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 US Provisional Application No. 61 / 223,993, filed July 8, 2009, which is incorporated herein by reference.

[0002] [Technical field] The present invention provides pharma- ceutically acceptable sodium thiosulfate (e.g., sodium thiosulfate pentahydrate) and pharma- ceutically acceptable compositions thereof. The present invention also provides a method for measuring total non-purgeable organic carbon in a sample containing sodium thiosulfate. The present invention further provides a method for producing pharma-ceutically acceptable sodium thiosulfate. The present invention still further provides a method of treatment comprising administering pharma-ceutically acceptable sodium thiosulfate.

[0003] [Background technology] Sodium thiosulfate has numerous industrial applications, including such uses as removing chlorine from solutions, bleaching paper pulp, and extracting silver from ores. Sodium thiosulfate is also used as a mordant in photographic fixatives, transition coloring and printing, and as a component of medicines. Although thousands of metric tons of sodium thiosulfate pentahydrate are produced annually, only a few hundred kilograms are utilized pharmaceuticalally for the production of sodium thiosulfate injections, which have recently been shown to treat prussic acid poisoning, or for the production of lotions containing sodium thiosulfate pentahydrate for the treatment of tinea versicolor. Sodium thiosulfate pentahydrate has previously been reported to be effective in the treatment of calciphylaxis (Ackermann et al., Archives of Dermatology 2007, 143(10): 1336-1337). It has also been reported to be an effective treatment for preventing platinum-induced toxic inner ear damage and nephrotoxicity associated with the use of platinum-containing chemotherapy agents (Skinner, Current Opinions in Oncology 1995, 7(4): 310-315).

[0004] Pharmaceutical manufacturing is regulated by the United States Food and Drug Administration (FDA). Based on the passage of the Federal Food Drug and Cosmetic Act in1938, the FDA requires that new pharmaceutical products and their corresponding active ingredients should be manufactured according to the high requirements of "pharmaceutical grade" Good Manufacturing Practices as detailed in the Code of Federal Regulations 21 (CFR211). Due to the relatively small amounts of sodium thiosulfate pentahydrate traditionally used in pharmaceutical formulations, there have been no raw material suppliers that manufacture sodium thiosulfate pentahydrate according to "pharmaceutical grade" Good Manufacturing Practices.

[0005] In addition to regulating manufacturing practices, the FDA has strict 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 the passage of the Federal Food, Drug, and Cosmetic Act of 1938. As specified in the act, the FDA requires that new drugs and their active ingredients should be manufactured according to good manufacturing practices of "pharmaceutical grade" and meet applicable quality standards. When the Food, Drug, and Cosmetic Act was passed in 1938, drugs that were already on the market were classified as "grandfathered drugs" and were allowed to remain on the market without formal FDA approval if the drug and its labeling were not changed. Any change to the drug or its labeling makes the "grandfathered drug" a "new" drug that is subject to the specifications and quality standards imposed by the FDA. The currently available sodium thiosulfate pentahydrate injection, labeled only for use in treating production poisoning, and sodium thiosulfate pentahydrate-containing lotion, labeled only for use in treating tinea versicolor, are "grandfathered medications." As a result, the drug formulations and corresponding quality specifications have remained unchanged for decades.

[0006] In anticipation of receipt of New Drug Applications for drugs containing sodium thiosulfate pentahydrate, the FDA recently announced that sodium thiosulfate pentahydrate raw material for new drug products must be manufactured according to "pharmaceutical grade" good manufacturing practices and must comply with a new set of quality specifications. This new set of quality specifications is more extensive and stringent than the existing quality specifications. Currently available sodium thiosulfate raw material does not meet this new set of FDA quality standards and is not suitable for use in new drug formulations. As a result, in order to translate recent sodium thiosulfate research findings into FDA-approved clinical therapies, there is a clear and unmet need for purified sodium thiosulfate raw material manufactured according to "pharmaceutical grade" good manufacturing practices and that meets the new set of quality specifications.

[0007] Another hurdle in developing pharmaceutical grade sodium thiosulfate pentahydrate is the lack of an effective analytical method to measure the total non-removable organic carbon 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 must be removed before measuring the organic carbon content in the sample. This is typically accomplished by adding 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 and any remaining non-removable (non-volatilized) total organic carbon is converted to carbon dioxide at a temperature of approximately 680° C. The amount of carbon dioxide produced is then measured using an infrared meter. However, this conventional method cannot be used to analyze samples containing sodium thiosulfate. Upon exposure to acid, sodium thiosulfate pentahydrate decomposes into sulfur, which can precipitate during analysis. Salts from sodium thiosulfate pentahydrate can also precipitate during analysis. Precipitation can damage laboratory equipment and can interfere with analysis. Therefore, a need also exists for an analytical method to measure the irremovable total organic carbon in samples containing sodium thiosulfate pentahydrate.

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

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

[0010] The present invention also provides a method for measuring total irremovable organic carbon in a sample containing sodium thiosulfate, comprising the steps of: (a) contacting the sample with a volume of an 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 volume of an oxidizing agent; and (d) converting organic carbon in the sample solution to carbon dioxide under supercritical water oxidation (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 process for preparing sodium thiosulfate comprising 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 with activated carbon; and (f) crystallizing sodium thiosulfate pentahydrate from the solution.

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

[0013] The present invention also provides a method for treating or preventing platinum-induced toxic inner ear disorders (e.g., associated with the use of cisplatin or other platinum-containing drugs), comprising administering a therapeutically effective amount of the sodium thiosulfate of the present invention to a subject suffering from or at risk of suffering from platinum-induced toxic inner ear disorders, e.g., associated with the use of cisplatin or other platinum-containing drugs.

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

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

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

[0017] The present invention also provides a method of treating a dermatological disease or skin-related condition, including but not limited to bacterial infection of the skin, fungal infection of the skin, viral infection of the skin, fungal infection of the nail, bacterial infection of the nail, viral infection of the nail, fungal infection of the nail bed, bacterial infection of the nail bed, viral infection of the nail bed, psoriasis, scleroderma, inflammation of the skin, inflammation of the nail, and inflammation of the nail bed, comprising administering to a subject having a dermatological disease or skin-related condition a therapeutically effective amount of the sodium thiosulfate of the present invention.

[0018] Detailed Description To facilitate understanding of the disclosure herein, a number of terms are defined below.

[0019] Generally, the nomenclature used herein and the laboratory procedures in inorganic chemistry, analytical chemistry, organic chemistry, medicinal chemistry and pharmacology are well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In the event that there are a plurality of definitions for a term used herein, the definition in this section prevails unless otherwise specified.

[0020] The term "subject" refers to animals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with reference to a mammalian subject (e.g., a human subject). In one embodiment, the subject is suffering from or at risk of suffering from a disease, disorder, or condition, or a symptom thereof, which can be treated, prevented, or alleviated by administration of sodium thiosulfate.

[0021] The term "host" refers to a unicellular or multicellular organism in which a virus can replicate, including, but not limited to, cells, cell lines, and animals (eg, humans).

[0022] "Treat," "treating," or "treatment" is intended to include the alleviation or elimination of one or more of the disorders, diseases, or conditions, or symptoms associated with the disorders, diseases, or conditions, or the alleviation or eradication of the cause of the disorders, diseases, or conditions themselves.

[0023] The terms "prevent", "preventing" and "prevention" are intended to include methods of delaying and / or arresting the onset of a disorder, disease or condition and / or its attendant symptoms, of barring a subject from acquiring a disease, or of reducing the risk that a subject will acquire a disorder, disease or condition.

[0024] The term "therapeutically effective amount" is intended to include an amount of a compound (e.g., sodium thiosulfate) that, when administered, is sufficient to treat or prevent the development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound (e.g., sodium thiosulfate) sufficient to elicit the biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or clinician.

