WO2014037927A1 - Compositions de chlorate et utilisation de chlorate dans le traitement de l'exposition aux rayonnements - Google Patents

Compositions de chlorate et utilisation de chlorate dans le traitement de l'exposition aux rayonnements Download PDF

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Publication number
WO2014037927A1
WO2014037927A1 PCT/IB2013/058440 IB2013058440W WO2014037927A1 WO 2014037927 A1 WO2014037927 A1 WO 2014037927A1 IB 2013058440 W IB2013058440 W IB 2013058440W WO 2014037927 A1 WO2014037927 A1 WO 2014037927A1
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chlorate
composition
radiation
administration
solid
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PCT/IB2013/058440
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English (en)
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Dominic King-Smith
Rainer Martin
Henrich GUNTERMANN
Thomas Isensee
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Nuvo Research Gmbh
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Publication of WO2014037927A1 publication Critical patent/WO2014037927A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the present application relates to compositions comprising chlorate and uses of chlorate for treating subjects who have been exposed to radiation. More particularly, the application relates to the use of chlorate compositions for treating subjects with acute radiation syndrome.
  • Ionizing radiation is present naturally in the environment. Normal background levels of radiation carry little risk to the general public. However, exposure to elevated levels of ionizing radiation can cause a large spectrum of health effects. The nature and severity of the health effects depends primarily on the dose of radiation and the exposure time.
  • ROS reactive oxygen species
  • Tissue injuries induced by ionizing radiation differ depending on the target organ and cell type.
  • Organs and cells with high sensitivity to radiation include the immune system, the skin, the hematopoietic system, the gut, the lungs, the kidneys, the spermatogenic cells and the vascular system.
  • ARS acute radiation syndrome
  • Symptoms of ARS may include, but are not limited to, nausea, vomiting, diarrhea, loss of appetite, fatigue, skin damage, hair loss, fever, diminished organ function, seizures, coma, and death.
  • the symptoms of ARS typically develop within several days/weeks/months following exposure to ionizing radiation depending on the radiation dose.
  • a number of treatments for ARS are under development. Treatment options that have or are being investigated include cytokine therapy, stem cell therapy, and the administration of various chemical and natural agents that act as antioxidants or immunomodulators.
  • WF10 (often referred to in older literature as tetrachlorodecaoxide or TCDO) is an intravenous (i.v.) aqueous solution containing the anions chlorite (0.425% w/v), chlorate (0.15% w/v), chloride (0.2% w/v), and sulfate (0.07% w/v) with sodium as the cation.
  • the active principle of WF10 has been reported to be chlorite (McGrath ef al. (2002), Curr. Opin. Investig. Drugs, 3(3):365-373; PCT patent application publication no. 2007/009245).
  • WF10 is sold under the trade name Immunokine ® in Thailand where it is approved as an adjunctive treatment for cancer patients suffering from post-radiation syndromes. Its effect on local and total-body irradiation in animals has also been studied (Kempf ef al. (1994), Oncology 51 :510-514; Mason et al. (1993), Radiation Research 136:229-235; Pope et al. (1989), The British journal of Radiology 62:381-383; Sassy ef al. (1991), Onkol. 167:191-193). Ivankovic et al. studied the acute effect of i.v.
  • WF10 contains a carbonate buffer to maintain alkaline environment (pH of >10) to maintain the stability of the active chlorite ion.
  • a highly basic solution such as WF10
  • WF10 by intravenous infusion can result in phlebitis (inflammation of the vein) unless the infusion is performed slowly, and only after WF10 is diluted using about 250 - 500 mL of saline, For this reason a WF10 infusion might typically be administered over a period such as 1.5 hours resulting in patient inconvenience and significant utilization of medical resources.
  • administration of WF10 by i.v. requires clinical supervision and eliminates its use as an "at home" remedy.
  • the present application is directed to the use of chlorate as an effective agent in the treatment of subjects who have been exposed to radiation.
  • the present application includes compositions and uses of chlorate that are expected to have a wider therapeutic index than currently approved radiation treatments.
  • chlorate has a more favorable toxicological profile than chlorite, the reported active principle in WF10 (Bureau EC-EC. lUCLID Dataset-Substance ID: 7758-19-2. European Comission - European Chemicals Bureau; 2000. p. 56; Health Canada. Guidelines for Canadian Drinking Water Quality: Guideline Technical Document — Chlorite and Chlorate. Water Quality and Health Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario. Health Canada 2008).
