Pharmaceutical composition containing sodium thiosulfate

Abstract

To provide a unit dosage form containing a pharmaceutically acceptable sodium thiosulfate (for example, sodium thiosulfate pentahydrate).SOLUTION: There is provided a unit dosage form which contains 10 ppm or less of non-removable organic carbon, 0.05 ppm or less of mercury, 2 ppm or less of aluminum, 0.003 wt.% or less of selenium, and on an anhydrous basis measured by ion chromatography, 98 wt.% or more and 102 wt.% or less of sodium thiosulfate, 10 ppm or less of heavy metals, 200 ppm or less of chlorides, 0.001 wt.% or less of sulfides, 0.002 wt.% or less of iron, 0.01 wt.% or less of calcium, 0.005 wt.% or less of potassium, 0.1% or less of sulfites, 0.5% or less of sulfates and 3 ppm or less of arsenic, 0.001 wt.% or less of lead or the like, wherein a 10% aqueous solution at 25°C is colorless and has a pH of 6.0 to 8.0.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] This application claims priority to U.S. Provisional Application No. 61 / 223,993, filed Jul. 8, 2009, which is incorporated herein by reference in its entirety.

[0002] 〔Technical Field〕 The present invention provides pharmaceutically acceptable sodium thiosulfate (e.g., sodium thiosulfate pentahydrate) and its pharmaceutically acceptable compositions. The present invention also provides a method for measuring total organic carbon in a sample containing sodium thiosulfate that cannot be removed. The present invention further provides a method for producing pharmaceutically acceptable sodium thiosulfate. The present invention still further provides a method of treatment comprising the step of administering pharmaceutically acceptable sodium thiosulfate.

[0003] 〔Background Art〕 Sodium thiosulfate has a number of industrial applications, including uses such as removing chlorine from solutions, bleaching paper pulp, and extracting silver from ores. Sodium thiosulfate is also used as a photographic fixer, a mordant in the coloring of transfers and prints, and as a component of pharmaceuticals. It can be said that thousands of metric tons of sodium thiosulfate pentahydrate are produced each year, and only a few hundred kilograms are pharmaceutically utilized for the production of sodium thiosulfate injections recently shown to be useful in the treatment of cyanide poisoning, or for the production of lotions containing sodium thiosulfate pentahydrate for the treatment of vitiligo. It has been reported that sodium thiosulfate pentahydrate is effective in the treatment of calciphylaxis (Ackermann et al., Archives of Dermatology 2007, 143(10): 1336 - 1337). It has also been reported to be effective in the treatment for preventing platinum-induced ototoxicity and nephrotoxicity associated with the use of platinum-containing chemotherapeutic agents (Skinner, Current Opinions in Oncology 1995, 7(4): 310 - 315).

[0004] The manufacture of pharmaceuticals is regulated by the U.S. Food and Drug Administration (FDA). Based on the passage of the Federal Food, Drug and Cosmetic Act in 1938, the FDA requires that new pharmaceuticals and their corresponding active ingredients be manufactured in accordance with the high standards of "Pharmaceutical Grade" Good Manufacturing Practices, as detailed in Federal Standard 21 (CFR 211). Because sodium thiosulfate pentahydrate has traditionally been used in pharmaceutical formulations in relatively small quantities, there have been no raw material suppliers that manufacture sodium thiosulfate pentahydrate in accordance with "Pharmaceutical Grade" Good Manufacturing Practices.

[0005] In addition to regulating manufacturing practices, the FDA sets stringent quality standards for each new drug and its corresponding active ingredient. A drug is classified as “new” if it was introduced to the market after passing the U.S. Federal Food, Drug, and Cosmetic Act of 1938. As specified in this Act, the FDA requires that new drugs and their active ingredients be manufactured in accordance with “pharmaceutical grade” good manufacturing practices and meet applicable quality standards. When the Food, Drug, and Cosmetic Act was enacted in 1938, drugs already on the market were classified as “grandfathered drugs,” and were permitted to remain on the market without formal FDA approval as long as the drug and its labeling remained unchanged. Any change to the drug or its labeling would classify the “grandfathered drug” as a “new” drug subject to the standards and quality criteria imposed by the FDA. Currently available sodium thiosulfate pentahydrate injections, labeled solely for use in the treatment of production poisoning, and sodium thiosulfate pentahydrate lotions, labeled solely for use in the treatment of tinea versicolor, are "grandfathered medications." As a result, the formulations and corresponding quality standards for these drugs have remained unchanged for decades.

[0006] In anticipation of new drug applications for pharmaceuticals containing sodium thiosulfate pentahydrate, the FDA recently announced that sodium thiosulfate pentahydrate raw materials for new pharmaceuticals must be manufactured in accordance with "pharmaceutical grade" good manufacturing practices and adhere to a new set of quality standards. These new quality standards are more extensive and stringent than existing standards. Currently available sodium thiosulfate raw materials do not meet these new FDA quality standards and are not suitable for use in the formulation of new pharmaceuticals. As a result, there is a clear and unresolved need for purified sodium thiosulfate raw materials that are manufactured in accordance with "pharmaceutical grade" good manufacturing practices and meet the new set of quality standards in order to translate recent research findings on sodium thiosulfate into FDA-approved clinical treatments.

[0007] Another hurdle in developing pharmaceutical-grade sodium thiosulfate pentahydrate is the lack of an effective analytical method to measure the total organic carbon that cannot be removed in samples containing sodium thiosulfate pentahydrate. This is one of the quality standards imposed by the FDA. Conventional methods for measuring total organic carbon require that any inorganic carbon be removed before measuring the organic carbon content in the sample. This is typically achieved by adding an acid. At low pH, inorganic carbon and volatile organic carbon are converted to carbon dioxide and removed from the sample. The sample is then placed in a combustion chamber with a catalyst, where all remaining, non-removable (non-volatile) total organic carbon is converted to carbon dioxide at a temperature of approximately 680°C. Subsequently, the amount of carbon dioxide produced is measured using an infrared detector. However, this conventional method cannot be used to analyze samples containing sodium thiosulfate. When exposed to acid, sodium thiosulfate pentahydrate decomposes into sulfur, which can precipitate during analysis. Salts from sodium thiosulfate pentahydrate can also precipitate during analysis. Precipitates can damage laboratory equipment and interfere with analysis. Therefore, there is also a need for analytical methods to measure the total organic carbon that cannot be removed in samples containing sodium thiosulfate pentahydrate.

[0008] [Summary of the Invention] The present invention provides sodium thiosulfate containing about 10 ppm or less of non-removable organic carbon (NPOC) (also known as non-volatile organic carbon). The present invention also provides sodium thiosulfate containing about 0.01% by weight or less of carbonate. The present invention also provides sodium thiosulfate containing about 0.05 ppm or less of mercury. The present invention also provides sodium thiosulfate containing about 0.003% by weight or less of selenium. The present invention also provides sodium thiosulfate containing about 2 ppm or less of aluminum. The present invention further provides sodium thiosulfate containing about 10 ppm or less of non-removable organic carbon, about 0.01% by weight or less of carbonate, about 0.05 ppm or less of mercury, about 0.003% by weight or less of selenium, and about 2 ppm or less of aluminum.

[0009] The present invention also provides a pharmaceutical composition comprising sodium thiosulfate and a pharmaceutically acceptable excipient, wherein the sodium thiosulfate contains about 10 ppm or less of unremovable organic carbon, and / or about 0.01% by weight or less of carbonate, and / or about 0.05 ppm or less of mercury, and / or about 0.003% by weight or less of selenium, and / or about 2 ppm or less of aluminum.

[0010] The present invention also provides a method for measuring the total organic carbon that cannot be removed in a sample containing sodium thiosulfate. This method comprises (a) contacting the sample with a predetermined amount of aqueous solution containing an inorganic acid to form an aqueous sample solution; (b) removing a precipitate from the aqueous sample solution; (c) contacting the sample solution with a predetermined amount of oxidizing agent; and (d) converting the organic carbon in the sample solution to carbon dioxide under supercritical hydroxide (SCWO) conditions. In one embodiment, the final volume of the inorganic acid is about 2% or more of the final volume of the sample solution, or the final volume of the oxidizing agent is about 20% or more of the final volume of the sample solution.

[0011] The present invention also provides a method for preparing sodium thiosulfate. This method comprises the steps of (a) contacting sodium sulfite with sulfur to obtain a reaction mixture; (b) filtering the reaction mixture to obtain a solution; (c) concentrating the solution; (d) exposing the solution to activated carbon; (e) filtering the solution together with activated carbon; and (f) crystallizing sodium thiosulfate pentahydrate from the solution.

[0012] The present invention also provides a method for treating acute poisoning, not limited to cyanide poisoning. This method comprises administering a therapeutically effective amount of sodium thiosulfate of the present invention to a subject having acute poisoning.

[0013] The present invention also provides a method for treating or preventing platinum-induced toxic inner ear disorders (e.g., those associated with the use of cisplatin or other platinum-containing agents). This method comprises administering a therapeutically effective amount of sodium thiosulfate of the present invention to a subject who has or is at risk of developing platinum-induced toxic inner ear disorders, for example, those associated with the use of cisplatin or other platinum-containing agents.

[0014] The present invention also provides a method for treating or preventing platinum-induced nephrotoxicity (e.g., associated with the use of cisplatin or other platinum-containing agents). This method comprises administering a therapeutically effective amount of sodium thiosulfate of the present invention to a subject who is suffering from or at risk of suffering from platinum-induced nephrotoxicity, for example, associated with the use of cisplatin or other platinum-containing agents.

[0015] The present invention also provides a method for treating calciphylaxis, comprising the step of administering a therapeutically effective amount of the sodium thiosulfate of the present invention to a subject having calciphylaxis.

[0016] The present invention also provides a method for treating vascular calcification, not limited to atherosclerosis. This method comprises administering a therapeutically effective amount of sodium thiosulfate of the present invention to a subject having vascular calcification, not limited to atherosclerosis.

[0017] The present invention also provides a method for treating dermatological diseases or skin-related conditions. These conditions include, but are not limited to, bacterial infections of the skin, fungal infections of the skin, viral infections of the skin, fungal infections of the nails, bacterial infections of the nails, viral infections of the nails, fungal infections of the nail bed, bacterial infections of the nail bed, viral infections of the nail bed, psoriasis, scleroderma, inflammation of the skin, inflammation of the nails, and inflammation of the nail bed. The method comprises the step of administering a therapeutically effective amount of sodium thiosulfate of the present invention to a subject having a dermatological disease or skin-related condition.

[0018] [Detailed explanation] To facilitate understanding of the disclosures herein, many terms are defined below.

[0019] In general, the terminology and experimental procedures used herein in inorganic chemistry, analytical chemistry, organic chemistry, medical chemistry, and pharmacology are well-known and commonly used in the respective fields. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art in which the disclosures herein pertain. If there are multiple definitions of a term used herein, the definitions in this section shall prevail unless otherwise specified.

[0020] The term “subject” refers to, but is not limited to, the following animals: primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used substitutably herein, for example, with respect to mammalian subjects (e.g., human subjects). In one embodiment, the subject is suffering from or at risk of suffering from a disease, disorder, or condition, which may be treated, prevented, or mitigated by the administration of sodium thiosulfate.

[0021] The term "host" refers to a single-celled or multicellular organism in which a virus can replicate, and includes, but is not limited to, cells, cell lines, and animals (e.g., humans).

[0022] "Treat," "the act of treating," and "treatment" are intended to include the alleviation or elimination of one or more symptoms of a disorder, disease, or condition, or associated with such disorder, disease, or condition, or the alleviation or eradication of the cause of such disorder, disease, or condition itself.

[0023] The terms "prevent," "preventing," and "prevention" are intended to include methods of delaying and / or preventing the onset of a disorder, disease, or condition and / or its associated symptoms, methods of preventing a subject from developing a disease, or methods of reducing the risk of a subject developing a disorder, disease, or condition.

[0024] The term “therapeutically effective dose” is intended to include an amount of a compound (e.g., sodium thiosulfate) that, when administered, is sufficient to treat, prevent, or alleviate to some extent the progression of one or more symptoms of a disorder, disease, or condition that is being treated. The term “therapeutically effective dose” also refers to an amount of a compound (e.g., sodium thiosulfate) that is sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human, as being sought by researchers, veterinarians, physicians, or clinicians.

[0025] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to a pharmaceutically acceptable material, composition, vehicle (e.g., liquid (water (e.g., deionized water or sterile water) or solid filler)), diluent, excipient, solvent, or encapsulating material. In one embodiment, any component is “pharmaceutically acceptable” insofar as it can coexist with other components of a pharmaceutical formulation and is suitable for use in contact with human and animal cells, tissues, or organs without causing excessive toxicity, hypersensitivity, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See: Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0026] The terms "about" or "approximately" mean an acceptable error for a particular value as measured by one of ordinary skill in the art. This depends in part on how the value is measured or determined. In certain embodiments, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" or "approximately" mean within 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, the value following the terms "about" or "approximately" is intended to be exact.

