Sodium nitrite-containing pharmaceutical compositions

REPUBLIC OF POLAND (12) TRANSLATION OF THE EUROPEAN PATENT (19) PL (11) PL / EP 2395834

<img file="PL2395834T3_D0001.tif" />

(13) (51)

Patent Office of the Republic of Poland (96) Date and number of the European patent application:

11.02.2010 10741692.7 (97) The grant of the European patent was announced: 31.07.2019 European Patent Bulletin 2019/31

EP 2395834 B1

T3

Int.CI.

A61K 33/00 (2006.01) C01B 21/50 (2006.01) A61K31 / 17 (2006.01)

A61K 31/4418 (2006.01)

A61K 31/4709 (2006.01)

A61K 31/519 (2006.01)

A61P 9/00 (2006.01)

A61P 11/00 (2006.01)

A61P 17/00 (2006.01)

A61P 43/00 (2006.01) (54) Title of the invention:

PHARMACEUTICAL COMPOSITIONS CONTAINING SODIUM NITRITE (30)

Priority:

11.02.2009 US 151820 P.

08.07.2009 US 224021 P (43) The application was announced:

21.12.2011 in the European Patent Bulletin No. 2011/51 (45) The filing of the patent translation was announced:

31.01.2020 Patent Office News 2020/01 (73) Patent holder:

Hope Medlcal Enterprlses, Inc. dba Hope Pharmaceutlcals, Scottsdale, US (72) The inventor (s):

CRAIG SHERMAN, Scottsdale, US ANTHONY JAMES LEPINE, Greendale, US CATHERINE MARIE SMITH, Grafton, US

KEVIN ROBERT WIRTZ, Belgium, US $ 2 ERICH SCHULZE, Lakka Elslnore, US

O (74) Proxy:

thing, pat. Agnieszka Marszałek

M SULIMA GRABOWSKA SIERZPUTOWSKA

S¹ OFFICE OF PATENTS AND TRADEMARKS SP.K.

Q_ iii Skr. Box. 6 j 00-956 Warsaw 10

ABOUT.

Attention:

Within nine months of publication of the information on the grant of the European patent, any person may lodge an objection to the European Patent Office regarding the granted European patent. The objection shall be made in the form of a reasoned statement. It is considered to be filed only when the opposition fee has been paid (Article 99 (1) of the Convention on the Grant of European Patents).

SGS-17341 / VAL

EP 2 395 834 B1

Description Field. [0001] Pharmaceutically acceptable sodium nitrite and pharmaceutical compositions thereof are provided. Also described herein are methods for determining total non-volatile organic carbon in a sample containing sodium nitrite. In addition, methods for making pharmaceutically acceptable sodium nitrite are provided herein. Furthermore, the sodium nitrite of the invention is further provided for use in methods of treatment.

BACKGROUND [0002] Sodium nitrite has many uses, such as applications as a food additive and a pharmaceutical ingredient. Although thousands of metric tons of sodium nitrite are produced annually, only a few kilograms are pharmaceutically used to produce an injection form containing sodium nitrite, according to current indications, as a treatment for cyanide poisoning. Sodium nitrite has been reported to be an effective treatment for hydrogen sulfide poisoning (Hall and Rumack, Vet Human Toxicol. 1997, 39, 152-154). Sodium nitrite has recently been reported to be an effective vasodilator that can be used to treat many conditions, including myocardial infarction, stroke, sickle cell disease, respiratory disease and bacterial, viral or fungal infections (WO 2005/004884, WO 2005 / 007173, US Patent Application Publication Nos. 2004/0105898, 2005/0036949 and 2008/0260865). Sodium nitrite has also been recently reported to potentiate angiogenesis and arteriogenesis, which can be used to treat ischemia-related conditions including angina and claudication. (Kumar et al., Proc. Natl. Acad. Sci. USA 2008, 105, 7540-7545). Sodium nitrite is also useful in reducing the risk of hospital acquired infections, such as nosocomial infections, arising from the introduction of medical devices such as catheters (US Patent Application Publication No. 2007/0239107).

[0003] The manufacture of pharmaceutical products in the United States is regulated by the Food and Drug Administration (FDA). Since the adoption of the Federal Food Drug and Cosmetic Act in 1938, the FDA requires that new pharmaceutical products and their corresponding active ingredients be manufactured in accordance with the stringent requirements of Good Manufacturing Practice regarding "pharmaceutical quality" as specified in the United States Code of Federal Regulations 21 CFR 211. Due to the relatively small amount of sodium nitrite that is currently used in the formulation of pharmaceutical products, no supplier of raw materials currently produces sodium nitrite in accordance with Good Manufacturing Practice regarding "pharmaceutical quality".

[0004] In addition to regulating manufacturing practice, the FDA establishes stringent quality specifications for each new pharmaceutical product and corresponding active ingredients. A pharmaceutical product is classified as "new" if it was placed on the market after the adoption of the Food Drug and Cosmetic Act in 1938. As prescribed in this Act, the FDA requires that new pharmaceutical products and their active ingredients be manufactured in accordance with Good Manufacturing Practice regarding "pharmaceutical quality" and meet applicable quality specifications. When the Food Drug and Cosmetic Act was adopted in 1938, pharmaceuticals that were already on the market were classified as "acquired rights drugs" and were allowed to remain on the market without the official approval of the FDA if this product and its labeling remain unchanged. Any change to the device or its labeling would cause the "acquired rights drug" to become a "new" drug that is regulated by FDA regulations and quality standards. The currently available injection form containing sodium nitrite, which is only indicated for use as a treatment for cyanide poisoning, is an 'acquired rights medicine'. Therefore, the product formulation and corresponding quality specifications have remained unchanged for decades.

[0005] Pending confirmation of the New Drug Application for a pharmaceutical product containing sodium nitrite, the FDA recently announced that the sodium nitrite raw material for a new pharmaceutical product must be manufactured in accordance with Good Manufacturing Practice regarding "pharmaceutical quality" and must adapt to the new kit quality specifications. This new set of quality specifications is more extensive and stringent than existing quality specifications. Currently available sodium nitrite raw material does not meet the requirements of the new set of FDA quality standards and is not suitable for use in the formulation of a new pharmaceutical product. Therefore, there is an obvious and unmet need for purified sodium nitrite raw material, which is manufactured in accordance with Good Manufacturing Practice regarding "pharmaceutical quality" and which meets the requirements of a new set of quality specifications to translate recent nitrite-related research discoveries into FDA approved clinical therapies.

[0006] Another obstacle to the production of pharmaceutical grade sodium nitrite is the lack of an effective analytical method for the determination of total non-volatile organic carbon in a sample containing sodium nitrite, which is one of the new quality standards imposed by the FDA. The traditional method of determining total non-volatile organic carbon requires the removal of any inorganic carbon before measuring the organic carbon content of the sample. This is usually achieved by adding acid. At low pH, inorganic carbon is converted to carbon dioxide, which is then removed from the sample. This sample is then placed in a combustion chamber with a catalyst and a temperature of about 680 ° C to convert organic carbon into carbon dioxide. The amount of carbon dioxide thus produced is then determined using an infrared radiation detector. However, this traditional method cannot be used to analyze a sample containing sodium nitrite. Sodium nitrite decomposes when subjected to temperatures above 538 ° C. Also, sodium nitrite is converted to nitric oxide when it is exposed to acid, and the nitric oxide produced in this way can enter the detector along with carbon dioxide, interfere with detection, and produce false signals. Furthermore, sodium nitrite may precipitate during analysis. Sodium nitrite salt deposits on the catalyst can contaminate the catalyst and prevent complete combustion. Deposits of sodium nitrite on optical elements can also reduce the intensity of light from a radiation source. Therefore, there is also a need for an analytical method for determining total non-volatile organic carbon in a sample containing sodium nitrite.

[0007] Another obstacle to the development of pharmaceutical grade sodium nitrite is the presence of anti-caking material in non-pharmaceutical grade sodium nitrite. Sodium nitrite is hygroscopic. To prevent water absorption over time and to facilitate industrial use, manufacturers of non-pharmaceutical grade sodium nitrite usually add anti-caking material with surfactant properties such as sodium alkyl naphthalene sulfonate. Even if a non-pharmaceutical grade sodium nitrite manufacturer that contains an anti-caking agent produces a batch of sodium nitrite without the addition of an anti-caking agent, trace amounts of the anti-caking agent may be present that exceed the new FDA-imposed quality standards. Therefore, any anti-caking material in sodium nitrite must be detected, quantified and limited to produce pharmaceutical grade sodium nitrite.

SUMMARY OF DISCLOSURE [0008] Sodium nitrite is provided which contains no more than 0.02% by weight of sodium carbonate and no more than 10 ppm of the anti-caking agent, wherein sodium nitrite has a weight loss on drying of not more than 0.25% by weight; wherein the water content of sodium nitrite is not more than 0.5% by weight; sodium nitrite contains not more than 0.4% by weight of sodium nitrate, not more than 0.005% by weight of insoluble substance, not more than 0.005% by weight of chloride, not more than 0.01% by weight of sulfate, not more than 0.001% by weight of iron , not more than 0.01% by weight of calcium, not more than 0.005% by weight of potassium, not more than 0.05 ppm of mercury, not more than 2 ppm of aluminum, not more than 3 ppm of arsenic and not more than 0.003% by weight of selenium; wherein sodium nitrite contains not more than 10 ppm, not more than 100 ppm, not more than 500 ppm, not more than 1000 ppm or not more than 5000 ppm volatile organic pollutants; wherein the total non-volatile organic carbon content of sodium nitrite is not more than 2.5 ppm or not more than 10 ppm; wherein sodium nitrite has a total number of aerobic microbial loads of not more than 100 CFU / g, a total number of yeasts and molds not more than 20 CFU / g, contains not more than 0.25 EU / mg bacterial endotoxins; wherein sodium nitrite contains not less than 97% by weight and not more than 101% by weight of sodium nitrite as measured by USP colorimetric test; and wherein the heavy metal content of sodium nitrite is not more than 10 ppm.

[0009] Also provided herein are pharmaceutical compositions that contain sodium nitrite and one or more pharmaceutically acceptable excipients.

[0010] Also described herein are methods for determining total non-volatile organic carbon in a sample containing sodium nitrite, which include the steps of: a) adding an inorganic acid in a predetermined amount to an aqueous sample solution that contains sodium nitrite; b) adding an oxidant in a predetermined amount to the sample solution; and c) transformation of organic carbon in the sample solution into carbon dioxide under supercritical oxidation; wherein the final amount of inorganic acid is not less than 2% of the final volume of the sample solution or the final amount of oxidant is not less than 20% of the final volume of the sample solution.

[0011] Also provided herein is a method of producing a pharmaceutically acceptable sodium nitrite, which comprises the steps of: (a) contacting sodium nitrite with water at a first temperature of 45 to 55 ° C in an inert atmosphere; (b) cooling the solution to a second temperature of 20 ° C to 30 ° C; (c) contacting water containing sodium nitrite with activated carbon; (d) contacting the mixture with ethyl alcohol; and (e) forming sodium nitrite at a third temperature of 0 ° C to 10 ° C in an inert atmosphere.

[0012] Also provided herein is the sodium nitrite of the invention for use in methods of treating acute poisoning including, but not limited to, cyanide poisoning and hydrogen sulfide poisoning, which methods comprise administering to a subject a therapeutically effective amount of the sodium nitrite provided herein.