[0025] The terms "pharmaceutical acceptable carrier", "pharmaceutical acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, vehicle (e.g., a liquid (such as water, e.g., deionized or sterile water) or a solid filler), diluent, excipient, solvent, or encapsulating material. In one embodiment, any component is "pharmaceutical acceptable" so long as it is compatible with other components of a pharmaceutical formulation, and is suitable for use in contact with cells, tissues, or organs of humans and animals without excessive toxicity, hypersensitivity, allergic response, immunogenicity, or other problem or complication 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 term "about" or "approximately" refers to 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 term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, the value following the term "about" or "approximately" is intended to be exact.

[0027] The terms "active pharmaceutical ingredient", "active ingredient" and "active substance" refer to a compound administered to a subject, alone or in combination with one or more pharma- ceutically 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" may be an optically active isomer of a compound described herein. As used herein, "active pharmaceutical ingredient", "active ingredient" and "active substance" may be an anhydrous, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate or other hydrate forms of sodium thiosulfate.

[0028] The term "sodium thiosulfate" includes anhydrous, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or other hydrate forms of sodium thiosulfate. In one embodiment, "sodium thiosulfate" referred to herein refers to sodium thiosulfate pentahydrate (NaSO.5H0). In another embodiment, the sodium thiosulfate refers to pharmaceutical grade. As used herein with respect to sodium thiosulfate, the term "pharmaceutical grade" means that the sodium thiosulfate is manufactured in accordance with "pharmaceutical grade" good manufacturing practice (GMP) as detailed in the Code of Federal Regulations 21 (CFR 211) and meets one or more of the purification levels listed herein.

[0029] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more of the 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, causing the compound to precipitate.

[0031] The terms "non-removable organic carbon (NPOC)" and "non-removable organic carbon (NVOC)" refer to organic carbon-based substances that are not volatilized and removed from a material when exposed to acid.

[0032] [Sodium thiosulfate] The present invention provides sodium thiosulfate in a purified form (e.g., sodium thiosulfate pentahydrate (NaSO.5HO)). 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 all of one or more of the FDA standards for sodium thiosulfate 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 Code of Federal Regulations 21 (CFR 211).

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

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

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

[0036] In one embodiment, the 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 color change after the addition of a few drops of iodine TS.

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

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

[0040] In one embodiment, the sodium thiosulfate pentahydrate provided herein contains from about 99% to about 100.5% by weight of sodium thiosulfate calculated on an anhydrous basis. In certain embodiments, the amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate provided herein is measured according to USP colorimetric analysis (USP XXXII (2009)).

[0041] In one embodiment, the sodium thiosulfate pentahydrate provided herein contains greater than or equal to about 98% and less than or equal to about 102% by weight sodium thiosulfate on an anhydrous basis as measured by ion chromatography.

[0042] In one embodiment, the sodium thiosulfate pentahydrate of the present invention contains from about 98% to about 102% by weight of sodium thiosulfate, calculated on an anhydrous basis. In certain embodiments, the amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate of the present invention is determined by ion chromatography. In certain embodiments, 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 provided herein has a pH of about 6.0 to about 8.0 when measured in a 10% solution at 25° C. In certain embodiments, the pH of the sodium thiosulfate provided herein is measured using a pH meter. In certain embodiments, the pH of the sodium thiosulfate provided herein is determined according to Method 791 in USP XXXII (2009).

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

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

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

[0047] In yet another embodiment, the sodium thiosulfate of the present invention contains about 0.005% or less by weight 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 with hot water, drying, cooling in a desiccator, and weighing.

[0048] In yet another embodiment, the sodium thiosulfate provided herein has about 200 ppm or less of chloride. In certain embodiments, the chloride content in the sodium thiosulfate provided herein is determined according to Method 221 in USP XXXII (2009).

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

[0050] In yet another embodiment, the sodium thiosulfate provided herein has about 0.001% or less by weight lead. In certain embodiments, the lead content in the sodium thiosulfate provided herein is determined according to Method 251 in USP XXXII (2009).

[0051] In yet another embodiment, the sodium thiosulfate provided herein has about 0.01% or less calcium by weight. In certain embodiments, the calcium content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the calcium content in the sodium thiosulfate provided herein is determined using flame emission spectrophotometry (FES).

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

[0053] In yet another embodiment, the sodium thiosulfate provided herein has about 0.005% or less potassium by weight. In certain embodiments, the potassium content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the potassium content in the sodium thiosulfate provided herein is determined using FES.

[0054] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.05% or less by weight sulfite, alternatively about 0.1% or less by weight sulfite. In certain embodiments, the sulfite content of the sodium thiosulfate provided herein is determined according to the method for determining sulfite in the American Chemical Society, Reagent Chemicals, 10th Edition, which is incorporated herein by reference in its entirety.

[0055] In yet another embodiment, the sodium thiosulfate provided herein 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 certain embodiments, the sulfate content in the sodium thiosulfate provided herein is determined according to the method for determining sulfate in the American Chemical Society, Reagent Chemicals, 10th Edition.

[0056] In yet another embodiment, the sodium thiosulfate provided herein contains less than or equal to about 0.001% by weight sulfide. In certain embodiments, the sulfide content of the sodium thiosulfate provided herein is determined by the addition of lead(II) nitrate using the methods described herein.

[0057] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.002% by weight or less of nitrogen compounds (e.g., N). In certain embodiments, the nitrogen compounds (e.g., N) content in the sodium thiosulfate provided herein is determined according to the method for determination of nitrogen compounds in the American Chemical Society, Reagent Chemicals, 10th Edition.

[0058] In yet another embodiment, the sodium thiosulfate of the present invention contains 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 of volatile organic impurities. In certain embodiments, the sodium thiosulfate of the present invention contains volatile organic impurities or specific solvents (e.g., ethanol) at or below certain limits set forth in ICH Q3C(R3). The disclosure of ICH Q3C(R3) is incorporated herein by reference in its entirety. In certain embodiments, the content of volatile organic impurities is determined according to Method 467 in USP XXXII (2009).

[0059] In yet 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 certain embodiments, the sodium thiosulfate of the present invention contains a total NPOC of about 12 ppm or less. In certain embodiments, the total NPOC in the sodium thiosulfate of the present invention is determined using the methods described herein. In certain embodiments, the total NPOC in the sodium thiosulfate of the present invention is determined by a method comprising the steps of: (a) contacting sodium thiosulfate with a quantity of an 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 quantity of an oxidizing agent; and (b) converting organic carbon in the sample solution to carbon dioxide under supercritical water oxidation (SCWO) conditions.

[0060] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.05 ppm or less of mercury. In certain embodiments, the mercury content of the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the mercury content of the sodium thiosulfate provided herein is determined using ICP-OES. In certain embodiments, the mercury content of the sodium thiosulfate provided herein is determined according to Method 261 in USP XXXII (2009).

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

[0062] In yet another embodiment, the sodium thiosulfate provided herein contains about 3 ppm or less of arsenic. In certain embodiments, the arsenic content of the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the arsenic content of the sodium thiosulfate provided herein is determined using ICP-OES. The arsenic content of the sodium thiosulfate provided herein is determined according to Method 211 in USP XXXII (2009).

[0063] In yet another embodiment, the sodium thiosulfate of the present invention contains about 0.003% or less by weight 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 yet another embodiment, the microbial load of the sodium thiosulfate provided herein is less than or equal to about 100 colony forming units per gram (CFU / g). The total aerobic microbial load of the sodium thiosulfate provided herein is determined according to Method 61 in USP XXXII (2009).

[0065] In yet another embodiment, the total yeast and mold count in the sodium thiosulfate provided herein is about 20 CFU / g or less. The total yeast and mold count in the sodium thiosulfate provided herein is determined according to Method 61 in USP XXXII (2009).

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

[0067] In yet another embodiment, the sodium thiosulfate provided herein contains an anti-caking agent residual of 0.01% or less by weight.