[0027] The terms "active pharmaceutical ingredient", "active ingredient", and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more of one or more pharmaceutically acceptable excipients, to treat, prevent, or alleviate one or more symptoms of a condition, disorder, or disease. As used herein, "active pharmaceutical ingredient", "active ingredient", and "active substance" can be optical isomers of the compounds described herein. As used herein, "active pharmaceutical ingredient", "active ingredient", and "active substance" can be the anhydrous, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or other hydrated form of sodium thiosulfate.

[0028] The term "sodium thiosulfate" includes the anhydrous, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or other hydrated form of sodium thiosulfate. In one embodiment, "sodium thiosulfate" as referred to herein means sodium thiosulfate pentahydrate (Na2S2O3·5H2O). In another embodiment, sodium thiosulfate refers to a pharmaceutical grade. When used herein with respect to sodium thiosulfate, the term "pharmaceutical grade" means that the sodium thiosulfate is manufactured in accordance with good manufacturing practices (GMP) of "pharmaceutical grade" as detailed in the United States Federal Regulations 21 (CFR211) and meets one or more of the purification levels listed herein.

[0029] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or a pharmaceutical composition thereof that is administered to a subject to treat, prevent, or alleviate one or more symptoms of a condition, disorder, or disease.

[0030] The term "anti-solvent" refers to a liquid that is added to a solvent to reduce the solubility of a compound in the solvent and cause precipitation of the compound.

[0031] The terms "non-purgeable organic carbon (NPOC)" and "non-volatile organic carbon (NVOC)" refer to organic carbon-based substances that do not volatilize from a material upon exposure to an acid and are not removed.

[0032] [[Sodium thiosulfate]] The present invention provides sodium thiosulfate in a purified form (e.g., sodium thiosulfate pentahydrate (Na2S2O3·5H2O)). In one embodiment, the present invention provides pharmaceutical grade sodium thiosulfate. In another embodiment, the present invention provides sodium thiosulfate in a form that meets or exceeds one or more of all of the FDA standards for use in pharmaceutical applications. In another embodiment, the present invention provides sodium thiosulfate in a form that is manufactured in accordance with good manufacturing practices (GMP) as detailed in the United States Federal Regulatory Standards 21 (CFR211).

[0033] In one embodiment, sodium thiosulfate is a solid.

[0034] In one embodiment, sodium thiosulfate is a colorless crystal.

[0035] In one embodiment, the appearance of a 10% solution containing sodium thiosulfate is clear and colorless.

[0036] In one embodiment, sodium thiosulfate is odorless.

[0037] In one embodiment, the presence of sodium thiosulfate in a 10% solution containing sodium thiosulfate of the present invention is identified by a yellow discoloration after adding a few drops of iodine TS.

[0038] In one embodiment, the presence of sodium in the sodium thiosulfate of the present invention is confirmed in accordance with Method 191 in USP XXXII (2009), which is incorporated herein by reference in its entirety.

[0039] In one embodiment, the presence of thiosulfate in sodium thiosulfate of the present invention is confirmed according to Method 191 in USP XXXII (2009).

[0040] In one embodiment, the sodium thiosulfate pentahydrate of the present invention contains approximately 99% or more and approximately 100.5% or less of sodium thiosulfate on an anhydrous basis. In a specific embodiment, the amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate of the present invention is measured according to USP colorimetric analysis (USP XXXII (2009)).

[0041] In one embodiment, the sodium thiosulfate pentahydrate of the present invention contains approximately 98% or more and approximately 102% or less by weight of anhydrous sodium thiosulfate as measured by ion chromatography.

[0042] In one embodiment, the sodium thiosulfate pentahydrate of the present invention contains approximately 98% or more and approximately 102% or less of sodium thiosulfate on an anhydrous basis. In a particular embodiment, the amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate of the present invention is determined by ion chromatography. In a particular embodiment, the amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate of the present invention is determined by ion chromatography using electrochemical conductivity detection as described herein.

[0043] In another embodiment, the sodium thiosulfate of the present invention has a pH of about 6.0 to about 8.0 when measured at 25°C in a 10% solution. In a particular embodiment, the pH of the sodium of the present invention is measured using a pH meter. In a particular embodiment, the pH of the sodium thiosulfate of the present invention is determined according to Method 791 in USP XXXII (2009).

[0044] In another embodiment, the sodium thiosulfate of the present invention has a water content of about 32% to about 37% by weight. In a particular embodiment, the water content of the sodium thiosulfate of the present invention is determined by the Karl Fischer method. In a particular embodiment, the water content of the sodium thiosulfate of the present invention is determined according to Method 921 in USP XXXII (2009).

[0045] In another embodiment, the heavy metal content of the sodium thiosulfate of the present invention is approximately 10 ppm or less. The heavy metal content of the sodium thiosulfate of the present invention is determined according to Method 231 in USP XXXII (2009).

[0046] In another embodiment, the sodium thiosulfate of the present invention contains about 0.01% by weight or less of carbonate. In a particular embodiment, the carbonate content of the sodium thiosulfate of the present invention is determined by contacting a sodium thiosulfate sample with an acid (e.g., phosphoric acid) to convert the carbonate to carbon dioxide, and then measuring the amount of carbon dioxide using a non-dispersive infrared detector.

[0047] In another embodiment, the sodium thiosulfate of the present invention contains about 0.005% by weight or less of insoluble matter. In a particular embodiment, the amount of insoluble matter in the sodium thiosulfate of the present invention is determined by dissolving 10 g of the sodium thiosulfate of the present invention in 100 mL of water, boiling the solution for 1 hour, filtering the solution, washing it with hot water, drying it, cooling it in a desiccator, and then weighing it.

[0048] In another embodiment, the sodium thiosulfate of the present invention contains approximately 200 ppm or less of chloride. In a particular embodiment, the chloride content in the sodium thiosulfate of the present invention is determined according to Method 221 in USP XXXII (2009).

[0049] In another embodiment, the sodium thiosulfate of the present invention contains about 0.002% by weight or less of iron. In a particular embodiment, the iron content of the sodium thiosulfate of the present invention is determined by ICP emission mass spectrometry (ICP-MASS). In a particular embodiment, the iron content of the sodium thiosulfate of the present invention is determined by ICP optical emission spectrometry (ICP-OES). In a particular embodiment, the iron content of the sodium thiosulfate of the present invention is determined according to Method 241 in USP XXXII (2009).

[0050] In another embodiment, the sodium thiosulfate of the present invention contains about 0.001% by weight or less of lead. In a particular embodiment, the lead content in the sodium thiosulfate of the present invention is determined according to Method 251 in USP XXXII (2009).

[0051] In another embodiment, the sodium thiosulfate of the present invention contains about 0.01% by weight or less of calcium. In a specific embodiment, the calcium content of the sodium thiosulfate of the present invention is determined using ICP-MS. In a specific embodiment, the calcium content of the sodium thiosulfate of the present invention is determined using flame emission spectroscopy (FES).

[0052] In another embodiment, the sodium thiosulfate of the present invention does not produce turbidity when an ammonium oxalate test solution prepared according to USP XXXII (2009) is added to an aqueous solution containing sodium thiosulfate (for example, 1 g of sodium thiosulfate dissolved in 20 mL of water).

[0053] In another embodiment, the sodium thiosulfate of the present invention contains about 0.005% by weight or less of potassium. In a specific embodiment, the potassium content of the sodium thiosulfate of the present invention is determined using ICP-MS. In a specific embodiment, the potassium content of the sodium thiosulfate of the present invention is determined using FES.

[0054] In another embodiment, the sodium thiosulfate of the present invention contains about 0.05% by weight or less of sulfite, or about 0.1% by weight or less of sulfite. In a particular embodiment, the sulfite content of the sodium thiosulfate of the present invention is determined in whole according to the method for determining sulfite in American Chemical Society, Reagent Chemicals, 10th Edition, which is incorporated herein by reference.

[0055] In another embodiment, the sodium thiosulfate of the present invention contains about 0.05% by weight or less, about 0.1% by weight or less, about 0.25% by weight or less, or about 0.5% by weight or less of sulfate (e.g., SO4). In a particular embodiment, the sulfate content in the sodium thiosulfate of the present invention is determined according to the sulfate determination method in American Chemical Society, Reagent Chemicals, 10th Edition.

[0056] In another embodiment, the sodium thiosulfate of the present invention contains about 0.001% by weight or less of sulfides. In a particular embodiment, the sulfide content in the sodium thiosulfate of the present invention is determined by the addition of lead(II) nitrate using the method described herein.

[0057] In another embodiment, the sodium thiosulfate of the present invention contains about 0.002% by weight or less of a nitrogen compound (e.g., N). In a particular embodiment, the content of the nitrogen compound (e.g., N) in the sodium thiosulfate of the present invention is determined according to the method for determining the nitrogen compound in American Chemical Society, Reagent Chemicals, 10th Edition.

[0058] In other embodiments, the sodium thiosulfate of the present invention contains volatile organic impurities in amounts of about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or 5000 ppm or less. In certain embodiments, the sodium thiosulfate of the present invention contains volatile organic impurities or certain solvents (e.g., ethanol) in amounts below certain limits as defined in ICH Q3C(R3). The disclosure of ICH Q3C(R3) is incorporated herein by reference in whole. In certain embodiments, the content of volatile organic impurities is determined according to Method 467 in USP XXXII (2009).

[0059] In another embodiment, the sodium thiosulfate of the present invention contains a total NPOC of about 60 ppb or less, about 2.5 ppm or less, about 8 ppm or less, about 10 ppm or less, about 20 ppm or less, about 25 ppm or less, or about 50 ppm or less. In a particular embodiment, the sodium thiosulfate of the present invention contains a total NPOC of about 12 ppm or less. In a particular embodiment, the total NPOC in the sodium thiosulfate of the present invention is determined using the method described herein. In a particular embodiment, the total NPOC in the sodium thiosulfate of the present invention comprises the steps of (a) contacting sodium thiosulfate with a predetermined amount of aqueous solution containing an inorganic acid to form an aqueous sample solution; (b) removing precipitate from the aqueous sample solution; (c) contacting the sample solution with a predetermined amount of oxidizing agent; and (converting organic carbon in the sample solution to carbon dioxide under supercritical hydroxide (SCWO) conditions).

[0060] In another embodiment, the sodium thiosulfate of the present invention contains mercury at a concentration of approximately 0.05 ppm or less. In certain embodiments, the mercury content of the sodium thiosulfate of the present invention is determined using ICP-MS. In certain embodiments, the mercury content of the sodium thiosulfate of the present invention is determined using ICP-OES. In certain embodiments, the mercury content of the sodium thiosulfate of the present invention is determined according to Method 261 in USP XXXII (2009).

[0061] In another embodiment, the sodium thiosulfate of the present invention contains about 2 ppm or less of aluminum. In a particular embodiment, the aluminum content in the sodium thiosulfate of the present invention is determined using ICP-MS. In a particular embodiment, the aluminum content in the sodium thiosulfate of the present invention is determined using ICP-OES. The aluminum content in the sodium thiosulfate of the present invention is determined according to Method 206 in USP XXXII (2009).

[0062] In another embodiment, the sodium thiosulfate of the present invention contains arsenic at a concentration of approximately 3 ppm or less. In a specific embodiment, the arsenic content of the sodium thiosulfate of the present invention is determined using ICP-MS. In a specific embodiment, the arsenic content of the sodium thiosulfate of the present invention is determined using ICP-OES. The arsenic content of the sodium thiosulfate of the present invention is determined according to Method 211 in USP XXXII (2009).

[0063] In another embodiment, the sodium thiosulfate of the present invention contains about 0.003% by weight or less of selenium. In certain embodiments, the selenium content of the sodium thiosulfate of the present invention is determined using ICP-MS. In certain embodiments, the selenium content of the sodium thiosulfate of the present invention is determined using ICP-OES. The selenium content of the sodium thiosulfate of the present invention is determined according to Method 291 in USP XXXII (2009).

[0064] In another embodiment, the total number of aerobic microorganisms in the microbial load of sodium thiosulfate according to the present invention is approximately 100 colony-forming units / gram (CFU / g) or less. The total number of aerobic microorganisms in the microbial load of sodium thiosulfate according to the present invention is determined according to Method 61 in USP XXXII (2009).

[0065] In another embodiment, the total number of yeasts and molds in the sodium thiosulfate of the present invention is approximately 20 CFU / g or less. The total number of yeasts and molds in the sodium thiosulfate of the present invention is determined according to Method 61 in USP XXXII (2009).

[0066] In another embodiment, the sodium thiosulfate of the present invention contains bacterial endotoxins of about 0.02 endotoxin units / milligram (EU / mg) or less, about 0.1 EU / mg or less, or about 0.25 EU / mg or less. The amount of bacterial endotoxin in the sodium thiosulfate of the present invention is determined according to Method 85 in USP XXXII (2009).