[0013] Also provided herein is the sodium nitrite of the invention for use in methods of treating a cardiovascular disease or cardiovascular related condition including, but not limited to, high blood pressure, pulmonary hypertension, angina, claudication, cerebral vasospasm and ischemic reperfusion injury of the tissues, which methods comprise administering to the subject a therapeutically effective amount of sodium nitrite provided herein.

[0014] Also provided herein is the sodium nitrite of the invention for use in methods of treating a respiratory disease or tracheo-pulmonary condition including, but not limited to, cystic fibrosis, pulmonary tuberculosis, fungal pneumonia, bacterial pneumonia, viral pneumonia, lung abscess , pulmonary hypertension, pulmonary embolism and pulmonary spasm, which methods comprise administering to the subject a therapeutically effective amount of sodium nitrite provided herein.

[0015] Also provided herein is the sodium nitrite of the invention for use in methods of treating a dermatological disease or skin related condition including, but not limited to, bacterial skin infection, fungal skin infection, viral skin infection, fungal nail infection, bacterial nail infection, infection viral nail, fungal infection of the nail bed, bacterial infection of the nail bed, viral infection of the nail bed, psoriasis, scleroderma, dermatitis, nail inflammation, and nail bed inflammation, which methods include administering to the subject a therapeutically effective amount of sodium nitrite provided herein.

[0016] Also provided herein is the sodium nitrite of the invention for use in methods of treating, preventing or reducing the risk of hospital acquired infections, such as hospital infections, which may result from the introduction of a device (e.g., a medical device) and / or the use of the device in body.

DETAILED DESCRIPTION [0017] To facilitate understanding of the disclosure provided herein, many terms are defined below.

[0018] In general, the names used herein and the laboratory procedures described herein in inorganic chemistry, analytical chemistry, organic chemistry, medical chemistry and pharmacology are those well known and widely used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there are many definitions for the term used here, those in this section prevail, unless otherwise stated.

The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably herein to refer, for example, to a mammal such as a human subject. In one embodiment, the subject has or is at risk of a disease, disorder or condition provided herein. In another embodiment, the patient has or is at risk of a disease, disorder or condition, wherein the disease, disorder or condition or symptoms thereof can be treated, prevented or alleviated by administration of sodium nitrite.

The term "host" refers to a single-cell or multi-cellular organism in which the virus can reproduce including, but not limited to, a cell, cell line, and animal, such as a human.

The terms "treat", "treating" and "treatment" are intended to include ameliorating or eliminating the disorder, disease or condition or one or more symptoms associated with the disorder, disease or condition; or to alleviate or remove the cause (s) of the disorder, disease or condition itself.

The terms "prevent", "prevent" and "preventing" are intended to include a method of delaying and / or preventing the occurrence of a disorder, disease or condition and / or associated symptom (s); protecting the individual from acquiring the disease; or reducing the risk of the subject acquiring the disorder, disease or condition.

The term "therapeutically effective amount" is intended to include the amount of compound that, when used, is sufficient to prevent the development or amelioration of one or more symptoms of the disorder, disease or condition being treated, to some extent. The term "therapeutically effective amount" also refers to the amount of compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human that a scientist, veterinarian, doctor or clinician is seeking to determine.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material . In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical preparation and that it is suitable for use in contact with human, animal cells, tissues or organs, without increased toxicity, irritation, allergic reaction, immunogenicity and other problems or complications commensurate with a reasonable benefit-risk ratio. See Remington: The Science and Practice of Pharmacy, 21. edition, Lippincott Williams &amp; Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Ed., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Red., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

The term "about" or "approximately" means an acceptable error for a particular value, as determined by one of ordinary skill in the art, which partly depends on how this value is measured or determined. In some embodiments, the term "about" or "approximately" means within a range of 1, 2, 3 or 4 standard deviations. In some embodiments, the term "about" or "approximately" means in the range of 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0, 5% or 0.05% of the given value or range. In some embodiments, it is contemplated that the values ​​preceding the term "about" or "approximately" are accurate.

The terms "active ingredient" and "active substance" refer to a compound that is administered to an individual alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent or ameliorate one or more symptoms of a condition, disorder or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of the compound described herein.

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

The term "anti-solvent" refers to a liquid that is added to a solvent to reduce the solubility of a compound in this solvent resulting in precipitation or crystallization of the compound.

The term "sodium phosphate" refers to sodium dihydrogen phosphate (NH2PO4), disodium hydrogen phosphate (Na2HPO4) or trisodium phosphate (NasPO4). In some embodiments, the sodium phosphate is sodium dihydrogen phosphate. In some embodiments, the sodium phosphate is disodium hydrogen phosphate. In some embodiments, the sodium phosphate is trisodium phosphate.

Sodium nitrite [0019] Provided are purified forms of sodium nitrite (NNO2), also known as monosodium nitrous acid. In one embodiment, a pharmaceutically acceptable sodium nitrite is provided herein. In another embodiment, sodium nitrite forms that meet all of the FDA standards for sodium nitrite for pharmaceutical use are provided herein.

[0020] In one embodiment, the pharmaceutically acceptable sodium nitrite is a white to off-white solid.

[0021] In one embodiment, the pharmaceutically acceptable sodium nitrite is positive in the test for sodium determined according to method <191> in USP XXXII (2009). [0022] In one embodiment, the pharmaceutically acceptable sodium nitrite is positive in the test for the presence of nitrite determined according to method <191> in USP XXXII (2009).

[0023] The sodium nitrite provided herein contains not less than 97% by weight and / or not more than 101% by weight of sodium nitrite. In some embodiments, the amount of sodium nitrite in the sodium nitrite provided herein is determined according to a USP colorimetric test (USP XXXII (2009)). In some embodiments, the amount of sodium nitrite in the sodium nitrite provided herein is determined by ion chromatography. In some embodiments, the amount of sodium nitrite in the sodium nitrite provided herein is determined by ion chromatography in combination with suppressive conductivity detection as described herein.

[0024] In another embodiment, the sodium nitrite provided herein has a pH value between 8 and 9, measured in a 10% solution at 25 ° C. In some embodiments, the pH of the sodium sodium provided herein is measured using a pH meter. In some embodiments, the pH of sodium sodium provided herein is determined according to Method 791 in USP XXXII (2009).

[0025] The sodium nitrite provided herein has a weight loss on drying not greater than 0.25% by weight. In some embodiments, the weight loss during drying of the sodium nitrite provided herein is quantified according to Method 731 in USP XXXII (2009).

[0026] The sodium nitrite provided herein has a water content of not more than 0.5% by weight. In some embodiments, the water content of the sodium nitrite provided herein is determined by the Karl Fischer method. In some embodiments, the water content of the sodium nitrite provided herein is quantified according to Method 921 in USP XXXII (2009).

[0027] The heavy metal content of the sodium nitrite provided herein is no more than 10 ppm heavy metal. The heavy metal content of the sodium nitrite provided herein is determined in accordance with Method 231 in USP XXXII (2009).

[0028] The sodium nitrite provided herein contains no more than 0.4% by weight of sodium nitrite. In some embodiments, the amount of sodium nitrate in the sodium nitrite provided herein is determined by ion chromatography in combination with suppressive conductivity detection as described herein.

[0029] The sodium nitrite provided herein contains no more than 0.02% by weight of sodium carbonate. In some embodiments, the amount of sodium carbonate in the sodium nitrite provided herein is determined by mixing the sample with an acid to convert the carbonate to carbon dioxide and to discharge carbon dioxide to a non-diffuse infrared radiation detector for measurement.

[0030] The sodium nitrite provided herein contains no more than 0.005% by weight of insoluble matter. In some embodiments, the amount of insoluble matter in the sodium nitrite provided herein is determined by dissolving 10 grams of sodium nitrite provided herein in 100 mL of water, the solution is refluxed for 1 hour, the solution is filtered, washed with hot water, dried, cooled in a desiccator and weighed.

[0031] The sodium nitrite provided herein contains no more than 0.005% by weight of chloride. In some embodiments, the chloride content of sodium nitrite provided herein is determined in accordance with Method 221 in USP XXXII (2009).

[0032] The sodium nitrite provided herein contains no more than 0.01% by weight of sulfate. In some embodiments, the sulfate content of the sodium nitrite provided herein is determined in accordance with Method 221 in USP XXXII (2009).

[0033] The sodium nitrite provided herein contains no more than 0.001% by weight of iron. In some embodiments, the iron content of the sodium nitrite provided herein is determined using inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the iron content of the sodium nitrite provided herein is determined using inductively coupled plasma emission spectroscopy (ICP-OES). In some embodiments, the iron content of sodium nitrite provided herein is determined according to method 241 in USP XXXII (2009).

[0034] The sodium nitrite provided herein contains no more than 0.01% by weight of calcium. In some embodiments, the calcium content of the sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the calcium content of the sodium nitrite provided herein is determined using flame emission spectrometry (FES).

[0035] The sodium nitrite provided herein contains no more than 0.005% by weight of potassium. In some embodiments, the potassium content of sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the potassium content of the sodium nitrite provided herein is determined using FES.

[0036] The sodium nitrite provided herein contains no more than 10 ppm, no more than 100 ppm, no more than 500 ppm, no more than 1000 ppm or no more than 5000 ppm ethanol. In some embodiments, the volatile organic pollutant content is determined in accordance with Method 467 in USP XXXII (2009).

[0037] In yet another embodiment, the sodium nitrite provided herein contains no more than 10 ppm, no more than 100 ppm, no more than 500 ppm, no more than 1000 ppm, or no more than 3000 ppm methanol. In some embodiments, the volatile organic pollutant content is determined in accordance with Method 467 in USP XXXII (2009).

[0038] The sodium nitrite provided herein contains no more than 2.5 ppm, no more than 6 ppm, no more than 8 ppm, or no more than about 10 ppm of total non-volatile organic carbon. In some embodiments, the sodium nitrite provided herein contains no more than 10 ppm of total non-volatile organic carbon (NVOC) or equivalent non-washable organic carbon (NPOC). In some embodiments, the sodium nitrite provided herein contains no more than 7.9 ppm of total non-volatile organic carbon. In some embodiments, the sodium nitrite provided herein contains no more than 5.6 ppm of total non-volatile organic carbon. In some embodiments, the total non-volatile organic carbon in the sodium nitrite provided herein is determined using the methods described herein.

[0039] The sodium nitrite provided herein contains no more than 0.05 ppm of mercury. In some embodiments, the mercury content of sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the mercury content of sodium nitrite provided herein is determined using ICP-OES. In some embodiments, the mercury content of the sodium nitrite provided herein is determined in accordance with Method 261 in USP XXXII (2009).

[0040] The sodium nitrite provided herein contains no more than 2 ppm aluminum. In yet another embodiment, the sodium nitrite provided herein contains no more than 0.2 ppm aluminum. In some embodiments, the aluminum content of sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the aluminum content of sodium nitrite provided herein is determined using ICP-OES. In some embodiments, the aluminum content of the sodium nitrite provided herein is determined in accordance with Method 206 in USP XXXII (2009).

[0041] The sodium nitrite provided herein contains no more than 3 ppm arsenic. In yet another embodiment, the sodium nitrite provided herein contains no more than 1 ppm arsenic. In some embodiments, the arsenic content of the sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the arsenic content of the sodium nitrite provided herein is determined using ICP-OES. In some embodiments, the arsenic content of the sodium nitrite provided herein is determined in accordance with Method 211 in USP XXXII (2009).

