacterial agents, e.g., benzyl alcohol and cresols. Preferably, the reconstitution solution is sterile water for injection. Alternatively, the reconstitution solution is sterile Phosphate Buffered Saline (PBS) or normal saline.

Another embodiment is a method for preparing a reconstituted composition comprising a therapeutically effective amount of STS formulation and optionally one or more pharmaceutically acceptable excipients, comprising the step of contacting the composition with a volume of a reconstitution vehicle. The reconstituted STS formulation may then be administered by injection or other routes.

Another embodiment is a reconstituted composition comprising a therapeutically effective amount of an STS formulation, a reconstitution vehicle, and optionally one or more pharmaceutically acceptable excipients.

Another embodiment is a prefilled syringe comprising a solution or suspension comprising a therapeutically effective amount of the STS formulation and optionally one or more pharmaceutically acceptable excipients. In one aspect, the syringe is filled with between about 0.01mL and about 5mL of STS formulation as described herein. In one aspect, the syringe is filled with between about 0.05mL and about 5mL, between about 1mL and about 2mL, between about 0.1mL and about 0.15mL, between about 0.1mL and about 0.5mL, between about 0.15mL and about 0.175mL, or about 0.5 to about 5mL of the filler. In one embodiment, the syringe is filled with 0.165mL of STS formulation described herein. In some aspects, the syringe is filled with about 0.01mL, about 0.02mL, about 0.03mL, about 0.04mL, about 0.05mL, about 0.06mL, about 0.07mL, about 0.08mL, about 0.09mL, about 0.1mL, about 0.2mL, about 0.3mL, about 0.4mL, about 0.5mL, about 0.6mL, about 0.7mL, about 0.8mL, about 0.9mL, about 1mL, about 1.2mL, about 1.5mL, about 1.75mL, about 2mL, about 2.5mL, about 3mL, about 4mL, or about 5mL of an STS formulation described herein. In view of the waste due to the "dead space" within the syringe and needle, the syringe is typically filled with an amount greater than the desired dose to be administered to the patient. There may also be a predetermined amount of waste when the syringe is primed by the physician so that it is ready for injection to the patient.

In one embodiment, the syringe is filled with the STS formulation described herein in the following dose volumes (e.g., the volume of drug intended to be delivered to the patient) according to the injection route: between about 0.01mL and about 5mL (e.g., between about 0.01mL and about 0.1mL, between about 0.1mL and about 0.5mL, between about 0.2mL and about 2mL, between about 0.5mL and about 5mL, or between about 1mL and about 5 mL).

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

The outlet of the syringe containing the medicament may be reversibly sealed to maintain the sterility of the medicament. This sealing may be achieved by sealing means known in the art, such as luer locks or tamper evident seals.

Another embodiment is a kit comprising one or more vials or prefilled syringes comprising a solution or suspension of one or more STS formulations as described herein. In one embodiment, such kits comprise a vial or prefilled syringe comprising an STS formulation as described herein in a blister pack or sealed sleeve. The interior of the blister pack or sleeve may be sterile. In one aspect, a vial or prefilled syringe as described herein may be placed inside such a blister package or sleeve prior to being subjected to sterilization (e.g., terminal sterilization). The kit may also include a file that includes prescription information or instructions for use.

Such kits may further comprise one or more needles for administering a STS formulation as described herein. Such kits may further include instructions for use, drug labeling, contraindications, warnings, or other relevant information. One embodiment described herein is a carton or package comprising: one or more vials or prefilled syringes contained within a blister pack, the vials or prefilled syringes comprising one or more STS formulations as described herein; an injector; a needle; and optionally a file or instructions for administration, drug labeling, contraindications, warnings, or other relevant information.

Terminal sterilization processes may be used to sterilize vials or syringes, and such processes may use, for example, autoclaving, ethylene oxide or hydrogen peroxide (H)₂O₂) Sterilization processes, and the like. The needle to be used with the syringe may be sterilized by the same method as the kit as described herein. In one aspect, the package is exposed to an autoclave or sterilizing gas until the exterior of the package is sterile. After this process, the outer surface of the syringe can remain sterile (while in its blister pack) for up to 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, or more. Thus, in one embodiment, the shelf life of a prefilled syringe (in its blister package) as described herein can be as long as 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, or even longer. In one embodiment, less than one part per million of the syringe has detectable microbes on the outside of the syringe after 18 months of storage. In one aspect, prefilled syringes have been sterilized using ethylene oxide, with sterility assurance levels of at least 10^-6. On the other hand, prefilled syringes have been sterilized using hydrogen peroxide at sterility assurance levels of at least 10^-6. A large amount of sterile gas should not enter the variable volume chamber of the syringe. As used herein, the term "substantial amount" refers to an amount of gas that results in an unacceptable change in the STS formulation solution or suspension within the variable volume chamber. In one embodiment, the sterilization process results in ≦ 10% (preferably ≦ 5%, ≦ 2%, ≦ 1%, ≦ 0.5%, ≦ 0.1%) of the STS formulation alkylation. In one embodiment, prefilled injectionThe vessel has been sterilized using ethylene oxide, but the outer surface of the syringe has 1ppm or less, preferably 0.2ppm or less ethylene oxide residue. In one embodiment, the prefilled syringe has been sterilized using hydrogen peroxide, but the outer surface of the syringe has 1ppm or less, preferably 0.2ppm or less, of hydrogen peroxide residue. In another embodiment, the prefilled syringe has been sterilized using ethylene oxide and the total ethylene oxide residue found outside the syringe and inside the blister package is 0.1mg or less. In another embodiment, the prefilled syringe has been sterilized using hydrogen peroxide and the total hydrogen peroxide residue found outside the syringe and inside the blister package is ≦ 0.1 mg.