[0067] In another embodiment, the sodium thiosulfate of the present invention contains a residue of 0.01% by weight or less of a solidification inhibitor.

[0068] In another embodiment, the sodium thiosulfate of the present invention is characterized by one or more of the following: It contains approximately 99% to 100.5% by weight of sodium thiosulfate on an anhydrous basis, as determined by the USP colorimetric analysis method; It contains approximately 98% to 102% by weight of sodium thiosulfate on an anhydrous basis, as determined by ion chromatography; A 10% solution has a pH of approximately 6 to 8 at 25°C; It has a water content of approximately 32% to 37% by weight; It is a colorless crystal; As a 10% solution, it has a clear and colorless appearance; It is odorless; The identification test for sodium is positive; The identification test for thiosulfate is positive; It does not produce turbidity when mixed with ammonium oxalate TS; The heavy metal content is approximately 10 ppm or less; It contains carbonates at a concentration of approximately 0.01% by weight or less; It contains insoluble matter of approximately 0.005% by weight or less; Contains chloride at approximately 200 ppm or less; It contains sulfides at a concentration of approximately 0.001% by weight or less; It contains approximately 0.05% by weight or less, or approximately 0.1% by weight or less, of sulfites; It contains sulfates in amounts of approximately 0.05% by weight or less, approximately 0.1% by weight or less, approximately 0.25% by weight or less, or approximately 0.5% by weight or less; Contains approximately 0.002% or less iron by weight; Contains approximately 0.01% or less calcium by weight; It contains less than approximately 0.005% by weight of potassium; It contains volatile organic impurities in concentrations of approximately 10 ppm or less, approximately 100 ppm or less, approximately 500 ppm or less, approximately 1000 ppm or less, or approximately 5000 ppm or less; It contains total NPOC of 60 ppb or less, approximately 2.5 ppm or less, approximately 8 ppm or less, approximately 10 ppm or less, approximately 20 ppm or less, approximately 25 ppm or less, or approximately 50 ppm or less; Contains mercury at approximately 0.05 ppm or less; Contains aluminum at approximately 2 ppm or less; It contains arsenic at a concentration of approximately 3 ppm or less; Contains less than 0.001% by weight of lead; It contains approximately 0.002% by weight or less of nitrogen compounds (e.g., N); It contains approximately 0.003% by weight or less of selenium; Contains a residue of 0.01% by weight or less of a solidification inhibitor; The total number of aerobic microorganisms in the microbial load is approximately 100 CFU / g or less; The total number of yeasts and molds is approximately 20 CFU / g or less; and It contains bacterial endotoxins of approximately 0.02 EU / mg or less, approximately 0.1 EU / mg or less, and approximately 0.25 EU / mg or less.

[0069] In yet another embodiment, the sodium thiosulfate of the present invention is characterized by one or more of the following: It contains approximately 99% to 100.5% by weight of sodium thiosulfate on an anhydrous basis, as determined by the USP colorimetric analysis method; It contains approximately 98% to 102% by weight of sodium thiosulfate on an anhydrous basis, as determined by ion chromatography; A 10% solution has a pH of approximately 6 to 8 at 25°C; It has a water content of approximately 32% to 37% by weight; It is a colorless crystal; As a 10% solution, it has a clear and colorless appearance; It is odorless; The identification test for sodium is positive; The identification test for thiosulfate is positive; It does not produce turbidity when mixed with ammonium oxalate TS; The heavy metal content is approximately 10 ppm or less; It contains carbonates at a concentration of approximately 0.01% by weight or less; It contains insoluble matter of approximately 0.005% by weight or less; Contains chloride at approximately 200 ppm or less; It contains sulfides at a concentration of approximately 0.001% by weight or less; It contains approximately 0.05% by weight or less, or approximately 0.1% by weight or less, of sulfites; It contains sulfates in amounts of approximately 0.05% by weight or less, approximately 0.1% by weight or less, approximately 0.25% by weight or less, or approximately 0.5% by weight or less; Contains approximately 0.002% or less iron by weight; Contains approximately 0.01% or less calcium by weight; It contains less than approximately 0.005% by weight of potassium; It contains volatile organic impurities in concentrations of approximately 10 ppm or less, approximately 100 ppm or less, approximately 500 ppm or less, approximately 1000 ppm or less, or approximately 5000 ppm or less; It contains total NPOC of 60 ppb or less, approximately 2.5 ppm or less, approximately 8 ppm or less, approximately 10 ppm or less, approximately 20 ppm or less, approximately 25 ppm or less, or approximately 50 ppm or less; Contains mercury at approximately 0.05 ppm or less; Contains aluminum at approximately 2 ppm or less; It contains arsenic at a concentration of approximately 3 ppm or less; Contains less than 0.001% by weight of lead; It contains approximately 0.002% by weight or less of nitrogen compounds (e.g., N); It contains approximately 0.003% by weight or less of selenium; The total number of aerobic microorganisms in the microbial load is approximately 100 CFU / g or less; The total number of yeasts and molds is approximately 20 CFU / g or less; and It contains bacterial endotoxins of approximately 0.02 EU / mg or less, approximately 0.1 EU / mg or less, and approximately 0.25 EU / mg or less.

[0070] In any particular embodiment, if it is stated that sodium thiosulfate "contains" a specific amount of a specific material (i.e., "contains" a specific amount "or less" of a specific material), then sodium thiosulfate does not contain a detectable amount of that material.

[0071] [Preparation of sodium thiosulfate] In one embodiment, the present invention provides a method for preparing sodium thiosulfate. This method comprises the steps of (a) contacting sodium sulfite with sulfur to obtain a reaction mixture; (b) filtering the reaction mixture to obtain a solution; (c) concentrating the solution; (d) exposing the solution to activated carbon; (e) filtering the solution together with activated carbon; and (f) crystallizing sodium thiosulfate pentahydrate from the solution.

[0072] Suitable solvents for use in the method of the present invention include, but are not limited to, water (including, but not limited to, water, purified water, ultrapure water, deionized water, and water for injection), methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methylethanol, 2-ethylmethanol, ethylene glycol, acetone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid, trichloroacetic acid, trifluoroacetic acid, and mixtures thereof. In one embodiment, the solvent is aqueous. In another embodiment, the solvent is water. In yet another embodiment, the solvent is a mixture of water and a solvent miscible with water. Solvents that can be miscible with water include, but are not limited to, methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methylethanol, 2-ethylmethanol, ethylene glycol, acetone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid, trichloroacetic acid, trifluoroacetic acid, and mixtures thereof.

[0073] In one embodiment, the solvent is water.

[0074] In one embodiment, the molar ratio of sulfur to sodium sulfite in the contact step is about 0.5 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, or about 1.2 to about 1.6. In one embodiment, the molar ratio of sulfur to sodium sulfite is about 1.5.

[0075] In one embodiment, the concentration of sodium sulfite in the contact step is about 0.1 to 100 M, about 1 to 10 M, about 1 to 5 M, about 1 to 4 M, about 1 to 3 M, about 1 to 2 M, about 1.2 to 1.8 M, or about 1.3 to 1.6 M. In one embodiment, the concentration of sodium sulfite in the contact step is about 1.3 M to about 1.5 M.

[0076] In certain embodiments, the contact step is performed within the following temperature ranges: approximately 40-150°C, approximately 70-120°C, approximately 90-110°C, approximately 90-100°C, or approximately 95-150°C. In one embodiment, the temperature during the contact step is approximately 90°C to approximately 100°C. In another embodiment, the temperature during the contact step is approximately 95°C to approximately 100°C. In yet another embodiment, the temperature during the contact step is approximately 97°C.

[0077] In certain embodiments, the contact step is carried out at one of the following predetermined pH levels: 13 or higher, 12 or higher, 11 or higher, 10 or higher, 9 or higher, 8 or higher, or 7 or higher. In certain embodiments, the predetermined pH levels are: approximately 6 to 11, approximately 6.5 to 10.5, approximately 7 to 10, approximately 7 to 9, approximately 7 to 8.5, or approximately 7 to 8. In certain embodiments, a base is added to the reaction mixture in the contact step to adjust it to the predetermined pH. In certain embodiments, the base is an inorganic base. In certain embodiments, the base is sodium hydroxide.

[0078] In certain embodiments, the filtering step is performed within the following temperature ranges: approximately 5 to approximately 100°C, approximately 10 to approximately 50°C, approximately 15 to approximately 40°C, approximately 20 to approximately 30°C, or approximately 20 to approximately 35°C. In certain embodiments, the filtering step is performed at room temperature (approximately 21°C).

[0079] In certain embodiments, the concentration step is carried out by evaporation of the solvent and includes concentrating the filtered solution to purify the concentrated solution. In certain embodiments, the filtered solution is concentrated to a specific gravity in the following ranges: about 1.20 to about 1.70, about 1.30 to about 1.60, about 1.40 to about 1.50, or about 1.40 to about 1.45. In certain embodiments, the concentration step is carried out in the following temperature ranges: about 5 to 100°C, about 20 to 80°C, about 30 to 70°C, about 40 to 60°C, or about 45 to 55°C. In certain embodiments, the concentration step is carried out at about 50°C. In certain embodiments, the concentration step is carried out under reduced pressure. In certain embodiments, the concentration step is carried out under the following pressures: approximately 100 to approximately 755 mmHg, approximately 300 to approximately 755 mmHg, approximately 500 to approximately 755 mmHg, approximately 600 to approximately 740 mmHg, or approximately 700 to approximately 730 mmHg. In certain embodiments, the concentration step is carried out at approximately 700 to approximately 730 mmHg.

[0080] In certain embodiments, the concentrated solution is mixed with activated carbon at a weight ratio of approximately 0.020% to 0.251% for approximately 30 to 47 minutes at approximately 50°C. In certain embodiments, the activated carbon step is carried out at a weight ratio of 0.025% or more activated carbon for approximately 30 minutes or more at approximately 50°C.

[0081] In certain embodiments, the solution containing activated carbon is filtered again at approximately 20–55°C or approximately 40–55°C. In certain embodiments, the refiltration step is carried out at approximately 50°C.

[0082] In certain embodiments, sodium thiosulfate pentahydrate is concentrated and crystallized from a solution that has been re-filtered using conventional methods (cooling, chilling, solvent evaporation, addition of an anti-solvent, or reverse addition to an anti-solvent).

[0083] To accelerate crystallization, the crystallization step may further include seeding the filtered solution. The crystallization step may also include a separation step, where the precipitate may be separated by conventional methods (filtration and centrifugation), followed by washing with a solvent, and then drying.

[0084] Other methods in the art, including spray drying, roller drying, freeze-drying, and melt crystallization, are also applicable to prepare the pharmaceutically acceptable sodium thiosulfate of the present invention.

[0085] [Characterization of the method: Determination of total organic carbon that cannot be removed in sodium thiosulfate] The present invention provides a method for measuring the total organic carbon that cannot be removed in a sample containing sodium thiosulfate. The method comprises (a) contacting the sample with a predetermined amount of aqueous solution containing an inorganic acid to form an aqueous sample solution; (b) removing a precipitate from the aqueous sample solution; (c) contacting the sample solution with a predetermined amount of an oxidizing agent; and (d) converting the organic carbon in the sample solution to carbon dioxide under supercritical hydroxide (SCWO) conditions. In one embodiment, the final volume of the inorganic acid is about 2% or more of the final volume of the sample solution, or the final volume of the oxidizing agent is about 20% or more of the final volume of the sample solution.

[0086] In one embodiment, the inorganic acid is phosphoric acid. In another embodiment, the inorganic acid is 6N phosphoric acid. In yet another embodiment, the final volume of the inorganic acid is about 2% or more and about 50% or less of the final volume of the sample solution. In yet another embodiment, the final volume of the inorganic acid is about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, about 40%, and about 50% of the final volume of the sample solution. In yet another embodiment, the final volume of the inorganic acid is about 6% of the final volume of the sample solution. In yet another embodiment, the inorganic acid is 6N phosphoric acid, and the final volume of the inorganic acid is about 6% of the final volume of the sample solution.

[0087] If precipitate is present in the aqueous sample solution, it can be readily removed from the sample solution by methods known to those skilled in the art. In certain embodiments, the precipitate is removed from the sample solution by filtration. In certain embodiments, the precipitate is removed from the sample solution by centrifugation.

[0088] In one embodiment, the oxidizing agent is sodium persulfate. In another embodiment, the oxidizing agent is a 30% sodium persulfate solution. In yet another embodiment, the final volume of the oxidizing agent is about 20% or more and about 90% or less of the final volume of the sample solution. In yet another embodiment, the final volume of the oxidizing agent is about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 90% of the final volume of the sample solution. In yet another embodiment, the final volume of the oxidizing agent is about 45% of the final volume of the sample solution. In yet another embodiment, the oxidizing agent is a 30% sodium persulfate solution, and the final volume of the oxidizing agent is about 45% of the final volume of the sample solution.