[0068] In yet another embodiment, the sodium thiosulfate provided herein is characterized by one or more of the following: Contains not less than about 99% and not more than about 100.5% by weight sodium thiosulfate on an anhydrous basis as determined in accordance with USP colorimetric analysis; Contains not less than about 98% and not more than about 102% by weight sodium thiosulfate on an anhydrous basis as determined according to an ion chromatography method; A 10% solution has a pH of about 6 to about 8 at 25°C; having a moisture content of about 32% to about 37% by weight; Appears as colorless crystals; As a 10% solution it has a clear and colorless appearance; It is odorless; positive identification test for sodium; positive identification test for thiosulfate; Does not produce turbidity when mixed with Ammonium Oxalate TS; Heavy metal content is approximately 10 ppm or less; Contains about 0.01% by weight or less of carbonate; Contains less than about 0.005% by weight insoluble matter; Contains approximately 200 ppm or less of chloride; Contains less than about 0.001% by weight of sulfides; Contains about 0.05% or less by weight, or about 0.1% or less by weight, of sulfites; Contains about 0.05% or less, about 0.1% or less, about 0.25% or less, or about 0.5% or less by weight of sulfate; Contains less than about 0.002% by weight iron; Contains less than about 0.01% by weight calcium; Contains less than about 0.005% by weight potassium; containing about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or about 5000 ppm or less of volatile organic impurities; Contains total NPOCs of 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; Contains approximately 0.05 ppm or less of mercury; Contains approximately 2 ppm or less of aluminum; Contains approximately 3 ppm or less of arsenic; Contains not more than 0.001% lead by weight; Contains less than about 0.002% by weight of nitrogen compounds (e.g., N); Contains less than about 0.003% by weight selenium; Contains less than 0.01% by weight of an anti-caking agent residual; The microbial load is approximately 100 CFU / g or less of total aerobic microorganisms; A total yeast and mold count of approximately 20 CFU / g or less; and Contains less than about 0.02 EU / mg, less than about 0.1 EU / mg, or less than about 0.25 EU / mg bacterial endotoxin.

[0069] In yet another embodiment, the sodium thiosulfate provided herein is characterized by one or more of the following; Contains not less than about 99% and not more than about 100.5% by weight sodium thiosulfate on an anhydrous basis as determined in accordance with USP colorimetric analysis; Contains not less than about 98% and not more than about 102% by weight sodium thiosulfate on an anhydrous basis as determined according to an ion chromatography method; A 10% solution has a pH of about 6 to about 8 at 25°C; having a moisture content of about 32% to about 37% by weight; Appears as colorless crystals; As a 10% solution it has a clear and colorless appearance; It is odorless; positive identification test for sodium; positive identification test for thiosulfate; Does not produce turbidity when mixed with Ammonium Oxalate TS; Heavy metal content is approximately 10 ppm or less; Contains about 0.01% by weight or less of carbonate; Contains less than about 0.005% by weight insoluble matter; Contains approximately 200 ppm or less of chloride; Contains less than about 0.001% by weight of sulfides; Contains about 0.05% or less by weight, or about 0.1% or less by weight, of sulfites; Contains about 0.05% or less, about 0.1% or less, about 0.25% or less, or about 0.5% or less by weight of sulfate; Contains less than about 0.002% by weight iron; Contains less than about 0.01% by weight calcium; Contains less than about 0.005% by weight potassium; containing about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or about 5000 ppm or less of volatile organic impurities; Contains total NPOCs of 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; Contains approximately 0.05 ppm or less of mercury; Contains approximately 2 ppm or less of aluminum; Contains approximately 3 ppm or less of arsenic; Contains not more than 0.001% lead by weight; Contains less than about 0.002% by weight of nitrogen compounds (e.g., N); Contains less than about 0.003% by weight selenium; The microbial load is approximately 100 CFU / g or less of total aerobic microorganisms; A total yeast and mold count of approximately 20 CFU / g or less; and Contains less than about 0.02 EU / mg, less than about 0.1 EU / mg, or less than about 0.25 EU / mg bacterial endotoxin.

[0070] In certain embodiments, when sodium thiosulfate is described as "comprising up to" a particular amount of a particular material, the 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 comprising 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 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), dimethylsulfoxide (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, it is a mixture of water and a solvent that is miscible with water. Water-miscible solvents 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), dimethylsulfoxide (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 contacting 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 contacting 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 contacting step is about 1.3 M to about 1.5 M.

[0076] In certain embodiments, the contacting step is carried out at a temperature in the following ranges: about 40 to 150°C, about 70 to 120°C, about 90 to 110°C, about 90 to 100°C, or about 95 to 150°C. In one embodiment, the temperature in the contacting step is about 90°C to about 100°C. In another embodiment, the temperature in the contacting step is about 95°C to about 100°C. In yet another embodiment, the temperature in the contacting step is about 97°C.

[0077] In certain embodiments, the contacting step is carried out at a predetermined pH of 13 or more, 12 or more, 11 or more, 10 or more, 9 or more, 8 or more, or 7 or more. In certain embodiments, the predetermined pH is about 6-11, about 6.5-10.5, about 7-10, about 7-9, about 7-8.5, or about 7-8. In certain embodiments, a base is added to the reaction mixture in the contacting step to adjust the pH 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 carried out at a temperature in the following ranges: about 5 to about 100° C., about 10 to about 50° C., about 15 to about 40° C., about 20 to about 30° C., or about 20 to about 35° C. In certain embodiments, the filtering step is carried out at room temperature (about 21° C.).

[0079] In certain embodiments, the concentrating step is performed by evaporation of the solvent, including 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 concentrating step is performed at a temperature in the following 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 concentrating step is performed at about 50°C. In certain embodiments, the concentrating step is performed under reduced pressure. In certain embodiments, the concentrating step is carried out under the following pressures: about 100 to about 755 mmHg, about 300 to about 755 mmHg, about 500 to about 755 mmHg, about 600 to about 740 mmHg, or about 700 to about 730 mmHg. In certain embodiments, the concentrating step is carried out at about 700 to about 730 mmHg.

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

[0081] In certain embodiments, the solution containing the activated carbon is filtered again at about 20-55° C., or at about 40-55° C. In certain embodiments, the filtering again step is performed at about 50° C.

[0082] In certain embodiments, sodium thiosulfate pentahydrate is crystallized from the concentrated and refiltered solution using conventional methods (cooling, chilling, solvent evaporation, addition of an anti-solvent, or back-addition to an anti-solvent).

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

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

[0085] Characterization of the method: Determination of irremovable total organic carbon in sodium thiosulfate. The present invention provides a method for measuring total irremovable organic carbon in a sample containing sodium thiosulfate, comprising the steps of: (a) contacting the sample with a volume of an 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 volume of an oxidizing agent; and (d) converting organic carbon in the sample solution to carbon dioxide under supercritical water oxidation (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%, about 50% of the final volume of the sample solution. In yet another embodiment, 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] Precipitates in an aqueous sample solution, if present, can be readily removed from the sample solution by methods known to those of skill in the art. In certain embodiments, precipitates are removed from the sample solution by filtration. In certain embodiments, precipitates are 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 according to any SCWO process known in the art, for example, as disclosed in U.S. Pat. Nos. 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, the disclosures of each of which are incorporated herein by reference in their entirety. In a specific embodiment, the SCWO process is performed in an InnovOx laboratory TOC Analyzer (GE Analytical Instruments, Inc., Boulder, CO.). The SCWO process takes advantage of the unique properties of TOC only under conditions near or above the thermodynamic critical points of water (i.e., 375° C. and 218 atm). The increase in pressure under supercritical water oxidation conditions dramatically increases the efficiency of the oxidation process by converting organic carbon in samples containing sodium thiosulfate to carbon dioxide.

[0090] In certain embodiments, the sample solution containing sodium thiosulfate is prepared by adding 5.0 g of a sample containing 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 measuring the amount of carbon dioxide formed after oxidation. In certain embodiments, the carbon dioxide is quantified using an infrared detector. In certain embodiments, the carbon dioxide is quantified using a non-dispersive infrared detector.

[0092] Pharmaceutical Compositions The pharmaceutical compositions herein comprise sodium thiosulfate as an active ingredient, alone or together with a pharma- ceutically acceptable vehicle, carrier, diluent, excipient, or mixture thereof.