  • chlorate-based formulations are suitable for long-term storage and administration to animals under neutral pH conditions, whereas formulations containing chlorite tend to be unstable unless stored at high pH and special precautions, such as long infusion times, may be necessary to administer such high pH formulations to an animal if side effects such as phlebitis are to be avoided.
  • the present application includes compositions comprising chlorate for the treatment of radiation exposure.
  • the present application includes compositions comprising chlorate for treating a condition arising from radiation exposure such as acute radiation syndrome.
  • the present application further includes a method for treating radiation exposure comprising administering an effective amount of chlorate to a subject in need thereof.
  • the present application includes a method for treating a condition arising from radiation exposure, for example, acute radiation syndrome, comprising administering an effective amount of chlorate to a subject in need thereof.
  • the condition is an acute radiation sub-syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.
  • the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.
  • the chlorate is in an aqueous solution. In other embodiments, the chlorate is in a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form. In further embodiments, the chlorate is an enteral composition, including an oral or rectal composition or a parenteral composition including a dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal composition.
  • enteral composition including an oral or rectal composition or a parenteral composition including a dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal composition.
  • the composition comprises, or consists essentially of, chlorate as the sole active ingredient, in another embodiment, the composition is chlorite-free. In a further embodiment, the composition is sulfate-free. In yet a further embodiment, the composition is carbonate-, bicarbonate-, and/or carbonic acid-free. In still a further embodiment, the composition is chloride-free. In another embodiment, the composition is carbonate-, bicarbonate-, carbonic acid-, sulfate-, chloride-, and/or chlorite- free. In yet a further embodiment the chlorate treatment is effected by administering to a subject a dosage form which is essentially free of water.
  • the composition comprises about 0.01 % to about 100% w/w of a chlorate salt.
  • the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion.
  • the composition is an aqueous solution comprising about 0.1 % to 2.5% or about 1.5% w/v chlorate ion.
  • the chlorate composition is formulated as a pharmaceutical composition for administration to subjects.
  • the pharmaceutical composition comprises, or consists essentially of chlorate, as the sole active ingredient.
  • the pharmaceutical composition is chlorite-free.
  • the pharmaceutical composition is sulfate-free.
  • the pharmaceutical composition is carbonate-, bicarbonate-, and/or carbonic acid- free.
  • the pharmaceutical composition is chloride- free or anhydrous.
  • the pharmaceutical compositions of the application are sold as ready-to-use unit doses or require dilution (e.g. with water or saline) prior to use.
  • the pharmaceutical compositions are concentrated prior to packaging and delivery to a pharmacist.
  • the chlorate is administered at least once a day, at least once every second day, at least once every third day, at least once every fourth day, or as required to treat a subject.
  • the chlorate is administered twice, three times or four times a day or as needed.
  • the chlorate is administered starting at least 2, 3, 4 or 5 days following radiation exposure.
  • subjects are treated with more than one cycle, for example, at least two, three, four or five cycles.
  • the chlorate is administered enterally, including orally or rectaily, or a parenterally including including dermally, intradermal ⁇ , intragastrally, intracutaneously, intravasally, intravenously, intramuscularly, intraperitoneally, intranasally, intravaginally, intrabuccally, percutaneously, subcutaneously, sublingually, topically, inhalatively or transdermally.
  • the chlorate is administered intravenously, In another embodiment, the chlorate is administered orally.
  • the subject has been exposed to at least 0.5 or 1 Gray of radiation within one hour, one day, one week or one month.
  • the application also includes a use of an effective amount of chlorate for treating a subject who has been exposed to radiation.
  • the appiication further includes a use of an effective amount of chlorate for treating a condition arising from radiation exposure.
  • the condition is acute radiation syndrome.
  • the condition is an acute radiation sub-syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.
  • the condition is an acute radiation sub-syndrome associated with one or more of neutropenia, thrombocytopenia, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.
  • the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.
  • the composition is for use in treating a subject and comprises about 0.01 % to about 100% w/w of a chlorate salt.
  • the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion.
  • the composition is in an aqueous solution comprising about 0.1 % to about 2.5% or about 1.5% w/v chlorate ion.
  • the composition comprises, or consists essentially of, chlorate as the sole active ingredient.
  • the composition is chlorite-free.
  • the composition is sulfate-free.