[0089] In certain embodiments, organic carbon in a sample containing sodium thiosulfate is oxidized, for example, according to any SCWO process known in the art, as disclosed below: U.S. Patents 2,944,396, 4,543,190, 5,387,398, 5,405,533, 5,501,799, 5,560,822, 5,804,066, 6,054,057, 6,056,883, 6,238,568, 6,519,926, 6,576,185, 6,709,602, and 6,773,581 (each of these disclosures is incorporated herein by reference in whole). In certain embodiments, the SCWO process is carried out using an InnovOx laboratory TOC Analyzer (GE Analytical Instruments, Inc., Boulder, CO.). The SCWO process utilizes the unique properties shown in the figure only under conditions near or above the thermodynamic critical point of water (i.e., 375°C and 218 atm). Increasing the pressure under supercritical water oxidation conditions dramatically increases the efficiency of the oxidation process by converting organic carbon in a sample containing sodium thiosulfate into carbon dioxide.

[0090] In certain embodiments, a sample solution containing sodium thiosulfate is prepared by adding a sample containing 5.0 g of sodium thiosulfate to water to make a 100 mL solution. In certain embodiments, the water used in this method has a total organic carbon content of 0.10 ppm or less.

[0091] In certain embodiments, the method includes a step of measuring the amount of carbon dioxide formed after oxidation. In certain embodiments, carbon dioxide is quantified using an infrared detector. In certain embodiments, carbon dioxide is quantified using a non-dispersive infrared detector.

[0092] [Pharmaceutical composition] Here, the pharmaceutical composition contains sodium thiosulfate alone or in combination with a pharmaceutically acceptable medium, carrier, diluent, excipient, or mixture thereof as the active ingredient.

[0093] Sodium thiosulfate may be administered alone or in combination with one or more other active ingredients. The pharmaceutical composition containing sodium thiosulfate may be formulated in various dosage forms for oral, parenteral (extraintestinal), and topical administration. The pharmaceutical composition may be formed as release formulations, including slow-acting, sustained-release, long-acting, pulsatile, controlled, accelerated, and rapid-acting formulations, as well as formulations with targeted, programmed release capabilities and those retained in the stomach. These formulations can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126).

[0094] In one embodiment, the above-mentioned pharmaceutical composition may be an oral dosage form comprising the sodium thiosulfate and one or more pharmaceutically acceptable excipients or carriers.

[0095] In another embodiment, the pharmaceutical composition may be a dosage form for parenteral administration comprising the sodium thiosulfate and one or more pharmaceutically acceptable excipients or carriers.

[0096] In another embodiment, the above-mentioned pharmaceutical composition may be a dosage form for topical administration (including pulmonary administration) comprising the sodium thiosulfate and one or more pharmaceutically acceptable excipients or carriers.

[0097] In another embodiment, the above pharmaceutical composition comprises the above sodium thiosulfate and water. In yet another embodiment, the above pharmaceutical composition contains approximately 1 g to approximately 1000 mL, approximately 1 mL to approximately 750 mL, approximately 1 mL to approximately 500 mL, approximately 1 mL to approximately 250 mL, approximately 1 mL to approximately 100 mL, approximately 1 mL to approximately 50 mL, and approximately 1 mL to approximately 25 mL of sodium thiosulfate in approximately 1 g to approximately 100 mL, approximately 1 g to approximately 75 g, approximately 1 g to approximately 50 g, approximately 1 g to approximately 25 g, and approximately 1 g to approximately 12.5 g in water. In other embodiments, the above-mentioned pharmaceutical composition contains approximately 5 g, approximately 10 g, approximately 12.5 g, approximately 15 g, approximately 20 g, approximately 25 g, approximately 30 g, approximately 50 g, approximately 75 g, or approximately 100 g or more of sodium thiosulfate in approximately 25 mL, approximately 50 mL, approximately 100 mL, approximately 25 mL, approximately 50 mL, approximately 75 g, or approximately 100 g or more of sodium thiosulfate in approximately 25 mL, approximately 50 mL, approximately 100 mL, approximately 25 mL, approximately 50 g, approximately 75 g, or approximately 100 g or more of sodium thiosulfate in approximately 5 mL, approximately 50 mL, approximately 100 mL, approximately 25 mL, approximately 250 mL, approximately 50 mL, approximately 75 g, or approximately 100 g or more of sodium thiosulfate in approximately 25 mL, approximately 50 mL, approximately 100 mL, approximately 250 mL, approximately 500 mL, approximately 75 mL, or approximately 1000 mL or more of water.

[0098] In one embodiment, the above pharmaceutical composition comprises sodium thiosulfate, one or more isotonic agents, and one or more pH adjusters. In another embodiment, the above pharmaceutical composition comprises sodium thiosulfate, one or more isotonic agents, one or more buffering agents, or one or more pH adjusters. In particular, the above pharmaceutical composition comprises sodium thiosulfate, potassium chloride, boric acid, and sodium hydroxide. In particular, the above pharmaceutical composition comprises sodium thiosulfate, potassium chloride, boric acid, sodium hydroxide, and water (for example, water for injection).

[0099] In one embodiment, the above pharmaceutical composition comprises sodium thiosulfate and salicylic acid. In another embodiment, the above pharmaceutical composition comprises, in solution, about 5 to about 50%, about 10 to about 40%, about 15 to about 30%, or about 20 to about 25% sodium thiosulfate and about 0.1 to about 2%, about 0.1 to about 1.5%, about 0.5 to about 1.5%, about 0.5 to about 1.25%, or about 0.5 to about 1% salicylic acid. In yet another embodiment, the above pharmaceutical composition comprises, in solution, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% or more sodium thiosulfate and about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, or about 2% salicylic acid.

[0100] The above pharmaceutical composition can be provided in a unit-dosage form or a multiple-dosage form. The unit-dosage form is a physical discontinuous unit suitable for administration to humans and animals and is individually packaged by known techniques. Each unit dosage contains a predetermined amount of the active ingredient sufficient to achieve the desired effect, together with the required pharmaceutical carrier or excipient. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. The unit-dosage form can be administered in one portion or in multiple portions. The multiple-dosage form comprises a plurality of the same unit-dosage forms packaged in one container for administration in separate unit-dosage forms. Examples thereof include vials, bottles of tablets or capsules, or pint or gallon bottles.

[0101] The above pharmaceutical composition can be administered once or multiple times at intervals. It is understood that the exact dosage and duration of treatment vary with the age, weight and physical condition of the patient being treated and can be determined by test methods or by estimation from in vivo or in vitro tests or diagnostic data. Further, it is understood that for a particular individual, a particular dosing schedule should be adjusted over time according to individual needs and the professional judgment of the person administering the agent or the person supervising the administration.

[0102] <A. Oral Administration> The above pharmaceutical compositions may be provided in solid, semi-solid, or liquid dosage forms for oral administration. For use, oral administration may be administered orally, on the tongue, or sublingually. Preferred oral dosage forms, but are not limited, include tablets, capsules, pills, lozenges, sweetened tablets (lozenges), pastilles, cachets, pellets, medicinal chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the above active ingredients, the above pharmaceutical compositions may, but are not limited, include one or more pharmaceutically acceptable carriers or excipients, including binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, and flavoring agents.

[0103] The binder or granulator imparts cohesiveness to the tablet so that it retains its original shape after compression. Preferred binders or granulators are, but are not limited to, starches such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); sugars such as sucrose, glucose, dextrose, molasses, and lactose sugars; acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch alabogalactan. Natural and artificial thickeners include arabogalactan, tragacanth gum powder, and guar gum sugar; cellulose such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose such as AVCEL-PH-101, AVCEL-PH-103, AVCEL RC-581, and AVCEL-PH-105 (FMC Corp., Marcus Hook, PA), and mixtures thereof. Preferred fillers, but not limited to, include talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler may be present in the above pharmaceutical composition at an amount of about 50 to about 99% by weight.

[0104] Preferred diluents, though not limited to them, include dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, tristarch, and sugar powders. Diluents of mannitol, lactose, sorbitol, sucrose, and inositol sugars, when present in sufficient quantities, can impart the ability of compressed tablets to disintegrate in the mouth upon chewing. Such compressed tablets can be used as chewable tablets.

[0105] Preferred disintegrants include, but are not limited to, agar; bentonite; cellulose such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins: alginic acid; thickeners such as guar gum and bee gum HV; citrus pulp; cross-linked cellulose such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clay; aligns; and mixtures thereof. The amount of disintegrant in the above pharmaceutical composition varies depending on the composition and is easily recognizable to those skilled in the art. The above pharmaceutical composition may contain about 0.5 to 15% by weight, or 1 to 5% by weight, of the disintegrant.

[0106] Preferred lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurylate; agar; starch; lycopodium; silica or silica gel such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The above pharmaceutical composition may contain about 0.1 to 5% by weight of the lubricant.

[0107] Preferred glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Colorants include permitted or authorized water-soluble FD&C dyes, alumina hydroxide suspensions of insoluble FD&C dyes, color lakes, and mixtures thereof. Color lakes are formed by adsorbing water-soluble dyes onto heavy metal hydrates to insolubilize the dyes. Flavoring additives include mixtures of natural flavors extracted from plants such as fruits, and artificial flavorings such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Preferred emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monolate (TWEEN® 20), polyoxyethylene sorbitan monolate 80 (TWEEN® 80), and triethanolamine oleate. Suspension and dispersant agents include sodium carboxymethylcellulose, pectin, tragacanth, bee gum, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparabens, benzoic add, sodium benzoate, and alcohol. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. The organic acids include citric acid and tartaric acid. The carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0108] It should be understood that many carriers and excipients can exhibit various functions even with the same composition.

[0109] The above pharmaceutical compositions include compressed tablets, tablet powders, chewable candies, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substrate that is resistant to stomach acid but dissolves or decomposes in the intestines to protect the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which has the advantage of covering undesirable tastes and aromas and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film made of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose phthalate acetate. Film coatings impart similar performance to sugar coatings. Multiple compression tablets are compression tablets formed by one or more compression cycles, and include layered tablets and compression-coated or dry-coated tablets.

[0110] Tablet formulations can be produced by combining the active ingredient in powder, crystalline, or granular form with one or more carriers or excipients, including the aforementioned binders, disintegrants, release-controlled polymers, lubricants, diluents, and / or colorants. Flavoring additives and sweeteners are particularly useful when forming chewable tablets or sweetened candies (lozenges).

[0111] The above pharmaceutical compositions may be provided in soft or hard capsules that can be manufactured from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules are known as dry-filled capsules (DFCs), consisting of two sections, one of which slips over the other to completely contain the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that have been plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to inhibit microbial growth. Preferred preservatives include methyl and propylparaben and sorbic acid, as described above. Liquid, semi-solid, and solid dosage forms may be contained within the capsules. Preferred liquid and semi-solid dosage forms include solutions and suspensions dissolved in propylene carbonate, vegetable oil, or triglycerides. Capsules containing the above solution can be prepared by the methods described in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. The capsules may also be coated with coatings known to those skilled in the art to modify the active ingredient or maintain its insolubility.

[0112] The above pharmaceutical compositions may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions may be two-layered, i.e., oil-in-water or water-in-oil, where one liquid is dispersed throughout the other liquid as fine particles. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Aqueous alcohol solutions may contain pharmaceutically acceptable di(lower alkyl)acetals of lower alkylaldehydes (e.g., acetaldehyde diethyl acetal); and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol or ethanol. Elixirs are clear, sugared aqueous alcohol solutions. Syrups are concentrated aqueous solutions of sugars, such as main clauthentic syrup, and may contain preservatives. As a liquid dosage form, for example, a solution of polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to suit the desired dose.

[0113] Other useful liquid and semi-solid dosage forms may, but are not limited, include the active ingredient and 1,2-dimethoxymethane, dialkylated mono- or polyalkylene glycol, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein the average molecular weight of polyethylene glycol is 350, 550, and 750. These compositions may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid, and esters thereof, and dithiocarbamate.

[0114] The above pharmaceutical composition for oral administration may be in the form of liposomes, micelles, microspheres, or nanosystems. The micelle dosage form can be prepared by the method described in U.S. Patent No. 6,350,458.

[0115] The above pharmaceutical composition may be in the form of non-foaming or foaming granules and powders for reconstitution into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used for non-foaming granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used for foaming granules or powders may include organic acids and a carbon dioxide source.

[0116] Colorants and flavoring additives can be used in all of the above dosage forms.

[0117] The above pharmaceutical composition may be in an immediate or modified release dosage form, including sustained, controlled, targeted, and programmed release forms.

[0118] The above pharmaceutical composition may be prepared with other active ingredients that do not interfere with the desired therapeutic effect or with a base that aids the desired effect.