[0093] Sodium thiosulfate may be administered alone or with one or more other active ingredients. The pharmaceutical compositions containing sodium thiosulfate may be formulated in various dosage forms for oral, parenteral (parenteral), and topical administration. The pharmaceutical compositions may be formulated as release dosage forms, including delayed-, sustained-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, and immediate-, targeted-, programmed-release, and gastric-retentive dosage forms. These dosage forms may be prepared according to conventional techniques 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 pharmaceutical composition may be in the form of an oral dosage form comprising the sodium thiosulfate and one or more pharma- ceutically acceptable excipients or carriers.

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

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

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

[0098] Also, in one embodiment, the pharmaceutical composition includes sodium thiosulfate, one or more isotonicity agents, and one or more pH adjusting agents. In another embodiment, the pharmaceutical composition includes sodium thiosulfate, one or more isotonicity agents, one or more buffering agents, or one or more pH adjusting agents. In particular, the pharmaceutical composition includes sodium thiosulfate, potassium chloride, boric acid, and sodium hydroxide. Also, in particular, the pharmaceutical composition includes sodium thiosulfate, potassium chloride, boric acid, sodium hydroxide, and water (e.g., water for injection).

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

[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 produce the desired effect, together with the required pharmaceutical carrier or excipient. Examples of the unit-dosage form include ampoules, syringes, and individually packaged tablets and capsules. The unit-dosage form can be administered in one or 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. For example, vials, bottles of tablets or capsules, or pint or gallon bottles can be exemplified.

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

[0102] <A. Oral Administration> The pharmaceutical composition may be provided in a solid, semi-solid, or liquid dosage form for oral administration. In use, oral administration may be buccal, lingual, or sublingual. Preferred oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated 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 active ingredient, the pharmaceutical composition may include one or more pharma- ceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, and flavorings.

[0103] Binders or granulators provide cohesiveness to the tablet to keep it intact after compression. Preferred binders or granulators include, but are not limited to, starches such as corn starch, potato starch, and pre-gelatinized (e.g., STARCH 1500); sugars such as sucrose, glucose, dextrose, molasses, and lactose; acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, and the like. Natural and synthetic thickeners such as arabogalactan, tragacanth powder, and guar gum sugar; celluloses such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA), and mixtures thereof. Preferred fillers include, but are not limited to, 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 pharmaceutical composition at about 50 to about 99% by weight.

[0104] Preferred diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, tristarch, and sugar powder. The diluents of mannitol, lactose, sorbitol, sucrose, and inositol sugar, when present in sufficient amounts, can impart the compressed tablet with the ability to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0105] Preferred disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; thickeners such as guar gum and veegum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical composition varies depending on the composition and is readily discernible to one skilled in the art. The pharmaceutical composition may contain about 0.5-15% by weight, or 1-5% by weight of 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 laurate, 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 pharmaceutical composition may contain about 0.1-5% by weight of the lubricant.

[0107] Preferred glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Coloring agents include permitted or approved water-soluble FD&C dyes, suspensions of insoluble FD&C dyes on alumina hydroxide, and color lakes and mixtures thereof. Color lakes are water-soluble dyes that have been insolubilized by adsorption onto heavy metal hydroxides. Flavoring agents include natural flavors extracted from fruits and other plants, and mixtures of artificial agents that impart a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Preferred emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monolate (TWEEN® 20), polyoxyethylene sorbitan monolate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl paraben, benzoic add, sodium benzoate, and alcohol. Wetting agents 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 can include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0108] It should be understood that many carriers or excipients serve different functions within the same composition.

[0109] The pharmaceutical compositions include compressed tablets, tablet powders, chewable candies, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated, 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 intestine to protect the active ingredient from the acidic environment in the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by a sugar coating, which has the advantage of masking unpleasant tastes and odors and protecting the tablet from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings provide similar performance to sugar coatings. Multiple compressed tablets are compressed tablets formed by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0110] Tablet dosage forms may be prepared by combining the active ingredient in powdered, crystalline, or granular form with carriers or excipients, including, alone or in combination with one or more of the above-mentioned binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and sweetened lozenges.

[0111] The pharmaceutical composition may be provided in a soft or hard capsule, which may be made of gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules are known as dry-filled capsules (DFC), which consist of two sections, one slipping over the other to completely enclose the active ingredient. Soft elastic capsules (SEC) are soft, gelatin-like, spherical shells plasticized with the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to inhibit microbial growth. Preferred preservatives include methyl and propyl parabens, sorbic acid, as described above. Liquid, semi-solid, and solid dosage forms may be contained within the capsule. Preferred liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, 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. Capsules can also be coated with any coating known to those skilled in the art to modify or maintain the insolubility of the active ingredients.

[0112] The pharmaceutical compositions may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions may be biphasic, i.e., one liquid dispersed throughout the other in the form of fine particles, oil-in-water or water-in-oil. Emulsions may contain a pharma- ceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharma-ceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may contain a pharma-ceutically acceptable di(lower alkyl)acetal of a lower alkyl aldehyde (e.g., acetaldehyde diethyl acetal); and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol or ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, such as, for example, sugar syrup, and may contain a preservative. For a liquid dosage form, for example, the solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, e.g., water, to be suitable for the desired administration.

[0113] Other useful liquid and semi-solid dosage forms include, but are not limited to, a composition comprising the active ingredient and 1,2-dimethoxymethane, dialkylated mono- or polyalkylene glycols, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where the average molecular weight of the 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, bisulfites, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamates.

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

[0115] The 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 may be utilized in all of the dosage forms described above.

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

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

[0119] <B. Parenteral Administration> The pharmaceutical composition may be administered by injection, infusion, or implantation for local or systemic administration. Parenteral administration includes administration into the vein, artery, peritoneal cavity, intrathecal space, intraventricular space, uterus, intrasternal space, intracranial space, muscle, intrasynovial space, bladder, and subcutaneous tissue.

[0120] The pharmaceutical compositions may be in a suitable form for parenteral administration, such as solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid upon injection. Such formulations may be made according to conventional techniques known to those skilled in the art of pharmacology (see Remington: The Science and Practice of Pharmacy, supra).

[0121] The pharmaceutical compositions for parenteral administration may include one or more pharma- ceutically acceptable carriers and excipients, which may include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents (e.g., but not limited to, potassium chloride, mannitol, sodium chloride, dextran, and glucose), buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents (including, but not limited to, acids such as boric acid, or bases such as sodium hydroxide), and inert gases.

[0122] Preferred aqueous vehicles may include, but are not limited to, water, saline, saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection.Non-aqueous vehicles may include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium chain triglycerides of coconut oil, and palm kernel oil. Water-miscible vehicles can include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethylsulfoxide.

[0123] Preferred antimicrobial agents or preservatives may include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl-para-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparaben, and sorbic acid. Preferred isotonicity agents may include, but are not limited to, sodium chloride, glycerin, dextrose. Preferred buffers may 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, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preferred emulsifying agents include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Preferred sequestering or chelating agents include, but are not limited to, EDTA. Preferred pH adjusting agents 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, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0124] The pharmaceutical composition may be in a single or multiple dosage form. Single dosage forms are packaged in ampoules, vials, or syringes. Multiple dosage forms for parenteral administration must contain an antibacterial agent in a bacteriostatic or fungistatic concentration. All compositions for parenteral administration must be sterilized by known techniques.

[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, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle at the time of use. In another embodiment, the pharmaceutical composition is prepared as a ready-to-use sterile suspension. In another embodiment, the pharmaceutical composition is provided as a dry water-insoluble product, which is reconstituted with a vehicle at the time of use. In another embodiment, the pharmaceutical composition may be provided as a ready-to-use sterile emulsion.

[0126] The pharmaceutical compositions may be provided in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

[0127] The pharmaceutical composition may be prepared as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In other embodiments, the pharmaceutical composition is dispersed in a solid internal matrix surrounded by an external polymeric membrane that is dispensable to body fluids and permits diffusion of the active ingredient from the pharmaceutical composition.