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 can include a syringe, a needle, and a container that includes the STS formulation for use with the syringe. In the case of a dry composition, the container may have one chamber containing the dry STS composition and a second chamber containing the reconstituted solution. In one embodiment, the injection device is a hypodermic syringe adapted such that a container with the STS formulation can be engaged with the injection device such that the liquid, suspension or reconstituted dry composition in the container is in fluid connection with the outlet of the injection device. Examples of administration devices include, but are not limited to, hypodermic syringes and pen injector devices.

Another embodiment includes a kit comprising a needle and a container containing the STS formulation composition and optionally further containing a reconstitution solution, the container being suitable for use with the needle. In one aspect, the container is a prefilled syringe. In another aspect, the container is a dual chamber syringe. On the other hand, the STS formulation is provided as a lyophilizate in a sealed vial and the reconstitution solution is provided in another receptacle, such as a sealed vial or a prefilled syringe. The lyophilisate is resuspended using the appropriate volume of reconstitution solution. In another aspect, the kit includes instructions, labels, or other written material.

Another embodiment is a cartridge containing a composition as described herein for use with a pen injector device. The cartridge may contain a single dose or multiple doses of the STS formulation.

In another embodiment, one or more STS formulations are administered simultaneously, wherein each STS formulation has a separate or related biological activity.

In an alternative embodiment, the STS formulation is combined with a second biologically active compound in such a way that the STS formulation 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 administering another compound to the same subject.

Another embodiment described herein is a method for reducing ototoxicity in a patient (e.g., a pediatric patient) that has cancer and is receiving a platinum-based chemotherapeutic drug for treating cancer. The method comprises administering to the patient an effective amount of STS. In one aspect, the STS comprises one or more of the STS formulations described herein. STS was found to significantly reduce the risk of ototoxicity, particularly in pediatric patient populations. Accordingly, one embodiment described herein is a method for reducing ototoxicity in a pediatric patient having cancer and receiving a platinum-based chemotherapeutic drug, the method comprising administering to the pediatric patient an effective amount of STS. In some aspects, the pediatric patient has incurred ototoxicity, and administration of the STS reduces the amount of ototoxicity incurred by the pediatric patient in the future.

The risk of a pediatric patient having a detectable ototoxicity, e.g., hearing loss ≧ 1 as measured by the Brookfield scale, is significantly reduced by treatment with STS following administration of a cisplatin-based chemotherapeutic drug. The risk of ototoxicity is associated with pediatric patients not receiving STS. Thus, in some embodiments, the likelihood of a pediatric patient incurring any ototoxicity is reduced by administration of the STS by about 10% to about 100%, about 30% to about 90%, or about 40% to about 70%, including each integer within the specified range. In some embodiments, the risk of a pediatric patient incurring any 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% by administration of the STS. In some aspects, the risk of incurring ototoxicity in a pediatric patient is about 50% according to the ASHA-defined hearing loss criteria.

Similarly, treatment of pediatric patients with STS may further reduce ototoxicity in pediatric patients with cancer and receiving platinum-based chemotherapeutic drugs for long term. It is known that, following treatment with STS, pediatric patients may exhibit ototoxicity weeks, months or even years following continued treatment with platinum-based chemotherapeutic drugs. Thus, another embodiment described herein is a method of chronically reducing ototoxicity in a pediatric patient having cancer and receiving a platinum-based chemotherapeutic drug, the method comprising administering to the pediatric patient an effective amount of sodium thiosulfate.

As described above, platinum-based chemotherapeutic agents such as cisplatin are believed to exert ototoxic effects by focusing in the ear cavity of a patient (e.g., pediatric patient). It is further contemplated herein that STS can reduce the amount of agent in the ear cavity by binding to and reducing the accumulation of platinum-based chemotherapeutic agents 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 having cancer and receiving a platinum-based chemotherapeutic drug, the method comprising administering an effective amount of sodium thiosulfate to the pediatric patient. In some aspects, the concentration of cisplatin in the ear cavity is reduced by about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% as compared to a pediatric patient receiving platinum-based chemotherapeutic drug without receiving STS. In some aspects, no concentration of cisplatin is detected in the ear cavity. In some aspects, patients administered STS are less prone to incurring ototoxicity because the amount of platinum-based chemotherapeutic drug in the ear cavity is reduced. The method for detecting cisplatin in the ear cavity comprises extracting a sample from the ear cavity and measuring the amount of cisplatin present in the sample, e.g., by High Performance Liquid Chromatography (HPLC) or other methods known in the art.

The methods described herein can also be used to prevent or inhibit ototoxicity in pediatric patients who have cancer and are receiving platinum-based chemotherapeutic drugs for treating cancer. Pediatric patients are found to be particularly prone to ototoxicity, and prophylactic treatment of pediatric patients may reduce ototoxicity in pediatric patients. Thus, another embodiment described herein is a method of prophylactically treating a pediatric patient having cancer and receiving a platinum-based chemotherapeutic drug with an effective amount of STS, wherein the treatment reduces the likelihood that the pediatric patient will incur ototoxicity.