  • the composition is carbonate-, bicarbonate-, and/or carbonic acid-free, in still another embodiment, the composition is chloride-free or anhydrous,
  • the chlorate is for use at least once a day, at least once every second day, at least once every third day or at least once every fourth day, or as required to treat a subject. In other embodiments the chlorate is administered twice, three times or four times a day or as needed. In other embodiments, the chlorate is for use starting at least 2, 3, 4 or 5 days following radiation exposure. In further embodiments, the chlorate is for use in more than one cycle, for example, at least two, three, four or five cycles.
  • the chlorate is for enteral, including oral and rectal use, or parenteral use including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhaltive, or transdermal use.
  • the chlorate is for intravenous or oral use.
  • the application also includes a composition for use in treating a subject who has been exposed to radiation, the composition comprising an effective amount of chlorate.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the chlorate is in an aqueous solution, or a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form.
  • the composition comprises, or consists essentially of, chlorate as the sole active ingredient.
  • the composition is chlorite-free.
  • the composition is sulfate-free.
  • the composition is carbonate-, bicarbonate-, and/or carbonic acid-free.
  • the composition is chloride-free or anhydrous.
  • the composition has a pH of about 4 to about 13, about 5 to about 12, about 6 to about 1 1 , about 7 to about 10, or about 8 to about 9.
  • the pH of the composition is adjusted according to an industry-recognized acceptable pH range for a desired route of administration.
  • the composition is adjusted to pH of about 5 to about 9 for administration by infusion (Infusion Nurses Society, Infusion Nursing Standards of Practice Supplement to January/February 201 1 Volume 34, Number 1 S ISSN 1533-1458).
  • infusion Nurses Society Infusion Nursing Standards of Practice Supplement to January/February 201 1 Volume 34, Number 1 S ISSN 1533-1458.
  • the buffer when the aqueous solution is buffered, is one that provides a pH of about 7 to about 13, or about 10 to about 13. In another embodiment, when the aqueous solution is buffered, the buffer is one that provides a pH of about 5 to about 1 1 , about 6 to about 10, about 7 to about 9, or about 6.5 to about 10.5.
  • suitable buffers carbonate buffers, phosphate buffers, acetic acid buffers, citric acid buffers, lactic acid buffers, tartaric acid buffers and maleic acid buffers are included.
  • the aqueous solution further includes sodium chloride, for example in an amount to render the solution isotonic.
  • the composition is formulated to comprise about 0.01 % to about 100% w/w of a chlorate salt.
  • the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion.
  • the composition is in an aqueous solution comprising about 0.1% to about 2.5% or about 1.5% w/v chlorate ion.
  • the composition is formulated for enteral administration, including oral or rectal administration, or parenteral administration including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccai, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal administration.
  • the chlorate is formulated for intravenous or oral administration.
  • the present application describes ARS treatment options that are expected to be safe, effective, inexpensive and well-tolerated. For example, the treatments are conveniently distributed and administered in a mass casualty situation and effective when administered after radiation exposure. This is desirable because exposure of a military or civilian population to radiation exposure may not be known or predictable in advance.
  • Figure 1 shows the percent survival of irradiated mice treated with a chlorate solution versus a saline solution. Irradiated mice treated with chlorate solution show a higher percent survival in the 32 days following treatment.
  • Figure 2 shows the "score" of irradiated mice treated with a chlorate solution versus a saline solution.
  • Figure 3 shows lower weight loss in irradiated mice treated with a with a chlorate solution versus a saline solution.
  • compositions comprising an "additional” or “second” component
  • the second component as used herein is chemically different from the other components or first component.
  • a “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.
  • agent indicates a compound or mixture of compounds that, when added to a composition, tend to produce a particular effect on the composition's properties.
  • chlorate is an active agent.
  • active agent means a compound or mixture of compounds having a pharmacological effect, in particular in treating radiation exposure.
  • sole active agent means that the listed agent is the only compound or mixture of compounds having a pharmacological effect in a composition.
  • chlorite-free means that the composition comprises no detectable levels chlorite or that the amount of chlorite present in the sample is small compared to the amount of chlorate.
  • the weight of chlorite in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.
  • sulfate-free means that the composition comprises no detectable levels of sulfate or that the amount of sulfate present in the sample is small compared to the amount of chlorate.
  • the weight of sulfate in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.
  • chloride-free means that the composition comprises no detectable levels of chloride or that the amount of chloride present in the sample is small compared to the amount of chlorate.
  • the weight of chloride in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.
  • carbonate-, bicarbonate-, and/or carbonic acid- free means that the composition comprises no detectable levels of carbonate-, bicarbonate-, and/or carbonic acid or that the amount of these substances present in the sample is small compared to the amount of chlorate .