[0128] Preferred inner matrices include hydrophilic polymers such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially 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 mucous membranes. The topical administration can include administration to the skin (intradermal), intracorneal, intracrown, 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] Pharmaceutically acceptable carriers and excipients suitable for topical administration include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

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

[0134] The pharmaceutical composition may be provided in the form of an ointment, cream, or gel. Preferred ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoic lard, olive oil, cottonseed oil, other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearic sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointments, including polyethylene glycols of various molecular weights; water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, which may be emulsifying vehicles including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient to the skin, but generally require antioxidants and preservatives.

[0135] Preferred cream bases can be oil-in-water or water-in-oil. Cream vehicles can be water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, typically contains petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume and typically contains a humectant. Emulsifiers in creams can be nonionic, anionic, cationic, or amphoteric surfactants.

[0136] Gels are semi-solid, suspension systems. Monolayer gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Preferred gelling agents may include crosslinked acrylic polymers such as carbomer, carboxypolyalkylene, CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth, xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersing agents such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0137] The pharmaceutical compositions may be administered rectally, urethrally, vaginally, or perivaginally in the form of suppositories, pessaries, bougies, poultices or patches, pastes, powders, cosmetics, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas, which may be prepared using conventional techniques (see Remington: The Science and Practice of Pharmacy, supra).

[0138] Rectal, urethral and vaginal suppositories are solid substrates for insertion into body orifices, which are solid at room temperature but melt or soften at body temperature to release the active ingredient into the orifice. Pharmaceutically acceptable carriers for use in rectal and vaginal suppositories include substrates or vehicles such as hardeners that provide a melting point near body temperature; and antioxidants such as bisulfites and sodium metabisulfite. Preferred vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), whale oil, paraffin, white and yellow waxes, and hydrogels such as optimal mixtures of mono-, di- and triglycerides of fatty acids, polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid, and glycerin gelatin. Combinations of various vehicles can be utilized. Rectal and vaginal suppositories can be obtained by compression or molding. The typical weight of a rectal and vaginal suppository is about 2-3 g.

[0139] The 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 pharmaceutical composition may be administered by inhalation into the nasal cavity or airways. The pharmaceutical composition may be provided in the form of an aerosol or solution, which may be used for drug delivery using a pressurized container, pump, spray, atomizer, such as an atomizer for generating a fine mist using electrohydrodynamics, or a nebulizer, alone or in combination with a suitable propellant. Propellants may include 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical composition may be provided as a dry powder for inhalation, alone or in combination with an insert carrier, such as lactose or phospholipids; and nasal drops. For intranasal administration, the powder may include a bioadhesive agent, including chitosan or cyclodextrin.

[0141] Solutions or suspensions for use in pressure vessels, pumps, sprays, atomizers, or nebulizers may be composed 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 methods such as the spiral jet mill method, the fluidized bed jet mill method, the supercritical fluid treatment method for forming nanoparticles, the high-pressure homogenization method, or the spray drying method.

[0143] Capsules, foaming agents, and cartridges for use in inhalers or nebulizers can be composed 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 can be configured for immediate release or modified release, such as delayed, sustained, pulsed, controlled, targeted, and programmed release.

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

[0146] Examples of modified release include, but are not limited to, those disclosed in 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; Examples include 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 pharmaceutical compositions in modified release dosage forms may be prepared using matrix sustained release devices using techniques 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 pharmaceutical composition in a modified release dosage form can be formed using an erodible matrix device that is a water-swellable, disintegrable, or soluble polymer, including, for example, synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0149] Materials that can be used to form the disintegratable matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, gum taragacanth, 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 ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), 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 hydroxyethyl cellulose (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-hydroxybutyric 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) chloromethacrylate.

[0150] In another embodiment, the pharmaceutical composition may be formed in a non-disintegrating matrix device. The active ingredient is dissolved or dispersed within the inert matrix and is released primarily by diffusion through the inert matrix after administration. Preferred materials for use as non-disintegrating matrix devices include, but are not limited to, polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, methylacrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin, butyl rubber ethylene terephthalate ... These include insoluble plastics such as hydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol copolymers, and ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, and hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydroxylated polyvinyl acetate, and lipid compounds such as carnauba wax, microcrystalline wax, and triglycerides.

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

[0152] The pharmaceutical compositions in modified release dosage forms may be prepared by techniques known to those skilled in the art, such as direct compression, compression followed by dry or wet granulation, compression followed by melt granulation, and the like.

[0153] [2. Osmotic Controlled Release Devices] The pharmaceutical composition in the dosage form for modified release can be prepared using an osmotic sustained release device. For example, it can be prepared by one-component system, two-component system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, the device includes at least two components: (a) a core containing an active ingredient; and (b) a semipermeable membrane with at least one release port, which encases the core. The semipermeable membrane controls the influx of water from the surrounding aqueous environment into the core, and releases the drug by release through the release port.

[0154] In addition to an active ingredient, the core of an osmotic device may include an osmotic agent for generating a motive force to move water from the surroundings into the core of the device. Examples of osmotic agents include water-swellable hydrophilic polymers known as "osmopolymers" or "hydrogels," including, but not limited to, 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), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers containing hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing polymeric PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0155] Other examples of osmogens include osmogens that can absorb water and affect an osmotic pressure gradient across the barrier of the surrounding coating. 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] Osmotic agents of different dissolution rates can be used to affect how quickly the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM™ EZ (SPI Pharma, Lewes, Del.) can be used to provide early delivery to quickly provide the desired efficacy in the first few hours, and then gradually and continuously release the amount needed to maintain the desired efficacy over a sustained period of time. In this case, the active ingredient is released at a rate that compensates for the amount of the active ingredient being metabolized and excreted.

[0157] The core may use 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 the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and water insoluble at physiological pH or can be rendered water insoluble by chemical modification such as crosslinking. For example, preferred polymers useful for forming the coating include plasticized, nonplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, 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-glutam ... Cane triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxyethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0159] The semipermeable membrane may be a hydrophobic microporous membrane, the pores of which are substantially gas-filled and non-wettable by aqueous solvents, but permeable to water vapor, as described, for example, in U.S. Patent No. 5,798,119. The hydrophobic and water vapor permeable membranes are generally made of hydrophobic membranes such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinylhalides, polyvinylidene fluorides, polyvinyl esters and ethers, natural and synthetic waxes, etc.

[0160] The delivery ports in the semipermeable membrane may be formed after coating by mechanical or laser drilling. Delivery ports may be formed in situ by dissolving a plug of water-soluble material or by rupturing a thin section of the membrane covering a cavity within the core. In addition, delivery ports may also be formed during the coating process, for example in the case of asymmetric membranes described in U.S. Patents 5,612,059 and 5,698,220.

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

[0162] The pharmaceutical composition in the osmotic sustained release dosage form may further use conventional excipients or carriers to improve performance or manufacturing process.

[0163] Osmotic controlled release dosage forms may 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 one embodiment, the pharmaceutical composition can be formulated as an AMT sustained release dosage form comprising an asymmetric permeable membrane surrounding a core comprising the active ingredient and pharma- ceutically acceptable excipients and carriers (see U.S. Pat. No. 5,612,059 and WO 2002 / 17918). AMT sustained release dosage forms can be prepared by methods and techniques known to those skilled in the art, such as direct compression, dry or wet granulation, and dip-coating.

[0165] In one embodiment, the pharmaceutical composition may be in the form of an ESC sustained release formulation comprising a permeable membrane covering a core having the active ingredient, hydroxycellulose, and other pharma- ceutically acceptable excipients or carriers.

[0166] 3. Multiparticulate Controlled Release Devices The pharmaceutical composition in a modified release dosage form may be formed as a multiparticulate sustained release device. The multiparticulate sustained release device comprises a multiplicity of particles, granules, or pellets having a diameter of about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. The multiparticulates can be obtained by methods known to those skilled in the art, such as wet or dry granulation, extrusion / spheronization, roller compaction, melt-congealing, and spray-coating onto core seeds (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 aid in forming the multiparticulates. The resulting particles may themselves constitute the multiparticulate device or may be coated with various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates may further be formed into capsules or tablets.