[0042] The sodium nitrite provided herein contains no more than 10 ppm (0.001% by weight) of the anti-caking agent. In some embodiments, the anti-caking agent is sodium alkyl naphthalene sulfonate. In some embodiments, the amount of sodium alkyl naphthalene sulfonate in the sodium nitrite provided herein is quantified using mass spectrometry and liquid chromatography methods as described herein.

[0043] The sodium nitrite provided herein contains no more than 0.003% by weight of selenium. In some embodiments, the selenium content of the sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the selenium content of the sodium nitrite provided herein is determined using ICP-OES. In some embodiments, the selenium content of the sodium nitrite provided herein is determined in accordance with Method 291 in USP XXXII (2009).

[0044] The total number of aerobic microbial load organisms in the sodium nitrite provided herein is no more than 100 CFU / g. The total number of aerobic microbial load aerobes in the sodium nitrite provided herein is quantified in accordance with Method 61 in USP XXXII (2009).

[0045] The total number of yeasts and molds in the sodium nitrite provided herein is no more than 20 CFU / g. The total number of yeasts and molds in the sodium nitrite provided herein is quantified in accordance with Method 61 in USP XXXII (2009).

[0046] The sodium nitrite provided herein contains no more than 0.25 EU / mg bacterial endotoxins. The amount of bacterial endotoxins in the sodium nitrite provided herein is quantified in accordance with Method 85 in USP XXXII (2009).

[0047] In yet another embodiment, the sodium nitrite provided herein contains less than 0.1 ppm sodium phosphate. In some embodiments, the sodium nitrite provided herein contains no detectable amount of sodium phosphate. In some embodiments, the sodium phosphate is disodium hydrogen phosphate. In some embodiments, the sodium phosphate is trisodium phosphate.

[0048] In one embodiment, the sodium nitrite provided herein has the following characteristics:

it contains not less than 97% by weight and / or not more than about 101% by weight of sodium nitrite;

has a positive result in the sodium test;

has a positive result in the test for thiosulphate;

has a pH between 8 and 9 when measured in a 10% solution at 25 ° C;

has a weight loss on drying of not more than 0.25% or 0.01% by weight;

has a water content not exceeding 0.5% by weight;

has a heavy metal content not exceeding 10 ppm;

it contains not more than 0.4% by weight of sodium nitrate;

contains not more than 0.02%, 0.01% or 0.001% by weight of sodium carbonate;

it contains not more than 0.005% or 0.001% by weight of insoluble matter; it contains not more than 0.005% by weight of chloride;

it contains not more than 0.01% by weight of sulfate;

it contains not more than 0.001% by weight of iron;

it contains not more than 0.01% by weight of calcium;

it contains not more than 0.005% or about 0.001% by weight of potassium;

contains not more than 0.1% by weight of ethanol or not more than 10 ppm, not more than 100 ppm, not more than 500 ppm, not more than 1000 ppm or not more than 5000 ppm ethanol;

Contains not more than 10 ppm, not more than 100 ppm, not more than 500 ppm, not more than 1000 ppm or not more than 3000 ppm methanol;

Contains not more than 2.5 ppm, not more than 5.6 ppm, not more than 6 ppm, not more than 7.9 ppm, not more than 8 ppm or not more than about 10 ppm of total non-volatile organic carbon; and in one embodiment not more than 10 ppm;

contains not more than 0.05 ppm mercury;

contains not more than 2 ppm or 0.2 ppm aluminum;

contains not more than 3 ppm or 1 ppm of arsenic;

it contains not more than 10 ppm or 0.001% by weight of anti-caking agent; contains not more than 0.003% or 0.001% by weight of selenium (ICP-OES or equivalent);

has a total aerobic microbial load of not more than 100 CFU / g;

has a total number of yeasts and molds not exceeding 20 CFU / g;

contains not more than 0.25 EU / mg or 0.018 EU / mg bacterial endotoxins; and contains less than 0.1 ppm sodium phosphate.

[0049] In one embodiment, the sodium nitrite provided herein with the characteristics described herein is prepared by the method provided herein. In one embodiment, sodium nitrite with one or more of the features listed in Table 1 is provided.

Preparation of sodium nitrite [0050] Also described herein are methods for preparing pharmaceutically acceptable sodium nitrite, which include the steps of: a) contacting sodium nitrite of a non-pharmaceutical grade (wherein non-pharmaceutical grade sodium nitrite includes, but is not limited to, sodium nitrite pharmaceutical grade) with the first solvent at the first temperature; b) heating the mixture to a second temperature; c) cooling the mixture to a third temperature; d) contacting the mixture with activated carbon; e) cooling the mixture to a fourth temperature; and f) contacting the mixture with a second solvent. In some embodiments, the method further comprises the isolation step after one or more of the steps provided herein, in which sodium nitrite is isolated in an inert atmosphere (e.g. N2 or Ar) by a conventional method such as filtration or centrifugation followed by drying (e.g. drying in a vacuum oven, air drying or drying in a desiccator). The first solvent may be a polar solvent such as water (including, but not limited to, water, purified water, ultra pure water and water for injections). The second solvent may be an organic solvent such as ethyl alcohol.

[0051] In one embodiment, there is provided a method of producing a pharmaceutically acceptable sodium nitrite, which comprises the steps of: (a) contacting sodium nitrite with water at a first temperature of 45 to 55 ° C in an inert atmosphere; (b) cooling the solution to a second temperature of 20 ° C to 30 ° C; (c) contacting water containing sodium nitrite with activated carbon; (d) contacting the mixture with ethyl alcohol; and (e) forming sodium nitrite at a third temperature of 0 ° C to 10 ° C in an inert atmosphere.

[0052] In some embodiments, sodium nitrite is dried in an inert atmosphere at an elevated temperature not higher than the melting point of sodium nitrite. In some embodiments, the elevated temperature is 60-70 ° C or &lt;65 ° C. In particular embodiments, the elevated temperature is 60 ° C or 65 ° C.

[0053] Suitable solvents for use in the method provided herein further include methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, acetone, A, A-dimethylformamide (DMF), A, A-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), A-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid, trichloroacetic acid, trifluoroacetic acid and mixtures thereof. In yet another embodiment, the solvent is a mixture of water and a water-miscible solvent including, but not limited to, methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, acetone, A, A-dimethylformamide (DMF), A, A-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), A-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid, trichloroacetic acid, trifluoroacetic acid and their mixture.

[0054] In some embodiments, sodium nitrite is prepared from a solution or suspension of sodium nitrite in a solvent using conventional methods including, but not limited to, cooling, cooling, evaporating the solvent, or adding an anti-solvent.

[0055] The method of producing sodium nitrite described herein may include the steps of: a) preparing a solution of sodium nitrite in a solvent at a first temperature in an inert atmosphere; and b) the production of sodium nitrite at a second temperature under an inert atmosphere. To accelerate the formation of sodium nitrite, the method may also include a seeding step by inoculating the solution with sodium nitrite crystals in an inert atmosphere before or during step (b). In some embodiments, the method further comprises an isolating and drying step as described herein.

[0056] In some embodiments, the solution of step (a) is prepared as a saturated or near saturated solution at the first temperature. This saturated or near-saturated solution is prepared by dissolving a sufficient amount of sodium nitrite in water at a temperature that is higher than the first temperature so as to obtain a saturated or near-saturated solution after allowing the solution to cool to the first temperature. A sufficient amount of sodium nitrite can be determined by the solubility of sodium nitrite in the solvent at a first temperature that is known in the art or can be determined using a method known to a person skilled in the art.

[0057] In the method for producing sodium nitrite provided by the present invention, the first temperature is in the range of 45 to 55 ° C; the second temperature is in the range of 20 to 30 ° C and the third temperature is in the range of 0 to 10 ° C.

[0058] In some embodiments, the fourth temperature ranges from -100 to 100 ° C, from about -50 to about 50 ° C, from about -10 to about 30 ° C, from about 0 to about 20 ° C, or from about 0 to about 10 ° C. To maximize the efficiency and effectiveness of the method provided herein, the third temperature is set to be lower than the second temperature.

[0059] In one embodiment, the sodium nitrite provided herein is obtained by evaporating the solvent from the solution at a second temperature. Evaporation of the solvent can be facilitated by providing heat and / or a vacuum to the solution.

[0060] In yet another embodiment, sodium nitrite is obtained by cooling the solution to a fourth temperature.

[0061] In yet another embodiment, sodium nitrite is prepared by adding an anti-solvent to the solution at a fourth temperature. Suitable anti-solvents include, but are not limited to, methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, acetone, Α, Α-dimethylformamide (DMF), .V..V-dimethylacetamide , acetonitrile (ACN), dimethyl sulfoxide (DMSO), V-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid, trichloroacetic acid, trifluoroacetic acid and mixtures thereof.

[0062] When two solvents are used as a solvent / anti-solvent pair, sodium nitrite has a higher solubility in the solvent than in the anti-solvent. Optionally, the solvent and anti-solvent in the solvent / anti-solvent pair are at least partially mixed. In some embodiments, the solvent is water. In some embodiments, the anti-solvent is a water-miscible solvent. In some embodiments, the anti-solvent is ethanol.

[0063] In yet another embodiment, sodium nitrite is prepared by adding an anti-solvent to the solution at a fourth temperature. In one embodiment, the solvent is water and the anti-solvent is ethanol.

[0064] In some embodiments, the solution (a) is stirred at room temperature under an inert atmosphere for up to 15, 30, 45 or 60 minutes or longer.

[0065] In some embodiments, one or more of the steps provided herein is carried out under an inert atmosphere (e.g., N2 or Ar).

[0066] In some embodiments, the purification step or filtration step is carried out between one or more steps provided herein.

[0067] In some embodiments, the filtration steps are carried out using a glass microfiber filter (e.g. &lt;1.6 mm). In other embodiments, the filtration steps are carried out using an Aurora filter, Cogeim filter or Estrella filter.

[0068] Other methods known in the art may also be suitable for the preparation of the pharmaceutically acceptable sodium nitrite provided herein including spray drying, roller drying, freeze drying and melt crystallization.

Characterization methods

1. Determination of total non-volatile organic carbon in sodium nitrite [0069] Also described herein are methods for determining total non-volatile organic carbon in a sample containing sodium nitrite, which includes the steps of: a) adding an inorganic acid in a predetermined amount to an aqueous sample solution that contains sodium nitrite ; b) adding an oxidant in a predetermined amount to the sample solution; and c) converting organic carbon in the sample solution into carbon dioxide under supercritical oxidation; wherein the final amount of inorganic acid is not less than about 2% of the final volume of the sample solution or the final amount of oxidant is not less than about 20% of the final volume of the sample solution.

[0070] The inorganic acid may be phosphoric acid. The inorganic acid may be 6 N phosphoric acid. The final amount of inorganic acid may be not less than about 2% and not more than about 50% of the final volume of the sample solution. The final amount of inorganic acid may be 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% or about 50% of the final volume of the sample solution. The final amount of inorganic acid may be about 6% of the final volume of the sample solution. The inorganic acid may be 6 N phosphoric acid, and the final amount of inorganic acid is about 6% of the final volume of the sample solution.

[0071] The oxidant may be sodium persulfate. The oxidizing agent may be a 30% sodium persulfate solution. The final amount of oxidant may be not less than about 20% but not more than about 90% of the final volume of the sample solution. The final amount of oxidant can be 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. The final amount of oxidant can be about 45% of the final volume of the sample solution. The oxidant may be a 30% sodium persulfate solution and the final amount of oxidant is about 45% of the final volume of the sample solution.