[0119] <B. Parenteral Administration> The above pharmaceutical composition may be administered by injection, infusion, or implantation for local or systemic administration. Parenteral administration includes administration into the vein, artery, intraperitoneal, intrathecal, intraventricular, intrauterine, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous.

[0120] The above pharmaceutical compositions may be in preferred parenteral dosage forms, such as solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for liquid-based solutions or suspensions upon injection. Such dosage forms may be manufactured according to conventional methods known to those skilled in the art of pharmacology (see Remington: The Science and Practice of Pharmacy, supra).

[0121] The above-mentioned pharmaceutical composition for parenteral administration comprises one or more pharmaceutically acceptable carriers and excipients, and may include, but is not limited to, an aqueous medium, a water-miscible medium, a non-aqueous medium, an antimicrobial or antiseptic agent for inhibiting microbial growth, a stabilizer, solubility enhancers, isotonic agents (e.g., but not limited to potassium chloride, mannitol, sodium chloride, dextran, and glucose), a buffer, an antioxidant, a local anesthetic, a suspending and dispersing agent, a wetting or emulsifying agent, a complexing agent, a metal encapsulant or chelating agent, an antifreeze, a lyoprotectant, a thickener, a pH adjuster (e.g., but not limited to an acid such as boric acid, or a base such as sodium hydroxide), and an inert gas.

[0122] Preferred aqueous media include, but are not limited to, water, saline solutions, physiological saline, phosphate-buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringers solution. Non-aqueous media include, but are not limited to, plant-derived non-volatile oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides from coconut oil, and palm seed oil. The media that can be miscible with water are not limited to, but may include ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0123] Preferred antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl-para-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propylparabens, and sorbic acid. Preferred isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Preferred buffering agents include, but are not limited to, phosphoric acid and citric acid. Preferred antioxidants include bisulfites and sodium metabisulfite. Preferred local anesthetics include, but are not limited to, procaine hydrochloride. Preferred suspending or dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preferred emulsifiers include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Preferred metal saturators or chelating agents include, but are not limited to, EDTA. Preferred pH adjusters include, but are not limited to, sodium chloride, hydrochloric acid, citric acid, and lactic acid. Preferred complexing agents include, but are not limited to, α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0124] The above pharmaceutical compositions may consist of one or more dosage forms. A single dosage form is packaged in an ampoule, vial, or shrink. Multiple dosage forms for parenteral administration must contain an antimicrobial agent in a bacteriostatic or fungal concentration. All parenteral administration compositions must be sterilized by known methods.

[0125] In one embodiment, the pharmaceutical composition may be provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition may be provided as a sterile, dry, water-soluble product comprising a lyophilized powder and a tablet for subcutaneous injection, which are reconstituted into a medium upon use. In another embodiment, the pharmaceutical composition is prepared as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a dry, water-insoluble product for reconstituting a medium upon use. In yet another embodiment, the pharmaceutical composition may be provided as a ready-to-use, sterile emulsion.

[0126] The above-mentioned pharmaceutical compositions may be provided as rapid-acting or modified release formulations, and include delayed-acting, sustained-release, pulsed, controlled, targeted, and programmed release formulations.

[0127] The above-mentioned pharmaceutical composition may be prepared as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot for injection. In other embodiments, the pharmaceutical composition is dispersed in a solid internal matrix surrounded by an external polymer membrane that is not required in body fluids and allows for the dispersion of the active ingredient from the pharmaceutical composition.

[0128] Preferred internal matrices include hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticizable or nonplastic polyvinyl chloride, plasticizable nylon, plasticizable polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partial hydroxylated polyvinyl acetate.

[0129] Preferred external polymer membranes can include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyl oxyethanol copolymers.

[0130] <C. Topical administration> The pharmaceutical composition can be topically administered to the skin, orifices, and mucosa. The topical administration can include administration to the skin (intradermal), intracorneal, intracoronal, intraocular, eye, ear, transdermal, nose, vagina, urethra, respiratory tract, and rectum.

[0131] The pharmaceutical composition can be in any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and skin patches. The topical administration of the pharmaceutical composition can include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0132] Pharmacopoeia-acceptable carriers and excipients preferred for topical administration include, but are not limited to, aqueous media, water-miscible media, non-aqueous media, antimicrobial or antiseptic agents that inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, and dispersants, wetting or emulsifying agents, complexing agents, metal encapsulants or chelating agents, penetration enhancers, antifreeze agents, lyoprotectants, thickeners, and inert gases.

[0133] The above pharmaceutical compositions may be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or by microneedle or needle-free injection such as POWDERJECT® (Chiron Corp., Emeryville, CA) or BIOJECT® (Bioject Medical Technologies Inc., Tualatin, OR).

[0134] The above pharmaceutical compositions may be provided in the form of ointments, creams, or gels. Preferred ointment media include oily or hydrocarbon media containing lard, benzoin lard, olive oil, cottonseed oil, other oils, and white petrolatum; emulsifying or absorption vehicles such as hydrophilic petrolatum, hydroxystearin sulfate, and dehydrated lanolin; water-removable media such as hydrophilic ointments; water-soluble ointments containing polyethylene glycol of various molecular weights; and water-in-oil (W / O) or oil-in-water (O / W) emulsions that may contain emulsifying hecicles containing cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These media soften the skin but generally require antioxidants and preservatives.

[0135] A preferred cream base may be oil-in-water or water-in-oil. The cream medium may be washable with water and may contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, generally contains petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase is usually not essential but exceeds the volume of the oil phase and generally contains a wetting agent. Emulsifiers in creams can be nonionic, anionic, cationic, or amphoteric surfactants.

[0136] The gel is a semi-solid, suspension system. A single-layer gel contains an organic polymer that is substantially uniformly dispersed throughout the liquid carrier. Preferred gelling agents may include cross-linked acrylic polymers such as carbomer, carboxypolyalkylene, and CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0137] The above-mentioned pharmaceutical compositions may be administered rectally, to the urethral orifice, vagina, or perivaginally in the form of suppositories, pessaries, bougies, patches or humps, pastes, powders, cosmetics, creams, plasters, contraceptives, ointments, solutions, lotions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional methods (see Remington: The Science and Practice of Pharmacy, supra).

[0138] Rectal, urethral, ​​and vaginal suppositories are solid substrates for insertion into bodily orifices, solid at room temperature but melting or softening at body temperature to release the active ingredient into the orifice. Pharmacopoeiatically acceptable carriers used in rectal and vaginal suppositories include substrates or media such as curing agents that provide a melting point near body temperature, and antioxidants such as bisulfites and sodium metabisulfite. Preferred media, though not limited to, include cocoa butter, glycerin-gelatin, carbowax (polyoxyethylene glycol), whale oil, paraffin, white and yellow waxes, and optimal mixtures of mono-, di-, and triglycerides of fatty acids; hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerin-gelatin. Various combinations of media are available. Rectal and vaginal suppositories can be obtained by compression or molding. The typical weight of a rectal and vaginal suppository is approximately 2-3 g.

[0139] The above pharmaceutical compositions may also be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0140] The above pharmaceutical compositions may be administered by inhalation into the nasal cavity or airway. The pharmaceutical compositions may be provided in the form of aerosols or solutions, which may be used for drug delivery, alone or in combination with appropriate propellants, by atomizers such as pressure vessels, pumps, sprays, or electrohydrodynamic devices for generating fine mist. Examples of propellants include 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may be provided as dry powders for inhalation, and may be used alone or in combination with insertion carriers such as lactose or phospholipids; and nasal drops, etc. For intranasal administration, the powders may contain a bioadhesive agent, such as chitosan or cyclodextrin.

[0141] Solutions or suspensions for use in pressure vessels, pumps, sprays, atomizers, or nebulizers may be configured to include ethanol, aqueous ethanol, or other preferred dispersants, stabilizers, or propellants as solvents for sustained release of active ingredients; and / or surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0142] The above pharmaceutical composition can be micronized to a size suitable for delivery by inhalation. For example, it is about 50 μm or less, or 10 μm or less. Particles of the above size can be prepared using known techniques such as the spiral jet mill method, fluidized bed jet mill method, supercritical fluid processing method for forming nanoparticles, high-pressure homogenization method, or spray drying method.

[0143] Capsules, foaming agents, and cartridges for use in inhalers or nebulizers may be configured to include a powder mixture of the above pharmaceutical composition; preferred powder substrates such as lactose and starch; and performance modifiers such as l-leucine, mannitol, or magnesium stearate. Lactose may be an anhydrate or a monohydrate. Other preferred excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The above pharmaceutical composition for inhalation / intranasal administration may further include preferred flavors such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin.

[0144] The above pharmaceutical composition for topical administration may be configured for immediate release or modified release, such as delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0145] <D. Modified Release> The above-mentioned pharmaceutical compositions may be in modified release dosage forms. Here, "modified release" refers to a dosage form in which the rate or location of release of the active ingredient differs from that of an immediate release dosage form administered via the same route. Modified release dosage forms include delayed-, extended-, sustained-, pulsed-, controlled, accelerated, and rapid-acting, targeted, programmed-release, and gastric-retained dosage forms. The above-mentioned pharmaceutical compositions in modified release dosage forms may utilize various devices and methods known to those skilled in the art, including, but not limited to, matrix-sustained-release devices, osmotic-sustained-release devices, multiparticulate-controlled-release devices, ion-exchange resins, enteric-coated coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can be modified by changing the particle size or polymorphism of the active ingredient.

[0146] Examples of modified emissions include, but are not limited to, U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; The following can be cited: 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

[0147] [1. Matrix Controlled Release Devices] The above-mentioned pharmaceutically acceptable formulations in modified release dosage forms can be manufactured using matrix sustained-release devices of a technology known to those skilled in the art (see Takada et al in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).

[0148] In one embodiment, the above-mentioned pharmaceutical composition in the modified release dosage form can be formed using an erodible matrix device which is a water-swellable, disintegrating, or soluble polymer, such as an artificial polymer, and naturally derived polymers and derivatives such as polysaccharides and proteins.

[0149] Materials that can be used to form a disintegrating matrix are not limited to, but include: chitin, chitosan, dextran, and pullulan; agar gum, acacia gum, karaya gum, locust bean gum, taragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), and cellulose propionate (CP). Cellulose derivatives such as cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; fatty acid glycerol esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®), Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyl acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) chloride methacrylate.

[0150] In other embodiments, the pharmaceutical composition may be formed in a non-disintegrating matrix device. The active ingredient is dissolved or dispersed within an inert matrix and released primarily by dispersion through the inert matrix after administration. Preferred materials used as the non-disintegrating matrix device are, but are not limited to, polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / p-uropyrene copolymer, ethylene / ethyl acrylate copolymer, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, and butyl rubber epichloro This material includes insoluble plastics such as hydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, and ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plastic nylon, plastic polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymer, as well as hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partial hydroxylated polyvinyl acetate, carnauba wax, microcrystalline wax, and lipid compounds such as triglycerides.

[0151] In a matrix sustained-release system, the desired release rate can be controlled by, for example, the type of polymer used, the polymer viscosity, the particle size of the polymer and / or active ingredient, the ratio of the active ingredient and polymer in the composition, and other factors such as the proportion of excipients and carriers.

[0152] The above-mentioned pharmaceutical compositions in modified release formulations can be prepared by techniques known to those skilled in the art, for example, by direct compression, dry or wet granulation after compression, melt granulation after compression, etc.

[0153] [2. Osmotic Controlled Release Devices] The above-mentioned pharmaceutical compositions in modified release dosage forms can be manufactured using osmotic sustained-release devices. For example, they can be manufactured by one-component systems, two-component systems, asymmetric membrane technology (AMT), and extruding core systems (ECS). Generally, the devices include at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane enclosing the core, having at least one release port. The semipermeable membrane controls the inflow of water from the surrounding aqueous environment into the core, and releases the drug through the release port.

[0154] In addition to the active ingredients, the core of an osmotic device may contain permeable substances that generate the force to move water from the surroundings to the device's core. Examples of permeable substances include, but are not limited to, water-swellable hydrophilic polymers called "osmopolymers" or "hydrogels," such as hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), methyl methacrylate and PVA / PVP copolymers containing hydrophobic monomers such as vinyl acetate, hydrophilic polyurethanes containing high molecular weight PEO blocks, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0155] Other examples of permeable substances include osmogens, which can absorb water and influence the osmotic gradient across the surrounding coating barrier. Preferred osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfate, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0156] Penetrating agents with different dissolution rates are used to influence how quickly the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM® EZ (SPI Pharma, Lewes, DE) can be used for early delivery to rapidly impart the desired therapeutic effect within the first 2-3 hours, and then for gradual and continuous release of the amount necessary to maintain the desired effect over a sustained period. In this case, the active ingredient is released at a rate that compensates for the amount that is metabolized and excreted.

[0157] The above core can be used with a wide variety of other excipients and carriers to enhance the performance, stability, and processing of the dosage form.