[0168] [4.Targeted Delivery] The pharmaceutical compositions may also be formulated to be targeted to a particular tissue, receptor, or other body site to be treated, and may include liposome-, resealed erythrocyte-, and antibody-based delivery systems. See, for example, but not by way of limitation, 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.

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

[0170] In one embodiment, a method for treating or preventing platinum-induced ototoxicity, e.g., associated with the use of cisplatin or other platinum-containing drugs, comprises administering a therapeutically effective amount of sodium thiosulfate to a patient who is at risk for platinum-induced ototoxicity associated with the use of cisplatin or other platinum-containing drugs. In some embodiments, the subject is a mammal, and in other embodiments, the subject is a human.

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

[0172] In another aspect, a method for treating or preventing vascular calcification, including but not limited to atherosclerosis, comprising administering a therapeutically effective amount of sodium thiosulfate to a subject suffering from or at risk for vascular calcification, including but not limited to atherosclerosis. In some aspects, the subject is a mammal, and in other aspects, the subject is a human.

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

[0174] In another aspect, a method of treating a skin disease or skin related disorder including, but not limited to, 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 bed, viral infections of the nail bed, psoriasis, scleroderma, inflammation of the skin, inflammation of the nail, inflammation of the nail bed, comprising administering to a patient with a skin disease or skin related disorder a therapeutically effective amount of sodium thiosulfate.

[0175] Depending on the disorder, disease or condition being treated and the condition of the patient, sodium thiosulfate may be administered by routes such as oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intrasystemic injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) and may be formulated in a preferred dosage unit, alone or with pharma- ceutically acceptable carriers, adjuvants and vehicles, for the optimal route of administration.

[0176] The dosage of the drug may be in the form of 1, 2, 3, 4, 5, 6 or more sub-doses, spaced apart as needed to provide a suitable daily dose. The dosage or sub-doses may be in the form of dosage units containing about 10 ng to about 1000 g, about 10 mg to about 100 g, about 500 mg to about 50 g, about 1 g to about 25 g, or about 5 g to about 12.5 g of active ingredient per dosage unit, and the dosage may be modified and administered as a continuous infusion if the patient's condition requires.

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

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

[0179] As used herein, "in combination" includes the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. The first therapy (e.g., a prophylactic and / or therapeutic agent such as a compound) may be 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 concomitantly 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 second therapy (e.g., a prophylactic and / or therapeutic agent) may be administered to the patient. Three therapies are also included in the present invention.

[0180] The term "synergistic" includes a combination of sodium thiosulfate with other therapies (e.g., prophylactic and / or therapeutic agents) currently used in the treatment, prevention, or management of a disease that provides more than the additive effects of the therapies. A combination therapy (e.g., a combination of prophylactic and / or therapeutic agents) may reduce the dosage of one or more therapies to a patient with a disease and / or reduce the frequency of administration of the agents. Reducing the dosage of a therapeutic agent (e.g., a prophylactic and / or therapeutic agent) and / or administering it less frequently can reduce the toxicity associated with administering the agent to a patient without reducing the efficacy of the agent in preventing or treating a disease. In addition, a synergistic effect can also increase the efficacy of the agents in preventing or treating a disease. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic and / or therapeutic agents) can avoid or reduce side effects associated with a single therapy.

[0181] Sodium thiosulfate may be used in combination with or in place of other drugs. In combination therapy, effective dosages of two or more drugs are administered together, whereas in alternation or sequential therapy, effective dosages of each drug are administered sequentially or sequentially. Dosages are determined based on absorption, inactivation, and excretion rates of the drugs, as well as other factors known to those skilled in the art. Dosage values ​​also vary depending on the severity of the disorder to be alleviated. It is also understood that for a particular patient, a particular dosing regimen or schedule may need to be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the drug.

[0182] The compositions may be administered in combination with other classes of compositions, including, but not limited to, vasodilators such as sodium nitrite; keratolytic agents such as salicylic acid; endothelin-converting enzyme (ECE) inhibitors such as phosphoramidon; thromboxane receptor antagonists such as ifetroban; potassium channel openers; thrombin inhibitors such as hirudin; growth factor inhibitors such as modulators of PDGF activity; platelet-activating factor (PAF) antagonists; GPIIb / IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, anti-platelet 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 (dual NEP-ACE inhibitors) such as omapatrilat and gemopatilat; HMG inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisvastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin). CoA reductase inhibitors;squalene synthetase inhibitors;fibrates;bileacid sequestrants such as questran;niacin;anti-atherosclerotic agents such as ACAT inhibitors;MTP inhibitors;calcium channel blockers such as amlodipine besylate;potassium channel activators;alpha-adrenergic agents;beta-adrenergic agents such as carvedilol and metoprolol;antiarrhythmics;Diuretics such as chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorthiazide, trichlormethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator (APSAC); Thrombolytic agents such as 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; mineralocorticoid 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 agents; antiproliferative agents such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer and cytotoxic agents (e.g., alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazines); antimetabolites such as folate antagonists, purine analogs, and pyrimidine analogs;antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents such as glucocorticoids (e.g., cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents such as ecteinascidins; pacitaxel, docetaxel, and epothilones. These may include microtubule stabilizers such as AF; topoisomerase inhibitors such as vinca alkaloids, epidophyllotoxins, and taxanes; prenyl-protein transferase inhibitors; cyclosporine; steroids such as prednisone and dexamethasone; cytotoxins 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, mitotane, hexamethylmelamine, gold compounds, and platinum coordination complexes such as cisplatin, satraplatin, and carboplatin.

[0183] Sodium thiosulfate may be provided as a product using packaging materials known to those of skill in the art, see U.S. Patents 5,323,907; 5,052,558; 5,033,252. For example, pharmaceutical packaging materials may include, but are not limited to, plastic packets, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and other packaging materials suitable for the selected dosage form and administration and treatment.

[0184] The kit, used by a medical professional, simplifies administration of sufficient amounts of the active ingredient to a patient. In one embodiment, the kit includes a container, a dosage form of sodium thiosulfate.

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

[0186] The kit may further include a device for use in administering the active ingredient, including, but not limited to, a syringe, a needleless drip bag, a patch, and an inhaler. The kit may include condoms for administration of the active ingredient.

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

[0188] The present disclosure may be further understood by the following non-limiting examples.

[0189] [Example] As used herein, the symbols and conventions used in the processes, schemes and examples herein are consistent with those used in contemporaneous scientific publications, such as, for example, the Journal of the American Chemical Society or The Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. In particular, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (grams), mg (milligrams, mL (milliliters), μL (microliters); mM (millimoles); μM (micromoles); mmol (millimoles); eq. (equilibrium); hr or hrs (hours); min (minutes).

[0190] In all of the following examples, standard laboratory and purification methods known to those skilled in the art may be utilized. Unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, all reactions were carried out at room temperature. The methodology described in the following examples is intended to demonstrate applicable chemistry through the use of specific examples and is not indicative of 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 charged to a 500 gallon reactor apparatus that was inerted using an Oricon Ross combination pH electrode. The slurry was stirred and 161.4 kilograms of sodium sulfite was charged to the reactor. The reactor was heated between 95-100°C for four hours. After four 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 a 50% by weight solution of sodium hydroxide was added to the reactor contents to raise the pH of the slurry in the reactor to 7.4. The reactor contents were filtered through Estella filter paper. The resulting filtrate was sterilized under vacuum at 50-100°C with a specific gravity of 1.40. While maintaining the temperature of the solution at 50+ / -5°C, 300g of activated charcoal was added to the solution. The solution was stirred for 1 hour and 3 minutes, and then filtered through a bag filter paper to remove the activated charcoal. The filtered solution was cooled to 20+ / -5°C and 15 grams of sodium thiosulfate pentahydrate crystals were added to the solution. The solution was then cooled to 5+ / -5 degrees and stirred for 15 hours and 2 minutes. The contents of the reactor, consisting of both solids and liquids, were filtered using Aurora filter paper in an inert environment. Aqueous solution of the mother material was used to wash the solids from the walls of the reactor. The solids were placed on a drying tray and placed in a desiccator under full vacuum with nitrogen flow at 35°C for 8 hours. Drying continued until after 8 hours, when in-process testing confirmed that the moisture content of the material (loss on drying) was between 34.0 and 36.8%. The dried solids had a final weight of 112.5 kilograms. (Yield 36%)

[0192] The analysis of sodium thiosulfate pentahydrate obtained from the purification method up to this Example 1 is summarized in Table 1.