[0072] Organic carbon in a sample containing sodium nitrite can be oxidized according to any SCWO processes known in the art, such as those disclosed in US Patent Nos. 2,944,396, 4543190, 5387398, 5405533, 5501799, 5560822, 5804066, 6054057, 6056883, 6238568, 6519926, 6576185, 6709602 and 6773581. The SCWO process can be carried out in a TOC InnovOx laboratory analyzer (GE Analytical Instruments, Inc., Boulder, CO.). Supercritical Oxidation (SCWO) processes utilize the unique properties of water in conditions close to or exceeding the thermodynamic critical point of water (375 ° C and 218 atm). The increased pressure under supercritical oxidation conditions significantly increases the efficiency of the oxidation process by converting organic carbon to carbon dioxide in a sample containing sodium nitrite.

[0073] A solution of a sample containing sodium nitrite can be prepared by adding 5.0 g of a sample containing sodium nitrite to water to produce a 100 ml solution. The water used in this process may have no more than 0.10 ppm of total organic carbon.

[0074] The method may further comprise the step of determining the amount of carbon dioxide produced after oxidation. Carbon dioxide can be quantified using an infrared detector. Carbon dioxide can be quantified using a non-scattered infrared radiation detector.

2. Quantification of nitrite and nitrate in sodium nitrite [0075] Also described herein is a method for the quantification of nitrite and nitrate in a sample containing sodium nitrite, which comprises the steps of: (a) separating nitrite and nitrate by ion chromatography; and (b) quantifying the individual amounts of nitrite and nitrate using suppressive conductivity detection. Ion chromatography can be carried out isocratically. The aqueous mobile phase may contain sodium carbonate and sodium bicarbonate. The aqueous mobile phase may contain 2.7 mM sodium carbonate and 0.3 mM sodium bicarbonate.

3. Quantification of alkylnaphthalenesulfonates in sodium nitrite [0076] Also described herein is a method for the quantification of alkylnaphthalenesulfonates in a sample containing sodium nitrite, which includes the quantification of alkylnaphthalenesulfonates by mass spectrometry and liquid chromatography.

4. Quantification of Nitrogen Oxide Impurities in Sodium Nitrite [0077] Also described herein is a method for the quantification of nitrogen oxides impurity in a sample containing sodium nitrite, which includes the quantification of nitrogen oxides impurities using a nitric oxide electrode (NOx).

Pharmaceutical compositions [0078] Pharmaceutical compositions are provided herein comprising the sodium nitrite provided herein as the active ingredient, alone or in combination with a pharmaceutically acceptable vehicle, carrier, diluent or excipient, or a mixture thereof.

[0079] The compound provided herein may be administered alone or in combination with one or more other active ingredients. Pharmaceutical compositions that contain the sodium nitrite provided herein can be formulated into various dosage forms for oral, parenteral and topical administration. Pharmaceutical compositions may also be formulated in modified release dosage forms, including delayed, prolonged, long-term, prolonged, pulsed, controlled, accelerated and fast, directed, programmed release, and gastric retained dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, above; Modified-Release Drug Deliver Technology, Rathbone et al., Ed., Drugs and Pharmaceutical Science, Marcel Dekker , Inc .: New York, NY, 2003; vol. 126).

[0080] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration that includes the sodium nitrite provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0081] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprises sodium nitrite provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0082] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for local administration, including pulmonary administration, which comprises sodium nitrite provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0083] In one embodiment, the pharmaceutical composition comprises the sodium nitrite provided herein and water. In another embodiment, the pharmaceutical composition contains about 300 mg of sodium nitrite provided herein in about 10 ml of water.

[0084] In one embodiment, the pharmaceutical composition provided herein further comprises an acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is acetic acid or ascorbic acid. In some embodiments, the sodium nitrite and acid constituting the pharmaceutical composition provided herein are mixed together when the composition is administered to a subject. In certain embodiments, the pharmaceutical composition provided herein is administered in or with a medical device or device (see US Patent Application Publication No. 2007/0239107).

[0085] In some embodiments, the sodium nitrite in the pharmaceutical composition provided herein is not acidified (e.g., un acidified).

[0086] The pharmaceutical compositions provided herein may be provided in unit dosage form or in multi-dose form. Dosage unit form as used herein refers to a physically discrete unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of active ingredient (s) sufficient to obtain the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit dosage forms include an ampoule, a syringe and individually packaged tablet or capsule. The unit dosage form can be administered in parts or multiples thereof. The multi-dose form is a number of identical unit dosage forms packaged in a single container for administration as a separate unit dosage form. Examples of multi-dose forms include a vial, a bottle with tablets or capsules, or a bottle with a pint or gallon capacity.

[0087] The pharmaceutical compositions provided herein may be administered once or several times at intervals. It should be understood that the exact dosage and duration of treatment may vary depending on the age, weight and condition of the patient being treated, and can be determined empirically using known test protocols or by extrapolating in vivo or in vitro or diagnostic test data. It should further be understood that for any particular individual, the specific dosage regimen should be adjusted over time, depending on the individual needs and professional judgment of the person administering or supervising the administration of the formulations.

A. Oral Administration [0088] The pharmaceutical compositions provided herein may be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, hard pastilles, pastilles, starch capsules, pellets, medicated chewing gum, granules, powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions , solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient (s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, agents lubricants, coloring agents, dye migration inhibitors, sweeteners and flavors.

[0089] Binders or granulating agents impart cohesiveness to the tablet to ensure that the tablet will remain intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch and pregelatinized starch (e.g. STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, psyllium husks, psyllium, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegro with modase, arabic tragacanth and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose , such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrans, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or filler may be present in an amount from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

[0090] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, may give some compressed tablets properties that allow them to break down in the mouth as a result of chewing. Such compressed tablets can be used in the form of chewable tablets.

[0091] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses such as croscarmellose; crosslinked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacryline potassium salt; starches such as corn starch, potato starch, tapioca starch and pre-gelatinized starch; clays; aligny; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of preparation and is easily determined by those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[0092] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, 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 gels such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and Cab-O-Sil® (Cabot Co. from Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant.

[0093] Suitable lubricants include colloidal silicon dioxide, CAB-OSIL® (Cabot Co. from Boston, MA) and asbestos-free talc. Coloring agents include any of the approved, certified, water-soluble FD&amp;C dyes, water-insoluble FD&amp;C dyes suspended in alumina hydrate, and lakes and mixtures thereof. Lacquer is a combination of adsorption of a water-soluble dye with hydrated heavy metal oxide, which leads to an insoluble form of the dye. Flavors include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerol and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN^® 20), polyoxyethylene sorbitan 80 monooleate (TWEEN® 80) and triethanolamine oleate. Dispersing and dispersing agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum, acacia, carbomethylcellulose sodium, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Preservatives include glycerol, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerol, sorbitol, ethyl alcohol and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0094] It should be understood that many carriers and excipients may perform several functions, even in the same formulation.

[0095] The pharmaceutical compositions provided herein may be provided as compressed tablets, crushed tablets, chewable lozenges, fast dissolving tablets, multiple compressed tablets or enteric coated tablets, sugar coated tablets or coated tablets. Enteric-coated tablets are compressed tablets coated with substances that are resistant to gastric acid but dissolve or disintegrate in the intestines, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed sugar-coated tablets that may be beneficial in masking undesirable flavors or aromas and in protecting tablets from oxidation. The coated tablets are compressed tablets that are covered with a thin film or coating of water-soluble material. Coating coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate. The coating in the form of a coating gives the same general characteristics as the sugar coating. Repeatedly compressed tablets are compressed tablets produced by more than one compression cycle, including layered tablets, and compression-coated or dry-coated tablets.

[0096] Tablet active dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants , diluents and / or pigments. Flavors and sweeteners are particularly useful for making tablets and hard chewable tablets.

[0097] The pharmaceutical compositions provided herein may be provided in the form of hard or soft capsules, which may be prepared from gelatin, methyl cellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two parts, one being slid into the other, as a result of which the active ingredient is completely closed. A soft flexible capsule (SEC) is a soft spherical casing, such as a gelatin casing, which is softened by the addition of glycerol, sorbitol or a similar polyol. Soft gelatin sheaths may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and propylparabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Patent Nos. 4,328,245; 4409239; and 4,410,545. Capsules can be coated in a manner known to those skilled in the art to modify or prolong the dissolution of the active ingredient.

[0098] The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. The emulsion is a two-phase system in which one liquid is dispersed in the form of small balls in another liquid, which can be of the oil-in-water or water-in-oil type. The emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifying agent and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable acetal, such as di (lower alkyl) acetal lower alkyl aldehyde, e.g. acetaldehyde diethyl acetal; and a water miscible solvent containing one or more hydroxyl groups such as propylene glycol and ethanol. Potions are transparent, sweetened and water-alcohol solutions. Syrups are concentrated aqueous sugar solutions, for example sucrose, and may also contain a preservative. Liquid dosage forms, for example, a solution in polyethylene glycol, may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0099] Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredient (s) provided herein and dialkylated mono- or polyalkylene glycol, including 1,2-dimethoxymethane, diglyme, triglym, tetraglyme, polyethylene glycol dimethyl ether 350, polyethylene glycol dimethyl ether 550, polyethylene glycol dimethyl ether 750, wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These preparations may also contain 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, acid phosphoric, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

[0100] Pharmaceutical compositions provided for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US Patent No. 6,350,458.

[0101] The pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent granules and powders for reconstitution to obtain a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may contain diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may contain organic acids and a source of carbon dioxide.

[0102] Coloring and flavoring agents can be used in all of the above dosage forms.

[0103] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, directed, and programmed release.

[0104] The pharmaceutical compositions provided herein may be formulated with other active ingredients that do not interfere with the desired therapeutic effect or with substances that enhance the desired effect.

B. Parenteral administration [0105] The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion or implant, for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intra-bladder and subcutaneous administration.

[0106] The pharmaceutical compositions provided herein can be formulated into any dosage form that is suitable for parenteral administration, such as solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared by conventional methods known to those skilled in the pharmaceutical arts (see Remington: The Science and Practice of Pharmacy, supra).

[0107] Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or anti-microbial preservatives, stabilizers , solubilizing agents, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusting agents and inert gases.

[0108] Suitable aqueous media include, but are not limited to, water, saline, saline, or phosphate buffered saline (PBS), sodium chloride, injectable Ringer's solution, injectable dextrose solution, sterile water for injection, dextrose and lactated Ringer's solution for injection. Non-aqueous media include, but are not limited to, non-volatile vegetable oils, 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 from coconut oil and palm kernel oil. Water-miscible media include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N, N -dimethylacetamide and dimethyl sulfoxide.

[0109] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercury compounds, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparabens and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerol and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are as described herein including sodium bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan 80 monooleate, and triethanolamine oleate. Suitable masking or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl ^ -cyclodextrin, sulfobutyl ether, β-cyclodextrin and sulfobutyl ether 7 - ('> - cyclodextrin (CAPTISOL®, CyDex, Lenexa ).

[0110] The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. Single dose preparations are packaged in an ampoule, vial or syringe. Multiple-dose parenteral preparations must contain a bacteriostatic or fungistatic concentration. All parenteral preparations must be sterile, as is known and realized in the art.