It has been determined that certain genetic variations may lead to an increased likelihood of ototoxicity in pediatric patients and an increased severity of ototoxicity in patients. The TPMT, COMT and ABCC3 genes have been shown to expose pediatric patients to greater risk of incurring ototoxicity. See Ross et al, "Genetic variants of TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy (Genetic variants in TPMT and COMT are associated with hearing impaired in children receiving cisplatin chemotherapy)", "Nature genetics (Nat. Genet.) 41: 1345-1349 (2009); pussegooda et al, "Replication of TPMT and ABCC3 gene variants is highly correlated with cisplatin-induced hearing loss in children (Replication of TPMT and ABCC3 genetic variants is high associated with cispin-induced hearing loss in children)", clinical pharmacology and therapeutics (Clin. Pharmacol. Ther.) -94: 243-251(2013). In addition, recent studies have shown that a single nucleotide polymorphism of the acpp 2 gene at locus rs1872328 is associated with cisplatin-based ototoxicity. See Xu, k. et al, "Common variants of ACYP2 affect susceptibility to cisplatin-induced hearing loss" (Common variants in ACYP2 involved in hearing loss-induced loss) ", nature genetics 47 (3): 263-266(2015). Thus, in some embodiments, pediatric patients receiving cisplatin-based chemotherapeutic drugs are identified as being at high risk of having genetic variation in one or more of the genes TPMT, COMT, ABCC3, and acp 2 and are treated with STS to reduce likelihood, prevent, inhibit, or treat ototoxicity.

In some embodiments described herein, the pediatric patient has cancer and is receiving a platinum-based chemotherapeutic drug. In other embodiments, the pediatric patient has not yet had a diagnosed cancer, but is being treated with a platinum-based chemotherapeutic drug. Any platinum-based drug would be expected to be cleared by STS and reduce ototoxicity. Thus, in some embodiments, the platinum-based chemotherapeutic agent comprises cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthroline, picoplatin, and satraplatin. In some aspects, the platinum-based chemotherapeutic agent is cisplatin.

The amount of platinum-based chemotherapeutic drug 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 aspects, the amount of platinum-based chemotherapeutic drug (e.g., cisplatin) per administration cycle is from about 1mg/kg to about 5mg/kg, including each integer within the specified range. In some aspects, the amount of platinum-based chemotherapeutic drug (e.g., cisplatin) per administration cycle is about 10mg/m²To about 300mg/m²、10mg/m²To about 100mg/m²Or about 40mg/m²To about 80mg/m²Each integer within the specified range is included.

A number of cancers are treated with platinum-based chemotherapeutic drugs in pediatric patients to whom STS may be administered. In some aspects of the embodiments described herein, a pediatric patient has cancer that is being treated with a platinum-based chemotherapeutic drug followed by STS, wherein the cancer is localized or disseminated. In some aspects, the cancer is a low risk, moderate risk, or high risk (e.g., metastatic) cancer. In some aspects, the cancer is low or moderate risk. In some aspects, cancer treated with platinum-based chemotherapeutic drugs is localized and not disseminated or metastatic. Non-limiting and exemplary cancers that can be treated with the platinum-based chemotherapeutic drug 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 being treated with a platinum-based chemotherapeutic drug and STS. In some aspects, the pediatric patient has low-risk hepatoblastoma cancer or moderate-risk hepatoblastoma cancer and is being treated with a platinum-based chemotherapeutic drug and STS.

In some embodiments, the STS is administered to a pediatric patient receiving treatment with a platinum-based chemotherapeutic agent prior to, concurrently with, or after administration of a platinum-based chemotherapeutic drug. In some aspects, the STS is administered 0 minutes or about 5 minutes to about 96 hours after administration of the platinum-based chemotherapeutic drug, including each time integer within the specified range. In some aspects, the STS is administered from about 30 minutes to about 24 hours, from about 1 hour to about 12 hours, from about 1 hour to about 8 hours, or from about 4 hours to about 7 hours after administration of the platinum-based chemotherapeutic drug, including each time integer within the specified range. In one aspect, the STS is administered about 6 hours after the administration of the platinum-based chemotherapeutic agent.

Administration of STS can be performed in any manner known for administration of STS. For example, STS can be administered parenterally or enterally. If administered parenterally, 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.

An effective amount of STS is an amount of STS that can prevent, reduce or inhibit ototoxicity in a pediatric patient receiving a platinum-based chemotherapeutic agent. In some embodiments, the amount of STS administered is about 0.5g/m²To about 50g/m²About 1g/m²To about 25g/m²Or 15g/m²To about 25g/m²Each integer within the specified range is included. In some embodiments, the amount of STS administered is about 1g/m²About 2g/m²About 4g/m²About 6g/m²About 8g/m²About 10g/m²About 15g/m²About 20g/m²About 25g/m²About 30g/m²About 40g/m²Or about 50g/m². An effective amount of STS is administered prior to, concurrently with, or following each cycle of platinum-based chemotherapy.

Some further embodiments described herein are dosing regimens for treating cancer in a pediatric patientThe dosing regimen comprises administration of a platinum-based chemotherapeutic drug and STS. One embodiment is a dosing regimen for treating hepatoblastoma in a pediatric patient comprising administering about 1mg/kg to about 5mg/kg or about 10mg/m of a platinum-based chemotherapeutic drug per cycle²To about 300mg/m²The dosage of (a), including each integer within the range; and further administering about 5g/m per cycle of the platinum-based chemotherapeutic agent²To about 25g/m²Contains each integer within the specified range. In one aspect, the STS is administered from about 2 hours to about 6 hours after administration of the platinum-based chemotherapeutic drug, including each integer within the ranges.

Ototoxicity after administration of the platinum-based chemotherapeutic drug and STS should be measured after a period of time following the last treatment with the platinum-based chemotherapeutic drug and STS. In some aspects, ototoxicity is measured after a time period of at least 3 days to about 3 months, 1 week to about 2 months, or 1 week to about 4 weeks, inclusive, of each integer within a specified time frame, after the last treatment with the platinum-based chemotherapeutic drug and STS. In one aspect, ototoxicity is measured after a period of at least 4 weeks from the last treatment with the platinum-based chemotherapeutic drug and STS.