[0193] [Table 1]

[0194] Example 2: Determination of total non-removable organic carbon in sodium thiosulfate pentahydrate Total non-purgeable organic carbon (NPOC) was determined using an InnovOx research TOC analyzer (GE Analytical Instruments, Boulder, Inc.). Water was used as the standard, and reagents and prepared samples had total organic carbon (TOC) less than 0.10 ppm. 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. Compressed nitrogen has less than 1 ppm CO2 and less than 1 ppm TMC.

[0195] Phosphoric acid (6N) used as the acidifying solution was prepared by adding approximately 100 mL of water to a 250 mL volumetric flask, then slowly adding 100 mL of phosphoric acid and adding additional water to bring the final volume to 250 mL. Phosphoric acid (6%) solution was prepared by adding 120 mL of 6N phosphoric acid to a 2,000 mL volumetric flask and adding water to bring the volume to 100 mL at room temperature.

[0196] Sodium persulfate solution (30%) used as an oxidizing agent was prepared by adding 150 0.1 g of sodium persulfate to a 500 mL volumetric flask and, after the sodium persulfate was dissolved, adding additional water to bring the final volume to 500 mL. The solution was allowed to sit for 3 days before use and was used during the 14 day preparation.

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

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

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

[0200] [Table 2]

[0201] Calibration curve requirements are: i) the correlation coefficient (r) of the mean of the replicates must be greater than or equal to 0.99; ii) the RSD for the 2 and 10 ppm TOC standards must be less than or equal to 15%; iii) the limit of quantitation (LOQ) must be less than or equal to 3 ppm, as calculated below: LOQ = (10)(A)(B) / (C-D) and iv) the limit of detection (LOD) must be less than or equal to 1 ppm, calculated as follows: LOD = (3)(A)(B) / (C-D) where: A is the carbon concentration in the 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 the 0.5 ppm TOC standards; and D is the average TOC concentration determined in the blank preparations.

[0202] The samples were analyzed using the following instrument parameters, shown in Table 3:

[0203] [Table 3]

[0204] A 2 ppm TOC standard was run before and after sample analysis.

[0205] System suitability requirements are i) the RSD for the 2 ppm TOC standard must be less than or equal to 15%; ii) the percent theoretical response (%T) for the 2 ppm TOC standard determination must be greater than or equal to 80% and less than or equal to 120%, calculated as follows: %T=100xA / B; where: A is the result determined by the analytical instrument (ppm); and B is the 2 ppm TOC standard (ppm); iii) For all samples that had a sample response at or above the LOQ up to 5x the LOQ, the RSD must be less than 25%; or for all samples that had a sample response above 5x the LOQ, the RSD must be less than 15%.

[0206] The total non-removable organic carbon in each sample was calculated as follows: NPOC=AxB / C; where: A is the result determined by the analyzer (ppm); 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 (registered trademark) - 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 or precipitation and be clearly different from the blank; iii) The specificity solution containing sulfate, sulfite, and chloride must be lighter gray than the standard solution vial, and white precipitation is expected; iv) The sulfide - additive of the specificity solution containing sulfate, sulfite, and chloride must not have a darker gray 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 or precipitation and be clearly different from the blank; iii) The specificity solution containing sulfate, sulfite, and chloride must be lighter gray than the standard solution vial, and white precipitation is expected; iv) The sulfide - additive of the specificity solution containing sulfate, sulfite, and chloride must not have a darker gray 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. Duplicate vials of these solutions were tested for potential interferences. Further, these tests were each conducted using 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 1 g / L (concentration of Pb(II)). A gray or yellowish-brown test solution was observed.

[0217]

Table 5

[0218] The test methods were 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 in the drug product sample (sodium thiosulfate pentahydrate) was measured by the detection of a yellowish-brown color above 4 ppm. According to the procedure, the detection limit of sulfide in the drug product sample 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 using ion chromatography with electrochemical resistive detection on a Dionex IonPac AS12A analytical column (P / N 046034, Dionex Corporation, Sunnyvale, CA) eluted with 13.5 mM sodium carbonate (ACS reagent grade) and 1.5 mM sodium bicarbonate (ACS reagent grade) in deionized water at 1.5 mL / min with a detection range of 50 μS to 15 min. The ion exchange column was run at room temperature with a suppression voltage of 100 mA.

[0224] For fluidized bed preparation, stock sodium carbonate solution (500 mM) was prepared by adding 26.5 g sodium carbonate (ACS reagent grade) to a 500 mL volumetric flask, then adding deionized water to bring the volume to 500 mL at room temperature, and stock sodium bicarbonate solution (500 mM) was prepared by adding 10.5 g sodium bicarbonate (ACS reagent grade) to a 500 mL volumetric flask, then adding deionized water to bring the volume to 500 mL at room temperature. Fluidized beds were prepared by adding 54 mL of stock sodium carbonate solution and 6 mL of stock sodium bicarbonate solution to a 2 L volumetric flask, then adding deionized water to bring the 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, then adding deionized water to bring the volume to 100 mL at room temperature. A sodium thiosulfate standard was prepared by adding 10.0 mL of the stock sodium thiosulfate solution to a 100 mL volumetric flask, then adding deionized water to bring the volume to 100 mL at room temperature. A linearity standard was prepared by diluting the sodium thiosulfate standard sample (12.5 mL) to 25.0 mL with deionized water.

[0226] Thiosulfate-containing samples were prepared in duplicate: first, a 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 at room temperature to bring the volume to 100 mL.

[0227] The suitability of the method was determined by first injecting a sodium thiosulfate standard, followed by an injection of deionized water to ensure there was no influence from the previous one that could interfere with the analysis. The sodium thiosulfate standard was subsequently injected six times. The percent relative standard deviation (%RSD) of the area of ​​the thiosulfate peak was calculated. The first injection was used to calculate the tailing factor and the theoretical plate number according to Method 621 USP 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 number (N) for thiosulfate should be NLT 3,000. The %RSD area for the six injections and each subsequent calibration injection should be NMT 3.0%.

[0228] Sodium thiosulfate standards were injected in duplicate and the % area difference between the duplicate injections was determined. The % area difference between the duplicate injections should be NMT 2% and the error in the analytical value should be NMT 2.0%. The average area of ​​the determined reaction was then used to calculate the concentration of the previous 6 injections and the percentage difference of the calculated concentration from the actual concentration was determined.

[0229] The sample solution diluent was injected once to check for any influence from the previous one and any other peaks arising from the diluent. The peak area of ​​the reaction at the retention time of thiosulfate should be NMT1% of the area of ​​the reaction for the thiosulfate standard.

[0230] Linearity standard samples were injected in duplicate. For the linearity standards, the average peak area should be 47% and 53% of the average peak area for the method suitability injections. For the linearity standards, the % difference between duplicate injections should be NMT2%.

[0231] Each sample solution was injected in duplicate. The % difference between the duplicates was calculated. The % difference between the sodium thiosulfate assay concentrations between the duplicate preparations was also calculated.

[0232] The instrument was validated by reanalysing sodium thiosulfate standards in duplicate after every sixth injection and after the last sample injection. For each sample, the % difference between duplicate injections should be NMT 2.0% and the % difference between the assay concentrations of thiosulfate in duplicate preparations should be NMT 2%. The concentrations of sodium thiosulfate pentahydrate samples were calculated based on peak area in comparison to the concentration of the thiosulfate standard.