[0111] In one embodiment, the pharmaceutical compositions are provided in the form of sterile ready-to-use solutions. In another embodiment, the pharmaceutical compositions are provided in the form of sterile dry soluble products, including lyophilized powders and subcutaneous tablets, for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as sterile, ready-to-use suspensions. In yet another embodiment, the pharmaceutical compositions are provided in the form of sterile, dry insoluble products for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided in the form of sterile ready-to-use emulsions.

[0112] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, directed, and programmed release.

[0113] Pharmaceutical compositions may be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix that is surrounded by an external polymeric membrane that is insoluble in body fluids, but which allows the active ingredient to diffuse into the pharmaceutical compositions.

[0114] Suitable internal matrices include poly (methyl methacrylate), poly (butyl methacrylate), plasticized or non-plasticized poly (vinyl chloride), plasticized nylon, plasticized poly (ethylene terephthalate), natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, copolymers ethylene-vinyl acetate, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked poly (vinyl alcohol) and cross-linked partially hydrolyzed poly (vinyl acetate).

[0115] Suitable external polymer membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, polyvinyl chloride vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubbers, ethylene vinyl alcohol copolymer, ethylene / vinyl acetate terpolymer / vinyl alcohol and ethylene / vinyloxyethanol copolymer.

C. Topical Administration [0116] The pharmaceutical compositions provided herein can be administered topically to the skin, to the holes, or to the mucosa. As used herein, topical administration includes (intra) dermal, conjunctival, intraocular, intraocular, ocular, ear, transdermal, intranasal, intravaginal, urethral, ​​respiratory and rectal administration.

[0117] The pharmaceutical compositions provided herein can be formulated into any dosage form that is 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, membranes, sprays, rinses, sprays, suppositories, bandages, patches on the skin. The topical formulation of pharmaceutical compositions provided herein may also contain liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0118] Pharmaceutically acceptable carriers and excipients suitable for use in the topical preparations provided herein include, but are not limited to, aqueous media, water-miscible media, non-aqueous media, antimicrobials, or anti-microbial preservatives, stabilizers, solubilizing agents, agents isotonizing, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickeners and inert gases.

[0119] Pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT ™ (Chiron Corp., Emeryville, CA) and BIOJECT ™ (Bioject Medical Technologies Inc., Tualatin, OR).

[0120] The pharmaceutical compositions provided herein may be provided in the form of ointments, creams and gels. Suitable ointment bases include oily or hydrocarbon bases, including lard, benzoin lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsified or absorption media, such as hydrophilic petrolatum, hydroxystearin sulfate and anhydrous lanolin; substrates removable with water, such as hydrophilic ointment; water soluble ointment bases, including polyethylene glycols of varying molecular weight; emulsion substrates in the form of water-in-oil (W / O) or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy, above ). These media are emollients, but generally require the addition of antioxidants and preservatives.

[0121] A suitable cream base may be oil-in-water or water-in-oil type. Cream bases may be washable under the influence of water and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also called the "internal" phase, which generally consists of petroleum jelly and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually has, although not necessarily, a larger volume than the oil phase and usually contains a humectant. The emulsifying agent in the cream formulation may be a nonionic, anionic, cationic or amphoteric surfactant.

[0122] Gels are semi-solid suspension type systems. Single-phase gels contain organic macromolecules distributed substantially evenly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers such as carbomers, carboxypolyalkylenes, CARBOPOL®; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and poly (vinyl alcohol); cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. Dispersing agents such as alcohol and glycerol may be added to form a uniform gel, or the gelling agent may be dispersed by trituration, mechanical mixing and / or mixing.

[0123] The pharmaceutical compositions provided herein may be administered rectally, into the urethra, vaginally or perivaginally in the form of suppositories, globules, dilators, compresses or cataplasms, pastes, powders, dressings, creams, patches, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or rectal liquids. Such dosage forms can be prepared by conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

[0124] Rectal, urethral and vaginal suppositories are solids for insertion into the body's holes that are solid at ordinary temperatures but melt or soften at body temperature releasing the active ingredient (s) inside the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories contain bases or excipients, such as stiffeners, that achieve a melting point close to body temperature when formulated using the pharmaceutical compositions provided herein; and antioxidants as described herein including sodium bisulfite and sodium metabisulfite. Suitable bases include, but are not limited to, cocoa butter (theobromic oil), a mixture of glycerol and gelatin, Carbowax (polyoxyethylene glycol), spermacet, paraffin, white and yellow wax and appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels such like poly (vinyl alcohol), hydroxyethyl methacrylate, polyacrylic acid; glocerożelatynę. Combinations of different substrates can be used. Rectal and vaginal suppositories can be made by pressing or molding. The typical weight of a rectal and vaginal suppository is from about 2 to about 3 g.

[0125] The pharmaceutical compositions provided herein may be administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel forming solutions, powders for solution making, gels, ocular therapeutic systems and implants.

[0126] The pharmaceutical compositions provided herein may be administered via the nasal or inhalatory route. The pharmaceutical compositions can be delivered in the form of an aerosol or delivery solution by means of a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a subtle mist, or a nebulizer, alone or in combination with a suitable propellant such as 1,1,1 , 2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may also be provided in the form of a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. When applied to the nose, the powder may contain a bioadhesive, including chitosan or cyclodextrin.

[0127] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer may be formulated to contain ethanol, aqueous ethanol or a suitable alternative agent to disperse, dissolve or prolong the release of the active ingredient provided, propellant as solvent; and / or a surfactant such as sorbitan trioleate, oleic acid or oligo (lactic acid).

[0128] The pharmaceutical compositions provided herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less or about 10 micrometers or less. Particles of this size can be prepared using a comminution method known to those skilled in the art, such as spiral mill jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0129] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base such as lactose or starch; and an efficacy modifier such as Z-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Pharmaceutical compositions provided for inhaled / intranasal administration may further contain appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin.

[0130] Topical pharmaceutical compositions provided herein can be formulated for immediate release or modified release, including delayed, sustained, pulsed, controlled, directed, and programmed release.

D. Modified Release [0131] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or site of release of the active ingredient (s) is different from that of an immediate dosage form when administered via the same route. Modified release dosage forms include delayed, prolonged, long-term, prolonged, pulsed, controlled, accelerated and fast, targeted, programmed release and gastric retained dosage forms. Pharmaceutical compositions in a modified release dosage form can be prepared by a variety of modified release therapeutic systems and methods known to those of skill in the art, including, but not limited to, controlled release matrix therapeutic systems, osmotically controlled release therapeutic systems, and controlled therapeutic systems release in the form of many particles, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes and their combinations. The release rate of the active ingredient (s) can also be modified by changing the particle size and polymorphism of the active ingredient (s).

[0132] Examples of modified release include, but are not limited to, those described in US Patent Nos .: 3845770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358; and 6699500.

1. Matrix Controlled Release Therapy Systems [0133] The modified release pharmaceutical compositions provided herein can be prepared using a controlled release matrix therapeutic system known to those skilled in the art (see, Takada et al. "Encyclopedia of Controlled Drug Delivery" vol. 2, Mathiowitz ed., Wiley, 1999).

[0134] In one embodiment, the modified release pharmaceutical dosage compositions provided herein are formulated using an erodible matrix therapeutic system that is swellable, erodible or water soluble polymers, including synthetic polymers and naturally occurring polymers and derivatives thereof, such like polysaccharides and proteins.

[0135] Materials useful for making the erodible matrix include, but are not limited to, chitin, chitosan, dextran and pullulan; agar gum, arabic gum, karaya gum, carob gum, tragacanth, carrageenans, ghatti gum, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulose, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), butyrate cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethylhydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; poly (vinyl alcohol); poly (vinyl acetate); fatty acid and glycerol esters; polyacrylamide; poly (acrylic acid); copolymers of ethacrylic acid and methacrylic acid (EUDRAGIT® Rohm America, Inc., Piscataway, NJ, USA); poly (2-hydroxyethyl methacrylate); polylactides; 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 butyl methacrylate homopolymers and copolymers, methyl methacrylate, ethyl methacrylate, ethyl acrylate, 2-dimethylaminoethyl methacrylate and methacrylate (trimethylaminoethyl) chloride. [0136] In further embodiments, the pharmaceutical compositions are formulated using a non-erodible matrix therapeutic system. The active ingredient (s) are dissolved or dispersed in an inert matrix and released primarily by diffusion through the inert matrix after administration. Materials suitable for use as an erodible matrix therapeutic system include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, poly (methyl methacrylate), poly (butyl methacrylate), chlorinated polyethylene, poly (chloride) vinyl), methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol and vinyl ethylene / polyethylene ethylene / vinyl alcohol copolymer ), plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers and hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax and triglycerides.

[0137] In a matrix release system, the desired release kinetics can be controlled, for example, by the type of polymer used, polymer viscosity, polymer particle size and / or active ingredient (s), ratio of active ingredient (s) ) to polymer and other excipients or carriers in the compositions.

[0138] The modified-release pharmaceutical compositions provided herein can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation, followed by compression, melt granulation, and then compression.

2. Osmotically controlled release therapeutic systems [0139] The modified release dosage pharmaceutical compositions provided herein can be prepared using an osmotically controlled release therapeutic system, including single chamber system, dual chamber system, asymmetric membrane (AMT) technology and extruded core system (ECS). In general, such therapeutic systems contain at least two components: (a) a core that contains active ingredient (s); and (b) a semipermeable membrane with at least one delivery opening that encapsulates the core. The semi-permeable membrane regulates the flow of water from the aqueous environment of use to the core to cause release of the drug as it is forced through the delivery opening (s).

[0140] In addition to the active ingredient (s), the core of the osmotic therapeutic system optionally includes an osmotic agent that generates a driving force for the transport of water from the environment of use to the therapeutic system core. One class of osmotic agents that are water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels," includes, but are 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), cross-linked PVP, poly (vinyl alcohol) (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxyethyl cellulose (HEC) HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

[0141] Another class of osmotic agents are osmogens, which are capable of absorbing water by affecting the osmotic pressure gradient through the barrier surrounding the coating. Suitable 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 sulfite, 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, versenic acid, glutamic acid, ptoluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

[0142] Osmotic agents with different dissolution rates can be used to affect how quickly the active ingredient (s) is / are initially delivered from this dosage form. For example, amorphous sugars such as MANNOGEM ™ EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first few hours to achieve the desired therapeutic effect immediately, and gradual and continuous release of the remaining amount to maintain the desired level of effect therapeutic or prophylactic for an extended period. In this case, the active ingredient (s) is / are released at such a rate as to replace the amount of active ingredient that is metabolized and excreted.

[0143] The core may also contain a wide selection of other excipients and carriers described herein to improve the performance of the dosage form or to promote stability or processing.