  • the weight of these substances in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.
  • aqueous solution means a solution wherein the solvent is primarily water, although small amounts, for example, less than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % (v/v) of a non-aqueous solvent may be present.
  • composition and "pharmaceutical composition” as used herein are equivalent terms referring to a composition of matter for pharmaceutical use.
  • parenteral means taken into the body or administered in a manner other than through the gastrointestinal tract.
  • an "effective amount” as used herein means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art.
  • an "effective amount of chlorate” is optionally the amount of chlorate that is sufficient to treat a subject who has been exposed to radiation or who is suffering from the effects of radiation exposure or acute radiation syndrome.
  • water as used herein as an ingredient in the compositions of the application refers to pharmaceutically-acceptable water.
  • w/v means the number of grams of a substance in 100 mL of a composition.
  • w/w means the number of grams of a substance in 100 g of a composition.
  • v/v means the number of mL of a substance in 100 mL of a composition.
  • pharmaceutically acceptable means compatible with the treatment of animals, in particular, humans.
  • treating means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of disease, prevention of disease spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable.
  • Treating and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treating” and “treatment” as used herein also include prophylactic treatment.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent and optionally consists of a single administration, or alternatively comprises a series of applications.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active ingredient or agent, the activity of the compositions described herein, and/or a combination thereof, It will also be appreciated that the effective dosage of the agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required, For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • cycle refers to a part of a treatment method that comprises a period of treatment with active agent followed by a period of no treatment or treatment with placebo.
  • one treatment cycle can comprise administration or use of an active agent for 1 to 20 days followed by no administrations or administration or use of a placebo for 1 to 20 days.
  • the periods of treatment and no treatment/placebo need not be the same in duration or amounts.
  • subject includes all members of the animal kingdom, including mammals, and suitably refers to humans.
  • radiation exposure refers to being subjected or exposed to ionizing radiation. Radiation exposure can occur as a result of a catastrophic event such as a nuclear accident, the explosion of an atomic bomb, exposure to a sterilization irradiator or interplanetary travel. Radiation exposure includes both whole body radiation exposure and radiation exposure to only part of the body.
  • radiation exposure comprises exposure to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of less than 1 minute, or up to 5 minutes, 10 minutes, 30 minutes, 60 minutes, 1 hour, 6 hours, 12 hours, 24 hours, two days, one week, two weeks, three weeks or one month.
  • radiation exposure comprises exposure to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of more than one month or one year.
  • condition arising from radiation exposure refers to any medical symptom, disease, illness, injury, condition or syndrome that results from radiation exposure.
  • the condition may arise directly or indirectly from radiation exposure.
  • a condition arising from radiation exposure is acute radiation syndrome.
  • ARS acute radiation syndrome
  • acute radiation syndrome refers to an acute illness caused by irradiation of a significant portion of the body to a high dose of penetrating radiation in a short period of time.
  • acute radiation syndrome is caused by exposure to at least 1 Gray of radiation within less than an hour.
  • ARS is also known as radiation toxicity, radiation poisoning or radiation sickness.
  • LD50/30 means the median dose of radiation necessary to kill 50% of an animal in a 30 day observation period following acute radiation injury.
  • the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • the foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.
  • the term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • compositions in particular pharmaceutical compositions, comprising chlorate, and methods and uses thereof for treating radiation exposure.
  • the chlorate is comprised in a compound of the formula X m (CI0 3 ) n , where X is a cationic moiety and m and n are integers necessary to provide a net valency of 0. While these compounds are in solution, free chlorate "CIO3 " " is formed.
  • the chlorate source is in the form of an alkaline or alkaline earth metal salt, non-limiting examples of which include sodium chlorate (NaCI0 3 ), calcium chlorate and magnesium chlorate. In one embodiment, the chlorate source is sodium chlorate.
  • the chlorate source is in the form of an acid, a non-limiting example of which is chloric acid, wherein chlorate is derived from the acid through neutralization.
  • the composition has a pH of about 4 to about 13, about 5 to about 12, about 6 to about 1 1 , about 7 to about 10, or about 8 to about 9.
  • the pH of the composition is adjusted according to an industry-recognized acceptable pH range for a desired route of administration. For example, the composition is adjusted to pH of about 5 to about 9 for administration by infusion (Infusion Nursing Standards of Practice Supplement to January/February 2011 Volume 34, Number 1 S ISSN 533- 1458).