Ototoxicity after administration of the platinum-based chemotherapeutic agent and STS can be measured multiple times and for up to several years after the last administration of the STS and platinum-based chemotherapeutic agent. Audiometry methods for measuring hearing loss are well known to those of ordinary skill in the art and are used in conjunction with various scales to assess ototoxicity. Assessment of ototoxicity allows for example assessment of any potential ototoxicity or long-term prevention of ototoxicity by STS. Assessment of ototoxicity can be determined by one or more criteria known in the art. For example, ototoxicity may comprise an assessment by: tinnitus function index, Brooks rating, child Cancer team 1996 years research scale (Children's Cancer Group 1996 study scale), Boston's Hospital Scale (Children's Hospital Boston scale), Chang and Chinosomanna scale, American Speech and Speech Hearing Association standards, Common Terminology for Adverse Events Scale (CTCAE pediatric grading), or the International pediatric Oncology Boston ototoxicity Scale, or a combination of these scales. See Gurney et al, "Oncology", journal of clinical Oncology (j.clin.on.) -30 (19): 2303-2306(2012). In most cases, the measurement of hearing function should be done prior to treatment with an ototoxic drug such as cisplatin or another platinum-based chemotherapeutic drug. This establishes a baseline measure of hearing function against which any potential ototoxic effects can be compared. Thus, prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both, the increase or decrease in hearing change or ototoxicity is calculated relative to the baseline measurement.

The Brookfield scale is defined as follows: hearing loss < 40dB at all frequencies, indicating a 0 th order or minimum hearing loss; hearing loss ≧ 40dB at only 8,000Hz, which indicates a grade 1 or mild hearing loss; hearing loss ≧ 40dB at 4,000Hz and higher, indicating a 2-level or moderate hearing loss; hearing loss ≧ 40dB at 2,000Hz and higher, which indicates a 3-level or significant hearing loss; or a hearing loss of ≧ 40dB at 1,000Hz and higher, which indicates a 4-level or severe hearing loss.

The CTCAE scale is based on hearing at 1, 2, 3, 4, 6 and 8 kHz. Level 1 is a threshold offset of > 20dB at 8kHZ for at least 1 ear; level 2 is a threshold offset of > 20dB for at least 1 ear at 4kHz and above; class 3 is a hearing loss sufficient to indicate therapeutic intervention including hearing aids, with a threshold shift of > 20dB at 3kHz and higher for at least 1 ear; the indicated speech and language svcs; and level 4 is the audiological indication of the cochlear implant and the indicated speech and language svcs.

The children cancer group 1996 research scale is defined as follows: HL losses at 6,000 and/or 8,000Hz ≧ 40dB indicate rank 1; HL loss > 25dB at 3,000 and/or 4,000Hz indicates rank 2; HL loss > 25dB at 2,000Hz indicates grade 3; and HL loss of 40dB at 2,000Hz indicates level 4. The boston children hospital scale is defined as follows: hearing loss < 20dB at 500-; non-functional hearing loss; hearing loss > 20dB above 4,000 Hz; loss of functionality: a slight hearing loss, indicating level 1, which may lead to a reduction in music appreciation; hearing loss > 20dB at 4,000Hz and higher; loss of functionality: significant hearing loss of educational significance, indicating level 2; hearing loss > 20dB at 2,000Hz and higher; loss of functionality: severe hearing loss requiring the use of a hearing aid, indicating class 3.

The Chang and Chinosomatana scale is defined as ≦ 20dB at 1, 2, and 4kHz indicating normal hearing; (1a) not less than 40dB at any frequency of 6 to 12 kHz; (1b) > 20 and < 40dB at 4kHz indicate level 1a and level 1b, respectively; (2a) not less than 40dB at 4kHz and higher frequency; (2b) > 20 and < 40dB indicate 2a and 2b levels, respectively, at any frequency below 4 kHz; ≧ 40dB at 2 or 3kHz and higher indicates level 3; and ≧ 40dB at 1kHz and higher indicates 4-level.

The american speech and language hearing association standard is defined as follows: (1) the reduction is more than or equal to 20dB at any frequency; (2) a reduction of ≧ 10dB at two or more adjacent frequencies; or (3) a loss of response at three adjacent frequencies at which a response was previously obtained. ASHA further specifies that significant changes in hearing sensitivity must be confirmed by repeated tests to be considered effective.

The international pediatric oncology boston ototoxicity scale is defined as follows: HL of less than or equal to 20dB at all frequencies indicates normal hearing; > 20dB HL (e.g., 25dB HL or greater); SNHL above 4,000Hz (e.g., 6 or 8kHz) indicates order 1; > 20dB HL SNHL at 4,000Hz and higher is indicated as grade 2; > 20dB HL SNHL at 2,000Hz or 3,000Hz and higher is indicated as grade 3; and SNHL > 40dB HL (e.g., 45dB HL or more) at 2,000Hz is indicated as level 4.

The tinnitus function 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 indices are defined as follows: an average score of 14 (range 0-17) is no tinnitus; an average score of 21 indicates a low tinnitus level; a mean score of 42 was moderate tinnitus; an average score of 65 is a high tinnitus rating; and an average score of 78 was very high grade tinnitus. A range can be broken down to < 25 for relatively mild tinnitus or no tinnitus; 25-50 indicate significant tinnitus problems; > 50 indicates a tinnitus level requiring active intervention.