[0158] Materials that can be used to form semipermeable membranes include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water-permeable and water-insoluble at physiological pH, or that can be changed to water-insoluble by chemical modification such as crosslinking. For example, preferred polymers useful for forming coatings include plastic, non-plastic, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propinate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carboxylate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfate, CA butyl sulfate, CA p-toluenesulfonate, agar acetate, amylose triacetate, β-glutan acetate, β-glutan Examples include canthariacetate, acetaldehyde dimethyl acetate, carob triacetate, hydroxyethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters, poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halogens, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0159] The semipermeable membrane can be a hydrophobic microporous membrane. The pores of the membrane are substantially filled with gas and are not wettable with aqueous solvents, but are permeable to water vapor, as described, for example, in U.S. Patent 5,798,119. The hydrophobic and water vapor permeable membrane is generally composed of hydrophobic membranes such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halogens, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0160] The delivery ports of the above semipermeable film can be formed after coating by mechanical or laser drilling. The delivery ports can also be formed in situ by dissolving a stopper made of water-soluble material or by tearing a thin portion of the film covering a cavity inside the core. In addition, the delivery ports can be formed during the coating process, for example, in the case of the asymmetric films described in U.S. Patents 5,612,059 and 5,698,220.

[0161] The total amount and rate of release of the active ingredient can be substantially controlled by the thickness and porosity of the semipermeable membrane, the core configuration, and the number, size, and location of the delivery ports.

[0162] In the above-mentioned pharmaceutical composition in an osmotically sustained-release dosage form, conventional excipients or carriers may be used to improve performance or the manufacturing process.

[0163] Osmotically sustained-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[0164] In some embodiments, the pharmaceutical composition may be formed as an AMT sustained-release dosage form comprising an asymmetric permeable membrane covering a core containing the active ingredient and pharmaceutically acceptable excipients or carriers (see U.S. Patents 5,612,059 and WO 2002 / 17918). The AMT sustained-release dosage form may be prepared by known methods and techniques known to those skilled in the art, such as direct compression, dry or wet granulation, and dip coating.

[0165] Furthermore, in one embodiment, the above-mentioned pharmaceutical composition may be an ESC-sustained-release dosage form comprising a permeable membrane covering a core having an active ingredient, hydroxycellulose, and other pharmaceutically acceptable excipients or carriers.

[0166] [3. Multiparticulate Controlled Release Devices] The above-mentioned pharmaceutical compositions in modified release dosage forms can be formed as multi-particle sustained-release devices. These multi-particle sustained-release devices contain numerous particles, granules, or pellets with diameters of approximately 10 μm to 3 mm, 50 μm to 2.5 mm, or 100 μm to 1 mm. The multi-particles are obtained by methods known to those skilled in the art, such as wet or dry granulation, extrusion / spheronization, roller compression, melt-congealing, and spray coating of core species (see, for example, *Multiparticulate Oral Drug Delivery*; Marcel Dekker: 1994; and *Pharmaceutical Pelletization Technology*; Marcel Dekker: 1989).

[0167] Other excipients or carriers may be mixed with the pharmaceutical composition to help form multiparticles. The resulting particles may constitute a multiparticle device themselves, or they may be coated with various film-forming materials, such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticles may further be formed into capsules or tablets.

[0168] [4.Targeted Delivery] The above-mentioned pharmaceutical compositions may also be shaped to target specific tissues, receptors, or other body parts to be treated, and may include liposomes, resealed red blood cells, and antibody-based delivery systems. For example, but not limited to, U.S. Patents 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874 can be referenced.

[0169] [How to use] In one embodiment, a method for treating diagnosed or suspected cyanide poisoning comprises the step of administering a therapeutically effective amount of sodium thiosulfate to a patient with cyanide poisoning or at risk thereof. In one embodiment, the subject is a mammal, and in another embodiment, the subject is a human.

[0170] In one embodiment, for example, is a method for treating or preventing platinum-induced toxic hearing loss associated with the use of cisplatin or other platinum-containing agents, comprising the step of administering a therapeutically effective amount of sodium thiosulfate to a patient with or at risk of platinum-induced toxic hearing loss associated with the use of cisplatin or other platinum-containing agents. In one embodiment, the subject is a mammal, and in another embodiment, the subject is a human.

[0171] In other embodiments, a method for treating or preventing platinum-induced nephtotoxicity associated with the use of cisplatin or other platinum-containing agents, comprising the step of administering a therapeutically effective amount of sodium thiosulfate to a patient with or at risk of platinum-induced nephtotoxicity associated with the use of cisplatin or other platinum-containing agents. In some embodiments, the subject is a mammal, and in other embodiments, the subject is a human.

[0172] In other embodiments, the present invention relates to a method for treating or preventing vascular calcification, including atherosclerosis, and includes, but is not limited to, the step of administering a therapeutically effective amount of sodium thiosulfate to a patient with or at risk of vascular calcification, including atherosclerosis. In some embodiments, the subject is a mammal, and in other embodiments, the subject is a human.

[0173] In one embodiment, the method for treating a calciphylaxis-related disorder includes the step of administering a therapeutically effective amount of sodium thiosulfate to a patient with a calciphylaxis-related disorder. In one embodiment, the subject is a mammal, and in another embodiment, the subject is a human.

[0174] In other embodiments, but not limited to, a method for treating skin diseases or skin-related disorders including tinea versicolor, bacterial infections of the skin, fungal infections of the skin, viral infections of the skin, fungal infections of the nails, bacterial infections of the nails, viral infections of the nails, fungal infections of the nail beds, bacterial infections of the nail beds, viral infections of the nail beds, psoriasis, scleroderma, inflammation of the skin, inflammation of the nails, and inflammation of the nail beds, comprising the step of administering a therapeutic amount of sodium thiosulfate to a patient with a skin disease or skin-related disorder.

[0175] Depending on the disorder, disease, or illness being treated and the patient's condition, sodium thiosulfate may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, intraventricular (ICV), intratrasystemic injection or infusion, subcutaneous injection, or implant), inhalation, nasally, vaginally, rectally, sublingually, or topically (e.g., percutaneously or topically), and may be formed in preferred dosage units, alone or with pharmaceutically acceptable carriers, adjuvants, and media, for the optimal route of administration.

[0176] The dosage of the drug can be set as appropriate, with appropriate intervals between doses, in the form of 1, 2, 3, 4, 5, 6, or more sub-doses. The dosage or sub-doses can be administered in the form of dose units containing approximately 10 ng to 1000 g, approximately 10 mg to 100 g, approximately 500 mg to 50 g, approximately 1 g to 25 g, or approximately 5 g to 12.5 g of the active ingredient per dose unit. The dosage can also be changed if required by the patient's condition, and it may be administered as a continuous intravenous infusion.

[0177] In some embodiments, preferred dose levels are approximately 0.001 to approximately 100 g / kg of patient body weight (g / kg per day), approximately 0.01 to approximately 50 mg / kg per day, approximately 0.01 to approximately 25 mg / kg per day, or approximately 0.05 to approximately 10 mg / kg per day, and may be administered in one dose or in multiple doses. Preferred dose levels are approximately 0.01 to approximately 100 mg / kg per day, approximately 0.05 to approximately 50 mg / kg per day, or approximately 0.1 to approximately 10 mg / kg per day. Within this range, doses are approximately 0.01 to approximately 0.1, approximately 0.1 to approximately 1.0, approximately 1.0 to approximately 10, or approximately 10 to approximately 50 mg / kg per day.

[0178] [Combination Therapy] Sodium thiosulfate can be used in combination with other therapeutic agents useful for the treatment and / or prevention of diseases and disorders.

[0179] Here, "in combination" includes the use of one or more treatments (e.g., one or more prophylactic and / or therapeutic drugs). However, the use of the term "in combination" is not limited to the order in which the treatments (e.g., prophylactic and / or therapeutic drugs) are administered to a patient with a disease or illness. The first treatment (e.g., a prophylactic and / or therapeutic agent such as a compound) is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior), and the second treatment (e.g., a prophylactic and / or therapeutic agent) is administered to the patient concurrently or consecutively (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). The present invention also includes the case of administering three treatments.

[0180] The term "synergistic" includes combinations of sodium thiosulfate with other treatments currently used for the management, prevention, or treatment of a disease (e.g., prophylactic and / or therapeutic drugs) that produce effects beyond the additive effects of the treatment itself. Combination treatments (e.g., combinations of prophylactic and / or therapeutic drugs) can reduce the dosage of one or more therapeutic drugs and / or the frequency of drug administration to patients with a disease. Reducing the dosage of therapeutic drugs and / or administering them less frequently can reduce the toxicity associated with the administration of these drugs to the patient without diminishing their effectiveness in preventing or treating the disease. In addition, synergistic effects can also enhance the effectiveness of drugs in preventing or treating the disease. Finally, synergistic effects of combinations of treatments (e.g., combinations of prophylactic and / or therapeutic drugs) can avoid or reduce side effects associated with individual treatments.

[0181] Sodium thiosulfate can be used in combination with other drugs or as a substitute for other drugs. In combination therapy, effective doses of two or more drugs are administered together. In alternative or sequential therapy, effective doses of each drug are administered sequentially or sequentially. The dosage is determined based on other factors known to those skilled in the art, as well as the absorption, inactivation, and elimination rates of the drugs. The dosage value also varies depending on the severity of the disorder to be alleviated. It is also understood that for specific patients, specific dosing plans and schedules should be adjusted over the long term according to the individual's needs and the professional judgment of the person administering or supervising the drugs.

[0182] The above composition may be administered in combination with other classes of compositions, for example, but not limited to, vasodilators such as sodium nitrite; keratolytic agents such as salicylic acid; endothelin-converting enzyme (ECE) inhibitors such as phosphoramidone; thromboxane receptor antagonists such as ifetroban; potassium channel openers; thrombin inhibitors such as hirudin; growth factor inhibitors such as PDGF activity modifiers; platelet-activating factor (PAF) antagonists; GPIIb / IIIa blockers (e.g., abciximab, eptifibatide, and triofiban); P2Y(AC) antagonists (e.g., clopidogrel) Antiplatelet agents such as ticlopidine (and CS-747) and aspirin; anticoagulants such as warfarin; low molecular weight heparins such as enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors such as omapatrilat and gemopatrilat (dual NEP-ACE inhibitors); HMGs such as pravastatin, lovastatin, atrovastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisvastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or bisastatin). CoA reductase inhibitors; squalene synthase inhibitors; fibrates; bile acid metal ion sequestering agents such as Questran; niacin; anti-atherosclerotic agents such as ACAT inhibitors; MTP inhibitors; calcium channel inhibitors such as amlodipine besylate; potassium channel activators; alpha-adrenergic agents; beta-adrenergic agents such as carvedilol and metoprolol; antiarrhythmic drugs;Diuretics such as chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorthiazide, trichlormethiazide, polythiazide, benzothiazide, ethacrine, ticlinafene, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and APSAC (anisoylated plasminogen streptokinase activator) Antidiabetic drugs such as thrombolytic agents (complex); biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-γ agonists; inorganic corticosteroid receptor antagonists such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; PDE III inhibitors (e.g., cilostazol), PDE Phosphodiesterase inhibitors such as V inhibitors (e.g., sildenafil, tadalafil, and vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory drugs; antiproliferative substances such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents such as nitrogen mustard, alkyl sulfonates, nitrosourea, etilenimine, and triazines); antimetabolites such as folic acid antagonists, purine analogs, and pyrimidine analogs;Antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-alparaginase; farnesyl protein transferase inhibitors; hormonal agents such as glucocorticoids (e.g., cortisone), estrogen / antiestrogen, androgen / antiandrogen, progestin, luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents such as ecteinascidins; paciaxel, docetaxel, and epothilones This may include microtubule stabilizers such as AF; plant-derived substances such as vinca alkaloids, epipodophyllotoxins, and taxanes; topoisomerase inhibitors such as prenyl protein transferase inhibitors; cyclosporine; steroids such as prednisone and dexamethasone; cytotoxicities such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenidap; anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin, and leflunimide; cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; and other agents such as hydroxyurea, procarbazine, mitotan, hexamethylmelamine, gold compounds, and platinum equivalent complexes such as cisplatin, satoraplatin, and carboplatin.

[0183] Sodium thiosulfate may be provided as a product using packaging materials known to those skilled in the art. See U.S. Patents 5,323,907; 5,052,558; 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, plastic wrappers, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and packaging materials preferred for selected dosage forms and administration and handling.

[0184] Kits used by healthcare professionals simplify the administration of sufficient amounts of the active ingredient to patients. In one embodiment, the kit includes a container and a dosage form of sodium thiosulfate.

[0185] In one embodiment, the kit is a container containing a dosage form of sodium thiosulfate, the container containing one or more drugs.

[0186] The kit may further include devices used for administering the active ingredient. Examples, but not limited to, include syringes, needleless drip pouches, patches, and inhalers. The kit may also include condoms for administering the active ingredient.