  • chlorate is used as an aqueous composition comprising chlorate.
  • the composition is an unbuffered aqueous solution.
  • the composition is a buffered aqueous solution,
  • the buffer when the aqueous solution is buffered, the buffer is one that provides a pH of about 7 to about 13, or about 10 to about 13.
  • the buffer when the aqueous solution is buffered, the buffer is one that provides a pH of about 5 to about 1 1 , about 6 to about 10, about 7 to about 9, or about 6.5 to about 10.5.
  • aqueous solution further includes sodium chlonde, for example in an amount to render the solution isotonic.
  • the aqueous composition is ready-to- use or is diluted (e.g. with water or saline) prior to administration.
  • the aqueous composition is used for i.v. infusion, i.v. push or is administered subcutaneously or intramuscularly.
  • the chlorate is used as an oral composition.
  • the compositions for oral administration include, but are not limited to, solid, semi-solid, gel, paste, liquid, crystalline or encapsulated forms. Non-limiting examples of these forms include capsules, tablets, suspensions, powders, modified-release formulations, solutions, emulsions and syrups.
  • the chlorate is used as an inhalant or suppository.
  • the composition comprises about 0.01 % to about 100% w/w of a chlorate salt.
  • the composition includes about 0.1 % to about 80%, about 0.2% to about 50%, about 0.25% to about 20%, about 0.5% to about 10%, about 1 % to about 5%, about 1.25% to about 2.5% or about 1.5% w/v chlorate ion.
  • the compositions of the present application include about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% w/v chlorate ion.
  • the composition comprises, or consists essentially of, chlorate as the sole active ingredient.
  • the compositions are chlorite-free.
  • the compositions are sulfate-free and/or chloride-free.
  • the composition is carbonate-, bicarbonate-, and/or carbonic acid-free.
  • the composition includes a chlorate salt, optionally sodium chlorate, which is formulated for administration at a dose of about 0.01 mg/kg to about 40 mg/kg body weight.
  • the composition is formulated for administration of chlorate at a dose of about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight.
  • the composition is formulated for administration of chlorate at a dose of about 0.1 , 0.2, 0.5, 1.0, 2.0, 5.0 or 10.0 mg/kg body weight.
  • the composition is formulated for administration of chlorate at a fixed dose that is not adjusted for body weight (e.g. 1 , 2.5, 5, 10, 25, 50, 100 or 250 mg/day for an adult).
  • the composition includes a pharmaceutically acceptable carrier, excipient, buffer and/or stabilizer.
  • Suitable pharmaceutically acceptable carriers include essentially chemically inert and nontoxic materials that do not interfere with the effectiveness of the biological activity of the pharmaceutical composition.
  • Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., USA, 2000).
  • Suitable pharmaceutical carriers include, but are not limited to, water, saline solutions, glycerol solutions, ethanol, N-(1 (2,3-dioleyioxy)propyi)N,N, N-trimethyiammonium chloride (DOTMA), diolesylphosphotidyl-ethanolamine (DOPE), and liposomes.
  • DOTMA N-(1 (2,3-dioleyioxy)propyi)N,N, N-trimethyiammonium chloride
  • DOPE diolesylphosphotidyl-ethanolamine
  • liposomes include, but are not limited to, water, saline solutions, glycerol solutions, ethanol, N-(1 (2,3-dioleyioxy)propyi)N,N, N-trimethyiammonium chloride (DOTMA), diolesylphosphotidyl-ethanolamine (DOPE), and liposomes.
  • Such compositions contain a
  • compositions of the application are formulated for administration to a subject such as a human.
  • the compositions are formulated for enteral administration, including oral or rectal administration.
  • the compositions are formulated for parenteral administration, including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal administration.
  • the chlorate is administered, or formulated for administration, or used, intravenously, orally, inhalativeiy, rectally or parenterally including dermally, intradermal ⁇ , intragastrally, intracutaneousiy, intravasally, intravenously, intramuscularly, intraperitoneal ⁇ , intranasally, intravaginally, intrabuccally, percutaneously, subcutaneously, sublingually, topically or transdermal!y.
  • the chlorate is administered intravenously.
  • the chlorate is administered orally.
  • compositions are formulated in oral dosage forms that are modified release, for example immediate release and timed-release (e.g. delayed release or suspended release), formulations.
  • oral formulations comprise a coating or other mechanism for releasing the active agent(s) lower down in the digestive track, such as in the large or small intestine.