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 frequency combination thereof, wherein the change in hearing is calculated relative to a baseline measurement prior to the patient receiving the platinum-based chemotherapeutic drug or sodium thiosulfate, or both. In some aspects, an increase in ototoxicity can be determined as a decrease in hearing measured by a 20dB loss at a single frequency; hearing loss measured by 10dB loss at two consecutive frequencies; or a loss of response at three consecutive test frequencies at which a response was previously obtained. In further aspects, the increase in ototoxicity is measured as a bilateral high frequency hearing loss characterized by: hearing loss < 40dB at all frequencies, indicating a 0 th order or minimum hearing loss; hearing loss ≧ 40dB at only 8,000Hz, which indicates a grade 1 or mild hearing loss; hearing loss ≧ 40dB at 4,000Hz and higher, indicating a 2-level or moderate hearing loss; hearing loss ≧ 40dB at 2,000Hz and higher, which indicates a 3-level or significant hearing loss; or a hearing loss of ≧ 40dB at 1,000Hz and higher, which indicates a 4-level or severe hearing loss. In still other aspects, the increase in ototoxicity is measured as a decrease in hearing, characterized by: hearing loss ≦ 20dB at all frequencies, indicating a 0-level hearing loss; HL > 20dB above 4,000Hz, which indicates a grade 1 hearing loss; HL > 20dB at 4,000Hz and higher, which indicates a level 2 hearing loss; HL > 20dB at 2,000Hz or 3,000Hz, which indicates a 3-grade hearing loss; or HL > 40dB at 2,000Hz and higher, which indicates a 4-level hearing loss. In other aspects, an increase in ototoxicity can be measured by a decrease in the functional index of tinnitus.

It was found that administration of STS to pediatric patients treated with platinum-based chemotherapeutic drugs did not exacerbate renal or other toxicity. Thus, in some aspects, patients receiving STS do not experience more severe adverse events or do not experience an increased incidence of adverse events compared to patients not administered STS. These adverse events include grade 3 or 4 neutropenia, reduced glomerular filtration rate, elevated serum creatinine, infection, hypomagnesias, hypernatremia, vomiting, or nausea. In other aspects, the relapse free survival or overall survival of a pediatric patient administered STS is not reduced as compared to a patient not administered STS.

The methods described herein are well suited for reducing or preventing ototoxicity in any pediatric patient of any age or reducing the likelihood of incurring ototoxicity in any pediatric patient of any age. Thus, in some described embodiments, a pediatric patient treated according to a method described herein may be a newborn, or a pediatric patient may be about 1 month old, about 2 months old, about 3 months old, about 4 months old, about 5 months old, about 6 months old, about 7 months old, about 8 months old, about 9 months old, about 10 months old, about 11 months old, about 12 months old, about 1 year old, about 1.5 years old, about 2 years old, about 2.5 years old, about 3 years old, about 3.5 years old, about 4 years old, about 4.5 years old, about 5 years old, about 5.5 years old, about 6 years old, 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 11.5 years old, about 12, about 12.5 years old, about 13.5 years old, about 13.14 years old, about 14.5 years old, about 15.5 years old, about 15 years old, about 16 years old, about 16.5 years old, about 16 years old, about 16.5 years old, about 5 years old, about 16 years old, about 5.5 years old, about 18.5 years, about 19 years, about 19.5 years, about 20 years, about 20.5 years, or about 21 years old. In some aspects, the pediatric patient is about 12 years or less, about 5 years or less, about 2 years or less, or about 1 year or less.

Indications and uses

In one embodiment, the injectable sodium thiosulfate described herein is suitable for preventing Cisplatin (CIS) chemotherapy-induced ototoxicity in patients from 1 month to < 18 years of age with localized non-metastatic solid tumors.

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 when the infused CIS is no more than 6 hours. In one aspect, the recommended dose of sodium thiosulfate for injection for preventing CIS-induced ototoxicity as described herein is weight-based and normalized to body surface area as shown below.

Dosage form and strength

Sodium thiosulfate for injection as described herein is a sterile solution containing 80mg/mL (8g/100mL) of sodium thiosulfate in a disposable vial for Intravenous (IV) administration.

Sodium thiosulfate for injection as described herein was administered as a 15 minute infusion 6 hours after completion of each CIS administration when the infused CIS did not exceed 6 hours. Pre-treatment with an anti-emetic agent is recommended to reduce the incidence of nausea and vomiting.

The timing of the injection administration of sodium thiosulfate is critical relative to CIS chemotherapy, as earlier treatments may reduce CIS efficacy, while later treatments may be less effective in preventing ototoxicity.

Sodium thiosulfate for injection can only be administered 1 to 6 hours after CIS infusion. Sodium thiosulfate for injection is not used if the CIS infusion is over 6 hours, or if a subsequent CIS infusion is planned to be performed within 6 hours.

Contraindication

Sodium thiosulfate for injection as described herein is banned for: patients known to be allergic to either Sodium Thiosulfate (STS) or the inactive ingredients of sodium thiosulfate for injection; and neonates under 1 month because of the risk of hypernatremia.

Description of the invention

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. Water solution tableAlmost neutral, with a pH in the range of 6.5 to 9.0. Molecular formula is Na₂S₂O₃. The molecular weight is 158.11 g/mol. The structural formula is as follows:

sodium thiosulfate for injection as described herein is a sterile, preservative-free, clear solution for intravenous injection. Each vial contained 80mg/mL anhydrous sodium thiosulfate (united states pharmacopeia, USP), water for injection (USP), boric acid or sodium phosphate as a buffer component, and sodium hydroxide and/or hydrochloric acid for pH adjustment.

Mechanism of action

Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea. The cochlea is very sensitive to oxidative stress, which has been shown to be associated with CIS-induced hearing loss. The mechanism of protection of STS against ototoxicity is not completely understood, but may involve increasing the levels of endogenous antioxidants, scavenging reactive oxygen species, and direct interaction between CIS and thiol groups in STS. STS has the ability to enter cells at least partially through sodium sulfate co-transporter 2 and can cause intracellular effects such as increased levels of antioxidant glutathione and inhibition of intracellular oxidative stress.