[0187] The kit may further include a pharmaceutically acceptable medium that can be used to administer one or more active ingredients. For example, if the active ingredient is solid and needs to be reconstituted for parenteral administration, the kit may include a sealed container of a medium preferred for dissolving the active ingredient and forming a sterile, particulate solution suitable for parenteral administration. Pharmaceutically acceptable mediums include, but are not limited to, aqueous mediums such as water, sodium chloride infusion, Ringer's infusion, dextrose infusion, dextrose and sodium chloride infusion, and lactated Ringer's solution used in intravenous USPs; but are not limited to mediums miscible with water such as ethyl alcohol, polyethylene glycol, and polypropylene glycol; and but are not limited to non-aqueous mediums such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0188] This disclosure may be further understood by the following non-limited embodiments.

[0189] [Examples] Where used herein, the symbols and conventions, outlines and examples used in the processes herein, whether or not specific abbreviations are specifically defined, are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. In particular, but not limited to, the following abbreviations may be used in the examples and throughout this specification: g (gram), mg (milligram), mL (milliliter), μL (microliter); mM (millimole); μM (micromoles); mmol (millimole); eq. (equilibrium); hr or hrs (hours); min (minute).

[0190] In all of the following examples, standard experimental and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius (°C). Unless otherwise indicated, all reactions were carried out at room temperature. The methodologies described in the following examples are intended to demonstrate the available chemistry through the use of specific examples and do not represent the scope of the disclosure.

[0191] [Example 1: Preparation of pharmaceutical-grade sodium thiosulfate pentahydrate] Under nitrogen, 57 kilograms of sulfur and deionized water (799.1 kilograms) were packed into a 500-gallon reactor inactivated using an Oricon Ross combination pH electrode. The slurry was stirred, and 161.4 kilograms of sodium sulfite were packed into the reactor. The reactor was heated between 95 and 100°C for 4 hours. After 4 hours, the pH of the slurry in the reactor was 7.3. The reactor was cooled to 20 ± 5°C. The pH of the cooled slurry was 6.6. 300 grams of 50 wt% sodium hydroxide solution was added to the reactor contents to raise the pH of the slurry in the reactor to 7.4. The contents of the reactor were filtered through Estella filter paper. The resulting filtrate was sterilized under vacuum at 50–100°C with a specific gravitational force of 1.40. While maintaining the solution temperature at 50 ± 5°C, 300 g of activated carbon was added to the solution. The solution was stirred for 1 hour and 3 minutes, and then filtered through a bag of filter paper to remove the activated carbon. The filtered solution was cooled to 20 ± 5°C, and 15 g of sodium thiosulfate pentahydrate crystals were added to the solution. The solution was then cooled to 5 ± 5°C and stirred for 15 hours and 2 minutes. The contents of the reactor, consisting of both solid and liquid, were filtered using Aurora filter paper in an inert environment. The source aqueous solution was used to wash the solid from the reactor walls. The solid was placed on a dry dish and left to stand in a drying oven under complete vacuum with a nitrogen stream at 35°C for 8 hours. Drying continued for 8 hours, until it was confirmed in-process tests that the moisture content of the material (loss due to drying) was between 34.0 and 36.8%. The final weight of the dried solid was 112.5 kilograms. (Yield 36%).

[0192] Table 1 summarizes the analysis of sodium thiosulfate pentahydrate obtained from the purification method to Example 1.

[0193] [Table 1]

[0194] [Example 2: Method for determining all organic carbon that cannot be removed from sodium thiosulfate pentahydrate] All non-removable organic carbon (NPOC) was determined using an InnovOx research TOC analyzer (GE Analytical Instruments, Boulder, Inc.). Water was used as the standard solution, and all reagents and prepared samples had TOC levels of 0.10 ppm or less. Phosphoric acid was ACS reagent grade. Sodium persulfate was obtained from General Electric (GE Part # APK68050-01, Fairfield, Connecticut). Sucrose USP was used as the standard sample. Compressed nitrogen has CO2 and TMC levels of 1 ppm or less.

[0195] The 6N phosphoric acid solution used was prepared by adding approximately 100 mL of water to a 250 mL volumetric flask, then slowly adding 100 mL of phosphoric acid, and finally adding additional water until the final volume reached 250 mL. The 6% phosphoric acid solution was prepared by adding 120 mL of 6N phosphoric acid to a 2,000 mL volumetric flask, and then adding water until the volume reached 100 mL at room temperature.

[0196] A 30% sodium persulfate solution used as an oxidizing agent was prepared by adding 0.1 g of sodium persulfate to a 500 mL volumetric flask, and after the sodium persulfate had dissolved, adding water until the final volume was 500 mL. The solution could be left to stand for 3 days before use and was used during the 14-day preparation period.

[0197] Sucrose stock standard solution (250 ppm carbon based on 0.50 mg carbon / 1.2 mg sucrose) was prepared by dissolving 9 mg of sucrose in 15 mL of water. TOC standard (10 ppm) was prepared by adding 4 mL of sucrose stock standard solution to 100 mL of volumetric flask, and then adding water to bring the volume to 100 mL at room temperature. TOC standard (2 ppm) was prepared by adding 10 ppm TOC standard solution to 50 mL of volumetric flask, and then adding water to bring the volume to 50 mL at room temperature. TOC standard solution (0.5 ppm) was prepared by adding 5 mL of 10 ppm TOC standard solution to 100 mL of volumetric flask, and then adding water to bring the volume to 100 mL at room temperature.

[0198] A sodium thiosulfate pentahydrate sample solution was prepared by adding 5.0 g of the sample to a 100 mL volumetric flask, and then adding 6% phosphoric acid solution at room temperature to bring the total volume to 100 mL. The sample solution was centrifuged for 15 minutes and allowed to stand overnight to allow the precipitate to settle.

[0199] The InnovOx instrument was calibrated using the instrument parameters shown in Table 2, with a 6% phosphoric acid solution (blank) and 0.5 ppm, 2 ppm, and 10 ppm TOC standard solutions.

[0200] [Table 2]

[0201] The calibration curve requirements are as follows: i) the mean correlation coefficient (r) of reproducibility must be 0.99 or higher; ii) the RSD for 2 and 10 ppm TOC standard solutions must be 15% or less; iii) the limit of quantification (LOQ) must be 3 ppm or less, as calculated below: LOQ = (10)(A)(B) / (CD) and iv) The limit of detection (LOD) must be less than 1 ppm, as calculated below: LOD = (3)(A)(B) / (CD) Here: A is the carbon concentration in a 0.5 ppm TOC standard solution; B is the standard deviation of the TOC concentration determined in the blank preparation; C is the average TOC concentration determined in a 0.5 ppm TOC standard solution; further D is the average TOC concentration determined in the blank preparation.

[0202] The samples were analyzed using the parameters of the following apparatus, as shown in Table 3.

[0203] [Table 3]

[0204] The 2ppmTOC standard was applied before and after sample analysis.

[0205] The system conformance requirements are i) the RSD to the 2ppmTOC standard is 15% or less; and ii) the theoretical response %(%T) to the 2ppmTOC standard determination must be between 80% and 120%, calculated as follows: %T=100xA / B; Here: A is the result (ppm) determined by the analysis device; further B is the 2 ppm TOC standard (ppm); iii) For all samples that reacted with a sample of LOQ or a sample of LOQ or greater than 5 times LOQ, the RSD must be 25% or less; or for all samples that reacted with a sample of 5 times LOQ or greater, the RSD must be 15% or less.

[0206] The total amount of organic carbon that could not be removed in each sample was calculated as follows: NPOC = A x B / C; Here: A is the result (ppm) determined by the analysis device; B is the dilution volume (mL) of the sample; further, C was the mass (g) of the sample.

[0207] In the calculation of all non-removable organic carbon, when A was less than the LOD, A of the composition was replaced with the LOD for the calculation to obtain the upper limit of the value of all non-removable organic carbon. When A was less than the LOQ but greater than the LOD, the calculated value of all non-removable organic carbon obtained an approximate value, and the LOQ set the upper limit value of all non-removable organic carbon.

[0208] [Example 3: Method for Determining Sulfide Impurities in Sodium Thiosulfate Pentahydrate Drug Substance] This procedure describes the procedure of wet chemical test conditions for the detection of impurity sulfides in sodium thiosulfate pentahydrate drug substance and drug product samples. Sulfide impurities, if present in the sample, are detected as lead(II) sulfide, which produces a gray precipitate. The method detection limit is set at 10 ppm or 10 μg / g of sulfide based on a drug product concentration of 250 mg / mL of sodium thiosulfate pentahydrate in solution and the use of 1 mL of the drug product in the test.

[0209] <a. Procedure> The NaOH (0.01N) reagent was prepared by dissolving approximately 4.0 g of sodium hydroxide (ACS reagent grade) in 1,000 mL of deionized water. The solution was further diluted volumetrically from 10 mL to 100 mL to obtain a 0.01N sodium hydroxide solution. Alternatively, commercially available 0.01N sodium hydroxide may also be used.

[0210] The lead nitride reagent (1 mg / mL) was prepared by precisely weighing 40 ± 2 mg of lead nitride (ACS reagent grade) and dissolving the lead nitride in 25 mL of deionized water.

[0211] The sodium sulfide standard solution (50 mg / L sulfide) was prepared by precisely weighing 37 ± 2 mg of sodium sulfide into a 100 mL volumetric flask. The sulfide was dissolved and diluted to volume with 0.01 N sodium hydroxide.

[0212] For example, a 250 mg / mL deionized aqueous solution was prepared. Samples were tested in particular in 10 - mL test tubes or 4 - mL glass vials with Teflon® - lined caps. At the same time, the test vials were prepared as shown in Table 4.

[0213]

Table 4

[0214] As quality control, the four tests must meet the following requirements: i) The blank vial must be clearly transparent and colorless; ii) The standard solution vial must have no obvious dark gray color or precipitate different from the blank; iii) The specificity solution containing sulfate, sulfite, and chloride must be lighter gray than the standard solution vial, and a white precipitate is expected; iv) The sulfide - additive of the specificity solution containing sulfate, sulfite, chloride must have no darker gray color than the corresponding non - additive solution.

[0215] <b. Method Specificity> The requirements for specificity are: i) The blank vial must be clearly transparent and colorless; ii) The standard solution vial must have no obvious dark gray color or precipitate different from the blank; iii) The specificity solution containing sulfate, sulfite, chloride must be lighter gray than the standard solution vial, and a white precipitate is expected; iv) The sulfide - additive of the specificity solution containing sulfate, sulfite, chloride must have no darker gray color than the corresponding non - additive solution. All the requirements described in the procedure were met.

[0216] The test solutions were prepared to contain 1 mg / mL of sodium sulfate, sodium sulfite, and sodium chloride, respectively. Two vials of these solutions were tested for potential interference. Additionally, these tests were each performed with a sulfide additive to determine the interference of sulfide detection. The results are summarized in Table 5. The sulfide standard solution was prepared at a concentration of 50 mg / mL sulfide, and the lead sulfide reagent was prepared at a concentration of 1 g / L (Pb(II)). A gray or yellowish-brown test solution was observed.

[0217]

Table 5

[0218] The test method was shown to be specific for sulfates, sulfites, and chlorides.

[0219] <c. Detection Limit> As shown in Tables 6 and 7, the presence of sulfide in blank (water) or reagent product samples (sodium thiosulfate pentahydrate) was measured by the detection of a yellowish-brown color at 4 ppm or higher. According to the procedure, the detection limit of sulfide in the reagent sample product of sodium thiosulfate pentahydrate was measured to be 4 ppm.

[0220] The detection limit was measured to be 4 ppm, well below the limit value (10 ppm).

[0221]

Table 6

[0222]

Table 7

[0223] 〔Example 4: Method for Measuring Thiosulfate in Sodium Thiosulfate Pentahydrate〕 The concentration of sodium thiosulfate pentahydrate in the drug product was measured by ion chromatography using electrochemical resistance detection on a Dionex IonPac AS12A analytical column (P / N 046034, Dionex Corporation, Sunnyvale, CA), where elution was performed using 13.5 mM sodium carbonate (ACS reagent grade) and 1.5 mM sodium bicarbonate (ACS reagent grade) in deionized water at a rate of 1.5 mL / min over a detection range of 50 μS to 15 minutes. The ion exchange column was electrophoresed at room temperature with a suppression voltage of 100 mA.

[0224] For the preparation of the fluidized bed, a stock sodium carbonate solution (500 mM) was prepared by adding 26.5 g of sodium carbonate (ACS reagent grade) to a 500 mL volumetric flask, followed by the addition of deionized water to bring the total volume to 500 mL at room temperature. A stock sodium bicarbonate solution (500 mM) was prepared by adding 10.5 g of sodium bicarbonate (ACS reagent grade) to a 500 mL volumetric flask, followed by the addition of deionized water to bring the total volume to 500 mL at room temperature. The fluidized bed was prepared by adding 54 mL of stock sodium carbonate solution and 6 mL of stock sodium bicarbonate solution to a 2 L volumetric flask, followed by the addition of deionized water to bring the total volume to 2 L at room temperature.