[0144] Materials useful for forming a semi-permeable membrane include various types of acrylic compounds, vinyl compounds, ethers, polyamides, polyesters and cellulose derivatives that are water-permeable and insoluble in water at physiologically relevant pH or are susceptible to being insoluble in water by chemical modification, such as cross-linking. Examples of suitable polymers useful for forming a coating include plasticized, non-plasticized and fortified cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl carbamate-CA, CAP, methyl carbamate-CA, succinate-CA, cellulose acetate trimellitate (CAT), dimethylaminoacetate-CA, ethyl carbonate-CA, chloroacetate-CA, ethyl oxalate-CA, methylsulfonate-CA, butylsulfonate-CA, p-toluenesulfonate-CA, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, carob rubber triacetate, hydroxylated ethylene vinyl acetate, EC; PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic acids) and their esters and poly (methacrylic acids) and their esters and copolymers, starch, dextran , dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0145] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by an aqueous medium, but are permeable to water vapor as disclosed in US Patent No. 5798119. Such a hydrophobic, but water vapor permeable membrane usually consists of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, poly (acrylic acid) derivatives, polyethers, polysulfones, polyether sulfones, polystyrenes, poly (vinyl halides), poly (fluoride) vinylidene), polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0146] The delivery hole (s) in the semi-permeable membrane can be formed after coating, by mechanical or laser drilling. The delivery hole (s) may also be formed in situ as a result of erosion of the plug from water-soluble material or by breaking the thinner portion of the membrane over the cavity in the core. In addition, delivery holes can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in US Patent Nos. 5,611,059 and 5,698,220.

[0147] The total amount of active ingredient (s) released and the rate of release can be essentially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core and the number, size and position of the delivery holes.

[0148] Pharmaceutical compositions in osmotically controlled release dosage form may further comprise additional conventional excipients or carriers as described herein to promote the operation or processing of the formulation.

[0149] Osmotically controlled release dosage forms can be prepared by conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, above; 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).

[0150] In some embodiments, the pharmaceutical compositions provided herein are formulated as a controlled release type AMT that contains an asymmetric osmotic membrane coating the core containing the active ingredient (s) and other pharmaceutically acceptable excipients or carriers. See, US Patent Nos. 5,611,059 and WO 2002/17918. AMT type controlled release dosage forms can be prepared by conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating.

[0151] In some embodiments, the pharmaceutical compositions provided herein are formulated as an ESC controlled release dosage form that includes an osmotic membrane coating the core comprising the active ingredient (s), hydroxyl ethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

3. Controlled Release Multi-Particle Therapy Systems [0152] The modified release dosage form pharmaceutical compositions provided herein can be prepared as a multi-particle controlled release therapeutic system that contains a plurality of particles, granules or pellets, with a diameter ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm or from about 100 pm to about 1 mm. Such a multi-particle system can be produced by methods known to those skilled in the art, including dry and wet granulation, extrusion / spheronization, roller compactor processing, solidification of the molten mass and after spray coating of the embryo cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989 [0153] Other excipients or carriers described herein can be mixed with pharmaceutical compositions to facilitate processing and the formation of multi-particle systems. The resulting particles may themselves be a multi-particle therapeutic system, or they may be coated with various film-forming materials, such as enteric polymers, water-swellable and water-soluble polymers. Multi-particle systems can be further processed into a capsule or tablet.

4. Targeted Delivery [0154] The pharmaceutical compositions provided herein can also be formulated to be targeted to a specific tissue, receptor or other area of ​​the subject's treated body, including as delivery systems based on liposomes, resealed erythrocytes, and antibodies. Examples include, but are not limited to, US Patent No. 6,316,652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542; and 5709874.

Sodium nitrite for use in methods of treatment [0155] In one embodiment, there is provided sodium nitrite of the invention for use in methods of treating cyanide poisoning, which methods comprise administering to a subject a therapeutically effective amount of sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of sodium thiosulfate (e.g. sodium thiosulphate pentahydrate). In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of pharmaceutical grade sodium thiosulfate (e.g., pharmaceutical grade sodium thiosulfate). Suitable forms and methods for the preparation of pharmaceutical grade sodium thiosulfate for co-administration with sodium nitrite are provided in U.S. Provisional Application No. 61/223993, filed July 8, 2009, entitled SODIUM THIOSULFATE-CONTAINING PHARMACEUTICAL COMPOSITIONS (Agent No. 11709-007-888) ), as well as Example 6 herein. In some embodiments, pharmaceutical grade sodium thiosulfate has one or more of the following characteristics:

it contains not less than 99% by weight and / or not more than 100.5% by weight of sodium thiosulphate on an anhydrous basis;

has a pH between 6 and 8 when measured in a 10% solution at 25 ° C;

has a water content of 32% to 37% by weight;

has the appearance of colorless crystals;

has a clear and colorless appearance as a 10% solution;

has no smell;

has a positive result in the sodium test;

has a positive result in the test for thiosulphate;

it is not cloudy when mixed with ammonium oxalate TS;

has a heavy metal content not exceeding 10 ppm; contains not more than 0.01% by weight of carbonate;

it contains not more than 0.005% by weight of an insoluble substance;

contains not more than 200 ppm of chloride;

it contains not more than 0.001% by weight of sulphide;

it contains not more than 0.05% or not more than 0.1% by weight of sulfite;

it contains not more than 0.05%, not more than 0.1%, not more than 0.25% or not more than 0.5% by weight of sulfate;

it contains not more than 0.002% by weight of iron; it contains not more than 0.01% by weight of calcium;

it contains not more than 0.005% by weight of potassium;

Contains not more than 10 ppm, not more than 100 ppm, not more than 500 ppm, not more than 1000 ppm or not more than 5000 ppm organic volatile pollutants; Has a total NVOC or NPOC content of not more than 60 ppb, not more than 2.5 ppm, not more than 8 ppm, not more than 10 ppm, not more than 20 ppm, not more than 25 ppm or not more than 50 ppm ;

contains not more than 0.05 ppm mercury;

contains not more than 2 ppm aluminum;

contains not more than 3 ppm arsenic;

it contains not more than 0.001% by weight of lead;

it contains not more than 0.002% by weight of nitrogen compounds (as N);

it contains not more than 0.003% by weight of selenium;

has a total aerobic microbial load of not more than 100 CFU / g;

has a total number of yeasts and molds not exceeding 20 CFU / g; and contains not more than 0.02 EU / mg, not more than 0.1 EU / mg or not more than 0.25 EU / mg bacterial endotoxins.

[0156] In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0157] In another embodiment, there is provided sodium nitrite of the invention for use in methods of treating hydrogen sulfide poisoning, which methods comprise administering to a subject a therapeutically effective amount of sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0158] In yet another embodiment, sodium nitrite of the invention is provided herein for use in a method of treating a cardiovascular disease or condition associated with the cardiovascular system including, but not limited to, high blood pressure, pulmonary hypertension, cerebral vasospasm, angina, claudication, peripheral arterial disease, critical limb ischemia and ischemic reperfusion injury, which method comprises administering to the subject a therapeutically effective amount of sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0159] In some embodiments, the cardiovascular related condition is one or more of the conditions of pulmonary hypertension (e.g., neonatal pulmonary hypertension, primary pulmonary hypertension and secondary pulmonary hypertension), systemic hypertension, skin ulceration, acute renal failure, chronic renal failure, intravascular thrombosis and ischemic event in the central nervous system.

[0160] In yet another embodiment, there is provided a sodium nitrite according to the invention for use in a method of treating a condition associated with elevated blood pressure, which method comprises administering to the subject a therapeutically effective amount of the sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0161] In yet another embodiment, the sodium nitrite of the invention is provided for use in a method of increasing blood flow to tissues, for example, tissues in areas of low oxygen pressure, which method comprises administering to the subject a therapeutically effective amount of the sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0162] In yet another embodiment, sodium nitrite of the invention is provided for use in a method that stimulates the growth of new blood vessels, for example, in tissues in areas of poor circulation and low oxygen pressure, which method comprises administering to the subject a therapeutically effective amount of nitrite provided sodium. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0163] In some embodiments, the reduced blood flow to the tissue is caused, directly or indirectly, by at least one of the following conditions: sickle cell anemia, thalassemia, disease caused by the presence of hemoglobin C, disease caused by the presence of hemoglobin SC, sickle cell disease, hereditary thalassemia, hereditary spherocytosis, hereditary elliptocytosis, hereditary ovalocytosis, glucose-6-phosphate deficiency and deficiency of other red blood cell enzymes, nocturnal seizure hemoglobin (PNH) cold hemoglobinuria (PCH), thrombocytopenic purpura / haemolytic uraemic syndrome (TTP / HUS), idiopathic autoimmune hemolytic anemia, drug-induced immune hemolytic anemia, secondary immunological hemolytic anemia, non-immunological hemolytic anemia caused by chemical or physical means, malaria, tropical malaria, bartonellosis, babesiosis, Clostridium infection, influenza infection, haemophilic infection response to transfusion, rhabdomyolysis (myoglobinemia), transfused blood transfusion, hemoglobin transfusion, red blood cell transfusion, extracorporeal circulation, coronary artery disease, ischemic heart syndrome, angina, iatrogenic hemolysis, vascular plastic, myocardial ischemia, tissue ischemia, hemolysis caused by intravascular devices, hemodialysis, systemic hypertension, pulmonary hypertension skin, acute renal failure, chronic renal failure, intravascular thrombosis and ischemic event in the central nervous system. In some embodiments, the tissue is tissue affected by an ischemic process.

[0164] In yet another embodiment, there is provided a sodium nitrite according to the invention for use in a method of treating a hemolytic condition, which method comprises administering to the subject a therapeutically effective amount of the sodium nitrite provided herein. In one embodiment, the subject is a mammal. In another embodiment, the individual is human. In some embodiments, the sodium nitrite administered to the subject is not acidified.

[0165] In some embodiments, the hemolytic state includes one or more of sickle cell anemia, thalassemia, disease caused by hemoglobin C, disease caused by hemoglobin SC, sickle thalassemia, hereditary spherocytosis, hereditary elliptosis, hereditary ovalocytosis, glucose 6-phosphate deficiency and deficiency of other red blood cell enzymes, nocturnal paroxysmal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria (PCH), thrombotic thrombocytopenic purpura / haemolytic uremic syndrome (TTP / HTJS), idiopathic autoimmune hemolytic anemia, drug-induced immunological hemolytic anemia, secondary immune haemolytic anemia, non-immunological hemolytic anemia caused by chemical or physical agents, malaria, bacteria, malaria, malaria, malaria, malaria Clostridium severe infection caused by haemophilus influenzae type B, extensive burns, transfusion responses, rhabdomyolysis (myoglobinemia), infused blood transfusion, extracorporeal circulation and hemodialysis.

[0166] In yet another embodiment, the sodium nitrite of the invention is provided for use in methods of treating a respiratory disease or tracheo-pulmonary condition including, but not limited to, cystic fibrosis, pulmonary tuberculosis, fungal pneumonia, bacterial pneumonia, viral pneumonia, lung abscess, pulmonary hypertension, pulmonary embolism and pulmonary spasm, which methods comprise administering to the subject a therapeutically effective amount of sodium nitrite provided herein.

[0167] In yet another embodiment, sodium nitrite of the invention is provided herein for use in methods of treating a dermatological disease or skin-related condition including, but not limited to, bacterial skin infection, skin fungal infection, skin viral infection, fungal nail infection, bacterial infection nail, viral nail infection, fungal infection of the nail bed, bacterial infection of the nail bed, viral infection of the nail bed, psoriasis, scleroderma, dermatitis, nail inflammation and nail bed inflammation, which methods include administering to the subject a therapeutically effective amount of the sodium nitrite provided herein.

[0168] In yet another embodiment, the sodium nitrite of the invention is provided for use in methods of treating, preventing or reducing the risk of hospital acquired infections, such as hospital infections, which may result from the introduction of a device (e.g., medical device) and / or use of the device in the body. In one embodiment, the infection is caused or associated with S. aureus. Such applications and devices are disclosed in US Patent Application Publication No. 2007/0239107. Examples of such devices include, but are not limited to, urological catheters, endotracheal tubes, vascular catheters, vascular catheter ports, wound drainage tubes, gastric tubes. In some embodiments, the sodium nitrite administered to a subject is acidified or administered in combination with an acidifying agent (e.g., acid).