  • modified-release formulations include, for example, bolus release, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, suspended release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • timed-release compositions are formulated, e.g.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes are, for example, formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines
  • the application includes methods for treating subjects who have been exposed to radiation comprising administering an effective amount of chlorate to a subject in need thereof.
  • the application also includes the use of chlorate for treating subjects who have been exposed to radiation.
  • the application also includes methods for treating subjects who have been exposed to radiation comprising administering an effective amount of the chlorate compositions described herein to a subject in need thereof.
  • the application also includes the use of the chlorate compositions described herein for treating subjects who have been exposed to radiation.
  • Also provided in the present application are methods for treating acute radiation syndrome comprising administering an effective amount of chlorate to a subject in need thereof.
  • the application also includes the use of chlorate for treating subjects who have acute radiation syndrome,
  • Also provided in the present application are methods for treating acute radiation syndrome comprising administering an effective amount of the chlorate compositions described herein to a subject in need thereof.
  • the application also includes the use of the chlorate compositions described herein for treating subjects who have acute radiation syndrome.
  • the present application further includes a methods and uses for treating other conditions arising from radiation exposure, comprising administering an effective amount of chlorate, or the compositions comprising chlorate as described herein, to a subject in need thereof.
  • the condition is an acute radiation sub-syndrome associated with one or more of neutropenia, thrombocytopenia, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.
  • the condition is an acute radiation sub- syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.
  • the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.
  • the methods of the application comprise treating a subject who has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of partial- or whole-body radiation.
  • the methods comprise treating a subject who has been exposed to at least 0.25, 0.5, , 2, 3, 4, 5, 6, 7, 8, 9 or 0 Gray of whole-body radiation.
  • the subject has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of less than 1 minute, or up to 5 minutes, 10 minutes, 30 minutes, 60 minutes, 1 hour, 6 hours, 12 hours, 24 hours, two days, one week, two weeks, three weeks or one month. In other embodiments, the subject has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of more than one month or one year.
  • the treatment is administered or used once a day. In another embodiment, the treatment is administered or used twice a day. In still another embodiment, the treatment is administered or used three times a day or four times a day. In a further embodiment, the treatment is administered or used at least once a day for one, two, three, four, five, six or seven days. In still a further embodiment, the treatment is administered at least once a day for a longer term such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks. In an even further embodiment, the treatment is administered or used at least once a day until the condition has ameliorated to where further treatment is not necessary.
  • the treatment period may also comprise cycles, for example, administration or use once daily for about three to seven days, followed by a period of rest for about 5 to 20 days, to constitute one cycle of treatment.
  • patients are treated with more than one cycle, for example, at least two, three, four or five cycles.
  • the effective dosage of the agent used for the treatment or prophylaxis increases or decreases over the course of a particular treatment or prophylaxis regime.
  • the effective dosage of the agent decreases over the course of a particular treatment regimen.
  • chronic administration is required.
  • the compositions are administered to the subject, or used, in an amount and for a duration sufficient to treat the subject.
  • compositions of the present application are useful and effective when administered to treat radiation exposure.
  • the amount of the chlorate used or that is present in the composition will be the amount that is therapeutically effective, i.e., an amount that will result in the effective treatment of the condition (e.g., radiation exposure) when administered or used.
  • the therapeutically effective amount will vary depending on the subject and the severity of the affliction and can be determined routinely by one of ordinary skill in the art.
  • compositions comprising about 0.1 % to about 80%, about 0.2% to about 50%, about 0.25% to about 20%, about 0.5% to about 10%, about 1 % to about 5%, about 1.25% to about 2.5% or about 1.5% w/v chlorate ion are administered to the subject.
  • compositions comprising about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% w/v chlorate ion are administered to the subject or used.
  • compositions that are chlorite-, sulfate-, chloride- carbonate-, bicarbonate-, and/or carbonic acid-free are administered to the subject or used.
  • compositions comprising, or consisting essentially of, chlorate as the sole active ingredient are administered to the subject or used.
  • the treatment is administered or used at least one day or at least one week after radiation exposure. In other embodiment, the treatment is administered or used 2, 3, 4, 5, or 6 days, optionally 4 days, after radiation exposure.
  • the treatment is administered or used at a dose of about 0.01 mg/kg to about 40 mg/kg body weight of chlorate. In further embodiments, the treatment is administered or used at a dose of about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight. In particular embodiments, treatment is administered or used at a dose of about 0.1 , 0.2, 0.5, 1.0, 2.0, 5.0 or 10.0 mg/kg body weight of chlorate. In alternate embodiments, the treatment is administered or used at a fixed dose that is not adjusted for body weight (e.g. 1 , 2.5, 5, 10, 25, 50, 100 or 250 mg/day for an adult).