[0225] A stock sodium thiosulfate standard solution (1 g / L) was prepared by adding 0.1 g of sodium thiosulfate pentahydrate to a 100 mL volumetric flask, and then adding deionized water at room temperature to bring the volume to 100 mL. A sodium thiosulfate standard sample was prepared by adding 10.0 mL of stock sodium thiosulfate solution to a 100 mL volumetric flask, and then adding deionized water at room temperature to bring the volume to 100 mL. A linear standard solution was prepared by diluting the sodium thiosulfate standard sample (12.5 mL) with deionized water to 25.0 mL.

[0226] The thiosulfate-containing samples were prepared in two batches. First, the stock sample solution was prepared by adding 2.0 mL of sample to a 100 mL volumetric flask, followed by the addition of deionized water to a volume of 100 mL at room temperature.

[0227] The suitability of the method was measured by the initial injection of a sodium thiosulfate standard sample, followed by the injection of deionized water, to ensure that there was no influence from previous samples that could interfere with the analysis. The sodium thiosulfate standard sample was subsequently injected six more times. The percentage relative standard deviation (%RSD) of the peak area of ​​the thiosulfate was calculated. The initial injection was used to calculate the Tailing coefficient and the theoretical plate value according to Method 621USP XXXII (2009). The %RSD of the peak area for the first six injections of the thiosulfate peak should be NMT 2.0%. The theoretical plate value (N) of the thiosulfate should be NLT 3,000. The %RSD area for the six injections and each subsequent calibration injection should be NMT 3.0%.

[0228] The sodium thiosulfate standard sample was injected twice, and the difference in area (%) between the two injections was determined. The difference in area (%) between the two injections must be NMT 2%, and the error of the analytical value must be NMT 2.0%. Therefore, the average area of ​​the determined reaction was used to calculate the concentrations of the previous six injections, thereby determining the difference in the percentage of concentration calculated from the actual concentrations.

[0229] The sample solution diluent was injected once to check for influence from previous samples and other peaks arising from the diluent. The peak area of ​​the reaction at the retention time of the thiosulfate should be 1% of the NMT of the reaction area relative to the thiosulfate standard sample.

[0230] The linear standard solution sample was injected twice. For the linear standard solution, the mean peak area should be 47% and 53% of the mean peak area for the method-appropriate injection. For the linear standard solution, the percentage difference between the two injections should be NMT 2%.

[0231] Each sample solution was injected in a double-barrel. The percentage difference between the two barrels was calculated. The percentage difference between the sodium thiosulfate assay concentrations between the two barrel preparations was also calculated.

[0232] The instrument was verified for accuracy by re-analyzing the sodium thiosulfate standard sample in a double-batch system after every six injections and after the final sample injection. For each sample, the percentage difference between the double-batch injections should be NMT 2.0%, and the percentage difference between the assay concentrations of thiosulfate in the double-batch preparations should be NMT 2%. The concentration of the sodium thiosulfate pentahydrate sample was calculated based on the peak area in comparison to the concentration of the thiosulfate standard solution.

[0233] [Example 5: Measurement of trace levels of sodium thiosulfate pentahydrate carbonate] All glassware was thoroughly washed at least three times with deionized water. Glassware used for gravimetric measurements may be dried in a dryer, and in extreme cases, care was taken to prevent contamination of the glassware with organic matter. Glassware used only for dilution was pre-washed at least three times with an oxidizing agent aqueous solution prepared by adding approximately 1-2 mL of concentrated phosphoric acid to 4,000 mL of deionized water, and then thoroughly washed with deionized water immediately before use. During gravimetric measurements, sterilized plastic spatulas were used instead of metal spatulas to reduce potential contamination.

[0234] A stock solution of sodium carbonate for the preparation of carbonate standards was prepared by dissolving 0.177 g of sodium carbonate (ACS reagent grade) in 100.0 mL of deionized water.

[0235] The trace carbonate concentration was 1,000 mg / L, equivalent to a carbon concentration of 200 mg / L. A series of carbonate calibration standards were prepared by pipetting 100, 200, 400, 800, and 1,000 μL of sodium carbonate stock solution into separate 200 mL volumetric flasks, and then adding deionized water to bring the volume to 200 mL at room temperature. The trace concentrations were 0.5, 1.0, 2.0, 4.0, and 5.0 mg / mL of carbonate, respectively. Care was taken to ensure that all carbonate solutions were tightly sealed and stored in a cool place away from excessive heat.

[0236] The sample was accurately weighed to approximately 0.01 mg and prepared by transferring an amount equivalent to less than 1.0 mg / L of carbon (5.0 mg / L carbonate) of the sample to a 100 mL volumetric flask. For the target substance being sodium thiosulfate pentahydrate with a critical carbonate content of ≤0.01%, if the sample contains 0.01% carbonate, then 1.00 g of the sample in 100 mL of water will produce 1 mg / L carbonate, equivalent to 0.2 mg / L of carbon. Subsequently, 20 mL of deionized water was added to the 100 mL volumetric flask to dissolve the sample. The sample solution was titrated with 0.1 N iodide VS (approximately 40 mL) until a persistent yellow color was observed (cat. # 318981, Sigma-Aldrich, St. Louis, MO). Deionized water was added at room temperature to a volume of 100 mL.

[0237] All inorganic carbon was measured using a Shimadzu TOC-V analyzer in IC mode. In IC mode, the sample was simultaneously acidified with phosphoric acid to convert inorganic carbon (carbonates and bicarbonates) to carbon dioxide, and then sent to a non-dispersive infrared detector for quantification. Pre-washed TOC vials were used in the analyzer, with each vial completely filled with its respective standard solution, leaving no space at the top. The vials were protected with lids.

[0238] In the standard setup, three measurements were performed for each vial (standard, sample, or blank). Three measurements constituted one run. Three rums of the blank (deionized water) were performed to ensure the analyzer was equilibrated and the results were consistent.

[0239] Each calibration standard was run once. The %RSD and mean reaction area were determined from three injections of each standard. Linear regression of the mean area against the standard concentration was performed against the calibration standard to determine the slope, intercept, and correlation coefficient. Blanks were included in the linear regression analysis but were not corrected to zero. One run was performed for each sample. The %RSD and mean peak area were determined from three injections, from which the carbonate concentration was calculated based on the calibration standard.

[0240] The analyzer was calibrated after the final sample injection by performing measurements after every six sample measurements and one blank measurement, followed by one run with a 2.0 mg / L calibration standard. Carbonate recovery was calculated from both %RSD and calibration standard curves.

[0241] As a quality control measure, the area (reaction) %RSD for three injections of each standard must be less than or equal to (NMT) 10%, and the calibration curve for carbonates must have a correlation coefficient of (NLT) 0.995 or higher. The area %RSD for the first blank and subsequent calibration blank injections must be less than or equal to (NMT) 15%. The area %RSD for subsequent calibration standard (2.0 mg / L) injections must be less than or equal to (NMT) 10%. The % recovery of consecutive 2.0 mg / L calibration standards must be between 85% and 115%.

[0242] The percent correlation standard deviation (%RSD) is the standard deviation divided by the expected value of 100.

[0243] [Example 6: Pharmaceutical preparation containing sodium thiosulfate pentahydrate] Table 8 lists injections and solutions containing sodium thiosulfate pentahydrate of the pharmaceutical grade used in the examples.

[0244] [Table 8]

[0245] Abbreviations: NF, International Prescription; qs, Quality Sufficiency; USP, American International Pharmacopoeia; Water for WFI Infusion.

[0246] The embodiments described above provide a person skilled in the art with all disclosures and descriptions of the methods for manufacturing and using the embodiments of these claims, and are not limited to those disclosed herein. Any modifications that would be obvious to a person skilled in the art are made within the scope of the following claims. All publications, patents, and patent applications referenced herein are included herein by reference as such publications, patents, or patent applications are expressly and each is indicated by reference herein.

Claims

1. A unit preparation containing pharmaceutical grade sodium thiosulfate, The sodium thiosulfate of the above pharmaceutical grade has the following characteristics, in unit formulations: It contains organic carbon that cannot be removed, at a concentration of 10 ppm or less; Contains mercury at a concentration of 0.05 ppm or less; Contains less than 2 ppm of aluminum; Contains 0.003% by weight or less of selenium; It contains 98% to 102% by weight of sodium thiosulfate on an anhydrous basis, as measured by ion chromatography; It has a heavy metal content of 10 ppm or less; Contains less than 200 ppm of chloride; Contains 0.001% by weight or less of sulfides; Contains 0.002% by weight or less of iron; Contains less than 0.01% by weight of calcium; Contains less than 0.005% by weight of potassium; Contains less than 0.1% sulfites; Contains less than 0.5% sulfate; Contains arsenic at a concentration of 3 ppm or less; Contains 0.001% by weight or less of lead; The total number of aerobic microorganisms in the microbial load is 100 CFU / g or less; The total number of yeasts and molds is 20 CFU / g or less; Contains bacterial endotoxins of 0.02 EU / mg or less; It contains 0.002% by weight or less of nitrogen compounds; It contains 0.005% by weight or less of insoluble matter; It contains a residue of 0.01% by weight or less of a solidification inhibitor; It contains volatile organic impurities below the ICH Q3C (R3) limit; A 10% aqueous solution at 25°C is colorless and has a pH of 6.0 to 8.

0.

2. The above-mentioned pharmaceutical grade of sodium thiosulfate contains 8 ppm or less of organic carbon that cannot be removed. The unit formulation according to claim 1.

3. The sodium thiosulfate of the above pharmaceutical grade is anhydrous. The unit formulation according to claim 1.

4. Contained in vials, The unit formulation according to claim 1.

5. A unit formulation containing a pharmaceutical composition, The above pharmaceutical composition contains a pharmaceutical grade of sodium thiosulfate contained in a pharmaceutically acceptable aqueous carrier. The sodium thiosulfate used in the preparation of the above pharmaceutical composition has the following characteristics in its unit formulation: It contains organic carbon that cannot be removed, at a concentration of 10 ppm or less; Contains mercury at a concentration of 0.05 ppm or less; Contains less than 2 ppm of aluminum; Contains 0.003% by weight or less of selenium; It contains 98% to 102% by weight of sodium thiosulfate on an anhydrous basis, as measured by ion chromatography; It has a heavy metal content of 10 ppm or less; Contains less than 200 ppm of chloride; Contains 0.001% by weight or less of sulfides; Contains 0.002% by weight or less of iron; Contains less than 0.01% by weight of calcium; Contains less than 0.005% by weight of potassium; Contains less than 0.1% sulfites; Contains less than 0.5% sulfate; Contains arsenic at a concentration of 3 ppm or less; Contains 0.001% by weight or less of lead; The total number of aerobic microorganisms in the microbial load is 100 CFU / g or less; The total number of yeasts and molds is 20 CFU / g or less; Contains bacterial endotoxins of 0.02 EU / mg or less; It contains 0.002% by weight or less of nitrogen compounds; It contains 0.005% by weight or less of insoluble matter; It contains a residue of 0.01% by weight or less of a solidification inhibitor; It contains volatile organic impurities below the ICH Q3C (R3) limit.

6. The above-mentioned pharmaceutically acceptable aqueous carrier is sterile water injection solution. The unit formulation according to claim 5.

7. The above-mentioned pharmaceutical grade of sodium thiosulfate contains 8 ppm or less of organic carbon that cannot be removed. The unit formulation according to claim 6.

8. The above pharmaceutical composition is formulated for intravenous administration. The unit formulation according to claim 6.

9. The above pharmaceutical composition is formulated for intravenous administration. The unit formulation according to claim 6.

10. The above pharmaceutical composition further comprises an isotonic agent and one or more pH adjusters. The unit formulation according to claim 6.

11. The above pharmaceutical composition is sterile and suitable for intravenous administration. The above isotonic agent is potassium chloride at a concentration of 4.40 mg / mL. The pH adjusting agents mentioned above are sodium hydroxide and 2.80 mg / mL of boric acid. The unit formulation according to claim 10.

12. The above-mentioned pharmaceutical grade of sodium thiosulfate exists as sodium thiosulfate pentahydrate at a concentration of 250.0 mg / mL (concentration measured on an anhydrous basis). The unit formulation according to claim 11.

13. The sodium thiosulfate of the above pharmaceutical grade used in the preparation of the above pharmaceutical composition is anhydrous. The unit formulation according to claim 6.

14. The above pharmaceutical composition contains 140 mg of boric acid and 220 mg of potassium chloride. The unit formulation according to claim 11.

15. The above-mentioned pharmaceutically acceptable grade of sodium thiosulfate is present as 12.5 g of sodium thiosulfate pentahydrate (concentration measured on an anhydrous basis), The unit formulation according to claim 14.

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