[0169] In certain embodiments, provided herein are methods for preparing or making a medicament for treating, preventing, or treating a disease or disorder provided herein, or symptoms thereof.

[0170] Depending on the condition, disorder or disease to be treated, and on the condition of the subject, the sodium nitrite provided herein may be administered by the oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intravenous (ICV), by injection or infusion into the subarachnoid reservoir, subcutaneous injection or implant), inhalation, intranasal, vaginal, rectal, sublingual or local (e.g. transdermally or locally) and can be formulated alone or together in a suitable dosage unit with pharmaceutically acceptable carriers, excipients and vehicles suitable for each route of administration.

[0171] The dose may be one, two, three, four, five, six or more divided doses which are administered at appropriate intervals throughout the day. The dose or divided doses may be administered in the form of dosage units containing from about 10 ng to about 1000 mg, from about 20 ng to about 5 mg, from about 50 ng to about 1 mg, from about 50 ng to about 0.2 mg, or from about 50 ng to about 0.5 mg of active ingredient (s) per dosage unit, and if the patient's condition requires it, the dose may be alternatively administered as a continuous infusion.

[0172] In some embodiments, a suitable dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg / kg per day), about 0.01 to about 50 mg / kg per day, about 0.01 up to about 25 mg / kg per day or about 0.05 to about 10 mg / kg per day, which can be administered in single or multiple doses. A suitable dosage level can be 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. In this range, the dose may be 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.

[0173] In certain embodiments of the methods provided herein, a therapeutically effective amount of sodium nitrite administered to a subject does not induce methaemoglobin toxic levels, and in many embodiments does not cause the production of clinically significant amounts of methaemoglobin in the subject. In some embodiments, an effective amount of sodium nitrite administered to a subject causes the subject to produce no more than about 25%, no more than about 20%, no more than about 10%, no more than about 8%, no more than about 5%, no more than about 3%, no more than about 2%, no more than about 1% methaemoglobin.

[0174] In certain embodiments of the methods provided herein, a therapeutically effective amount of sodium nitrite is administered once or more times a day, for a week, for a month, for a year or more. In certain embodiments of the methods provided herein, a therapeutically effective amount of sodium nitrite is administered sporadically or chronically. In certain embodiments of the methods provided herein, a therapeutically effective amount of sodium nitrite is administered sporadically or continuously for one or more hours, days, weeks, months, years or more.

Combination Therapy [0175] The sodium nitrite provided herein may also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of the diseases and conditions given herein.

[0176] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not limit the order in which therapies (eg, prophylactic and / or therapeutic agents) are used in an individual with a disease or disorder. First therapy (e.g. a prophylactic or therapeutic agent such as a compound provided herein can be used before (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 before), simultaneously with or after (e.g. after 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 from) administering a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also being considered.

[0177] As used herein, the term "synergistic" includes a combination of the sodium nitrite provided herein and other therapy (e.g., a prophylactic or therapeutic agent) that has been or is being used to treat, prevent or manage a disease or disorder that is more effective than additive effects of therapy. Synergistic effect of combining therapy (e.g. combination of prophylactic or therapeutic agents) allows the use of lower doses for one or more treatments, and / or less frequent use of said therapies to a subject with a disorder. The possibility of using smaller doses in therapy (e.g. preventive or therapeutic agent) and / or less frequent use of said therapy, reduces the toxicity associated with the use of said therapy in an individual without reducing the effectiveness of said therapy in preventing or treating the disorder). In addition, the synergistic effect may lead to improved efficacy of agents in preventing or treating a disorder. Finally, thanks to the synergistic effect of combining therapy (e.g. combination of prophylactic or therapeutic measures), you can avoid or reduce the adverse or unwanted side effects associated with using each therapy alone.

[0178] The sodium nitrite provided herein may be administered in combination or alternating with another therapeutic agent. In combination therapy, effective doses of two or more agents are administered together, while in alternation or sequential therapy, the effective dose of each agent is administered sequentially or sequentially. The doses administered will depend on the rate of absorption, inactivation and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage levels will also vary depending on the severity of the condition to be alleviated. It should further be understood that for any particular individual, specific dosing regimens and modes should be adjusted over time, according to the individual needs and professional judgment of the person administering or supervising the administration of the composition.

[0179] The compounds provided herein may be administered in combination with other classes of compounds, including, but not limited to, endothelin converting enzyme (ECE) inhibitors such as phosphoramidone; thromboxane receptor antagonists such as ifetroban; agents that open potassium channels; thrombin inhibitors such as hirudin; growth factor inhibitors such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents such as GPIIb / IIIa blockers (e.g. abciximab, eptifibatide and tirofiban), P2Y (AC) antagonists (e.g. clopidogrel, 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 gemopatrilat; HMG CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; antiatherosclerotic 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; anti-arrhythmic drugs; diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, thiprinfen, chlorothalonone, furosenid, muzolimine, bumetanonil, triumononyl ammonium; thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated streptokinase and plasminogen activator complex (APSAC); anti-diabetic agents such as biguanides (e.g. metformin), glucosidase inhibitors (e.g. acarbose), insulins, meglitinides (e.g. repaglinide), sulfonylureas (e.g. glimepiride, glyburide and glipizide), thiazolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone) and PPAR-gamma agonists; mineralocorticoid receptor antagonists such as spironolactone and eplerenone; and growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors such as PDE III inhibitors (e.g. cilostazol) and PDE V inhibitors (e.g. sildenafil, tadalafil and vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory agents; antiproliferative agents such as methotrexate, FK506 (tacrolimus), mycophenolate mofetil; chemotherapeutic agents; immunosuppressive agents; anti-cancer and cytotoxic agents (e.g. alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines and triazenes); anti-metabolites such as folate antagonists, purine analogs and pyrimidine analogues; antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin and fileamycin; enzymes such as L-asparaginase; protein farnesyltransferase inhibitors; hormonal agents such as glucocorticoids (e.g. cortisone), estrogens / anti-estrogens, androgens / anti-androgens, progestins and luteinizing hormone releasing hormone antagonists, and octreotide acetate; microtubule terminating agents such as ecteinascidins; microtubule stabilizing agents such as paclitaxel, docetaxel and epothilones AF; plant-derived products such as vinca alkaloids, epipodophyllotoxins and taxanes; and topoisomerase inhibitors; protein prenylotransferase inhibitors; and cyclosporins; steroids such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-alpha inhibitors such as tenidap; anti-TNF antibodies or soluble TNF receptor such as etanercept, rapamycin and leflunimide; cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; and various agents such as sodium thiosulfate, hydroxycarbamide, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes such as cisplatin, satraplatin and carboplatin.

[0180] The sodium nitrite provided herein can also be provided as an industrial article using packaging materials well known to those skilled in the art. See e.g.

U.S. Patent No. 5,323,907; 5052558; and 5033252. Examples of pharmaceutical packaging include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, pouches, vials, containers, syringes and any packaging material suitable for the chosen formulation and intended mode of administration and treatment.

[0181] Also described herein are kits that a practitioner may simplify administering to the subject appropriate amounts of active ingredients. The kit described herein may include a container and a dosage form of sodium nitrite provided herein.

[0182] Kits may include a container containing the dosage form of sodium nitrite provided herein, in a container containing one or more other therapeutic agents described herein.

[0183] The kits described herein may further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-free injectors, drip bags, patches and inhalers. The kits described herein may also contain condoms for the administration of active ingredients.

[0184] The kits described herein may further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in solid form, which must be reconstituted for parenteral administration, the kit may contain a sealed container with a suitable vehicle in which the active ingredient may be dissolved to form a particle-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous media, including, but not limited to, USP water for injection, sodium chloride injection, Ringer's injection, dextrose for injection, dextrose and sodium chloride, and Ringer's injection with lactate for injection; water-miscible substrates, including, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous media including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

[0185] Sodium nitrite can also be used in conjunction with a medical device. Exemplary medical devices are shown in US Patent Application Publication No. 2007/0239107. Examples of such devices include, but are not limited to, urological catheters, endotracheal tubes, vascular catheters, vascular catheter ports, wound drainage tubes, gastric tubes. The device may contain or be coated with the sodium nitrite provided herein. In the case of a urinary catheter, sodium nitrite may be in the inflatable or expandable part that is introduced into the subject, it may be in a collection bag, or it may be in wires associated with the device.

[0186] The disclosure will be further understood by the following non-limiting examples.

EXAMPLES [0187] As used herein, the symbols and conventions used in these methods, schemes and examples, regardless of whether the specific abbreviation is defined in a particular way, are consistent with those used in modern scientific literature, for example in the Journal of American Chemical Society or Journal of Biological Chemistry. In particular, but without limitation, the following abbreviations may be used in the examples and throughout the description: g (grams); mg (milligrams); ml (milliliters); pl (microliters); mM (millimolar); μΜ (micromolar); mmol (millimoles); eq. (equivalent); h or h (hours); min (minutes).

[0188] For all of the following examples, standard treatment and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (degrees Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The methodologies illustrated in the examples below are intended to be examples of suitable chemical reactions as a result of using specific examples.

Example 1

Preparation of pharmaceutical grade sodium nitrite [0189] Deionized water (18.3 L) was placed in a 50-gallon inertized reactor under a nitrogen atmosphere. 15 kilograms of non-pharmaceutical grade sodium nitrite were added to the reactor. The reactor was again inerted with nitrogen. The mixture was slowly heated to 50 ° C and then stirred for an additional 10 min to give a clear solution. [0190] The solution was cooled to 25 ° C and transferred to a 55 gallon plastic drum. 60 grams of activated carbon were added to the drum and the solution was stirred for 30 minutes.

[0191] The drum contents were filtered and transferred to a 50 gallon reactor. The 50 gallon reactor was cooled to 5 ° C and then stirred at this temperature until crystallization was observed. 50 kg of ethanol was placed in the reactor and stirred at 5 ° C for 30 minutes. The resulting suspension was filtered. An additional 19.7 kilograms of ethanol was placed in a 50 gallon reactor and rinsed towards the filter.

[0192] Solid material was transferred from the filter to drying trays. The solid material was dried under full vacuum at less than 65 ° C for 12 hours using a blow of nitrogen in an oven.

[0193] The production yield in this batch was 59%.

[0194] The analysis of the sodium nitrite provided from the purification procedure is summarized in Table 1.

TABLE 1.