  • the treatment is administered or used sequentially at the same dose. In alternate embodiments, the treatment is administered or used sequentially at different doses (e.g. step regimen). In further embodiments, the treatment is administered or used at least once a day, at least once every second day, at least once every third day, at least once every fourth, or as required to treat the subject. Optionally, the treatment is administered or used starting at least 2, 3, 4 or 5 days following radiation exposure. Subjects may also be treated with more than one cycle, for example, at least two, three, four or five cycles.
  • the application also includes methods for treating chronic radiation syndrome.
  • Chronic radiation syndrome is caused by months or years of chronic exposure to ionizing radiation.
  • a subject with chronic radiation exposure has been exposed to between 0.5 to 2.0 Gray of radiation at a dose rate of at least 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 1.5 or 2 Gray per year.
  • the application additionally includes methods for treating Delayed Effects of Acute Radiation Exposure (“DEARE”).
  • DEARE includes for example leukemia and other malignancies as well as radiation cystitis, mucocitis and proctitis which may occur months to years after an acute exposure to radiation.
  • chlorate or a chlorate composition as a preventive or prophylactic measure against radiation exposure.
  • the chlorate or chlorate compositions are administered to a subject prior to radiation exposure.
  • the subject is a radiation worker, a clinician or patient that may be exposed to radiation during a medical procedure, or personnel at risk of being exposed to radiation during military operations.
  • the chlorate or chlorate compositions are administered to military or civilian populations after a nuclear attack with either an atomic bomb or a dirty bomb as part of a post-exposure treatment or "radiation countermeasure".
  • chlorate or chlorate compositions to treat subjects exposed to radiation in the event of a nuclear accident at a power plant.
  • the application also includes methods for treating subjects who are suspected of being exposed to radiation or who may have been exposed to radiation comprising administering to the subjects an effective amount of chlorate or the chlorate compositions described herein.
  • the subject may or may not display symptoms of radiation exposure. IV. Examples
  • An aqueous solution was prepared by dissolving 97.5 mg of A.C.S. grade sodium chlorate (Aldrich) in water for injection to make a total volume of 50.0 mL. The mixture was swirled or shaken to obtain a homogenous solution. The concentration of chlorate in the solution was 1528 ppm (0.15% w/v). Unbuffered sodium chlorate solutions have a pH of approximately 4.5 to 8.5 depending, for example, on the amount of dissolved CO 2 in the solution.
  • mice Twenty-eight female Balb/C mice were irradiated and treated with either an unbuffered sodium chlorate (NaCIO " 3) solution (14 mice) or a saline (NaCI) solution (14 mice).
  • the mice were injected intraperitoneally with chlorate (0.15% w/v, Example 1) or saline solution for 5 consecutive days following radiation exposure with treatment commencing 4 days after radiation insult.
  • the sodium chlorate solution was diluted with saline before administration such that the total injection volume was about 200 microliters.
  • the sterile isotonic saline solution was injected at the same volume (about 200 microliters). Percent survival, weight loss and other measureable factors were assessed following treatment.
  • mice 9-10 weeks old, were subjected to 7 Gray of whole-body X-irradiation.
  • the mice were removed from their cages and placed in a PLEXIGLAS box of size 22 cm X 4.5 cm X 30 cm (each individual mouse chamber was 3cm x 3.5cm x 7cm).
  • the animals were irradiated in the PLEXIGLAS box operably connected to an orthovoltage unit (Serial No., D3225; Gulmay Medical Ltd., Surrey, UK), operating at 200 kV.
  • a filter comprising 2.0mm Cu and 0.3mm Al was used in the irradiator between the X-ray tube and the animals.
  • the 7 Gray dose was provided in approximately 6.02 minutes of irradiation.
  • mice were injected intraperitonealty with 0.25 mlJkg body weight of the chlorate treatment solution (Example 1) diluted with isotonic saline to a volume of approximately 200 ⁇ _ (14 mice) or approximately 200 ⁇ _ of the placebo solution (14 mice) for 5 consecutive days commencing on the fourth day following radiation exposure.
  • the treatment solution contained 0.15% w/v chlorate.
  • the p!acebo was a saline solution. Percent survival, weight loss and other measureable factors were assessed following treatment.