Pharmacodynamics of medicine

STS at a ratio corresponding to 6.4 to 12.8g/m²The dose of sodium thiosulfate for injection prevents ototoxicity. In preliminary clinical studies, lower STS dose levels (equivalent to 5.1 g/m)²Sodium thiosulfate for injection) resulted in a lower maximum plasma level (3.9mM) and showed no hearing protection.

A 6 hour delay in STS treatment following CIS chemotherapy is important to circumvent the potential interference with CIS anti-tumor activity, supported by data from non-clinical and preliminary clinical studies. During CIS infusion, biologically active unbound CIS is distributed to cancer cells; it is cleared by renal excretion and rapid binding to proteins, resulting in inactivation of its tumor killing activity. The initial decline in unbound platinum in plasma was rapid with a half-life ranging from 0.6 to 1.35 hours. Coupled with the fact that STS distribution is largely confined to the extracellular space, administration of sodium thiosulfate for injection 6 hours after completion of each CIS infusion should prevent the tumor protective effect of STS. As shown in the study, treatment 6 hours after completion of each CIS infusion did not affect survival.

Based on the half-life of STS in plasma, negligible amounts remain 6 hours after STS infusion is complete. Therefore, subsequent CIS infusions should be administered no earlier than 6 hours after the sodium thiosulfate infusion is completed to avoid pharmacodynamic interactions.

12.8g/m²Dose of sodium thiosulfate for injection delivered 162mmol/m²Sodium loading of (a). Comparable STS doses resulted in a brief, small increase in serum sodium levels. This transient increase in sodium was independent of age, body surface area, body weight, total daily STS dose, or CIS cycle when assessed using non-compartmental pharmacokinetic analysis at the recommended sodium thiosulfate dose level for injection.

Pharmacokinetics

Absorption of

STS is poorly absorbed after oral administration and must be administered intravenously. At the end of the venous infusion of STS, plasma STS levels reach a maximum and then decline rapidly with a half-life of about 20 to 50 minutes. Return to pre-dose levels within 3 to 6 hours post-infusion. More than 95% of the STS is excreted in the urine within the first 4 hours after administration. There was no plasma accumulation when STS was administered for 2 consecutive days.

In children and adults, infusion amounts to 12.8g/m²The maximum STS plasma level was approximately 13.3mM after 15 minutes of injection with a dose of sodium thiosulfate. STS plasma levels vary in a dose-proportional manner. Age does not appear to affect the maximum plasma level or subsequent decline of STS. Population pharmacokinetic models incorporating growth and maturation variables of pediatric populations show that the predicted STS plasma levels at the end of infusion are consistent with recommended sodium thiosulfate dose levels for injection for a specified age and weight range.

Distribution of

STS does not bind to human plasma proteins. STS is an inorganic salt and thiosulfate anions do not readily pass through the membrane. Thus, the distribution amount seems to be limited mainly to the extracellular space and is estimated to be 0.23L/kg in adults. In animals, STS has been found to be distributed in the cochlea. Distribution across the blood brain barrier or placenta appears to be absent or limited. Thiosulfate is an endogenous compound that is ubiquitous in all cells and organs. Endogenous serum thiosulfate levels in adult volunteers were 5.5 ± 1.8 μ M.

Exclusion

Metabolism: metabolites of STS have not been identified as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate metabolism does not involve CYP enzymes; it is metabolized by thiosulfate-transferase and thiosulfate reductase activities to sulfite, which is rapidly oxidized to sulfate.

And (3) excretion: STS (thiosulfate) is excreted by glomerular filtration. After administration, the level of STS (thiosulfate) in urine is high, and about half of the STS dose is recovered unchanged in urine, almost all excreted within the first 4 hours after administration. STS renal clearance correlates well with inulin clearance as a measure of GFR.

Excretion of endogenously produced thiosulfate in bile after STS administration was very low and did not increase. Mass balance studies have not been performed, but it is expected that non-renal clearance will primarily result in renal sulfate excretion. A small portion of STS sulfanyl sulfur may become part of the endogenous cellular sulfur metabolism.

Pharmaceutical product and storage and handling

Sodium thiosulfate for injection is provided in the form of a 100mL clear, colorless, sterile solution in a flint glass vial with a 20mm stopper and capped with an aluminum top closure. Sodium thiosulfate for injection contains anhydrous sodium thiosulfate (80 mg per mL) per 100mL for intravenous administration (8g of STS per vial).

Sodium thiosulfate for injection should be stored at a controlled room temperature between 15 ℃ and 30 ℃.

It will be apparent to one of ordinary skill in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, reactions, and applications described herein may be made 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 given embodiment of the given 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 includes all actual or potential combinations of the embodiments, aspects, options, examples and preferences described herein. The exemplary compositions and formulations described herein may omit any components, substitute for, or include any components disclosed elsewhere herein. The ratio of the mass of any component of any composition or formulation to the mass of any other component in the formulation or to the total mass of other components in the formulation disclosed herein is disclosed herein as if the ratio had been explicitly disclosed. To the extent that the meaning of any term in any patent or publication incorporated by reference conflicts with the meaning of the term used in the present disclosure, the meaning of the term or phrase in the present disclosure shall govern. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference for their specific teachings.

Examples of the invention

Example 1

Synthesis process

An overview of the synthesis process is shown in figure 1. The synthesis of sodium thiosulfate (wet) was accomplished by reacting 1.0 molar equivalent of aqueous sodium sulfite with 1.1 molar equivalent of elemental sulfur at 90 ℃ for up to 3 hours in the presence of 0.00013 molar equivalent of cetylpyridinium chloride (CPC), as shown in scheme I.