<td>Analysis</td><td>Test result</td>

<td>USP test</td><td> 99,2%</td>

<td>Ion chromatography</td><td> 99,8%</td>

<td>Sodium</td><td>Compatible^and</td>

<td>Nitrite</td><td>Compatible^and</td>

<td>pH of a 10% solution at 25 ° C</td><td> 7,9</td>

<td>Weight loss during drying</td><td> &lt;0,01%</td>

<td>Heavy metals</td><td>NMT 10 ppm</td>

<td>Sodium Nitrate</td><td> &lt; 0,05%</td>

<td>Sodium carbonate</td><td> &lt; 0,01%</td>

<td>Insoluble substance</td><td> 0,001%</td>

<td>Chloride</td><td> &lt; 0,005%</td>

<td>Sulfate</td><td> &lt; 0,01%</td>

<td>Iron</td><td> &lt;0,001%</td>

<td>Carbon</td><td> &lt; 0,01%</td>

<td>Potassium</td><td> &lt;0,001%</td>

<td>Ethanol</td><td>&lt;0.1% (1000 ppm)</td>

<td>Total non-volatile organic carbon or</td><td></td>

<td>equivalent</td><td>&lt;5.6 ppm</td>

<td>Mercury</td><td>&lt;0.05 ppm</td>

<td>Aluminum</td><td>&lt;2 ppm</td>

<td>Arsenic</td><td>&lt;1 ppm</td>

<td>Residual anti-caking agent</td><td>&lt;10 ppm</td>

<td>Selenium by the ICP-OES method or equivalent</td><td> &lt; 0,001%</td>

<td>Bacterial endotoxins</td><td>&lt;0.018 EU / mg</td>

<td colspan="2">a. Sodium and nitrite identification was performed by the presence of Method 191 tests as described in USP XXXII (2009).</td>

[0195] During drying, sodium nitrite was tested at various time intervals for weight loss during drying and water content. When the material meets the relevant specifications for weight loss during drying as well as water content, drying was stopped.

Example 2

Method for the determination of total non-volatile organic carbon in sodium nitrite [0196] Total non-volatile organic carbon was determined using a TOC InnovOx laboratory analyzer (GE Analytical Instruments, Inc., Boulder, CO.). Total organic carbon (TOC) in the water used to prepare the standard, reagent and sample was not more than 0.10 ppm. Phosphoric acid was a class D reagent. Sodium persulfate was obtained from General Electric. Sucrose according to USP was used as a reference standard. The compressed nitrogen contained no more than 1 ppm CO2 and no more than 1 ppm total hydrocarbon (THC).

[0197] The phosphoric acid (6 N) used as the acidifying solution was prepared by adding approximately 100 ml of water to a 250-ml volumetric flask, followed by slow addition of 100 ml of phosphoric acid and additional water added to make up the final volume of 250 ml.

[0198] The sodium persulfate solution (30%) used as the oxidant was prepared by adding to a 500-ml volumetric flask a 0.1 g sodium persulfate and adding additional water to make up the final volume of 500 ml, after dissolving the sodium persulfate. The solution was allowed to stand for 3 days before use and used within 14 days after preparation.

[0199] A standard stock solution of sucrose (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 standard stock solution to a 100 mL volumetric flask followed by the addition of water bringing the volume to 100 mL at room temperature. A TOC standard (2 ppm) was prepared by adding 10 mL of 10 ppm TOC standard to a 50-mL volumetric flask, followed by the addition of water bringing the volume to 50 mL at room temperature. A TOC standard (0.5 ppm) was prepared by adding to a 100-ml volumetric flask a 5-ml 10 ppm TOC standard, followed by the addition of water bringing the volume to 100 ml at room temperature.

[0200] A sodium nitrite sample solution was prepared by adding a 5.0 g sample to a 100-mL volumetric flask followed by the addition of water bringing the volume to 100 mL at room temperature.

[0201] The InnovOx device was calibrated with water and 0.5 ppm, 2 ppm and 10 ppm TOC standards using the following device parameters as shown in Table 2.

TABLE 2.

<td>Protocol Name</td><td>Calibration for sodium nitrite</td>

<td>number of points</td><td> 4</td>

<td>Range</td><td>0 - 1000 ppm</td>

<td>Acid</td><td> 6,0%</td>

<td>oxidizer</td><td> 45,0%</td>

<td>purging</td><td>4.0 min</td>

<td>Correction relative to blank</td><td>disabled</td>

<td>Automatic dilution</td><td>excluded</td>

<td>Type of calibration</td><td>Fri - Fri</td>

<td>Repeat</td><td> 7</td>

<td>Bounces</td><td> 2</td>

[0202] The requirements for the calibration curve were as follows i) the correlation coefficient (r) of replicate means must be not less than 0.99; (ii) RSD for 2 and 10 ppm TOC standards must be no more than 10%; iii) the limit of quantification (LOQ) must be no more than 3 ppm, calculated as follows:

LOQ = (10) (A) (B) / (CD) and iv) the detection limit (LOD) must be no more than 1 ppm, which is calculated as follows:

LOD = (3) (A) (B) / (CD) where:

A is the carbon concentration in 0.5 ppm of the TOC standard;

B is the standard deviation of the TOC concentration determined in the blank formulation;

C is the average TOC concentration measured in 0.5 ppm TOC standard; and

D is the average TOC concentration determined in the blank formulation. [0203] Samples were analyzed using the following device parameters as shown in Table 3.

TABLE 3.

<td>number of points</td><td> 4</td>

<td>Range</td><td>0 - 1000 ppm</td>

<td>Acid</td><td> 6,0%</td>

<td>oxidizer</td><td> 45,0%</td>

<td>purging</td><td>4.0 min</td>

<td>perfusion</td><td>dilution</td>

<td>Correction relative to blank</td><td>disabled</td>

<td>Calibration</td><td>Calibration for sodium nitrite</td>

<td>Repeat</td><td> 6</td>

<td>Bounces</td><td> 2</td>

[0204] Before and after analyzing each sample, an analysis was performed for a 2 ppm sample of the TOC standard.

[0205] The requirements for system suitability were as follows i) RSD for the 2 ppm TOC standard must be no more than 10%; (ii) the percentage of the theoretical response (% T) for 2 ppm TOC standard determinations must be not less than 90% and not more than 110%; as calculated as follows:

% T = 100 x A / B;

where:

A is the result determined by the analyzer (ppm); and

B is the concentration of 2 ppm of the TOC standard (ppm);

(iii) for any sample where the sample response was equal to or greater than LOQ, the RSD must be no more than 15%; iv) total organic carbon (TOC) was A x 20, where A was the result determined by the analyzer (ppm); if A is less than LOD, the result was calculated using LOD instead of A, which imposes higher TOC limits, if A is less than LOQ but greater than LOD, LOQ imposes higher TOC limits.

Example 3

Determination of nitrite and nitrate impurities in sodium nitrite [0206] Standards and samples were prepared in purified water and analyzed by ion chromatography (IC) using an ion exchange column (Dionex Ionpac AS12A) and suppression conductivity detection. Separation was achieved by isocratic elution with an aqueous mobile phase containing 2.7 mM sodium carbonate and 0.3 mM sodium bicarbonate. Efficacy parameters were assessed for suitability, specificity, linearity and range, LOD / LOQ, accuracy, recovery, precision, intermediate precision, specificity, system robustness and analytical solution stability. The LOD has been estimated to be 0.01 pg / ml for sodium nitrite and 0.04 pg / ml for sodium nitrite. It has been estimated that LOQ is 0.08 Lig / ml for both compounds.

[0207] The linearity for sodium nitrite was assessed using a series of standards at 60, 90, 120, 150 and 180 pg / ml. Each solution was injected in duplicate. The linearity in this method has been shown to be 60 to 180 pg / ml for sodium nitrite with a correction factor (R) of 0.9999.

[0208] The linearity for sodium nitrite was assessed using a series of standards ranging from 0.04 to 6.0 pg / ml. Each solution was injected in duplicate. Linearity in this method was shown to be from 0.152 to 6.067 pg / ml for sodium nitrate with a correction factor (R) of 0.9997.

Example 4

Detection of nitrogen oxides impurities in sodium nitrite [0209] The concentration of total nitrogen oxides (NOxS) in a solution containing sodium nitrite was quantified using a nitric oxide electrode (NOx) (Orion Model 94-46) by measuring the electrode response (mV) and expression in pg / ml or ppm nitrogen. The limit value for the detection of total nitrogen oxides pollutants is set at around 1 ppm. Before determining the total nitrogen oxides impurities, the pH meter was calibrated using buffers at pH 4.0 and 7.0. The linearity of the NOx electrode response was also determined using an acidified 0.1 M KCl solution and various amounts of 1000 ppm NOx standard, which was prepared by dissolving 492 ± 10 mg sodium nitrite in water to a final 100 ml. At pH &lt;1.8, nitrite at a concentration of 4.92 mg / ml is converted into an equivalent amount of nitrogen oxides and the corresponding concentration is 1000 mg / pl of nitrogen. Acidified 0.1 M KCl solution was prepared by mixing 15 ml 1 N HCl with 0.1 M KCl to a final volume of 500 ml. During the measurement, the solution was kept at 20 to 25 ° C and the pH of the sodium sample solution was not less than 6.7. The method has been shown to be specific for NOx in the presence of nitrate and nitrite.

Example 5

Quantification of alkylnaphthalenesulfonates in sodium nitrite [0210] A method for the quantification of alkylnaphthalenesulfonates (ANS) in a solution containing sodium nitrite (e.g. 50 mg / ml) has been developed. The method was used to detect ANS in the range of about 1 to about 200 ppm with a detection limit of 0.3 ppm. The mass spectrometer and liquid chromatography used were used to quantify ANS in a solution containing sodium nitrite.

[0211] Various ANS standards in water were prepared in the range from 1 ng / ml to 10 mg / ml to determine the optimal detection method and to optimize the detector parameters. Then, ANS standards were prepared with more added amounts ranging from 1 ppm to 500 ppm in sodium nitrite solution (50 mg / ml) to test the range and linearity of the method.

[0212] Efficacy parameters for specificity, linearity and range, LOD / LOQ, accuracy, precision and repeatability were evaluated. It has been shown that in the process in combination with quadratic regression, confirmed quantitative data in the range from 1 to 200 ppm with a correction factor (R) of 0.998 is obtained.

Reference example 6

Preparation of pharmaceutical grade sodium thiosulfate pentahydrate [0213] In a nitrogen atmosphere, 381.0 grams of sulfur and deionized water (3 L) were placed in a 12-liter inertized four-necked flask with torian, thermowell, reflux condenser, top stirrer and Orion pH probe with pH -metrem. The suspension was stirred and 1000.1 grams of sodium sulfite and deionized water (2 L) were placed into the flask. The initial temperature was 20.9 ° C and pH = 10.2. The suspension was heated for 4 hours to 97 ° C (pH after four hours = 7.5). Heat was removed and the reaction mixture was allowed to cool to room temperature overnight while stirring. The suspension was filtered using a 1.6 micron glass microfibre filter to obtain a clear yellow solution. The solution was then concentrated using a rotary vacuum evaporator at a bath temperature of 60 ° C +/- 5 ° C under a vacuum of 700-730 mm Hg. After 3 hours and 45 minutes, the solution had a specific weight of 1.405 and the solution had a weight of 2.821 grams. The solution was transferred under a nitrogen atmosphere to a 5-liter four-necked flask with torian, thermowell and upper stirrer. The solution was cooled to 25 ° C and a crystal sample of sodium thiosulfate pentahydrate was introduced into the solution. The solution was then cooled to 0 +/- 5 ° C and stirred for 45 minutes. Precipitation started when the solution reached 23.7 ° C. The white crystalline solid was filtered using a sintered glass funnel. The mother liquor was used to wash the solids from the reaction flask. The solid was transferred to drying vessels and placed in a vacuum oven at 20 ° C overnight. During drying, sodium thiosulfate pentahydrate was tested at various intervals for water content. When the material met the appropriate requirement for water content (i.e. about 32 to about 37% by weight), drying was stopped. The final weight of dried solid was 1016.2 grams (52% yield).

[0214] The examples outlined above are provided to provide those of ordinary skill in the art with full disclosure and description of how to make and use the claimed forms and is not intended to limit the scope of what is disclosed herein.