  • mice treated with the chlorate solution were higher than the percent survival of mice treated with saline over the 32 days following treatment ( Figure 1 ).
  • Mice in the control group succumbed to the effects of radiation more rapidly than the animals receiving chlorate and in a Cox regression model a mouse without treatment was calculated to be 1.42 times as likely to die at any time as a mouse receiving the chlorate solution. Score
  • mice were assigned a "score" based on bearing, ability, skin quality and fur quality according to the following evaluation procedure.
  • mice two times a day within an interval of 7 hours.
  • mice treated with saline showed a higher degree of weight loss over the 32 days following treatment than mice treated with the chlorate solution (Figure 3).
  • mice are irradiated and assigned to receive one of the following sterile aqueous solutions post insult (i) sodium chlorate 0.15% w/v (including a carbonate buffer and sufficient NaCI to make the solution isotonic, pH 11.4 - 12.7), (ii) sodium chlorate 0.15% w/v (including NaCI sufficient to render the solution isotonic, pH 7.0) or (iii) an isotonic saline solution (pH 7.0). Irradiation is performed as generally described in Example 2, using a single fixed radiation value selected in the range from about 5.0 to about 9.0 Gy.
  • mice are injected intraperitoneal ⁇ with either the chlorate or saline solutions for 8 consecutive days following radiation exposure commencing 4 days after radiation insult.
  • the sodium chlorate solutions are diluted with saline prior to administration such that the total injection volume is about 200 microliters.
  • the isotonic saiine solution in the control group is injected at the same volume (about 200 microliters).
  • the chlorate solutions are administered at 1 mL/kg on days 4, 5, 6 following radiation exposure and then at 0.5 mL/kg on days 7, 8, 9, 10 and 1 1 after radiation exposure.
  • the effects of the chlorate solutions versus saiine on the survival curves of the mice to day 30 are assessed, including differences in overall survival at day 30.
  • the dose modification factor can be defined as the ratio of LD50/30 radiation level with and without treatment and is a recommended measurement to determine the effectiveness of a radiation medical countermeasure.
  • a radiation medical countermeasure See for example Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride WH. Animal models for medical countermeasures to radiation exposure. Radiat Res.
  • mice are injected intraperitonealiy with the chlorate or saline solutions for 8 consecutive days following radiation exposure commencing 4 days after radiation insult.
  • the sodium chlorate solutions are diluted with saline prior to administration such that the total injection volume is about 200 microliters.
  • the isotonic saline solution is injected at the same volume (about 200 microliters).
  • the chlorate solution is administered at 1 mL/kg body weight on days 4, 5, 6 following radiation exposure and then at 0.5 mL/kg body weight on days 7, 8, 9, 10 and 1 1.
  • LD50/30 and other measureable factors with and without chlorate treatment are assessed and a dose modification factor is computed.
  • mice receive radiation at different doses followed by treatment with saline. Irradiation is performed as generally described in Example 2, except at the radiation values indicated below. The levels of radiation are 5.0, 6.0, 7.0, 7.5, 8.0 and 9.0 Gy. Saline is administered i.p. in an amount of 200 pL/day on days 4, 5, 6, 7, 8, 9, 10 and 1 1. The percent of animals surviving at 30 days past radiation exposure is then plotted vs radiation level (or analyzed numerically) to determine the LD50/30 radiation dose.
  • a sachet containing a predetermined amount of sodium chlorate in powder form is prepared.
  • the powder may additionally include a bulking agent such as sodium chloride.
  • a bulking agent such as sodium chloride.
  • the sachet is opened and its contents are dissolved in a specified amount of water.
  • the aqueous solution is consumed orally by the subject.
  • a capsule containing a predetermined amount of sodium chlorate is prepared.
  • the capsule is swallowed by the subject.
  • the capsule is designed to release its contents in the gastrointestinal tract of the subject.

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Abstract

La présente invention concerne l'utilisation de chlorate dans le traitement de sujets qui ont été exposés à un rayonnement. Plus particulièrement, l'invention concerne l'utilisation de chlorate pour le traitement de sujets ayant un syndrome d'irradiation aiguë. L'invention concerne également des compositions comprenant du chlorate et des procédés d'utilisation des compositions pour traiter les sujets qui ont été exposés à un rayonnement.
PCT/IB2013/058440 2012-09-10 2013-09-10 Compositions de chlorate et utilisation de chlorate dans le traitement de l'exposition aux rayonnements WO2014037927A1 (fr)

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