Scheme I

In some cases, the reaction is heated to about 90 ℃ and completed when 90 ℃ is reached. Without being bound by any theory, the reaction rate appears to depend on the size, surface area, and solubility of the sulfur (e.g., fines react faster than flakes). Once the reaction was complete, the mixture was cooled to 25 ℃, filtered through a 10 μm filter, and transferred to a crystallization vessel. The sodium thiosulfate solution was then cooled to below 2 ℃ and acetone was added slowly over at least 1 hour while maintaining the temperature < 2 ℃ (except during the initial nucleation when a 5-7 ℃ exotherm was observed). The slurry was then held at < 2 ℃ for at least 0.5 hour and transferred stepwise in batches to a filter dryer. After each slurry was added, the slurry was filtered to the point where the filtrate was just below the filter cake level; this process minimizes disruption of the resulting filter cake. The filter cake was then washed twice with acetone and filtered until no liquid flowed. The resulting "wet sodium thiosulfate" cake was then dried overnight at 45 ℃ while mixing under vacuum. As used herein, the term "wet sodium thiosulfate" refers to sodium thiosulfate that is not dehydrated.

Dewatering

The filtered methanol was used to fill the crystallization vessel and heated to 60 ℃. This warm methanol was then transferred to a filter dryer containing an overnight dried "wet sodium thiosulfate" filter cake. The filter cake was slurried with hot methanol and the filtrate removed by pressure. A second batch of hot methanol was added, mixed and the filtrate removed. This was followed by two additional washes with ambient temperature methanol and dried under vacuum at 55 ℃ overnight. This process produced anhydrous sodium thiosulfate.

Example 2

Grinding

Some batches of anhydrous sodium thiosulfate were ground using a jet mill to a particle size distribution d50 of 10-20 μm, 50% of the total. The particle size distribution of the unground anhydrous sodium thiosulfate synthesized as described herein is 50-75 μm. Without being bound by any theory, milling increases the surface area of the sodium thiosulfate particles and is believed to enhance the evaporation of any residual solvent or solvents.

Example 3

Analysis of

The dried and/or ground anhydrous sodium thiosulfate was collected and stored at ambient temperature. The samples were analyzed for trace element levels such as sodium sulfite, sulfur, acetone and methanol using HPLC, inductively coupled plasma mass spectrometry (ICP-MS), FTIR spectroscopy and X-ray powder diffraction. The specifications and representative data for anhydrous sodium thiosulfate synthesized as described using the above method are shown in table 4.

Example 4

X-ray powder diffraction characterization

Samples of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate as described herein were analyzed by X-ray powder diffraction (XRPD). Between 2mg and 50mg of the sample was placed in a zero background holder coated with a thin layer of petrolatum and leveled with a glass plate. XRPD data were obtained using copper ka radiation (40kV) from 2 ° to 40 ° 2 θ using a Bruker (Bruker) D8X-ray diffractometer in 0.05 ° steps (1 second/step). During collection, the sample was rotated at 15 RPM. Peak picking was performed in the Materials Data Jade 9.7.0 software.

The XRPD patterns of anhydrous sodium thiosulfate or sodium thiosulfate pentahydrate are shown in fig. 2A and 2B, respectively; the XRPD peaks are listed in tables 5 and 6, respectively. Significant peaks are shown in bold. The superposition of the anhydrous sodium thiosulfate pattern in 2A (lower panel) and the pentahydrate sodium thiosulfate pattern in 2B (upper panel) is shown in fig. 3.

Example 4

Sodium thiosulfate binding Capacity determination

High performance liquid chromatography-ultraviolet spectroscopy (HPLC-UV) assays were developed to quantify the binding capacity of thiosulphate to cisplatin. This method allows to compare the binding capacities of different batches of sodium thiosulfate or of pharmaceutical compositions containing sodium thiosulfate. The HPLC-UV method directly measures the reduction of cisplatin over time in the presence of different concentrations of sodium thiosulfate.

The method used a Waters Acquity H HPLC system with an Imtakt Scherzo SW-C18 mixed mode column. HPLC method conditions are summarized in table 7. The linear response of the method ranged from 3.3. mu.M (0.001mg/mL) to 666. mu.M (0.2mg/mL) cisplatin concentration. At dose-related concentrations, this range covers more than two orders of magnitude.

The assay was performed by mixing equal volumes of solutions containing 333. mu.M, 400. mu.M or 666. mu.M sodium thiosulfate with 666. mu.M cisplatin (the ratio of thiosulfate to cisplatin was 5: 1, 6: 1 or 10: 1, respectively). Each sample was transferred to an HPLC vial and placed in an autosampler chamber maintained at 24 ℃. Samples were injected into the HPLC system approximately every 30 minutes to obtain 4 time points for each sample. The gradient was run and retention time and peak area were obtained. The decrease in cisplatin concentration over time was monitored to obtain the rate of reaction (e.g., slope of line, [ cisplatin ]/min) and the half-life (time to reach 333/2 μ M cisplatin based on slope of line) was calculated. The control sample contained 333. mu.M cisplatin.

Exemplary results are summarized in table 8 and fig. 4.

Example 5

Preparation of formulations

The process for preparing the sodium thiosulfate formulation is shown in fig. 5. Anhydrous sodium thiosulfate was dissolved in sodium phosphate buffer (-10 mM sodium phosphate). Exemplary sodium thiosulfate drug formulations are shown in table 9. The pH is 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 vial was sealed with a septum and crimped. The sealed filled vials were autoclaved at 121 ℃ at 15psi for at least 0.5 hours to sterilize the contents. The vials were inspected, labeled, and stored at ambient temperature.