[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 weighing could be dried in a desiccator and, in extreme cases, handled to avoid contaminating the glassware with organic matter. Glassware used only for dilution was pre-washed at least three times with an aqueous oxidizer solution prepared by adding approximately 1-2 mL of concentrated phosphoric acid to 4,000 mL of deionized water, and then thoroughly washed immediately before use with deionized water. Sterile plastic spatulas were used instead of metal spatulas during weighing to reduce potential contamination.

[0234] A stock solution of sodium carbonate for 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 was 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 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] Samples were prepared by weighing out to the nearest 0.01 mg and transferring an amount of the sample equivalent to less than 1.0 mg / L of carbon (5.0 mg / L carbonate) into a 100 mL volumetric flask. For sodium thiosulfate pentahydrate drug substance with a critical carbonate content of ≦0.01%, a 1.00 g sample in 100 mL water would yield 1 mg / L of carbonate, equivalent to 0.2 mg / L of carbon, if the sample had 0.01% carbonate. 20 mL of deionized water was then 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 to bring the volume to 100 mL at room temperature.

[0237] Total inorganic carbon was measured on a Shimadzu TOC-V analyzer in IC mode. In IC mode, samples were simultaneously acidified with phosphoric acid to convert inorganic carbon (carbonate and bicarbonate) to carbon dioxide, followed by a non-dispersive infrared detector for quantification. Pre-cleaned TOC vials were used in the analyzer, and each vial was completely filled with the respective standard solution, with no head space in the vial. The vials were secured with lids.

[0238] During the standard run-up, triplicate measurements were made for each vial (standard, sample or blank). Three measurements constituted one run. Three rums of blank (deionized water) were performed to ensure that the analyzer was equilibrated and results were consistent.

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

[0240] The analyzer was calibrated after the last sample injection by performing every six sample runs and one blank run, followed by one run of the 2.0 mg / L calibration standard. The %RSD of both and the carbonate recovery were calculated from the calibration standard curve.

[0241] As quality controls, the area (response) %RSD of triplicate injections for each standard must be less than (NMT) 10% and the calibration curve for carbonate must have a correlation coefficient of greater than (NLT) 0.995. The area %RSD of the first blank and successive calibration blank injections must be less than (NMT) 15%. The area %RSD of subsequent calibration standard (2.0 mg / L) injections must be less than (NMT) 10%. The % recovery of successive calibration standards at 2.0 mg / L 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 formulations containing sodium thiosulfate pentahydrate Exemplary pharmaceutical grade sodium thiosulfate pentahydrate-containing infusion solutions are set forth in Table 8.

[0244] [Table 8]

[0245] Abbreviations: NF, Formula International; qs, quality sufficient; USP, United States International Pharmacopoeia; WFI, Water for Injection.

[0246] The examples described above provide one of ordinary skill in the art with a full disclosure and description of how to make and use the claimed embodiments, and are not intended to be limiting in scope to what is disclosed herein. Modifications obvious to one of ordinary skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each such publication, patent, or patent application were specifically and individually set forth herein by reference.

Claims

1. 1. A unit dosage form comprising pharmaceutical grade sodium thiosulfate, The pharmaceutical grade sodium thiosulfate has the following characteristics in a unit dosage form: Contains 10 ppm or less of irremovable organic carbon; Contains 0.05 ppm or less of mercury; Contains 2 ppm or less of aluminum; Contains not more than 0.003% by weight of selenium; Contains greater than or equal to 98% and less than or equal to 102% by weight sodium thiosulfate on an anhydrous basis as determined by ion chromatography; having a heavy metal content of 10 ppm or less; Contains 200 ppm or less of chloride; Contains less than 0.001% by weight of sulfides; Contains not more than 0.002% by weight of iron; Contains not more than 0.01% by weight of calcium; Contains not more than 0.005% by weight of potassium; Contains 0.1% or less sulfites; Contains 0.5% or less sulfate; Contains arsenic at 3 ppm or less; Contains 0.001% or less lead by weight; the microbial load is a total aerobic microbial count of 100 CFU / g or less; total yeast and mold counts of 20 CFU / g or less; Contains less than 0.02 EU / mg bacterial endotoxins; Contains not more than 0.002% by weight of nitrogen compounds; Contains less than 0.005% by weight of insoluble matter; Contains less than 0.01% by weight of an anti-caking agent residual; Contains volatile organic impurities below the limits of ICH Q3C(R3); A 10% aqueous solution at 25° C. is colorless and has a pH of 6.0-8.

0.

2. The pharmaceutical grade sodium thiosulfate contains less than 8 ppm of irremovable organic carbon.

2. The unit dosage form of claim 1.

3. The pharmaceutical grade sodium thiosulfate is anhydrous.

2. The unit dosage form of claim 1.

4. Contained in a vial, 2. The unit dosage form of claim 1.

5. A unit dosage form comprising a pharmaceutical composition, The pharmaceutical composition comprises pharmaceutical grade sodium thiosulfate in a pharma- ceutical acceptable aqueous carrier; The sodium thiosulfate used in the preparation of the pharmaceutical composition has the following characteristics, in a unit dosage form: Contains 10 ppm or less of irremovable organic carbon; Contains 0.05 ppm or less of mercury; Contains 2 ppm or less of aluminum; Contains not more than 0.003% by weight of selenium; Contains greater than or equal to 98% and less than or equal to 102% by weight sodium thiosulfate on an anhydrous basis as determined by ion chromatography; having a heavy metal content of 10 ppm or less; Contains 200 ppm or less of chloride; Contains less than 0.001% by weight of sulfides; Contains not more than 0.002% by weight of iron; Contains not more than 0.01% by weight of calcium; Contains not more than 0.005% by weight of potassium; Contains 0.1% or less sulfites; Contains 0.5% or less sulfate; Contains arsenic at 3 ppm or less; Contains 0.001% or less lead by weight; the microbial load is a total aerobic microbial count of 100 CFU / g or less; total yeast and mold counts of 20 CFU / g or less; Contains less than 0.02 EU / mg bacterial endotoxins; Contains not more than 0.002% by weight of nitrogen compounds; Contains less than 0.005% by weight of insoluble matter; Contains less than 0.01% by weight of an anti-caking agent residual; Contains volatile organic impurities below the limits of ICH Q3C(R3).

6. The pharma- ceutically acceptable aqueous carrier is sterile water for injection.

6. The unit dosage form of claim 5.

7. The pharmaceutical grade sodium thiosulfate contains less than 8 ppm of irremovable organic carbon.

7. The unit dosage form of claim 6.

8. The pharmaceutical composition is formulated for intravenous administration.

7. The unit dosage form of claim 6.

9. The pharmaceutical composition is formulated for intravenous administration.

7. The unit dosage form of claim 6.

10. The pharmaceutical composition further comprises an isotonicity agent and one or more pH adjusting agents.

7. The unit dosage form of claim 6.

11. The pharmaceutical composition is sterile and suitable for intravenous administration, The isotonicity agent is potassium chloride at 4.40 mg / mL; The pH adjuster is sodium hydroxide and 2.80 mg / mL boric acid.

11. The unit dosage form of claim 10.

12. The pharmaceutical grade sodium thiosulfate is present as 250.0 mg / mL sodium thiosulfate pentahydrate (concentration measured on an anhydrous basis).

12. The unit dosage form of claim 11.

13. The pharmaceutical grade sodium thiosulfate used in the preparation of the pharmaceutical composition is anhydrous.

7. The unit dosage form of claim 6.

14. The pharmaceutical composition contains 140 mg of boric acid and 220 mg of potassium chloride.

12. The unit dosage form of claim 11.

15. The pharmaceutical composition further comprises pharmaceutical grade sodium thiosulfate, The pharmaceutical grade sodium thiosulfate is present as 12.5 g of sodium thiosulfate pentahydrate (concentration measured on an anhydrous basis).

15. The unit dosage form of claim 14.

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