Example 6

The manufacturing process of anhydrous sodium thiosulfate as described herein includes the following steps:

step 1: chemically synthesizing a sodium thiosulfate aqueous solution;

step 2: sodium thiosulfate (wet) was crystallized and washed with acetone;

and step 3: dehydrating and separating anhydrous sodium thiosulfate; and

and 4, step 4: and (6) packaging.

The synthetic route is presented in scheme II, and each step is further described below.

Scheme II

Synthesis of sodium thiosulfate

The synthesis of aqueous sodium thiosulfate solution was accomplished by reacting 1.0 molar equivalent of aqueous sodium sulfite solution with 1.1 molar equivalent of solid elemental sulfur (trace metals) in the presence of catalytic amounts of cetylpyridinium chloride (0.00013 molar equivalents) under aqueous conditions at 95 ± 5 ℃ to form sodium thiosulfate. See scheme II. Reaction completeness was checked after 6 hours by measuring the amount of residual sodium sulfite present (e.g. < 0.15% w/w sulfite by HPLC-CAD). The completed reaction was then cooled to 20 ± 5 ℃ for at least 3 hours and held at 20 ± 5 ℃ 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 the product was transferred to a crystallization vessel.

Crystallization of sodium thiosulfate (wet)

The product solution was cooled to 0 ± 5 ℃ in a crystallizer dish with vigorous stirring and about 35% of the total acetone was added and mixed for at least 20 minutes while keeping the temperature not exceeding 10 ℃. After incubation at 0 + -5 deg.C for about 5 minutes to about 20 minutes, sodium thiosulfate seed crystals are added and crystallized at 0 + -5 deg.C for about 5 minutes to about 20 minutes. The remaining amount of acetone was added while maintaining the temperature at 0 ± 5 ℃. The slurry was then held at 0 ± 5 ℃ for at least 0.5 hour and then transferred to a filter dryer. The filtrate was removed by pressure filtration. After each slurry was added, the slurry was filtered to the point where the filtrate was just below the filter cake level; this process minimizes disruption of the resulting filter cake. The filter cake was then washed twice with acetone and N₂The gas is purged until no liquid flows out. Then theWith N at ambient temperature and atmospheric pressure₂The filter cake was purged for at least 1 hour to dry the resulting "wet sodium thiosulfate" filter cake. As used herein, the term "wet sodium thiosulfate" or "sodium thiosulfate (wet)" refers to sodium thiosulfate that is not dehydrated.

Dehydration and separation of anhydrous sodium thiosulfate

The filtered methanol heated to 60 + -5 deg.C was charged to a filter drier containing dry "wet" sodium thiosulfate material and stirred continuously at 45 + -5 deg.C for at least 3 hours. The material was purged with nitrogen for at least 2 hours. The temperature was then raised to 55 ± 5 ℃, and the solid was dried under vacuum for at least 24 hours. The residual solvent was then tested for volatile impurities using gas chromatography. The anhydrous sodium thiosulfate material was cooled to 20 ± 5 ℃ under slight nitrogen pressure.

Package (I)

Upon cooling, the anhydrous sodium thiosulfate drug was immediately transferred to a HDPE pail lined with a double layer LDPE bag and containing a desiccant between the LDPE liners. Before sealing, the barrel was purged with nitrogen.

The manufacturing specifications are shown in table 10.

The following pages show the manufacturing specifications for 10kg and 30kg batches of anhydrous sodium thiosulfate produced by the above method (tables 11 and 12).

Example 7

Anhydrous sodium thiosulfate, synthesized as described herein, is a crystalline material that exhibits sharp XRPD peaks (fig. 2A) and birefringent particles with a leaf-like and plate-like crystal morphology. Thermal analysis by Differential Scanning Calorimetry (DSC) showed a single, sharp endotherm with an onset temperature (apparent melting temperature) of 331.4 ℃ (fig. 4A). In thermogravimetric analysis (TGA), the weight loss from ambient temperature to 162 ℃ is negligible. From 162 ℃ to 309 ℃, the weight loss was 14.81%, followed by decomposition starting at 436 ℃ (fig. 4A). Dynamic gas phase sorption (DVS) isotherms show minimal weight change after equilibration to 0% relative humidity (fig. 4B). After adsorption, a weight gain of 165% was exhibited. Hysteresis was observed after desorption, with a weight loss of 51%.

In contrast, the DSC thermogram of sodium thiosulfate pentahydrate shows multiple endothermic events with maxima at 56 ℃, 111 ℃, 131 ℃ and 141 ℃ and a melting onset temperature of 331 ℃. A weight loss of 45.33% was observed in TGA from 25 ℃ to-300 ℃ followed by decomposition at 456 ℃. DVS isotherms showed a weight loss of 27% after drying. The weight of the adsorbed material increased 81%. Hysteresis was observed after desorption, with a weight loss of 51%.

Example 8

The process for preparing the sodium thiosulfate formulation for injection is shown in fig. 5. Anhydrous sodium thiosulfate was dissolved in borate buffer (4 mM boric acid). Exemplary sodium thiosulfate drug formulations are 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 vial was sealed with a septum, aluminum ring and crimped. The sealed filled vials were autoclaved at 121 ℃ at 15psi for at least 0.5 hours to sterilize the contents. The vials were inspected, labeled, and stored at ambient temperature.

Table 14 shows the manufacturing specifications for the sodium thiosulfate formulations for injection.

Example 9

Exemplary sodium thiosulfate drug formulations are shown in tables 15-23. These formulations were prepared as described herein.